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Publisher: Elsevier   (Total: 3162 journals)

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Showing 1401 - 1600 of 3162 Journals sorted alphabetically
Intl. J. of Adhesion and Adhesives     Hybrid Journal   (Followers: 18, SJR: 0.926, CiteScore: 2)
Intl. J. of Africa Nursing Sciences     Open Access   (SJR: 0.396, CiteScore: 1)
Intl. J. of Antimicrobial Agents     Hybrid Journal   (Followers: 10, SJR: 1.699, CiteScore: 4)
Intl. J. of Applied Earth Observation and Geoinformation     Hybrid Journal   (Followers: 34, SJR: 1.591, CiteScore: 4)
Intl. J. of Approximate Reasoning     Hybrid Journal   (Followers: 1, SJR: 0.866, CiteScore: 3)
Intl. J. of Biochemistry & Cell Biology     Hybrid Journal   (Followers: 6, SJR: 1.492, CiteScore: 3)
Intl. J. of Biological Macromolecules     Hybrid Journal   (Followers: 2, SJR: 0.917, CiteScore: 4)
Intl. J. of Cardiology     Hybrid Journal   (Followers: 16, SJR: 1.2, CiteScore: 2)
Intl. J. of Chemical and Analytical Science     Full-text available via subscription   (Followers: 4)
Intl. J. of Child-Computer Interaction     Hybrid Journal   (Followers: 2, SJR: 0.479, CiteScore: 3)
Intl. J. of Clinical and Health Psychology     Open Access   (Followers: 20, SJR: 1.345, CiteScore: 4)
Intl. J. of Coal Geology     Hybrid Journal   (Followers: 4, SJR: 2.186, CiteScore: 5)
Intl. J. of Critical Infrastructure Protection     Hybrid Journal   (Followers: 8, SJR: 0.648, CiteScore: 2)
Intl. J. of Dental Science and Research     Full-text available via subscription   (Followers: 1)
Intl. J. of Developmental Neuroscience     Hybrid Journal   (Followers: 8, SJR: 0.986, CiteScore: 2)
Intl. J. of Diabetes Mellitus     Open Access   (Followers: 9)
Intl. J. of Disaster Risk Reduction     Hybrid Journal   (Followers: 18, SJR: 0.769, CiteScore: 2)
Intl. J. of Drug Policy     Hybrid Journal   (Followers: 456, SJR: 1.441, CiteScore: 3)
Intl. J. of e-Navigation and Maritime Economy     Open Access   (Followers: 3)
Intl. J. of Educational Development     Hybrid Journal   (Followers: 14, SJR: 0.822, CiteScore: 1)
Intl. J. of Educational Research     Hybrid Journal   (Followers: 27, SJR: 0.617, CiteScore: 1)
Intl. J. of Electrical Power & Energy Systems     Open Access   (Followers: 24, SJR: 1.276, CiteScore: 5)
Intl. J. of Engineering Science     Hybrid Journal   (Followers: 5, SJR: 2.82, CiteScore: 6)
Intl. J. of Epilepsy     Full-text available via subscription   (Followers: 2, SJR: 0.126, CiteScore: 0)
Intl. J. of Fatigue     Hybrid Journal   (Followers: 38, SJR: 1.402, CiteScore: 3)
Intl. J. of Food Microbiology     Hybrid Journal   (Followers: 14, SJR: 1.366, CiteScore: 4)
Intl. J. of Forecasting     Hybrid Journal   (Followers: 28, SJR: 1.879, CiteScore: 3)
Intl. J. of Gastronomy and Food Science     Open Access   (Followers: 4, SJR: 0.422, CiteScore: 1)
Intl. J. of Gerontology     Open Access   (Followers: 8, SJR: 0.215, CiteScore: 0)
Intl. J. of Greenhouse Gas Control     Partially Free   (Followers: 5, SJR: 1.458, CiteScore: 4)
Intl. J. of Heat and Fluid Flow     Hybrid Journal   (Followers: 36, SJR: 0.947, CiteScore: 3)
Intl. J. of Heat and Mass Transfer     Hybrid Journal   (Followers: 269, SJR: 1.498, CiteScore: 4)
Intl. J. of Hospitality Management     Hybrid Journal   (Followers: 20, SJR: 2.027, CiteScore: 4)
Intl. J. of Human-Computer Studies     Hybrid Journal   (Followers: 18, SJR: 0.605, CiteScore: 3)
Intl. J. of Hydrogen Energy     Partially Free   (Followers: 20, SJR: 1.116, CiteScore: 4)
Intl. J. of Hygiene and Environmental Health     Hybrid Journal   (Followers: 7, SJR: 1.334, CiteScore: 4)
Intl. J. of Impact Engineering     Hybrid Journal   (Followers: 9, SJR: 2.124, CiteScore: 4)
Intl. J. of Industrial Ergonomics     Hybrid Journal   (Followers: 15, SJR: 0.795, CiteScore: 2)
Intl. J. of Industrial Organization     Hybrid Journal   (Followers: 24, SJR: 0.873, CiteScore: 1)
Intl. J. of Infectious Diseases     Open Access   (Followers: 8, SJR: 1.514, CiteScore: 3)
Intl. J. of Information Management     Hybrid Journal   (Followers: 308, SJR: 1.373, CiteScore: 6)
Intl. J. of Intercultural Relations     Hybrid Journal   (Followers: 12, SJR: 0.732, CiteScore: 2)
Intl. J. of Law and Psychiatry     Hybrid Journal   (Followers: 8, SJR: 0.546, CiteScore: 1)
Intl. J. of Law, Crime and Justice     Hybrid Journal   (Followers: 56, SJR: 0.362, CiteScore: 1)
Intl. J. of Machine Tools and Manufacture     Hybrid Journal   (Followers: 7, SJR: 2.7, CiteScore: 6)
Intl. J. of Management Education     Hybrid Journal   (Followers: 8, SJR: 0.597, CiteScore: 2)
Intl. J. of Marine Energy     Full-text available via subscription   (Followers: 1, SJR: 0.92, CiteScore: 2)
Intl. J. of Mass Spectrometry     Hybrid Journal   (Followers: 17, SJR: 0.61, CiteScore: 2)
Intl. J. of Mechanical Sciences     Hybrid Journal   (Followers: 13, SJR: 1.595, CiteScore: 4)
Intl. J. of Medical Informatics     Hybrid Journal   (Followers: 9, SJR: 1.247, CiteScore: 4)
Intl. J. of Medical Microbiology     Hybrid Journal   (Followers: 8, SJR: 1.717, CiteScore: 4)
Intl. J. of Mineral Processing     Hybrid Journal   (Followers: 10, SJR: 0.782, CiteScore: 2)
Intl. J. of Mining Science and Technology     Open Access   (Followers: 3, SJR: 1.323, CiteScore: 2)
Intl. J. of Multiphase Flow     Hybrid Journal   (Followers: 8, SJR: 1.218, CiteScore: 3)
Intl. J. of Naval Architecture and Ocean Engineering     Open Access   (Followers: 3, SJR: 0.571, CiteScore: 1)
Intl. J. of Neuropharmacology     Full-text available via subscription   (Followers: 1)
Intl. J. of Non-Linear Mechanics     Hybrid Journal   (Followers: 8, SJR: 1.032, CiteScore: 2)
Intl. J. of Nursing Sciences     Open Access   (Followers: 1, SJR: 0.285, CiteScore: 1)
Intl. J. of Nursing Studies     Hybrid Journal   (Followers: 15, SJR: 1.646, CiteScore: 4)
Intl. J. of Obstetric Anesthesia     Full-text available via subscription   (Followers: 13, SJR: 0.717, CiteScore: 2)
Intl. J. of Oral and Maxillofacial Surgery     Hybrid Journal   (Followers: 8, SJR: 1.137, CiteScore: 2)
Intl. J. of Orthopaedic and Trauma Nursing     Hybrid Journal   (Followers: 10, SJR: 0.369, CiteScore: 1)
Intl. J. of Osteopathic Medicine     Hybrid Journal   (Followers: 2, SJR: 0.297, CiteScore: 1)
Intl. J. of Paleopathology     Partially Free   (Followers: 8, SJR: 0.618, CiteScore: 1)
Intl. J. of Pavement Research and Technology     Open Access   (Followers: 6, SJR: 0.311, CiteScore: 1)
Intl. J. of Pediatric Otorhinolaryngology     Full-text available via subscription   (Followers: 1, SJR: 0.783, CiteScore: 1)
Intl. J. of Pediatric Otorhinolaryngology Extra     Full-text available via subscription   (Followers: 1, SJR: 0.11, CiteScore: 0)
Intl. J. of Pediatrics and Adolescent Medicine     Open Access   (Followers: 1, SJR: 0.144, CiteScore: 1)
Intl. J. of Pharmaceutics     Hybrid Journal   (Followers: 36, SJR: 1.172, CiteScore: 4)
Intl. J. of Plasticity     Hybrid Journal   (Followers: 7, SJR: 3.395, CiteScore: 6)
Intl. J. of Pressure Vessels and Piping     Hybrid Journal   (Followers: 25, SJR: 0.981, CiteScore: 2)
Intl. J. of Production Economics     Hybrid Journal   (Followers: 15, SJR: 2.401, CiteScore: 5)
Intl. J. of Project Management     Hybrid Journal   (Followers: 49, SJR: 1.463, CiteScore: 5)
Intl. J. of Psychophysiology     Hybrid Journal   (Followers: 5, SJR: 1.157, CiteScore: 3)
Intl. J. of Radiation Oncology*Biology*Physics     Hybrid Journal   (Followers: 32, SJR: 2.485, CiteScore: 3)
Intl. J. of Refractory Metals and Hard Materials     Hybrid Journal   (Followers: 5)
Intl. J. of Refrigeration     Full-text available via subscription   (Followers: 5, SJR: 1.471, CiteScore: 3)
Intl. J. of Research in Marketing     Hybrid Journal   (Followers: 20, SJR: 2.528, CiteScore: 3)
Intl. J. of Rock Mechanics and Mining Sciences     Hybrid Journal   (Followers: 8, SJR: 2.259, CiteScore: 4)
Intl. J. of Sediment Research     Full-text available via subscription   (Followers: 3, SJR: 0.663, CiteScore: 2)
Intl. J. of Solids and Structures     Hybrid Journal   (Followers: 15, SJR: 1.295, CiteScore: 3)
Intl. J. of Spine Surgery     Hybrid Journal   (Followers: 3, SJR: 0.793, CiteScore: 2)
Intl. J. of Surgery     Hybrid Journal   (Followers: 8, SJR: 0.834, CiteScore: 3)
Intl. J. of Surgery Case Reports     Open Access   (Followers: 4, SJR: 0.26, CiteScore: 1)
Intl. J. of Surgery Open     Open Access   (SJR: 0.116, CiteScore: 0)
Intl. J. of Surgery Protocols     Open Access   (Followers: 1, SJR: 0.141, CiteScore: 1)
Intl. J. of Sustainable Built Environment     Open Access   (Followers: 5, SJR: 0.746, CiteScore: 3)
Intl. J. of the Sociology of Law     Hybrid Journal   (Followers: 18)
Intl. J. of Thermal Sciences     Hybrid Journal   (Followers: 18, SJR: 1.429, CiteScore: 4)
Intl. J. of Transportation Science and Technology     Open Access   (Followers: 10)
Intl. J. of Veterinary Science and Medicine     Open Access   (Followers: 4)
Intl. J. of Women's Dermatology     Open Access   (SJR: 0.213, CiteScore: 0)
Intl. Medical Review on Down Syndrome     Full-text available via subscription  
Intl. Orthodontics     Full-text available via subscription   (Followers: 3, SJR: 0.239, CiteScore: 0)
Intl. Perspectives on Child and Adolescent Mental Health     Full-text available via subscription   (Followers: 5)
Intl. Review of Cell and Molecular Biology     Full-text available via subscription   (Followers: 6, SJR: 1.973, CiteScore: 4)
Intl. Review of Cytology     Full-text available via subscription  
Intl. Review of Economics & Finance     Hybrid Journal   (Followers: 26, SJR: 0.841, CiteScore: 2)
Intl. Review of Economics Education     Hybrid Journal   (Followers: 1, SJR: 0.632, CiteScore: 1)
Intl. Review of Financial Analysis     Hybrid Journal   (Followers: 7, SJR: 0.755, CiteScore: 2)
Intl. Review of Law and Economics     Hybrid Journal   (Followers: 21, SJR: 0.572, CiteScore: 1)
Intl. Review of Neurobiology     Full-text available via subscription   (Followers: 2, SJR: 1.497, CiteScore: 3)
Intl. Review of Research in Mental Retardation     Full-text available via subscription   (Followers: 7)
Intl. Soil and Water Conservation Research     Open Access   (SJR: 0.667, CiteScore: 2)
Intl. Strategic Management Review     Open Access   (Followers: 4)
Investigación en Educación Médica     Open Access  
Investigaciones de Historia Económica     Full-text available via subscription   (SJR: 0.264, CiteScore: 0)
Investigaciones Europeas de Dirección y Economía de la Empresa     Open Access  
IRBM     Full-text available via subscription   (SJR: 0.298, CiteScore: 1)
IRBM News     Full-text available via subscription   (SJR: 0.139, CiteScore: 0)
ISA Transactions     Full-text available via subscription   (Followers: 1, SJR: 1.115, CiteScore: 4)
iScience     Open Access  
ISPRS J. of Photogrammetry and Remote Sensing     Hybrid Journal   (Followers: 70, SJR: 3.169, CiteScore: 8)
Italian Oral Surgery     Full-text available via subscription   (Followers: 1)
ITBM-RBM     Full-text available via subscription   (Followers: 1)
ITBM-RBM News     Full-text available via subscription   (Followers: 1)
J. de Chirurgie Viscerale     Full-text available via subscription   (Followers: 1, SJR: 0.264, CiteScore: 0)
J. de Gynécologie Obstétrique et Biologie de la Reproduction     Full-text available via subscription  
J. de Mathématiques Pures et Appliquées     Full-text available via subscription   (Followers: 4, SJR: 3.571, CiteScore: 2)
J. de Mycologie Médicale / J. of Medical Mycology     Full-text available via subscription   (Followers: 2, SJR: 0.495, CiteScore: 2)
J. de Pédiatrie et de Puériculture     Full-text available via subscription   (SJR: 0.116, CiteScore: 0)
J. de Radiologie     Full-text available via subscription  
J. de Radiologie Diagnostique et Interventionnelle     Full-text available via subscription   (Followers: 2)
J. de Thérapie Comportementale et Cognitive     Full-text available via subscription   (SJR: 0.111, CiteScore: 0)
J. de Traumatologie du Sport     Full-text available via subscription   (Followers: 2, SJR: 0.152, CiteScore: 0)
J. des Anti-infectieux     Full-text available via subscription   (Followers: 2, SJR: 0.107, CiteScore: 0)
J. des Maladies Vasculaires     Full-text available via subscription  
J. Européen des Urgences     Full-text available via subscription   (Followers: 1)
J. Européen des Urgences et de Réanimation     Hybrid Journal   (SJR: 0.108, CiteScore: 0)
J. for Nature Conservation     Hybrid Journal   (Followers: 28, SJR: 0.894, CiteScore: 2)
J. for Nurse Practitioners     Hybrid Journal   (Followers: 12, SJR: 0.179, CiteScore: 0)
J. Français d'Ophtalmologie     Full-text available via subscription   (Followers: 3, SJR: 0.292, CiteScore: 0)
J. of Academic Librarianship     Hybrid Journal   (Followers: 1031, SJR: 1.224, CiteScore: 2)
J. of Accounting and Economics     Hybrid Journal   (Followers: 37, SJR: 6.875, CiteScore: 4)
J. of Accounting and Public Policy     Hybrid Journal   (Followers: 7, SJR: 0.91, CiteScore: 2)
J. of Accounting Education     Hybrid Journal   (Followers: 6, SJR: 0.882, CiteScore: 1)
J. of Accounting Literature     Hybrid Journal   (Followers: 7, SJR: 0.986, CiteScore: 3)
J. of Acupuncture and Meridian Studies     Open Access   (Followers: 1, SJR: 0.347, CiteScore: 1)
J. of Acute Medicine     Open Access   (SJR: 0.196, CiteScore: 1)
J. of Adolescence     Hybrid Journal   (Followers: 14, SJR: 1.01, CiteScore: 2)
J. of Adolescent Health     Hybrid Journal   (Followers: 23, SJR: 1.851, CiteScore: 4)
J. of Advanced Research     Open Access   (Followers: 2, SJR: 0.741, CiteScore: 4)
J. of Aerosol Science     Hybrid Journal   (Followers: 5, SJR: 0.828, CiteScore: 3)
J. of Affective Disorders     Hybrid Journal   (Followers: 18, SJR: 2.053, CiteScore: 4)
J. of African Earth Sciences     Hybrid Journal   (Followers: 11, SJR: 0.681, CiteScore: 2)
J. of African Trade     Open Access  
J. of Aging Studies     Hybrid Journal   (Followers: 11, SJR: 0.8, CiteScore: 2)
J. of Air Transport Management     Hybrid Journal   (Followers: 9, SJR: 0.981, CiteScore: 2)
J. of Algebra     Full-text available via subscription   (Followers: 5, SJR: 1.187, CiteScore: 1)
J. of Algorithms     Full-text available via subscription   (Followers: 4)
J. of Allergy and Clinical Immunology     Hybrid Journal   (Followers: 30, SJR: 5.049, CiteScore: 7)
J. of Allergy and Clinical Immunology : In Practice     Full-text available via subscription   (Followers: 12, SJR: 1.461, CiteScore: 3)
J. of Alloys and Compounds     Hybrid Journal   (Followers: 12, SJR: 1.02, CiteScore: 4)
J. of American Association for Pediatric Ophthalmology and Strabismus     Hybrid Journal   (Followers: 7, SJR: 0.752, CiteScore: 1)
J. of Analytical and Applied Pyrolysis     Hybrid Journal   (Followers: 3, SJR: 1.129, CiteScore: 4)
J. of Anesthesia History     Full-text available via subscription   (Followers: 1, SJR: 0.19, CiteScore: 0)
J. of Anthropological Archaeology     Hybrid Journal   (Followers: 79, SJR: 1.24, CiteScore: 2)
J. of Anxiety Disorders     Hybrid Journal   (Followers: 16, SJR: 2.043, CiteScore: 4)
J. of Applied Biomedicine     Open Access   (Followers: 2, SJR: 0.348, CiteScore: 2)
J. of Applied Developmental Psychology     Hybrid Journal   (Followers: 13, SJR: 1.339, CiteScore: 3)
J. of Applied Economics     Full-text available via subscription   (Followers: 8, SJR: 0.235, CiteScore: 1)
J. of Applied Geophysics     Hybrid Journal   (Followers: 15, SJR: 0.636, CiteScore: 2)
J. of Applied Logic     Full-text available via subscription   (SJR: 0.277, CiteScore: 1)
J. of Applied Mathematics and Mechanics     Full-text available via subscription   (Followers: 9, SJR: 0.321, CiteScore: 0)
J. of Applied Research and Technology     Open Access   (SJR: 0.255, CiteScore: 1)
J. of Applied Research in Memory and Cognition     Partially Free   (Followers: 12, SJR: 1.303, CiteScore: 2)
J. of Applied Research on Medicinal and Aromatic Plants     Hybrid Journal   (SJR: 0.355, CiteScore: 2)
J. of Approximation Theory     Hybrid Journal   (Followers: 1, SJR: 0.907, CiteScore: 1)
J. of Archaeological Science     Hybrid Journal   (Followers: 66, SJR: 1.885, CiteScore: 3)
J. of Archaeological Science : Reports     Hybrid Journal   (Followers: 17, SJR: 0.659, CiteScore: 1)
J. of Arid Environments     Hybrid Journal   (Followers: 14, SJR: 0.763, CiteScore: 2)
J. of Arrhythmia     Open Access   (SJR: 0.398, CiteScore: 1)
J. of Arthroplasty     Hybrid Journal   (Followers: 48, SJR: 2.373, CiteScore: 3)
J. of Arthroscopy and Joint Surgery     Full-text available via subscription   (Followers: 2, SJR: 0.103, CiteScore: 0)
J. of Asia-Pacific Biodiversity     Open Access   (SJR: 0.361, CiteScore: 1)
J. of Asia-Pacific Entomology     Full-text available via subscription   (Followers: 6, SJR: 0.373, CiteScore: 1)
J. of Asian Ceramic Societies     Open Access   (Followers: 2, SJR: 0.509, CiteScore: 2)
J. of Asian Earth Sciences     Hybrid Journal   (Followers: 13, SJR: 1.488, CiteScore: 3)
J. of Asian Economics     Hybrid Journal   (Followers: 1, SJR: 0.419, CiteScore: 1)
J. of Atmospheric and Solar-Terrestrial Physics     Hybrid Journal   (Followers: 146, SJR: 0.696, CiteScore: 2)
J. of Autoimmunity     Hybrid Journal   (Followers: 11, SJR: 2.046, CiteScore: 7)
J. of Ayurveda and Integrative Medicine     Open Access   (Followers: 3, SJR: 0.338, CiteScore: 1)
J. of Banking & Finance     Hybrid Journal   (Followers: 174)
J. of Basic & Applied Zoology : Physiology     Open Access   (Followers: 3)
J. of Behavior Therapy and Experimental Psychiatry     Hybrid Journal   (Followers: 4, SJR: 1.42, CiteScore: 3)
J. of Behavior, Health & Social Issues     Open Access   (Followers: 7)
J. of Behavioral and Experimental Economics     Full-text available via subscription   (Followers: 8, SJR: 0.593, CiteScore: 1)
J. of Behavioral and Experimental Finance     Full-text available via subscription   (Followers: 3, SJR: 0.475, CiteScore: 1)
J. of Biochemical and Biophysical Methods     Hybrid Journal   (Followers: 4)
J. of Biomechanics     Hybrid Journal   (Followers: 37, SJR: 1.147, CiteScore: 3)
J. of Biomedical Informatics     Partially Free   (Followers: 15, SJR: 1.028, CiteScore: 4)
J. of Biomedical Research     Full-text available via subscription   (Followers: 3, SJR: 0.712, CiteScore: 2)
J. of Bionic Engineering     Full-text available via subscription   (SJR: 0.584, CiteScore: 3)
J. of Bioscience and Bioengineering     Full-text available via subscription   (Followers: 31, SJR: 0.675, CiteScore: 2)
J. of Biotechnology     Hybrid Journal   (Followers: 63, SJR: 0.929, CiteScore: 3)
J. of Bodywork and Movement Therapies     Hybrid Journal   (Followers: 17, SJR: 0.522, CiteScore: 1)
J. of Bone Oncology     Open Access   (Followers: 1, SJR: 0.941, CiteScore: 3)
J. of Building Engineering     Hybrid Journal   (Followers: 2, SJR: 0.753, CiteScore: 3)
J. of Business Research     Hybrid Journal   (Followers: 22, SJR: 1.26, CiteScore: 3)
J. of Business Venturing     Hybrid Journal   (Followers: 26, SJR: 5.212, CiteScore: 9)

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Journal Cover
Journal of Autoimmunity
Journal Prestige (SJR): 2.046
Citation Impact (citeScore): 7
Number of Followers: 11  
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0896-8411 - ISSN (Online) 1095-9157
Published by Elsevier Homepage  [3162 journals]
  • A long-lived IL-2 mutein that selectively activates and expands regulatory
           T cells as a therapy for autoimmune disease
    • Abstract: Publication date: Available online 13 November 2018Source: Journal of AutoimmunityAuthor(s): Laurence B. Peterson, Charles J.M. Bell, Sarah K. Howlett, Marcin L. Pekalski, Kevin Brady, Heather Hinton, Denise Sauter, John A. Todd, Pablo Umana, Oliver Ast, Inja Waldhauer, Anne Freimoser-Grundschober, Ekkehard Moessner, Christian Klein, Ralf J. Hosse, Linda S. Wicker Susceptibility to multiple autoimmune diseases is associated with common gene polymorphisms influencing IL-2 signaling and Treg function, making Treg-specific expansion by IL-2 a compelling therapeutic approach to treatment. As an in vivo IL-2 half-life enhancer we used a non-targeted, effector-function-silent human IgG1 as a fusion protein. An IL-2 mutein (N88D) with reduced binding to the intermediate affinity IL-2Rβγ receptor was engineered with a stoichiometry of two IL-2N88D molecules per IgG, i.e. IgG-(IL-2N88D)2. The reduced affinity of IgG-(IL-2N88D)2 for the IL-2Rβγ receptor resulted in a Treg-selective molecule in human whole blood pSTAT5 assays. Treatment of cynomolgus monkeys with single low doses of IgG-(IL-2N88D)2 induced sustained preferential activation of Tregs accompanied by a corresponding 10–14-fold increase in CD4+ and CD8+ CD25+FOXP3+ Tregs; conditions that had no effect on CD4+ or CD8+ memory effector T cells. The expanded cynomolgus Tregs had demethylated FOXP3 and CTLA4 epigenetic signatures characteristic of functionally suppressive cells. Humanized mice had similar selective in vivo responses; IgG-(IL-2N88D)2 increased Tregs while wild-type IgG-IL-2 increased NK cells in addition to Tregs. The expanded human Tregs had demethylated FOXP3 and CTLA4 signatures and were immunosuppressive. These results describe a next-generation immunotherapy using a long-lived and Treg-selective IL-2 that activates and expands functional Tregsin vivo. Patients should benefit from restored immune homeostasis in a personalized fashion to the extent that their autoimmune disease condition dictates opening up the possibility for remissions and cures.
  • Shared gut, but distinct oral microbiota composition in primary Sjögren's
           syndrome and systemic lupus erythematosus
    • Abstract: Publication date: Available online 9 November 2018Source: Journal of AutoimmunityAuthor(s): Taco A. van der Meulen, Hermie J.M. Harmsen, Arnau Vich Vila, Alexander Kurilshikov, Silvia C. Liefers, Alexandra Zhernakova, Jingyuan Fu, Cisca Wijmenga, Rinse K. Weersma, Karina de Leeuw, Hendrika Bootsma, Fred K.L. Spijkervet, Arjan Vissink, Frans G.M. Kroese ObjectiveAlterations in the microbiota composition of the gastro-intestinal tract are suspected to be involved in the etiopathogenesis of two closely related systemic inflammatory autoimmune diseases: primary Sjögren's syndrome (pSS) and systemic lupus erythematosus (SLE). Our objective was to assess whether alterations in gut and oral microbiota compositions are specific for pSS and SLE.Methods16S ribosomal RNA gene sequencing was performed on fecal samples from 39 pSS patients, 30 SLE patients and 965 individuals from the general population, as well as on buccal swab and oral washing samples from the same pSS and SLE patients. Alpha-diversity, beta-diversity and relative abundance of individual bacteria were used as outcome measures. Multivariate analyses were performed to test associations between individual bacteria and disease phenotype, taking age, sex, body-mass index, proton-pump inhibitor use and sequencing-depth into account as possible confounding factors.ResultsFecal microbiota composition from pSS and SLE patients differed significantly from population controls, but not between pSS and SLE. pSS and SLE patients were characterized by lower bacterial richness, lower Firmicutes/Bacteroidetes ratio and higher relative abundance of Bacteroides species in fecal samples compared with population controls. Oral microbiota composition differed significantly between pSS patients and SLE patients, which could partially be explained by oral dryness in pSS patients.ConclusionspSS and SLE patients share similar alterations in gut microbiota composition, distinguishing patients from individuals in the general population, while oral microbiota composition shows disease-specific differences between pSS and SLE patients.
  • Prognostic models in primary biliary cholangitis
    • Abstract: Publication date: Available online 9 November 2018Source: Journal of AutoimmunityAuthor(s): Laura Cristoferi, Alessandra Nardi, Vincenzo Ronca, Pietro Invernizzi, George Mells, Marco Carbone Risk prediction modelling is important to better understand the determinants of the course and outcome of PBC and to inform the risk across the disease continuum in PBC enabling risk-stratified follow-up care and personalised therapy. Current prognostic models in PBC are based on treatment response to ursodeoxycholic acid because of the well-established relationship between alkaline phosphatase on treatment and long-term outcome. In addition, serum alkaline phosphatase correlates with ductular reaction and biliary metaplasia, which are hallmark of biliary injury. Considering the waiting time for treatment failure in high-risk patients is not inconsequential, efforts are focused on bringing forward risk stratification at diagnosis by predicting treatment response at onset.There is a need for better prognostic variables that are central to the disease process. We should take an integrative approach that incorporates multiple layers of information including genetic and environmental influences, host characteristics, clinical data, and molecular alterations for risk assessments. Biomarker discovery has an accelerated pace taking advantage of the emergence of large-scale omics platforms (genomics, epigenomics, transcriptomics, proteomics, metabolomics, and others) and whole-genome sequencing. In the digital era, applications of artificial intelligence, such as machine learning, can support the computing power required to analyse the vast amount of data produced by omics. The information is then used for the development of personalised risk prediction models that through clinical trials and hopefully industry partnerships can guide risk management strategies. We are facing an unprecedented opportunity for the integration of molecular diagnostics into the clinic, which promotes progress toward the personalised management of patients with PBC.
  • Changes in the composition of the upper respiratory tract microbial
           community in granulomatosis with polyangiitis
    • Abstract: Publication date: Available online 9 November 2018Source: Journal of AutoimmunityAuthor(s): Peter Lamprecht, Nicole Fischer, Jiabin Huang, Lia Burkhardt, Marc Lütgehetmann, Fabian Arndt, Ida Rolfs, Anja Kerstein, Christof Iking-Konert, Martin Laudien Dysbiosis¸ i.e. changes in microbial composition at a mucosal interface, is implicated in the pathogenesis of many chronic inflammatory and autoimmune diseases. To assess the composition of the microbial upper respiratory tract (URT) community in patients with granulomatosis with polyangiitis (GPA), we used culture-independent high-throughput methods. In this prospective clinical study, nasal swabs were collected from patients with GPA, patients with rheumatoid arthritis (RA, disease control), and healthy controls. Nasal bacterial taxa were assessed using V3–V4 region 16S rRNA amplicon sequencing. Staphylococcus aureus, Haemophilus influenza, and entero- and rhinoviruses were detected using qPCR. Unbiased metagenomic RNA sequencing (UMERS) was performed in a subset of samples to determine the relative abundance of bacterial, fungal, and viral species. A trend toward reduced microbiome diversity was detected in GPA samples compared with healthy controls. The abundance of bacterial taxa and microbial richness were significantly decreased in GPA samples compared with RA samples. The relative abundance of bacterial families shifted, with increased Planococcaceae and decreased Moraxellaceae, Tissierellaceae, Staphylococcaceae, and Propionibacteriaceae in GPA and RA. Further, decreased abundance of Corynebacteriaceae, and Aerococcaceae was observed in GPA samples. Significantly more colonization of S. aureus was seen in the nasal microbiome of GPA compared with RA and healthy control samples. H. influenzae colonization was also observed in GPA samples. UMERS detected the presence of rhinoviral sequences in some GPA samples. Thus, our study uncovered changes in the URT microbial composition in patients with GPA and RA, suggesting that both immunosuppression and disease background affect the URT microbiome. Complex alterations of host-microbiome interactions in the URT could influence chronic endonasal inflammation in GPA.
  • Novel mechanism for estrogen receptor alpha modulation of murine lupus
    • Abstract: Publication date: Available online 8 November 2018Source: Journal of AutoimmunityAuthor(s): Melissa A. Cunningham, Mara Lennard Richard, Jena R. Wirth, Jennifer L. Scott, Jackie Eudaly, Phil Ruiz, Gary S. Gilkeson Female sex is a risk factor for lupus. Sex hormones, sex chromosomes and hormone receptors are implicated in the pathogenic pathways in lupus. Estrogen receptor alpha (ERα) knockout (KO) mice are used for defining hormone receptor effects in lupus. Prior studies of ERα KO in lupus have conflicting results, likely due to sex hormone levels, different lupus strains and different ERα KO constructs. Our objective was to compare a complete KO of ERα vs. the original functional KO of ERα (expressing a short ERα) on disease expression and immune phenotype, while controlling sex hormone levels. We studied female lupus prone NZM2410 WT and ERα mutant mice. All mice (n = 44) were ovariectomized (OVX) for hormonal control. Groups of each genotype were estrogen (E2)-repleted after OVX. We found that OVXed NZM mice expressing the truncated ERα (ERα short) had significantly reduced nephritis and prolonged survival compared to both wildtype and the complete ERαKO (ERα null) mice, but surprisingly only if E2-repleted. ERα null mice were not protected regardless of E2 status. We observed significant differences in splenic B cells and dendritic cells and a decrease in cDC2 (CD11b+CD8−) dendritic cells, without a concomitant decrease in cDC1 (CD11b-CD8a+) cells comparing ERα short to ERα null or WT mice. Our data support a protective role for the ERα short protein. ERα short is similar to an endogenously expressed ERα variant (ERα46). Modulating its expression/activity represents a potential approach for treating female-predominant autoimmune diseases.
  • Novel therapeutic targets in autoimmune hepatitis
    • Abstract: Publication date: Available online 4 November 2018Source: Journal of AutoimmunityAuthor(s): Richard Taubert, Katharina Luise Hupa-Breier, Elmar Jaeckel, Michael P. Manns Autoimmune hepatitis (AIH) is an orphan disease characterized by an autoimmune attack against hepatocytes. The exact sequence of events that leads to a breach of tolerance is incompletely understood. Current hypotheses suggest that environmental agents such as toxins or infectious agents like viruses cause a tissue damage that initiates autoimmunity in genetically susceptible individuals. The growing knowledge of the multi-facetted immune dysregulation, which involves Th1/Th17 polarization and the suspected inability of regulatory T cells to revert autoimmunity in the otherwise tolerogenic milieu of the liver, offers multiple new therapeutic approaches and targets. Standard of care (SOC) is treatment with corticosteroids with or without azathioprine, which is sufficient to induce remission in the majority of patients. However, it rarely cures AIH or restores intrahepatic immune tolerance. Hence, life-long therapy is required in the majority of patients. In addition, several studies suggest a weakening of immune regulation mediated by intrahepatic T cells under current therapies. Furthermore, second line therapies for non-responders, intolerant or otherwise difficult to treat patients are urgently needed as this is relevant for at least one fifth of all patients with inefficacy or intolerance to SOC. Current second line therapies are mainly based on single center retrospective experiences and none of them have been approved by regulatory authorities for AIH, yet.This article highlights new therapeutic approaches based on our growing knowledge on the pathophysiology of AIH. It focuses on cell-based therapies that strengthen or restore immune tolerance. An additional focus lies on new therapeutic agents showing promising results in non-hepatic autoimmune diseases that have a potential for treating AIH. The dynamics in the whole field of innovative therapies for non-hepatic autoimmune diseases will hopefully improve the therapeutic armamentarium for AIH patients in the future.
  • PD-1 immunobiology in systemic lupus erythematosus
    • Abstract: Publication date: Available online 3 November 2018Source: Journal of AutoimmunityAuthor(s): Colleen S. Curran, Sarthak Gupta, Ignacio Sanz, Elad Sharon Programmed death (PD)-1 receptors and their ligands have been identified in the pathogenesis and development of systemic lupus erythematosus (SLE). Two key pathways, toll-like receptor and type I interferon, are significant to SLE pathogenesis and modulate the expression of PD-1 and the ligands (PD-L1, PD-L2) through activation of NF-κB and/or STAT1. These cell signals are regulated by tyrosine kinase (Tyro, Axl, Mer) receptors (TAMs) that are aberrantly activated in SLE. STAT1 and NF-κB also exhibit crosstalk with the aryl hydrocarbon receptor (AHR). Ligands to AHR are identified in SLE etiology and pathogenesis. These ligands also regulate the activity of the Epstein-Barr virus (EBV), which is an identified factor in SLE and PD-1 immunobiology. AHR is important in the maintenance of immune tolerance and the development of distinct immune subsets, highlighting a potential role of AHR in PD-1 immunobiology. Understanding the functions of AHR ligands as well as AHR crosstalk with STAT1, NF-κB, and EBV may provide insight into disease development, the PD-1 axis and immunotherapies that target PD-1 and its ligand, PD-L1.
  • Identification of novel susceptibility genes associated with seven
           autoimmune disorders using whole genome molecular interaction networks
    • Abstract: Publication date: Available online 1 November 2018Source: Journal of AutoimmunityAuthor(s): Sam Kara, Gerardo A. Pirela-Morillo, Conrad T. Gilliam, George D. Wilson Convergent evidence from multiple and independent genetics studies implicate a small number of genes that predispose individuals to multiple autoimmune disorders (AuD). These intersecting loci reinforced the hypothesis that disorders with overlapping etiology group into a cluster of closely related genes within a whole genome molecular interaction network. We tested the hypothesis that “biological network proximity” within a whole genome molecular interaction network can be used to inform the search for multigene inheritance. Using a set of nine previously published genome wide association studies (GWAS) of AuD genes, we generated AuD-specific molecular interaction networks to identify networks of associated genes. We show that all nine “seed genes” can be connected within a 35-member network via interactions with 26 connecting genes. We show that this network is more connected than expected by chance, and 13 of the connecting genes showed association with multiple AuD upon GWAS reanalysis. Furthermore, we report association of SNPs in five new genes (IL10RA, DGKA, GRB2, STAT5A, and NFATC2) which were not previously considered as AuD candidates, and show significant association in novel disease samples of Crohn's disease and systemic lupus erythematosus. Furthermore, we show that the connecting genes show no association in four non-AuD GWAS. Finally, we test the connecting genes in psoriasis GWAS, and show association to previously identified loci and report new loci. These findings support the hypothesis that molecular interaction networks can be used to inform the search for multigene disease etiology, especially for disorders with overlapping etiology.
  • Synaptotagmin-1 overexpression under inflammatory conditions affects
           secretion in salivary glands from Sjögren's syndrome patients
    • Abstract: Publication date: Available online 31 October 2018Source: Journal of AutoimmunityAuthor(s): Juan Cortés, Jorge Hidalgo, Sergio Aguilera, Isabel Castro, Mónica Brito, Hery Urra, Paola Pérez, María-José Barrera, Patricia Carvajal, Ulises Urzúa, Sergio González, Claudio Molina, Verónica Bahamondes, Marcela Hermoso, María-Julieta González Sjögren's syndrome (SS) is an autoimmune exocrinopathy associated with severe secretory alterations by disruption of the glandular architecture integrity, which is fundamental for a correct function and localization of the secretory machinery. Syt-1, PI(4,5)P2 and Ca2+ are significant factors controlling exocytosis in different secretory cells, the Ca2+ role being the most studied. Salivary acinar cells from SS-patients show a defective agonist-regulated intracellular Ca2+ release together with a decreased IP3R expression level, and this condition may explain a reduced water release. However, there are not reports where Syt-1, PI(4,5)P2 and Ca2+ in acinar cells of SS patients had been studied. In the present study, we analyzed the expression and/or localization of Syt-1 and PI(4,5)P2 in acinar cells of labial salivary gland biopsies from SS-patients and control individuals. Also, we evaluated whether the overexpression of Syt-1 and the loss of cell polarity induced by TNF-α or loss of interaction between acinar cell and basal lamina, alters directionality of the exocytosis process, Ca2+ signaling and α-amylase secretion in a 3D-acini model stimulated with cholinergic or β-adrenergic agonists. In addition, the correlation between Syt-1 protein levels and clinical parameters was evaluated. The results showed an increase of Syt-1 mRNA and protein levels, and a high number of co-localization points of Syt-1/STX4 and PI(4,5)P2/Ezrin in the acinar basolateral region of LSG from SS-patients. With regard to 3D-acini, Syt-1 overexpression increased exocytosis in the apical pole compared to control acini. TNF-α stimulation increased exocytic events in the basal pole, which was further enhanced by Syt-1 overexpression. Additionally, altered acinar cell polarity affected Ca2+ signaling and amylase secretion. Overexpression of Syt-1 was associated with salivary gland alterations revealing that the secretory dysfunction in SS-patients is linked to altered expression and/or localization of secretory machinery components together with impaired epithelial cell polarity. These findings provide a novel insight on the pathological mechanism implicated in ectopic secretory products to the extracellular matrix of LSG from SS-patients, which might initiate inflammation.
  • The utility of complement assays in clinical immunology: A comprehensive
    • Abstract: Publication date: Available online 31 October 2018Source: Journal of AutoimmunityAuthor(s): Thomas Lung, Lorenz Risch, Martin Risch, Benjamin Sakem, Reinhard Würzner, Urs Nydegger The multi-tasking organ liver, which is the major synthesis site of most serum proteins, supplies humoral components of the innate, – including proteins of the complement system; and, less intensely, also of the acquired immune system. In addition to hepatocyte origins, C1q, factor D, C3, C7 and other protein components of the complement system are produced at various body locations by monocytes/macrophages, lymphocytes, adipocytes, endometrium, enterocytes, keratinocytes and epithelial cells; but the contribution of these alternate sites to the total serum concentrations is slight. The two major exceptions are factor D, which cleaves factor B of the alternative pathway derived largely from adipocytes, and C7, derived largely from polymorphonuclear leukocytes and monocytes/macrophages. Whereas the functional meaning of the extrahepatic synthesis of factor D remains to be elucidated, the local contribution of C7 may up- or downregulate the complement attack. The liver, however, is not classified as part of the immune system but is rather seen as victim of autoimmune diseases, a point that needs apology. Recent histological and cell marker technologies now turn the hands to also conceive the liver as proactive autoimmune disease catalyst. Hosting non-hepatocytic cells, e.g. NK cells, macrophages, dendritic cells as well as T and B lymphocytes, the liver outreaches multiple sites of the immune system. Immunopharmacological follow up of liver transplant recipients teaches us on liver-based presence of ABH-glycan HLA phenotypes and complement mediated ischemia/regeneration processes. In clinical context, the adverse reactions of the complement system can now be curbed by specific drug therapy. This review extends on the involvement of the complement system in liver autoimmune diseases and should allow to direct therapeutic opportunities.Graphical abstractImage
  • The role of APRIL - A proliferation inducing ligand - In autoimmune
           diseases and expectations from its targeting
    • Abstract: Publication date: Available online 30 October 2018Source: Journal of AutoimmunityAuthor(s): Laurie Baert, Benoit Manfroi, Olivier Casez, Nathalie Sturm, Bertrand Huard Autoimmunity occurs when an adaptive immune response is directed against a self-antigen. As such, autoimmune reactions associated with the production of autoantibodies are common. These autoantibodies may either be pathogenic by inducing the initial damage to self, or exacerbate the reaction secondarily to the initial damage. In both cases, the pathway(s) leading to exposure of the immune system to the self-antigen inducing the production of autoantibodies is largely unknown. The latter is largely complicating the setting of putative prophylactic treatments. As a consequence, one possible way to control these diseases is to eliminate the cells producing antibodies. We will see that this approach is not yet part of any treatment in autoimmunity. Indeed, all the currently available non-specific immunosuppressive treatments do not target directly quiescent antibody-producing plasma cells. However, treatments aimed at depleting precursors of plasma cells, mature B-lymphocytes and/or antigen-experienced B cells not yet fully differentiated into plasma cells, are emerging. Such strategies were recently proven to be highly successful in several autoimmune disorders by two independent ways. The first way is by induction of B-cell cytotoxicity with an antibody directed against the surface antigen CD20. The second way is by antagonism of a key B-cell survival factor, the B-cell activation factor from the TNF superfamily (BAFF). In the present review, we will focus on the current knowledge regarding the role of a molecule related to BAFF, a proliferation-inducing ligand (APRIL), in autoimmune diseases, which acts on antibody-producing plasma cells. We will discuss expectations deriving from APRIL targeting in autoimmune diseases.
  • Etiopathogenesis of autoimmune hepatitis
    • Abstract: Publication date: Available online 29 October 2018Source: Journal of AutoimmunityAuthor(s): Annarosa Floreani, Paula Restrepo-Jiménez, Maria Francesca Secchi, Sara De Martin, Patrick S.C. Leung, Edward Krawitt, Christopher L. Bowlus, M. Eric Gershwin, Juan-Manuel Anaya Autoimmune hepatitis is a chronic inflammatory liver disease characterized by hypergammaglobulinemia, the presence of autoantibodies, and inflammation within the liver, including lymphocytic infiltrates and interface hepatitis. Autoimmune hepatitis shows a female predominance and can present at any age and in any ethnicity. The disease is thought to be a consequence of a break of immune tolerance leading to an autoimmune process that induces liver injury. The self-attack is triggered by T-helper cell-mediated liver autoantigen recognition and B-cell production of autoantibodies, and is sustained by impaired regulatory T cells number and function. Superimposed on a genetic predisposition, infections and environmental factors have been studied as triggering factors for the disease. Allelic variants in the HLA locus have been associated with susceptibility; associations with single nucleotide polymorphisms within non-HLA genes have also been assessed. Several factors have been described as triggers of autoimmune responses in predisposed individuals, including infections, alcohol, vitamin D deficiency, and an altered composition of the intestinal microbiome. Importantly, drugs and herbal agents may trigger classical autoimmune hepatitis, or may induce a liver disease with autoimmune features. Interactions between female hormones and genetic factors have been hypothesized to play a role in autoimmunity, although the exact role for these factors has not been fully established. Herein we present a review of the etiology of autoimmune hepatitis including de novo autoimmune hepatitis post-liver transplantation as well as animal models for its study.
  • The landscape and diagnostic potential of T and B cell repertoire in
           Immunoglobulin A Nephropathy
    • Abstract: Publication date: Available online 29 October 2018Source: Journal of AutoimmunityAuthor(s): Chen Huang, Xuemei Li, Jinghua Wu, Wei Zhang, Shiren Sun, Liya Lin, Xie Wang, Hongmei Li, Xiaolei Wu, Peng Zhang, Guoshuang Xu, Hanmin Wang, Hongbao Liu, Yuzhen Liu, Dapeng Chen, Li Zhuo, Wenge Li, Huanming Yang, Jian Wang, Ling Wang Immunoglobulin A Nephropathy (IgAN) is the most common glomerulonephritis worldwide. The pathologic hallmark of IgAN is immune complex deposited in glomerular mesangium, which induces inflammation and affects the kidney's normal functions. The exact pathogenesis of IgAN, however, remains obscure. Further, in current clinical practice, the diagnosis relies on needle biopsy of renal tissue. Therefore, a non-invasive method for diagnosis and prognosis surveillance of the disease is highly desirable. To this end, we investigated the T cell receptor beta chain (TCRB) and immunoglobulin heavy chain (IGH) repertoire in circulating lymphocytes and compared them with kidney infiltrating lymphocytes using immune repertoire high throughput sequencing. We found that some features of TCRB and IGH in renal tissues were remarkably different from that in the blood, including decreased repertoire diversity, increased IgA and IgG frequency, and more antigen-experienced B cells. The complementarity-determining region 3 (CDR3) length of circulating TCRB and IGH in IgAN patients was significantly shorter than that in healthy controls, which is the result of both VDJ rearrangement and clonal selection. The IgA1 frequency in the blood of IgAN patients is significantly higher than that in other Nephropathy (NIgAN) patients and healthy control. Importantly we identified a set of TCRB and IGH clones, which can be used to distinguish IgAN from NIgAN and healthy controls with high accuracy. These results indicated that the TCRB and IGH repertoire can potentially serve as non-invasive biomarkers for the diagnosis of IgAN. The characteristics of the kidney infiltrating and circulating lymphocytes repertoires shed light on IgAN detection, treatment and surveillance.
  • Prognosticating autoimmune encephalitis: A systematic review
    • Abstract: Publication date: Available online 26 October 2018Source: Journal of AutoimmunityAuthor(s): James Broadley, Udaya Seneviratne, Paul Beech, Katherine Buzzard, Helmut Butzkueven, Terence O'Brien, Mastura Monif ObjectiveTo perform a systematic review of the current scientific literature in order to identify variables associated with patient prognosis in autoimmune encephalitis.MethodsWe performed a systematic literature search using MEDLINE, Embase, PubMed and PsychInfo databases. We selected studies that explored the correlation between early clinical and paraclinical findings, and patient outcomes. Data was extracted, analyzed and recorded in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines.ResultsForty four publications detailing 2823 subjects matched our inclusion criteria. There was considerable heterogeneity in methodology, patient profile, investigation results and clinical outcome measures. Findings were often discrepant for cases of anti-NMDAR encephalitis when compared with other causes of autoimmune encephalitis. Delay in immunotherapy contributed to a variety of worse outcomes for patients with different subsets of autoimmune encephalitis. Altered consciousness, ICU admission and no use of immunotherapy were variables associated with poor prognosis in anti-NMDAR encephalitis. Older age, sex, the presence of status epilepticus, CSF abnormalities and MRI changes were unlikely to have significant prognostic value. The influence of antibody titers, autonomic dysfunction and underlying malignancy was unclear.ConclusionsA number of variables were identified to have potential predictive value for outcomes in autoimmune encephalitis. Heterogeneous study design, size and quality were major limiting factors in this review.
  • Molecular mimicry and autoimmunity
    • Abstract: Publication date: Available online 26 October 2018Source: Journal of AutoimmunityAuthor(s): Manuel Rojas, Paula Restrepo-Jiménez, Diana M. Monsalve, Yovana Pacheco, Yeny Acosta-Ampudia, Carolina Ramírez-Santana, Patrick S.C. Leung, Aftab A. Ansari, M. Eric Gershwin, Juan-Manuel Anaya Molecular mimicry is one of the leading mechanisms by which infectious or chemical agents may induce autoimmunity. It occurs when similarities between foreign and self-peptides favor an activation of autoreactive T or B cells by a foreign-derived antigen in a susceptible individual. However, molecular mimicry is unlikely to be the only underlying mechanism for autoimmune responses; other factors such as breach in central tolerance, non-specific bystander activation, or persistent antigenic stimuli (amongst others) may also contribute to the development of autoimmune diseases. Host genetics, exposure to microbiota and environmental chemicals are additional links to our understanding of molecular mimicry. Our current knowledge of the detailed mechanisms of molecular mimicry is limited by the issues of prolonged periods of latency before the appearance of disease, the lack of enough statistical power in epidemiological studies, the limitations of the potential role of genetics in human studies, the relevance of inbred murine models to the diverse human population and especially the limited technology to systematically dissect the human T-cell repertoire and B-cell responses. Nevertheless, studies on the role of autoreactive T-cells that are generated secondary to molecular mimicry, the diversity of the T-cell receptor repertoires of auto-reactive T-cells, the role of exposure to cryptic antigens, the generation of autoimmune B-cell responses, the interaction of microbiota and chemical adjuvants with the host immune systems all provide clues in advancing our understanding of the molecular mechanisms involved in the evolving concept of molecular mimicry and also may potentially aid in the prevention and treatment of autoimmune diseases.
  • Viral hepatitis, inflammation, and cancer: A lesson for autoimmunity
    • Abstract: Publication date: Available online 26 October 2018Source: Journal of AutoimmunityAuthor(s): Silvia Piconese, Ilenia Cammarata, Vincenzo Barnaba In the present review, we analyzed the various overlapping and non-mutually exclusive mechanisms that intersect and form complex and highly flexible immunological networks allowing the defense against liver infections and tumors. Liver immunity results from the combination of the skills of systemic and local immune system(s) to sense and recognize pathogen or tumor antigens, to sensitize a wide range of innate and adaptive immune cells, and to clear the “invaders”, through the establishment of a transient liver immunopathology state undergoing resolution/control of infections or tumors, and memory development. Then, a special emphasis is placed on discussing about the capacity of the immune system(s) to develop a state of chronic low-level immunopathology adapting through the intervention of simultaneous immunoregulatory mechanisms, when the liver is infected by highly mutable viruses (e.g., hepatitis B or C viruses [HBV or HCV]) capable to escape from the immune recognition. The establishment of chronic inflammation represents an advantage for the species survival, because it guarantees the long-term survival of human hosts despite the virus persistence. However, chronic inflammation, in the long run, can evolve towards severe consequences (decompensated cirrhosis and hepatocellular carcinoma) in some individuals, finding requiring the impelling need of discovering new therapeutic anti-viral and immunostimulatory agents addressed, in combination, to fight especially HBV that, in contrast to HCV, lacks antivirals capable to eradicate the virus. Finally, we discussed the concept proposing that the divergent immunoregulatory mechanisms that develop in persisting infections or tumors, on the one hand, and autoimmunity, on the other hand, are the mirror image of each other, whose understanding is also relevant for preparing novel immunotherapeutic approaches in autoimmune diseases.
  • The immunobiology of female predominance in primary biliary cholangitis
    • Abstract: Publication date: Available online 25 October 2018Source: Journal of AutoimmunityAuthor(s): Alessio Gerussi, Laura Cristoferi, Marco Carbone, Rosanna Asselta, Pietro Invernizzi Primary biliary cholangitis (PBC) is an autoimmune liver disease with a striking female preponderance. The mechanisms behind this predominance are still to be elucidated, although multiple theories have been postulated and investigated. Among the proposed involved factors, sex hormones have been the first to be studied, but unfortunately data have been inconclusive or conflicting. Similarly, fetal microchimerism has received a huge attention in the past, but data in PBC have been unsatisfactory especially if compared to other autoimmune diseases like systemic lupus erythematosus. Studies focused on genetic factors have generated more intriguing and robust data, reporting a few abnormalities on the X chromosome in PBC patients. However, these data are able to explain only a part of the phenotypic variability attributed to the genetic component, and most importantly, need to be validated in larger series. More recently, a novel mice model of PBC, characterised by a constitutive expression of Interferon-γ (IFN-γ), has been developed and it is notable for being the first one with female predominance. At the same time, there has been a wide interest in the role of microbiome in health and disease, as well as in epigenetics, which have tried to explain differences in biological phenotypes not covered by genetics. The aim of this review is to outline established knowledge on the topic and try to provide novel perspectives on the potential future applications of newer techniques addressing microbiome and epigenome, in order to further understand the biology of sex divergence in PBC.
  • The clinical usage and definition of autoantibodies in immune-mediated
           liver disease: A comprehensive overview
    • Abstract: Publication date: Available online 23 October 2018Source: Journal of AutoimmunityAuthor(s): Benedetta Terziroli Beretta-Piccoli, Giorgina Mieli-Vergani, Diego Vergani Autoimmune serology is key to the diagnosis and management of autoimmune liver diseases. Its correct use in clinical practice requires a basic knowledge of the laboratory techniques used for autoantibody detection. Indirect immunofluorescence (IIF) on triple rodent tissue is still the gold standard screening procedure for liver-relevant autoantibodies, while HEp2 cells and human ethanol-fixed neutrophils are used as substrates to characterize nuclear reactivities and to detect anti-neutrophil cytoplasm antibody, respectively. Assays based on purified or recombinant antigens are increasingly used, having the main advantage of being observer-independent and the disadvantage of detecting only autoantibodies whose antigenic target has been identified. The AIH-specific anti-soluble liver antigen antibody cannot be detected by IIF and a molecular-based assay should be used at the screening level. Since autoantibodies may be present in the context of viral hepatitides and other inflammatory liver diseases it is important to exclude these conditions before diagnosing autoimmune liver disease. Anti-nuclear antibody (ANA), most often with a homogeneous IIF pattern on HEp2 cells, characterizes type 1 autoimmune hepatitis (AIH), and is found in association with anti-smooth muscle antibody in about half of the cases. Two IIF ANA patterns are specific for primary biliary cholangitis, namely the rim-like/membranous pattern, and the multiple nuclear dots pattern. Anti-liver kidney microsomal antibody type 1 is the serological hallmark of type 2 AIH, often in association with anti-liver cytosol type 1 antibody. Atypical perinuclear anti-neutrophil antibody, referred to as perinuclear anti-neutrophil nuclear antibody, is frequently detected in primary sclerosing cholangitis, in AIH type 1 and in inflammatory bowel diseases. The anti-asiaglycoprotein receptor antibody is liver-specific but not disease-specific, and reliable commercial assays for its detection are lacking. Anti-mitochondrial antibody is the hallmark of primary biliary cholangitis (PBC), being disease-specific and present in about 95% of the PBC patients. Its incidental detection presages the future development of PBC.
  • Autoimmune sclerosing cholangitis: Evidence and open questions
    • Abstract: Publication date: Available online 23 October 2018Source: Journal of AutoimmunityAuthor(s): Benedetta Terziroli Beretta-Piccoli, Diego Vergani, Giorgina Mieli-Vergani Juvenile sclerosing cholangitis is a rare chronic hepatobiliary disorder characterized by inflammation of the intra- and/or extrahepatic bile ducts, bile duct dilatation, narrowing and obliteration, and, histologically, by inflammatory bile duct damage leading to periductular fibrosis. The diagnosis is based on endoscopic retrograde cholangiopancreatography or magnetic resonance cholangiopancreatography. In children, it may be associated to a variety of systemic and hepatic conditions: thus, the term “primary” sclerosing cholangitis should be reserved for the rare cases without a known cause. Small duct disease is diagnosed in the presence of histological features diagnostic of sclerosing cholangitis and normal cholangiography. Autoimmune sclerosing cholangitis (ASC) is a form of sclerosing cholangitis with strong autoimmune features overlapping with those of autoimmune hepatitis (AIH). It is a well-recognized nosological entity in paediatrics, where it accounts for the majority of sclerosing cholangitis cases. It is as prevalent as AIH in children, is equally frequent in males and females, half of the patients have concomitant inflammatory bowel disease, virtually all patients have raised immunoglobulin G levels and positive anti-nuclear and/or anti-smooth muscle antibodies. Half of the ASC patients respond well to standard immunosuppressive treatment for AIH with the addition of ursodeoxycholic acid, but the transplant rate is higher than in AIH, and post-transplant recurrence is frequent. A number of open questions remain: are ASC and AIH distinct entities or different manifestations of the same condition' What is the role of histology' Is small duct disease a specific entity' What is the relationship between ASC and adult primary sclerosing cholangitis' What is the role of inflammatory bowel disease' In addition, validated diagnostic criteria for ASC are needed.
  • IgG Fc N-glycosylation: Alterations in neurologic diseases and potential
           therapeutic target'
    • Abstract: Publication date: Available online 22 October 2018Source: Journal of AutoimmunityAuthor(s): Yannick Kronimus, Richard Dodel, Sebastian P. Galuska, Sascha Neumann Immunoglobulin G (IgG) is the most abundant antibody subclass of the human circulatory system and has important functions in the adaptive immune response. On the one hand, recognition and neutralization of antigens is mediated by the fab fragment, and on the other hand, processes such as phagocytosis, complement activation and inflammatory reactions are triggered by the Fc fragment. Here, the composition of conserved N-glycans attached to asparagine 297 of the IgG CH2 domain is a major critical factor that particularly modulates the effector functions of IgG. Additional attachments of fucoses, galactoses, N-acetylglucosamines, and sialic acids have been identified as factors that influence the affinity to a wide range of complement proteins and receptors and, thus, secondarily induce the secretion of pro- and anti-inflammatory cytokines. Consequently, alterations in the IgG Fc N-glycosylation pattern can provoke disruptions in the immunological state and are accompanied by various diseases, although the involvement of changed IgG glycosylation in disease outbreaks remains unknown. In addition to many autoimmune diseases, which have already been extensively reviewed, there are a number of further disorders related to altered IgG glycosylation patterns. In the present review, we focus on neurologic diseases, as in the last few years, an increasing number of studies have been published in this field. Due to the absence of reliable early biomarkers as well as therapeutic options in many cases, such analyses are of great interest and reveal possible future approaches.
  • Juvenile autoimmune hepatitis: A comprehensive review
    • Abstract: Publication date: Available online 19 October 2018Source: Journal of AutoimmunityAuthor(s): Christiane Sokollik, Valerie A. McLin, Diego Vergani, Benedetta Terziroli Beretta-Piccoli, Giorgina Mieli-Vergani Autoimmune hepatitis (AIH) is a rare, chronic disease that affects both adults and children, including infants. The disease is probably triggered by environmental factors in genetically predisposed individuals. The clinical presentation ranges from asymptomatic patients or patients with non-specific symptoms, such as fatigue, to fulminant liver failure, many children presenting with symptoms indistinguishable from those of acute hepatitis. Raised transaminase and immunoglobulin G (IgG) levels, in association with circulating autoantibodies, guide towards the diagnosis. The histological hallmark is interface hepatitis, which however is non-specific and may be absent. There are no bile duct changes on cholangiography. Presence of anti-nuclear antibody (ANA) and/or anti-smooth muscle antibody (SMA) is characteristic for type 1 AIH, whereas presence of anti-liver kidney microsomal type 1 (LKM1) antibody and/or anti-liver cytosol type 1 (LC1) antibody defines type 2 AIH. The latter accounts for about one third of the juvenile AIH cases, presents more acutely than type 1 AIH and is very rare in adults. Immunosuppressive therapy, based on steroids and azathioprine, is required, and in the vast majority of patients leads to clinical and biochemical remission, defined as absence of symptoms, normal transaminase and IgG levels, and negative or low-titer autoantibodies. In patients intolerant or non-responder to standard therapy, a number of second line drugs have been employed with variable results. For the rare cases who progress to end-stage liver disease, liver transplantation is life-saving, but recurrence of the disease is possible. A better understanding of the underlying pathogenic mechanisms will help to develop new, more effective and less toxic therapies, and to tailor treatment regimens to the individual patient.
  • Gut microbiota translocation promotes autoimmune cholangitis
    • Abstract: Publication date: Available online 17 October 2018Source: Journal of AutoimmunityAuthor(s): Hong-Di Ma, Zhi-Bin Zhao, Wen-Tao Ma, Qing-Zhi Liu, Cai-Yue Gao, Liang Li, Jinjun Wang, Koichi Tsuneyama, Bin Liu, Weici Zhang, Yongjian Zhou, M. Eric Gershwin, Zhe-Xiong Lian Gut microbiota and bacterial translocation have been implicated as significant contributors to mucosal immune responses and tolerance; alteration of microbial molecules, termed pathogen-associated molecular patterns (PAMP) and bacterial translocation are associated with immune pathology. However, the mechanisms by which dysregulated gut microbiota promotes autoimmunity is unclear. We have taken advantage of a well-characterized murine model of primary biliary cholangitis, dnTGFβRII mice, and an additional unique construct, toll-like receptor 2 (TLR2)-deficient dnTGFβRII mice coined dnTGFβRIITLR2−/− mice to investigate the influences of gut microbiota on autoimmune cholangitis. Firstly, we report that dnTGFβRII mice manifest altered composition of gut microbiota and that alteration of this gut microbiota by administration of antibiotics significantly alleviates T-cell-mediated infiltration and bile duct damage. Second, toll-like receptor 2 (TLR2)-deficient dnTGFβRII mice demonstrate significant exacerbation of autoimmune cholangitis when their epithelial barrier integrity was disrupted. Further, TLR2-deficiency mediates downregulated expression of tight junction-associated protein ZO-1 leading to increased gut permeability and bacterial translocation from gut to liver; use of antibiotics reduces microbiota translocation to liver and also decreases biliary pathology. In conclusion, our data demonstrates the important role of gut microbiota and bacterial translocation in the pathogenesis of murine autoimmune cholangitis.
  • Autoimmunity risk- and protection-associated IL7RA genetic variants
           differentially affect soluble and membrane IL-7Rα expression
    • Abstract: Publication date: Available online 17 October 2018Source: Journal of AutoimmunityAuthor(s): Christian Lundtoft, Julia Seyfarth, Sonja Oberstrass, Joachim Rosenbauer, Christina Baechle, Michael Roden, Reinhard W. Holl, Ertan Mayatepek, Sebastian Kummer, Thomas Meissner, Marc Jacobsen Interleukin-7 receptor α-chain (IL7RA) haplotypes are associated with susceptibility to autoimmune diseases including type 1 diabetes (T1D). Previous studies found lower soluble IL-7Rα (sIL-7Rα) serum levels of the protection-associated IL7RA haplotype assumed to reduce IL-7 availability for self-reactive T cells. Also, a risk-associated IL7RA haplotype is accompanied by lower sIL-7Rα serum concentrations but no underlying mechanisms have been described and the causative polymorphism remains unknown.Here, we characterized functional implications of the nonsynonymous rs1494558 (Thr66Ile), which tags the protection-associated IL7RA haplotype, in HEK293T cells and serum samples of T1D patients with different haplotype carriers. Influence of risk- and protection-associated haplotypes on IL-7Rα was analyzed.The risk-associated Ile66 variant affected gel mobility and impaired secretion of the sIL-7Rα as well as expression of the membrane-associated (m)IL-7Rα in HEK293T cells. Serum sIL-7Rα analyses confirmed differential gel mobility of the Ile66 variant and found decreased sIL-7Rα serum levels of T1D patients carrying the Ile66-tagged haplotype. Differences in glycosylation were not causative for differential mobility but enhanced the effects on impaired secretion. Comparison of protection- and risk-associated haplotypes in a cell line-based in vitro model identified dominant effects of the protective haplotype tagged by rs6897932 (Ile244) on mIL-7Rα expression, whereas the risk haplotype mainly affected the sIL-7Rα.This study identified novel functional effects of the Ile66 IL7RA variant and characterized features of autoimmunity risk- and protection-associated haplotypes. The findings add to our understanding of how these haplotypes regulate sIL-7Rα and mIL-7Rα expression in T cells causing differential susceptibility to autoimmune diseases.Graphical abstractImage 1
  • Structural mapping of hot spots within human CASPR2 discoidin domain for
           autoantibody recognition
    • Abstract: Publication date: Available online 15 October 2018Source: Journal of AutoimmunityAuthor(s): Wenjun Liang, Junying Zhang, Margaux Saint-Martin, Fei Xu, Nelly Noraz, Jianmei Liu, Jérôme Honnorat, Heli Liu Accumulating evidence has showed that anti-CASPR2 autoantibodies occur in a long list of neurological immune disorders including limbic encephalitis (LE). Belonging to the well-known neurexin superfamily, CASPR2 has been suggested to be a central node in the molecular networks controlling neurodevelopment. Distinct from other subfamilies in the neurexin superfamily, the CASPR subfamily features a unique discoidin (Disc) domain. As revealed by our and others' recent studies, CASPR2 Disc domain bears a major epitope for autoantibodies. However, structural information on CASPR2 recognition by autoantibodies has been lacking. Here, we report the crystal structure of human CASPR2 Disc domain at a high resolution of 1.31 Å, which is the first atomic-resolution structure of the CASPR subfamily members. The Disc domain adopts a total β structure and folds into a distorted jellyroll-like barrel with a conserved disulfide-bond interlocking its N- and C-termini. Defined by four loops and located in one end of the barrel, the “loop-tip surface” is totally polar and easily available for protein docking. Based on structure-guided epitope prediction, we generated nine mutants and evaluated their binding to autoantibodies of cerebrospinal fluid from twelve patients with limbic encephalitis. The quadruple mutant G69N/A71S/S77N/D78R impaired CASPR2 binding to autoantibodies from eleven LE patients, which indicates that the loop L1 in the Disc domain bears hot spots for autoantibody interaction. Structural mapping of autoepitopes within human CASPR2 Disc domain sheds light on how autoantibodies could sequester CASPR2 ectodomain and antagonize its functionalities in the pathogenic processes.
  • White blood cell mitochondrial DNA copy number is decreased in rheumatoid
           arthritis and linked with risk factors. A twin study
    • Abstract: Publication date: Available online 14 October 2018Source: Journal of AutoimmunityAuthor(s): Anders J. Svendsen, Qihua Tan, Marianne A. Jakobsen, Bharat Thyagarajan, Marianne Nygaard, Lene Christiansen, Jonas Mengel-From Low mitochondrial DNA copy number (mtDNA CN) has been associated with e.g. cancer, cardiovascular and autoimmune diseases. We aimed to study a potential association between mtDNA CN and rheumatoid arthritis (RA).The relative quantity of mitochondrial DNA compared to nuclear DNA was measured in peripheral white blood cells from 149 RA affected twin pairs and 1321 non-affected twin pairs. Multiple regression analysis including RA discordant twin pairs was performed in order to separate specific effects of RA and familial RA predisposition using non-RA affected twin pairs as reference group. In addition, we performed a twin pair level analysis including only RA discordant twin pairs evaluating the effect of cell type, auto antibodies and RA genetic risk factors.Both the RA twins and their non-affected co-twins had significantly lower mtDNA CN than non-affected twins (−28.7 and −23.1 mtDNA CN, respectively). Adjusting for cell count attenuated these differences (−23.1 mtDNA CN and −20.1 mtDNA CN respectively). Within RA discordant twin pairs PTPN22(T) positive RA twins had a significantly lower amount than their co-twins (−16.3 mtDNA CN). PTPN22(T) had no effect among twins from non-affected twin pairs.MtDNA CN is significantly lower in persons with established RA and in predisposed non-affected RA co-twins suggesting that mitochondrial variation may be involved in the RA disease pathways. Our results also suggest that the RA associated genetic risk factor, PTPN22(T), further decreases the mtDNA CN, but only in carriers with established RA.
  • Arginine methylation of FOXP3 is crucial for the suppressive function of
           regulatory T cells
    • Abstract: Publication date: Available online 11 October 2018Source: Journal of AutoimmunityAuthor(s): Yuki Kagoya, Hiroshi Saijo, Yukiko Matsunaga, Tingxi Guo, Kayoko Saso, Mark Anczurowski, Chung-Hsi Wang, Kenji Sugata, Kenji Murata, Marcus O. Butler, Cheryl H. Arrowsmith, Naoto Hirano Forkhead box transcription factor 3 (FOXP3) plays a pivotal role in the suppressive function of regulatory T cells. In addition to mRNA levels, FOXP3 activity can also be controlled by posttranslational mechanisms, which have not been studied in a comprehensive manner. Through extensive screening using selective inhibitors, we demonstrate that the inhibition of type I protein arginine methytransferases (PRMTs) attenuates the suppressive functions of regulatory T cells. FOXP3 undergoes methylation on arginine residues at positions 48 and 51 by interacting with protein arginine methyltransferase 1 (PRMT1). The inhibition of arginine methylation confers gene expression profiles representing type I helper T cells to FOXP3+ T cells, which results in attenuated suppressive activity. A methylation-defective mutant of FOXP3 displays less potent activity to suppress xenogeneic graft-versus-host disease in vivo. These results elucidate an important role of arginine methylation to enhance FOXP3 functions and are potentially applicable to modulate regulatory T cell functions.
  • A stochastic epigenetic Mendelian oligogenic disease model for type 1
    • Abstract: Publication date: Available online 8 October 2018Source: Journal of AutoimmunityAuthor(s): Chester A. Alper, Charles E. Larsen, Michael R. Trautwein, Dennis R. Alford The incidence of type 1 diabetes (T1D) and some other complex diseases is increasing. The cause has been attributed to an undefined changing environment. We examine the role of the environment (or any changing non-genetic mechanism) in causing the rising incidence, and find much evidence against it: 1) Dizygotic twin T1D concordance is the same as siblings of patients in general; 2) If the environment is responsible for both the discordance among identical twins of patients with T1D and its rising incidence, the twin concordance rate should be rising, but it is not; 3) Migrants from high-to low-incidence countries continue to have high-incidence children; 4) TID incidence among the offspring of two T1D parents is identical to the monozygotic twin rate. On the other hand, genetic association studies of T1D have revealed strong susceptibility in the major histocompatibility complex and many optional additive genes of small effect throughout the human genome increasing T1D risk. We have, from an analysis of previously published family studies, developed a stochastic epigenetic Mendelian oligogenic (SEMO) model consistent with published observations. The model posits a few required recessive causal genes with incomplete penetrance explaining virtually all of the puzzling features of T1D, including its rising incidence and the specific low T1D incidence rates among first-degree relatives of patients. Since historic selection against any causal gene could prevent T1D, we postulate that the rising incidence is because of increasing population mixing of parents from some previously isolated populations that had selected against different causal genes.
  • Epigenome-wide association study of peripheral blood mononuclear cells in
           systemic lupus erythematosus: Identifying DNA methylation signatures
           associated with interferon-related genes based on ethnicity and SLEDAI
    • Abstract: Publication date: Available online 7 October 2018Source: Journal of AutoimmunityAuthor(s): Stancy Joseph, Nysia I. George, Bridgett Green-Knox, Edward L. Treadwell, Beverly Word, Sarah Yim, Beverly Lyn-Cook Systemic lupus erythematosus (SLE or lupus) is a heterogeneous autoimmune disease characterized by the involvement of multiple organs and the production of antinuclear antibodies. DNA methylation plays an important role in the pathogenesis of lupus. We have performed an epigenome-wide DNA methylation study in lupus and healthy control (non-lupus) subjects to identify epigenetic patterns in lupus characterized ethnicity and SLE disease activity index (SLEDAI). A total of fifty-seven lupus patients (39 African American (AA) and 18 European American (EA)) and 33 healthy controls (17 AA and 16 EA) were studied. Differential DNA methylation between lupus patients and controls was assessed for approximately 485,000 CpG sites across the genome. We identified 41 differentially methylated sites (associated with 30 genes) between lupus and control s subjects, 85% of which were hypomethylated. Significant hypomethylation of differentially methylated sites was associated with several interferon-related genes, including MX1, IFI44L, PARP9, DT3XL, IFIT1, IFI44, RSAD2, PLSCR1, and IRF7. Several of these associated genes were also hypomethylated in comparisons between AA lupus and AA non-lupus subjects and between lupus patients with SLEDAI>6 and non-lupus subjects. Our analysis of gene expression data through RT-PCR confirmed these findings. Thus, the results indicate epigenetics susceptibility in lupus, which may be associated with SLEDAI score and ethnicity. In addition, our findings support the importance of the Type 1 interferon pathway in lupus pathogenesis.
  • ARID3a gene profiles are strongly associated with human interferon alpha
    • Abstract: Publication date: Available online 5 October 2018Source: Journal of AutoimmunityAuthor(s): Michelle L. Ratliff, Joshua Garton, Lori Garman, M. David Barron, Constantin Georgescu, Kathryn A. White, Eliza Chakravarty, Jonathan D. Wren, Courtney G. Montgomery, Judith A. James, Carol F. Webb Type I interferons (IFN) causes inflammatory responses to pathogens, and can be elevated in autoimmune diseases such as systemic lupus erythematosus (SLE). We previously reported unexpected associations of increased numbers of B lymphocytes expressing the DNA-binding protein ARID3a with both IFN alpha (IFNα) expression and increased disease activity in SLE. Here, we determined that IFNα producing low density neutrophils (LDNs) and plasmacytoid dendritic cells (pDCs) from SLE patients exhibit strong associations between ARID3a protein expression and IFNα production. Moreover, SLE disease activity indices correlate most strongly with percentages of ARID3a+ LDNs, but were also associated, less significantly, with IFNα expression in LDNs and pDCs. Hierarchical clustering and transcriptome analyses of LDNs and pDCs revealed SLE patients with low ARID3a expression cluster with healthy controls and identified gene profiles associated with increased proportions of ARID3a- and IFNα-expressing cells of each type. These data identify ARID3a as a potential transcription regulator of IFNα-related inflammatory responses and other pathways important for SLE disease activity.
  • Endogenous IL-10 maintains immune tolerance but IL-10 gene transfer
           exacerbates autoimmune cholangitis
    • Abstract: Publication date: Available online 28 September 2018Source: Journal of AutoimmunityAuthor(s): Yu-Hsin Hsueh, Hung-Wen Chen, Bi-Jhen Syu, Chia-I. Lin, Patrick S.C. Leung, M. Eric Gershwin, Ya-Hui Chuang The immunomodulatory effect of IL-10 as an immunosuppressive and anti-inflammatory cytokine is well known. Taking advantage of our established mouse model of autoimmune cholangitis using 2-octynoic acid conjugated ovalbumin (2-OA-OVA) induction, we compared liver pathology, immune cell populations and antimitochondrial antibodies between IL-10 knockout and wild type mice immunized with 2-OA-OVA. At 10 weeks post immunization, portal inflammation and fibrosis were more severe in 2-OA-OVA immunized IL-10 knockout mice than in wild type mice. This was accompanied by significant higher levels of collagen I and III expression, T, NK and NKT subsets in liver and IgG anti-mitochondrial autoantibodies (AMAs) compared to 2-OA-OVA immunized wild type mice, suggesting that endogenous IL-10 is necessary for the maintenance of immune tolerance in primary biliary cholangitis (PBC). Further, we investigated whether administration of exogenous IL-10 could prevent PBC by administration of IL-10 expressing recombinant adeno-associated virus (AAV-IL-10) either 3 days before or 3 weeks after the establishment of liver pathology. Interestingly, administration of AAV-IL-10 resulted in increased liver inflammation and fibrosis, accompanied by increases in IFN-γ in liver CD4+ T cell, granzyme B, FasL, and CD107a in liver CD8+ T and NKT cells, and granzyme B and FasL in liver NK cells of AAV-IL-10 administered mice compared with control mice. Furthermore, administration of AAV-IL-10 significantly increased levels of proinflammatory cytokines and chemokines (IFN-γ, TNF-α, CXCL9 and CXCL10) and collagen I and III production in naïve mice, together with increase in immune cell infiltration and collagen deposition in the liver, suggesting a role of IL-10 in fibrosis. In conclusion, our data demonstrate that endogenous IL-10 is critical in the maintenance of immune tolerance but exogenous administration of IL-10 exacerbates liver inflammation and fibrosis. Furthermore, the distinctive presence of inflammatory immune cell populations and collagen expression in AAV-IL-10 treated naïve mice cautions against the clinical use of exogenous IL-10 in patients with autoimmune cholangitis.
  • CRL4DCAF2 is required for mature T-cell expansion via Aurora B-regulated
           proteasome activity
    • Abstract: Publication date: Available online 21 September 2018Source: Journal of AutoimmunityAuthor(s): Keqi Fan, Fei Wang, Yiyuan Li, Lu Chen, Zhengjun Gao, Yu Zhang, Jin-yuan Duan, Tao Huang, Jiangyan Zhong, Rong-bei Liu, Xintao Mao, Hengyu Fan, Xing Guo, Jin Jin The proliferation of T cells in peripheral lymphoid tissues requires T cell receptor (TCR)-mediated cell cycle entry. However, the underlying mechanism regulating cell cycle progression in mature T cells is incompletely understood. Here, we have identified an E3 ubiquitin ligase, CRL4DCAF2, as a critical mediator controlling M phase exit in activated T cells. DCAF2 expression is induced upon TCR stimulation and its deficiency attenuates T cell expansion. Additionally, DCAF2 T cell-specific knockout mice display impaired peripheral T cell maintenance and reduced severity of various autoimmune diseases. Continuous H4K20me1 modification caused by DCAF2 deficiency inhibits the induction of Aurkb expression, which regulates 26S proteasome activity during G2/M phase. CRL4DCAF2 deficiency causes M phase arrest through proteasome-dependent mechanisms in peripheral T cells. Our findings establish DCAF2 as a novel target for T cell-mediated autoimmunity or inflammatory diseases.
  • GPR15+ T cells are Th17 like, increased in smokers and
           associated with multiple sclerosis
    • Abstract: Publication date: Available online 21 September 2018Source: Journal of AutoimmunityAuthor(s): Cecilie Ammitzbøll, Marina R. von Essen, Lars Börnsen, Eva Rosa Petersen, Oskar McWilliam, Rikke Ratzer, Romme Christensen Jeppe, Annette B. Oturai, Helle B. Søndergaard, Finn Sellebjerg Smoking is a risk factor for the development and progression of multiple sclerosis (MS); however, the pathogenic effects of smoking are poorly understood. We studied the smoking-associated chemokine receptor-like molecule GPR15 in relation to relapsing-remitting MS (RRMS). Using microarray analyses and qPCR we found elevated GPR15 in blood cells from smokers, and increased GPR15 expression in RRMS. By flow cytometry we detected increased frequencies of GPR15 expressing T and B cells in smokers, but no difference between patients with RRMS and healthy controls. However, after cell culture with the autoantigens myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein, frequencies of MBP-reactive and non-proliferating GPR15+CD4+ T cells were increased in patients with RRMS compared with healthy controls. GPR15+CD4+ T cells produced IL-17 and were enriched in the cerebrospinal fluid (CSF). Furthermore, in the CSF of patients with RRMS, GPR15+ T cells were associated with CCR6+CXCR3+/CCR6−CXCR3+ phenotypes and correlated positively with concentrations of the newly identified GPR15-ligand (GPR15L), myelin degradation and disability. In conclusion, we have identified a proinflammatory cell type linking smoking with pathogenic immune cell functions in RRMS.
  • T follicular helper cells restricted by IRF8 contribute to T cell-mediated
    • Abstract: Publication date: Available online 19 September 2018Source: Journal of AutoimmunityAuthor(s): Ruihua Zhang, Chen-feng Qi, Yuan Hu, Yanhong Shan, Yuan-Pang Hsieh, Feihong Xu, Geming Lu, Jun Dai, Monica Gupta, Miao Cui, Liang Peng, Jianjun Yang, Qingjie Xue, Ray Chen-Liang, Kang Chen, Yeyunfei Zhang, Wai-Ping Fung-Leung, J. Rodrigo Mora, Liwu Li, Herbert C. Morse The follicular helper T cell (TFH) are established regulators of germinal center (GC) B cells, whether TFH have pathogenic potential independent of B cells is unknown. Based on in vitro TFH cell differentiation, in vivo T cell transfer animal colitis model, and intestinal tissues of inflammatory bowel disease (IBD) patients, TFH and its functions in colitis development were analyzed by FACS, ChIP, ChIP-sequencing, WB, ELISA and PCR. Herein we demonstrate that intestinal tissues of patients and colon tissues obtained from Rag1−/− recipients of naïve CD4+ T cells with colitis, each over-express TFH-associated gene products. Adoptive transfer of naïve Bcl6−/− CD4+ T cells into Rag1−/− recipient mice abrogated development of colitis and limited TFH differentiation in vivo, demonstrating a mechanistic link. In contrast, T cell deficiency of interferon regulatory factor 8 (IRF8) resulted in augmentation of TFH induction in vitro and in vivo. Functional studies showed that adoptive transfer of IRF8 deficient CD4+ T cells into Rag1−/− recipients exacerbated colitis development associated with increased gut TFH-related gene expression, while Irf8−/−/Bcl6−/− CD4+ T cells abrogated colitis, together indicating that IRF8-regulated TFH can directly cause colon inflammation. Molecular analyses revealed that IRF8 suppresses TFH differentiation by inhibiting transcription and transactivation of the TF IRF4, which is also known to be essential for TFH induction. Our documentation showed that IRF8-regulated TFH can function as B-cell-independent, pathogenic, mediators of colitis suggests that targeting TFH could be effective for treatment of IBD.
  • IL-17A is functionally relevant and a potential therapeutic target in
           bullous pemphigoid
    • Abstract: Publication date: Available online 13 September 2018Source: Journal of AutoimmunityAuthor(s): Lenche Chakievska, Maike M. Holtsche, Axel Künstner, Stephanie Goletz, Britt-Sabina Petersen, Diamant Thaci, Saleh M. Ibrahim, Ralf J. Ludwig, Andre Franke, Christian D. Sadik, Detlef Zillikens, Christoph Hölscher, Hauke Busch, Enno Schmidt IL-17A has been identified as key regulatory molecule in several autoimmune and chronic inflammatory diseases followed by the successful use of anti-IL-17 therapy, e.g. in ankylosing spondylitis and psoriasis. Bullous pemphigoid (BP) is the most frequent autoimmune blistering disease with a high need for more specific, effective and safe treatment options. The aim of this study was to clarify the pathophysiological importance of IL-17A in BP. We found elevated numbers of IL-17A+ CD4+ lymphocytes in the peripheral blood of BP patients and identified CD3+ cells as major source of IL-17A in early BP skin lesions. IL17A and related genes were upregulated in BP skin and exome sequencing of 51 BP patients revealed mutations in twelve IL-17-related genes in 18 patients. We have subsequently found several lines of evidence suggesting a significant role of IL-17A in the BP pathogenesis: (i) IL-17A activated human neutrophils in vitro, (ii) inhibition of dermal-epidermal separation in cryosections of human skin incubated with anti-BP180 IgG and subsequently with anti-IL-17A IgG-treated leukocytes, (iii) close correlation of serum IL-17A levels and diseases activity in a mouse model of BP, (iv) IL17A-deficient mice were protected against autoantibody-induced BP, and (v) pharmacological inhibition of lL-17A reduced the induction of BP in mice. Our data give evidence for a pivotal role of IL-17A in the pathophysiology of BP and advocate IL-17A inhibition as potential novel treatment for this disease.
  • Autophagy: A new concept in autoimmunity regulation and a novel
           therapeutic option
    • Abstract: Publication date: Available online 13 September 2018Source: Journal of AutoimmunityAuthor(s): Srinivasa Reddy Bonam, Fengjuan Wang, Sylviane Muller Nowadays, pharmacologic treatments of autoinflammatory diseases are largely palliative rather than curative. Most of them result in non-specific immunosuppression, which can be associated with broad disruption of natural and induced immunity with significant and sometimes serious unwanted injuries. Among the novel strategies that are under development, tools that modulate the immune system to restore normal tolerance mechanisms are central. In these approaches, peptide therapeutics constitute a class of agents that display many physicochemical advantages. Within this class of potent drugs, the phosphopeptide P140 is very promising for treating patients with lupus, and likely also patients with other chronic inflammatory diseases. We discovered that P140 targets autophagy, a finely orchestrated catabolic process, involved in the regulation of inflammation and in the biology of immune cells. In vitro, P140 acts directly on a particular form of autophagy called chaperone-mediated autophagy, which seems to be hyperactivated in certain subsets of lymphocytes in lupus and in other autoinflammatory settings. In lupus, the “correcting” effect of P140 on autophagy results in a weaker signaling of autoreactive T cells, leading to a significant improvement of pathophysiological status of treated mice. These findings also demonstrated ex vivo in human cells, open novel avenues of therapeutic intervention in pathological conditions, in which specific and not general targeting is highly pursued in the context of the new action plans for personalized medicines.
  • Efficacy of the anti-IL 17 secukinumab in refractory Behçet's
           syndrome: A preliminary study
    • Abstract: Publication date: Available online 11 September 2018Source: Journal of AutoimmunityAuthor(s): Gerardo Di Scala, Alessandra Bettiol, Rafaela Diana Cojan, Martina Finocchi, Elena Silvestri, Giacomo Emmi ObjectiveTo evaluate the efficacy and safety of secukinumab in Behçet's patients with active mucocutaneous and articular manifestations refractory to previous treatments.MethodsWe retrospectively evaluated 5 patients treated with the IL17-inhibitor secukinumab and diagnosed with Behçet according to ISG/ICBD criteria. All patients had active mucocutaneous and articular manifestations refractory to colchicine, conventional DMARDs and at least one anti-TNFα agent. Four patients received secukinumab in the dose of 150 mg/monthly since also fulfilling the criteria for ankylosing spondylitis, while the fifth patient received secukinumab 300 mg/monthly because she met psoriatic arthritis criteria. Achievement of response was based on the number of oral ulcers, BASDAI and ASDAS for articular involvement, and BDCAF for Behçet activity. Complete response was defined as: i) decrease ≥50% in the number of oral ulcers; ii) BASDAI index
  • MicroRNA-183 and microRNA-96 are associated with autoimmune responses by
           regulating T cell activation
    • Abstract: Publication date: Available online 7 September 2018Source: Journal of AutoimmunityAuthor(s): Jacqueline Thiel, Christina Alter, Sina Luppus, Anja Eckstein, Susanne Tan, Dagmar Führer, Eva Pastille, Astrid M. Westendorf, Jan Buer, Wiebke Hansen MircoRNAs (miRs) are small molecules that regulate gene expression at the posttranscriptional level. They have been proposed to be involved in the regulation of several immune responses including autoimmunity. Here, we identified miR-183 and miR-96 to be highly expressed in CD4+ T cells from peripheral blood of Graves' orbitopathy (GO) patients as well as in human and murine T cells upon activation in vitro. By using Luciferase-based binding assays, we identified EGR-1 as target for miR-183 and miR-96. Overexpression of miR-183 and miR-96 in murine CD4+ T cells by retroviral gene transfer resulted in decreased EGR-1 and PTEN expression, elevated Akt phosphorylation and enhanced proliferation. In contrast, treatment of murine CD4+ T cells with specific antagomiRs increased EGR-1 and PTEN expression and interfered with the proliferative activity upon stimulation in vitro. Strikingly, adoptive transfer of miR-183 and miR-96 overexpressing antigen-specific T cells into INS-HA/Rag2KO mice accelerated the development of autoimmune diabetes, whereas transfer of antagomiR-treated cells delayed the disease onset. These results indicate that miR-183 and miR-96 have the ability to regulate the strength of T cell activation and thereby the development and severity of T cell-dependent autoimmune diseases.
  • Altered expression of microRNA-23a in psoriatic arthritis modulates
           synovial fibroblast pro-inflammatory mechanisms via phosphodiesterase 4B
    • Abstract: Publication date: Available online 1 September 2018Source: Journal of AutoimmunityAuthor(s): Sarah M. Wade, Michelle Trenkmann, Trudy McGarry, Mary Canavan, Viviana Marzaioli, Siobhan C. Wade, Douglas J. Veale, Ursula Fearon ObjectivesTo investigate the functional role of miR-23a in synovial fibroblasts (SFC) activation in psoriatic arthritis (PsA).MethodsDifferential expression of the miR-23a-27a-24-2 cluster was identified by real-time quantitative PCR in PsA synovial tissue and peripheral blood mononuclear cells (PBMC) compared to osteoarthritis (OA) and correlated with disease activity. For regulation experiments, PsA synovial fibroblasts (SFC) were cultured with Toll-like receptor (TLR) ligands and pro-inflammatory cytokines. PsA SFC were transfected with a miR-23a inhibitor to assess the functional effect on migration, invasion and expression of pro-inflammatory meditators. The direct interaction between miR-23a and predicted target mRNA, phosphodiesterase 4B (PDE4B), was examined by luciferase reporter gene assay, with the expression and regulation confirmed by RT-PCR and western blot. A PDE4 inhibitor was used to analyse the function of PDE4B signalling in both miR-23a and Poly(I:C)-induced PsA SFC activation.ResultsSynovial tissue expression of miR-23a was lower in PsA compared to OA and correlated inversely with disease activity and synovitis. TLR activation via Poly(I:C) and LPS, but not Pam3CSK4, significantly decreased miR-23a expression, with no significant effect observed in reponse to stimulation with pro-inflammatory cytokines. Decreased miR-23a expression enhanced PsA SFC migration, invasion and secretion of IL-6, IL-8, MCP-1, RANTES and VEGF. We identified PDE4B as a direct target of miR-23a and demonstrated enhanced mRNA and protein expression of PDE4B in anti-miR-23a transfected PsA SFC. Poly(I:C) and/or miR-23a-induced migration and enhanced cytokine expression was suppressed by the blockade of PDE4 signalling.ConclusionsIn PsA, dysregulated miR-23a expression contributes to synovial inflammation through enhanced SFC activation, via PDE4B signalling, and identifies a novel anti-inflammatory mechanism of PDE4 blockade.
  • A comprehensive review on the role of co-signaling receptors and Treg
           homeostasis in autoimmunity and tumor immunity
    • Abstract: Publication date: Available online 31 August 2018Source: Journal of AutoimmunityAuthor(s): Prabhakaran Kumar, Palash Bhattacharya, Bellur S. Prabhakar The immune system ensures optimum T-effector (Teff) immune responses against invading microbes and tumor antigens while preventing inappropriate autoimmune responses against self-antigens with the help of T-regulatory (Treg) cells. Thus, Treg and Teff cells help maintain immune homeostasis through mutual regulation. While Tregs can contribute to tumor immune evasion by suppressing anti-tumor Teff response, loss of Treg function can result in Teff responses against self-antigens leading to autoimmune disease. Thus, loss of homeostatic balance between Teff/Treg cells is often associated with both cancer and autoimmunity. Co-stimulatory and co-inhibitory receptors, collectively known as co-signaling receptors, play an indispensable role in the regulation of Teff and Treg cell expansion and function and thus play critical roles in modulating autoimmune and anti-tumor immune responses. Over the past three decades, considerable efforts have been made to understand the biology of co-signaling receptors and their role in immune homeostasis. Mutations in co-inhibitory receptors such as CTLA4 and PD1 are associated with Treg dysfunction, and autoimmune diseases in mice and humans. On the other hand, growing tumors evade immune surveillance by exploiting co-inhibitory signaling through expression of CTLA4, PD1 and PDL-1. Immune checkpoint blockade (ICB) using anti-CTLA4 and anti-PD1 has drawn considerable attention towards co-signaling receptors in tumor immunology and created renewed interest in studying other co-signaling receptors, which until recently have not been as well studied. In addition to co-inhibitory receptors, co-stimulatory receptors like OX40, GITR and 4-1BB have also been widely implicated in immune homeostasis and T-cell stimulation, and use of agonistic antibodies against OX40, GITR and 4-1BB has been effective in causing tumor regression. Although ICB has seen unprecedented success in cancer treatment, autoimmune adverse events arising from ICB due to loss of Treg homeostasis poses a major obstacle. Herein, we comprehensively review the role of various co-stimulatory and co-inhibitory receptors in Treg biology and immune homeostasis, autoimmunity, and anti-tumor immunity. Furthermore, we discuss the autoimmune adverse events arising upon targeting these co-signaling receptors to augment anti-tumor immune responses.
  • Lipocalin-2 is a pathogenic determinant and biomarker of neuropsychiatric
    • Abstract: Publication date: Available online 30 August 2018Source: Journal of AutoimmunityAuthor(s): Elise V. Mike, Hadijat M. Makinde, Maria Gulinello, Kamala Vanarsa, Leal Herlitz, Gaurav Gadhvi, Deborah R. Winter, Chandra Mohan, John G. Hanly, C.C. Mok, Carla M. Cuda, Chaim Putterman Neuropsychiatric manifestations in lupus (NPSLE) affect ∼20–40% of patients. In the central nervous system, lipocalin-2 (LCN2) can promote injury through mechanisms directly linked to NPSLE, including brain barrier disruption, neurotoxicity, and glial activation. Since LCN2 is elevated in lupus and has been implicated in neuroinflammation, we investigated whether LCN2 is required for the pathogenesis of NPSLE. Here, we investigated the effects of LCN2 deficiency on the development of neurobehavioral deficits in the B6.Sle1.Sle3 (Sle1,3) mouse lupus model. Sle1,3 mice exhibited depression-like behavior and impaired spatial and recognition memory, and these deficits were attenuated in Sle1,3-LCN2KO mice. Whole-brain flow cytometry showed a significant increase in brain infiltrating leukocytes in Sle1,3 mice that was not reduced by LCN2 deficiency. RNA sequencing on sorted microglia revealed that several genes differentially expressed between B6 and Sle1,3 mice were regulated by LCN2, and that these genes are key mediators of the neuroinflammatory cascade. Importantly, LCN2 is upregulated in the cerebrospinal fluid of NPSLE patients across 2 different ethnicities. Our findings establish the Sle1,3 strain as an NPSLE model, demonstrate that LCN2 is a major regulator of the detrimental neuroimmune response in NPSLE, and identify CSF LCN2 as a novel biomarker for NPSLE.
  • Evidence for a potential role of miR-1908-5p and miR-3614-5p in autoimmune
           disease risk using integrative bioinformatics
    • Abstract: Publication date: Available online 22 August 2018Source: Journal of AutoimmunityAuthor(s): Inken Wohlers, Lars Bertram, Christina M. Lill Genome-wide association studies (GWAS) have identified a large number of genetic risk loci for autoimmune diseases. However, the functional variants underlying these disease associations remain largely unknown. There is evidence that microRNA-mediated regulation may play an important role in this context. Therefore, we assessed whether autoimmune disease loci unfold their effects via altering microRNA expression in relevant immune cells.To this end, we performed comprehensive data integration of many large and publicly available datasets to combine information on autoimmune disease risk loci with RNA-Seq-based microRNA expression data. Specifically, we carried out microRNA expression quantitative trait loci (eQTL) analyses across 115 GWAS regions associated with 12 autoimmune diseases using next-generation sequencing data of 345 lymphoblastoid cell lines. Statistical analyses included the application and extension of a recently proposed framework (joint likelihood mapping) to microRNA expression data and microRNA target gene enrichment analyses of relevant GWAS data.Overall, only a minority of autoimmune disease risk loci may exert their pathophysiologic effects by altering microRNA expression based on JLIM. However, detailed functional fine-mapping revealed two independent GWAS regions harboring autoimmune disease risk SNPs with significant effects on microRNA expression. These relate to SNPs associated with Crohn's disease (CD; rs102275) and rheumatoid arthritis (RA; rs968567), which affect the expression of miR-1908-5p (prs102275 = 1.44e-20, prs968567 = 2.54e-14). In addition, an independent CD risk SNP, rs3853824, was found to alter the expression of miR-3614-5p (p = 5.70e-7). To support these findings, we demonstrate that GWAS signals for RA and CD were enriched in genes predicted to be targeted by both microRNAs (all with p 
  • Overall survival and mortality risk factors in Takayasu's arteritis: A
           multicenter study of 318 patients
    • Abstract: Publication date: Available online 17 August 2018Source: Journal of AutoimmunityAuthor(s): Adrien Mirouse, Lucie Biard, Cloé Comarmond, Marc Lambert, Arsène Mekinian, Yasmina Ferfar, Jean-Emmanuel Kahn, Ygal Benhamou, Laurent Chiche, Fabien Koskas, Philippe Cluzel, Eric Hachulla, Emmanuel Messas, Patrice Cacoub, Tristan Mirault, Matthieu Resche-Rigon, David Saadoun, French Takayasu network ObjectiveTo report the long term mortality in Takayasu arteritis (TA) and to identify prognosis factors.MethodsWe analyzed the causes of death and the factors associated with mortality in a cohort of 318 patients [median age at diagnosis was 36 [25–47] years and 276 (86%) patients were women] fulfilling American College of Rheumatology and/or Ishikawa criteria of TA. A prognostic score for death and vascular complications was elaborated based on a multivariate model.ResultsAmong 318 TA patients, 16 (5%) died after a median [IQR] follow-up of 6.1 [2.8–13.0] years. The median age at death was 38 [25–47] years with 88% of women. Main causes of death included mesenteric ischemia (n = 4, 25%) and aortic aneurysm rupture (n = 4, 25%). The mortality rate at 5 and 10 years was of 1.9% and 3.9%, respectively. Caucasians (p = 0.049) and smokers (p = 0.002) TA patients were more likely to die. There was an increased mortality in TA (SMR with 95% confidence interval, 2.73 [1.69–4.22]) as compared to age and sex matched healthy controls. We defined high risk patients for death and vascular complications according to the presence of two of the following factors (i.e a progressive clinical course, thoracic aorta involvement and/or retinopathy). In the high risk TA group, the 5-year incidence of death and vascular complication was 48.5% compared to 21.6% (p = 0.001) in those with low risk.ConclusionThe overall mortality in our Takayasu cohort was 5% after a median follow-up of 6.1 years. We identified specific characteristics that distinguish TA patients at highest risk for death and vascular complications.
  • Fingolimod modulates T cell phenotype and regulatory T cell plasticity
           in vivo
    • Abstract: Publication date: Available online 16 August 2018Source: Journal of AutoimmunityAuthor(s): Margarita Dominguez-Villar, Khadir Raddassi, Ann Caroline Danielsen, Joseph Guarnaccia, David A. Hafler Fingolimod is an approved therapeutic option for patients with relapsing-remitting multiple sclerosis that primarily functions by sequestering T cells in lymph nodes inhibiting their egress to the central nervous system. However, recent data suggests that Fingolimod may also directly affect the immune cell function. Here we examined the in vivo effects of Fingolimod in modulating the phenotype and function of T cell and Foxp3 regulatory T cell populations in patients with multiple sclerosis under Fingolimod treatment. Besides decreasing the cell numbers in peripheral blood and sera levels of pro-inflammatory cytokines, Fingolimod inhibited the expression of Th1 and Th17 cytokines on CD4+ T cells and increased the expression of exhaustion markers. Furthermore, treatment increased the frequency of regulatory T cells in blood and inhibited the Th1-like phenotype that is characteristic of patients with multiple sclerosis, augmenting the expression of markers associated with increased suppressive function. Overall, our data suggest that Fingolimod performs other important immunomodulatory functions besides altering T cell migratory capacities, with consequences for other autoimmune pathologies characterized by excessive Th1/Th17 responses and Th1-like regulatory T cell effector phenotypes.
  • Chimeric antigen receptor (CAR) T cells targeting a pathogenic MHC class
           II:peptide complex modulate the progression of autoimmune diabetes
    • Abstract: Publication date: Available online 16 August 2018Source: Journal of AutoimmunityAuthor(s): Li Zhang, Tomasz Sosinowski, R. Aaron, Joseph Ray Cepeda, Nitin S. Sekhar, Sean M. Hartig, Dongmei Miao, Liping Yu, Massimo Pietropaolo, Howard W. Davidson A primary initiating epitope in the NOD mouse model of Type 1 Diabetes (T1D) lies between residues 9 and 23 of the insulin B chain. The B:9-23 peptide can bind to the NOD MHC class II molecule (I-Ag7) in multiple registers, but only one, (register 3, R3), creates complexes able to stimulate the majority of pathogenic B:9-23-specific CD4+ T cells. Previously we generated a monoclonal antibody (mAb287) that targets this critical I-Ag7-B:9-23(R3) complex. When given weekly to pre-diabetic mice at either early or late stages of disease, mAb287 was able to delay or prevent T1D in the treated animals. Although the precise mechanism of action of mAb287 remains unclear, we hypothesized that it may involve deletion of antigen presenting cells (APCs) bearing the pathogenic IAg7-B:9-23(R3) complexes, and that this process might be rendered more efficient by re-directing cytotoxic T cells using a mAb287 chimeric antigen receptor (287-CAR). As anticipated, 287-CAR T cells secreted IFN-γ in response to stimulation by I-Ag7-B:9-23(R3) complexes expressed on artificial APCs, but not I-Ag7 loaded with other peptides, and killed the presenting cells in vitro. A single infusion of 287-CAR CD8+ T cells to young (5 week old) NOD mice significantly delayed the onset of overt hyperglycemia compared to untreated animals (p = 0.022). None of the 287-CAR CD8+ T cell treated mice developed diabetes before 18 weeks of age, while 29% of control-CAR T cell treated mice (p = 0.044) and 52% of the un-treated mice (p = 0.0001) had developed T1D by this time. However, the protection provided by 287-CAR CD8+ T cells declined with time, and no significant difference in overall incidence by 30 weeks between the 3 groups was observed. Mechanistic studies indicated that the adoptively transferred 287-CAR T cells selectively homed to pancreatic lymph nodes, and in some animals could persist for at least 1–2 weeks post-transfer, but were essentially undetectable 10–15 weeks later. Our study demonstrates that CAR T cells specific for a pathogenic MHC class II:peptide complex can be effective in vivo, but that a single infusion of the current iteration can only delay, but not prevent, the development of T1D. Future studies should therefore be directed towards optimizing strategies designed to improve the longevity of the transferred cells.
  • Increased sensitivity of Treg cells from patients with PBC to low dose
           IL-12 drives their differentiation into IFN-γ secreting cells
    • Abstract: Publication date: Available online 14 August 2018Source: Journal of AutoimmunityAuthor(s): Evaggelia Liaskou, Samita R. Patel, Gwilym Webb, Danai Bagkou Dimakou, Sarah Akiror, Mahesh Krishna, George Mells, Dave E. Jones, Simon J. Bowman, Francesca Barone, Benjamin A. Fisher, Gideon M. Hirschfield IL-12 is a pro-inflammatory cytokine that induces the production of interferon-γ (IFNγ) and favours the differentiation of T helper 1 (Th1) cells. In the presence of IL-12 human Treg cells acquire a Th1-like phenotype with reduced suppressive activity in vitro. Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease characterised by high Th1 and Th17 infiltrating cells, reduced frequencies of Treg cells, and a genetic association with IL-12 signalling. Herein, we sought to evaluate the IL-12 signalling pathway in PBC pathology, by studying human samples from patients with PBC, alongside those with primary Sjögren’s syndrome (pSS)(autoimmune disease with IL-12 signalling gene association), primary sclerosing cholangitis (PSC) (cholestatic liver disease without IL-12 gene association) and healthy individuals. Our data revealed that TLR stimulation of PBC (n = 17) and pSS monocytes (n = 6) resulted in significant induction of IL12A mRNA (p 
  • Interferon alpha: The key trigger of type 1 diabetes
    • Abstract: Publication date: Available online 14 August 2018Source: Journal of AutoimmunityAuthor(s): Angela Lombardi, Effie Tsomos, Sara S. Hammerstad, Yaron Tomer IFNα is a cytokine essential to a vast array of immunologic processes. Its induction early in the innate immune response provides a priming mechanism that orchestrates numerous subsequent pathways in innate and adaptive immunity. Despite its beneficial effects in viral infections IFNα has been reported to be associated with several autoimmune diseases including autoimmune thyroid disease, systemic lupus erythematosus, rheumatoid arthritis, primary biliary cholangitis, and recently emerged as a major cytokine that triggers Type 1 Diabetes. In this review, we dissect the role of IFNα in T1D, focusing on the potential pathophysiological mechanisms involved.Evidence from human and mouse studies indicates that IFNα plays a key role in enhancing islet expression of HLA-I in patients with T1D, thereby increasing autoantigen presentation and beta cell activation of autoreactive cytotoxic CD8 T-lymphocytes. The binding of IFNα to its receptor induces the secretion of chemokines, attracting monocytes, T lymphocytes, and NK cells to the infected tissue triggering autoimmunity in susceptible individuals. Furthermore, IFNα impairs insulin production through the induction of endoplasmic reticulum stress as well as by impairing mitochondrial function.Due to its central role in the early phases of beta cell death, targeting IFNα and its pathways in genetically predisposed individuals may represent a potential novel therapeutic strategy in the very early stages of T1D.
  • Mutations of deubiquitinase OTUD1 are associated with autoimmune disorders
    • Abstract: Publication date: Available online 10 August 2018Source: Journal of AutoimmunityAuthor(s): Dan Lu, Jia Song, Yizhe Sun, Fang Qi, Liang Liu, Yan Jin, Michael A. McNutt, Yuxin Yin Dysregulation of innate immunity accompanied by excessive interferon production contributes to autoimmune disease. However, the mechanism by which the immune response is modulated in autoimmune disorders is largely unknown. Here we identified loss-of-function mutations of OTUD1 associated with multiple autoimmune diseases. Under inflammatory conditions, inducible OTUD1 acts as an immune checkpoint and blocks RIG-I-like receptors signaling. As a deubiquitinase, OTUD1 directly interacts with transcription factor IRF3 and removes the K63-linked poly-ubiquitin chains on IRF3 Lysine 98, which inhibits IRF3 nuclear translocation and transcriptional activity. In contrast, OTUD1 mutants impair its suppressive effects on IRF3 via attenuating the OTUD1 deubiquinase activity or its association with IRF3. Moreover, we found FOXO3 signaling is required for OTUD1 induction upon antigenic stimulation. Our data demonstrate that OTUD1 is involved in maintaining immune homeostasis and loss-of-function mutations of OTUD1 enhance the immune response and are associated with autoimmunity.
  • HIF-1α-induced xenobiotic transporters promote Th17 responses in
           Crohn's disease
    • Abstract: Publication date: Available online 8 August 2018Source: Journal of AutoimmunityAuthor(s): Anyan Xie, René J. Robles, Samiran Mukherjee, Haohai Zhang, Linda Feldbrügge, Eva Csizmadia, Yan Wu, Keiichi Enjyoji, Alan C. Moss, Leo E. Otterbein, Francisco J. Quintana, Simon C. Robson, Maria Serena Longhi In Crohn's disease, pathogenic Th17-cells express low levels of CD39 ectonucleotidase and are refractory to the immunosuppressive effects of unconjugated bilirubin (UCB), an endogenous ligand for aryl-hydrocarbon-receptor (AhR). This resistance to AhR ligation might be associated with alterations in responses to hypoxia. Limited exposure to hypoxia appears beneficial in acute tissue injury. However, in protracted inflammation, hypoxemia may paradoxically result in Th17-cell activation. We report here that in vitro exposure of Th17-cells from Crohn's disease patients to hypoxia limits responsiveness to AhR stimulation by UCB, as reflected by lower CD39 levels. Blockade of hypoxia-inducible-factor-1alpha (HIF-1α) upregulates CD39 and favors Th17-cell regulatory responses. Resistance of Th17-cells to AhR signaling results, in part, from HIF-1α-dependent induction of ATP-binding cassette (ABC) transporters: multidrug-resistance-protein-1 (MDR1) and multidrug-resistance-associated-protein-4 (MRP4). Increased ABC transporters promote efflux of suppressive AhR ligands, such as UCB, from Th17-cells. Inhibition of MDR1, MRP4 and/or HIF-1α with ritonavir (RTV) reconstitutes AhR function in Th17-cells, enhancing therapeutic effects of UCB in dextran-sulfate-sodium-induced experimental colitis.Deleterious effects of hypoxia on Th17-cells in Crohn's disease can be ameliorated either by inhibiting HIF-1α or by suppressing ABC transporters to increase UCB availability as an AhR substrate. Targeting HIF-1α-ABC transporters could provide innovative therapeutic pathways for IBD.
  • Circulating follicular helper T cells exhibit reduced ICOS expression and
           impaired function in narcolepsy type 1 patients Running Head: Impaired TFH
           cell function in narcolepsy
    • Abstract: Publication date: Available online 6 August 2018Source: Journal of AutoimmunityAuthor(s): Xuan-Hung Nguyen, Yves Dauvilliers, Clémence Quériault, Corine Perals, Raphaelle Romieu-Mourez, Pierre-Emmanuel Paulet, Raphaël Bernard-Valnet, Nicolas Fazilleau, Roland Liblau Despite genetic and epidemiological evidence strongly supporting an autoimmune basis for narcolepsy type 1, the mechanisms involved have remained largely unknown. Here, we aimed to investigate whether the frequency and function of circulating follicular helper and follicular regulatory T cells are altered in narcolepsy type 1.Peripheral blood mononuclear cells were collected from 32 patients with narcolepsy type 1, including 11 who developed disease after Pandemrix® vaccination, and 32 age-, sex-, and HLA-DQB1*06:02-matched healthy individuals. The frequency and phenotype of the different circulating B cell and follicular T cell subsets were examined by flow cytometry. The function of follicular helper T cells was evaluated by assessing the differentiation of naïve and memory B cells in a co-culture assay.We revealed a notable increase in the frequency of circulating B cells and CD4+CXCR5+ follicular T cells in narcolepsy patients compared to age-, sex- and HLA-matched healthy controls. However, the inducible T-cell costimulator molecule, ICOS, was selectively down-regulated on follicular T cells from patients. Reduced frequency of activated ICOS+and PD1highblood follicular T cells was also observed in the narcolepsy group. Importantly, follicular T cells isolated from patients with narcolepsy type 1 had a reduced capacity to drive the proliferation/survival and differentiation of memory B cells.Our results provide novel insights into the potential involvement of T cell-dependent B cell responses in the pathogenesis of narcolepsy type 1 in which down-regulation of ICOS expression on follicular helper T cells correlates with their reduced function. We hypothesize that these changes contribute to regulation of the deleterious autoimmune process after disease onset.
  • Molecular mechanisms of autophagic memory in pathogenic T cells in human
    • Abstract: Publication date: Available online 1 August 2018Source: Journal of AutoimmunityAuthor(s): Pavanish Kumar, Leong Jing Yao, Suzan Saidin, Bhairav Paleja, Jorg van Loosdregt, Camillus Chua, Thaschawee Arkachaisri, Alessandro Consolaro, Marco Gattorno, Alberto Martini, Ken D. Pischel, Gary W. Williams, Martin Lotz, Salvatore Albani T-cell resilience is critical to the immune pathogenesis of human autoimmune arthritis. Autophagy is essential for memory T cell generation and associated with pathogenesis in rheumatoid arthritis (RA). Our aim here was to delineate the role and molecular mechanism of autophagy in resilience and persistence of pathogenic T cells from autoimmune arthritis.We demonstrated “Autophagic memory” as elevated autophagy levels in CD4+ memory T cells compared to CD4+ naive T cells and in Jurkat Human T cell line trained with starvation stress. We then showed increased levels of autophagy in pathogenic CD4+ T cells subsets from autoimmune arthritis patients. Using RNA-sequencing, transcription factor gene regulatory network and methylation analyses we identified MYC as a key regulator of autophagic memory. We validated MYC levels using qPCR and further demonstrated that inhibiting MYC increased autophagy. The present study proposes the novel concept of autophagic memory and suggests that autophagic memory confers metabolic advantage to pathogenic T cells from arthritis and supports its resilience and long term survival. Particularly, suppression of MYC imparted the heightened autophagy levels in pathogenic T cells. These studies have a direct translational valency as they identify autophagy and its metabolic controllers as a novel therapeutic target.
  • A comprehensive review on adult onset Still's disease
    • Abstract: Publication date: Available online 1 August 2018Source: Journal of AutoimmunityAuthor(s): Roberto Giacomelli, Piero Ruscitti, Yehuda Shoenfeld Adult-onset Still's disease (AOSD) is a systemic inflammatory disorder of unknown etiology usually affecting young adults; spiking fever, arthritis and evanescent rash are commonly observed during the disease. Other frequently observed clinical features include sore throat, hepatomegaly, splenomegaly, lymphadenopathy and serositis. Furthermore, AOSD patients may experience different life-threating complications. Macrophage activation syndrome (MAS) has been reported up to 15% of AOSD patients and it is considered to be the most severe complication of the disease being characterised by high mortality rate. During AOSD, laboratory tests reflect the systemic inflammatory process showing high levels of erythrocyte sedimentation rate and C-reactive protein. In addition, the ferritin levels are typically higher than those observed in other autoimmune, inflammatory, infectious, or neoplastic diseases. Analysing AOSD disease course, 3 different clinical patterns of AOSD have been identified: i. monocyclic pattern, characterised by a systemic single episode; ii. polycyclic pattern, characterised by multiple, ≤ 1 year lasting, flares, alternating with remissions; iii. chronic pattern, related to a persistently active disease with associated polyarthritis. At present, AOSD therapeutic strategy is aimed at targeting pro-inflammatory signs and symptoms, preventing organ damage and life-threating complications and minimising adverse effects of treatment. However, the treatment of AOSD remains largely empirical, lacking controlled clinical trials. High dosages of corticosteroids are usually the first line therapy when the systemic symptoms predominate. Despite this treatment, a large percentage of patients experiences several flares with an evolution toward the chronic disease course and up to 16% of patients die during the follow up, due to AOSD-related complications. On these bases, in the last years, biological agents have been successfully used in refractory cases. Finally, multiple recent lines of evidence have suggested new insights in AOSD pathogenesis unmasking further therapeutic targets. In fact, small molecules, used in experimental MAS models, might represent new therapeutic options.
  • NF-κB inducing kinase (NIK) is an essential post-transcriptional
           regulator of T-cell activation affecting F-actin dynamics and TCR
    • Abstract: Publication date: Available online 29 July 2018Source: Journal of AutoimmunityAuthor(s): Sonja M. Lacher, Christoph Thurm, Ute Distler, Alma N. Mohebiany, Nicole Israel, Maja Kitic, Anna Ebering, Yilang Tang, Matthias Klein, Guido H. Wabnitz, Florian Wanke, Yvonne Samstag, Tobias Bopp, Florian C. Kurschus, Luca Simeoni, Stefan Tenzer, Ari Waisman NF-κB inducing kinase (NIK) is the key protein of the non-canonical NF-κB pathway and is important for the development of lymph nodes and other secondary immune organs. We elucidated the specific role of NIK in T cells using T-cell specific NIK-deficient (NIKΔT) mice. Despite showing normal development of lymphoid organs, NIKΔT mice were resistant to induction of CNS autoimmunity. T cells from NIKΔT mice were deficient in late priming, failed to up-regulate T-bet and to transmigrate into the CNS. Proteomic analysis of activated NIK−/- T cells showed de-regulated expression of proteins involved in the formation of the immunological synapse: in particular, proteins involved in cytoskeleton dynamics. In line with this we found that NIK-deficient T cells were hampered in phosphorylation of Zap70, LAT, AKT, ERK1/2 and PLCγ upon TCR engagement. Hence, our data disclose a hitherto unknown function of NIK in T-cell priming and differentiation.
  • Contribution of ancient human remains analysis to the understanding of the
           variability in HLA-B gene variants in relation to the diagnosis of
    • Abstract: Publication date: Available online 29 July 2018Source: Journal of AutoimmunityAuthor(s): Imanol M. Laza, Nerea G. Ventades, Montserrat Hervella, Concepción de-la-Rúa Genetic investigations on ancient human remains affected by rheumatological pathologies are a research field of particular interest for identifying the pathogenesis of diseases, especially those having an autoimmune background such as spondyloarthopaties (SpA). Reliable studies concerning this topic require collaboration between multiple disciplines, usually starting from paleopathologic observations up to molecular genetic screening. Here, we focused our investigation in a medieval necropolis in the Basque Country (13th-15th century, N = 163), which presents a high frequency of joint pathologies through two approaches: on the one hand, the analysis of joint manifestations for the differential diagnosis of the SpA and, on the other hand, the determination of the alleles of the HLA-B gene. The morphological analysis allowed determining that 30% of the individuals had rheumatic bone manifestations, with SpA being the most frequent (45%). The genetic analysis of individuals with and without pathologies, based on the study of the HLA-B gene, allowed finding 17 alleles for this gene, with HLA-B40, HLA-B27 and HLA-B35 being the most frequent. Although these alleles have been traditionally described as genetic markers associated to the development of SpA, in this study they were also found in individuals with other rheumatic diseases (osteoarthritis and rheumatoid arthritis) and even in individuals without pathologies. These data confirm the complexity of the relationship of the HLA-B gene variants with SpA, since it is not possible to establish a diagnosis of SpA with these variants alone. However, we suggest that allele HLA-B40, in combination with some specific rheumatic bone manifestations, facilitates the diagnosis of SpA.
  • Foxa1 and Foxa2 in thymic epithelial cells (TEC) regulate medullary TEC
           and regulatory T-cell maturation
    • Abstract: Publication date: Available online 27 July 2018Source: Journal of AutoimmunityAuthor(s): Ching-In Lau, Diana C. Yánez, Anisha Solanki, Eleftheria Papaioannou, José Ignacio Saldaña, Tessa Crompton The Foxa1 and Foxa2 transcription factors are essential for mouse development. Here we show that they are expressed in thymic epithelial cells (TEC) where they regulate TEC development and function, with important consequences for T-cell development. TEC are essential for T-cell differentiation, lineage decisions and repertoire selection. Conditional deletion of Foxa1 and Foxa2 from murine TEC led to a smaller thymus with a greater proportion of TEC and a greater ratio of medullary to cortical TEC. Cell-surface MHCI expression was increased on cortical TEC in the conditional Foxa1Foxa2 knockout thymus, and MHCII expression was reduced on both cortical and medullary TEC populations. These changes in TEC differentiation and MHC expression led to a significant reduction in thymocyte numbers, reduced positive selection of CD4+CD8+ cells to the CD4 lineage, and increased CD8 cell differentiation. Conditional deletion of Foxa1 and Foxa2 from TEC also caused an increase in the medullary TEC population, and increased expression of Aire, but lower cell surface MHCII expression on Aire-expressing mTEC, and increased production of regulatory T-cells. Thus, Foxa1 and Foxa2 in TEC promote positive selection of CD4SP T-cells and modulate regulatory T-cell production and activity, of importance to autoimmunity.
  • Safety issues and recommendations for successful pregnancy outcome in
           systemic lupus erythematosus
    • Abstract: Publication date: Available online 27 July 2018Source: Journal of AutoimmunityAuthor(s): Simran Kaur Nahal, Carlo Selmi, M. Eric Gershwin Systemic lupus erythematosus (SLE) primarily affects women of childbearing age. One of the major changes in SLE focuses on the timing of a successful pregnancy. In the past, pregnancy was strongly discouraged in SLE, especially in the presence of risk factors such as nephritis, use of immunosuppressive therapies, or positivity of specific autoantibodies such as anti-phospholipids and anti-Ro/SSA, La/SSBA. Thanks to our better knowledge on the disease and management, pregnancy success rates in SLE patients have significantly improved care by the a multidisciplinary team which fosters a successful pregnancy with minimal complications for the mother and fetus when the disease is inactive or in remission. This approach is based on a counseling phase before pregnancy, to assess SLE activity phase, specific medications, risk factors, and continues through pregnancy and lactation with significantly improved pregnancy outcomes. Further, we can now better define the risk of disease flares during pregnancy based on a better understanding of the changes in maternal immunity and its relationship with SLE-associated autoimmunity and chronic inflammation. There is wide consensus that women with SLE can have successful pregnancies as long as conception is planned in a phase of inactive disease, and when the patient is closely managed by a rheumatologist, high-risk OB/GYN, neonatologist, and other medical specialists as indicated. Preconception counseling is essential to assess the risk of both fetal and maternal complications as well as identify life-threatening contraindications. Particular attention should be used in those SLE cases that have nephritis, APS or positivity for aPL, pulmonary hypertension, and positive anti-Ro/SSA or anti-La/SSB antibodies. In conclusion, the use of specific guidelines on the management of SLE before and during pregnancy and lactation, and a better understanding of the use of immunosuppressive therapies have significantly increased pregnancy success.
  • mTOR pathway activation in large vessel vasculitis
    • Abstract: Publication date: Available online 27 July 2018Source: Journal of AutoimmunityAuthor(s): A. Maciejewski-Duval, C. Comarmond, A. Leroyer, M. Zaidan, A. Le Joncour, A.C. Desbois, J.P. Fouret, F. Koskas, P. Cluzel, M. Garrido, P. Cacoub, D. Saadoun BackgroundMammalian target of rapamycin complex 1 (mTORC 1) drives the proinflammatory expansion of T helper (TH) type 1, TH17 cells and controls fibroblast proliferation, typical features of large vessel vasculitis (LVV) pathogenesis. Molecular pathways involved in arterial lesions of LVV are unknown.MethodsWe evaluate mTORC pathway activation in vascular aorta lesions and in T cell homeostasis of patients with LVV.ResultsProliferation of both endothelial cells and vascular smooth-muscle cells was shown in vascular lesions in LVV. The vascular endothelium of proliferating aorta vessels from patients with LVV showed indications of activation of the mTORC1 pathway (S6RP phosphorylation). In cultured vascular endothelial cells, sera from patients with LVV stimulated mTORC1 through the phosphorylation of S6RP. mTORC1 activation was found also in Th1 and Th17 cells both systemically and in inflamed vessels. Patients with LVV exhibited a diminished S6RP phosphorylation in Tregs. Inhibition of mTORC1 pathway with rapamycin, increase Tregs and decrease effector CD4+IFNγ+, CD4+IL17+ and CD4+IL21+ T cells in patients with LVV.ConclusionsWe provided evidence that mTORC1 pathway has a central role in driving T cell inflammation and vascular lesions in LVV. Targeting mTORC pathway may represent a new therapeutic option in patients with LVV.
  • In situ detection of PR3-ANCA+ B cells and alterations in the variable
           region of immunoglobulin genes support a role of inflamed tissue in the
           emergence of auto-reactivity in granulomatosis with polyangiitis
    • Abstract: Publication date: Available online 24 July 2018Source: Journal of AutoimmunityAuthor(s): Gesche Weppner, Olena Ohlei, Christoph M. Hammers, Konstanze Holl-Ulrich, Jan Voswinkel, Julia Bischof, Katrin Hasselbacher, Gabriela Riemekasten, Peter Lamprecht, Saleh Ibrahim, Christof Iking-Konert, Andreas Recke, Antje Müller Circulating anti-neutrophilic cytoplasmic autoantibodies targeting proteinase 3 (PR3-ANCA) are a diagnostic and pathogenic hallmark of granulomatosis with polyangiitis (GPA). It is, however, incompletely understood if inflamed tissue supports presence or emergence of PR3-ANCA+ B cells. In search of such cells in inflamed tissue of GPA, immunofluorescence staining for IgG and a common PR3-ANCA idiotype (5/7 Id) was undertaken. Few 5/7 Id+/IgG+ B cells were detected in respiratory and kidney tissue of GPA. To gain more insight into surrogate markers possibly indicative of an anti-PR3-response, a meta-analysis comprising IGVH and IGVL genes derived from respiratory tract tissue of GPA (231 clones) was performed. Next generation sequencing-based IGHV genes derived from peripheral blood of healthy donors (244.353 clones) and previously published IGLV genes (148 clones) served as controls. Additionally, Ig genes of three murine and five known human monoclonal anti-PR3 antibodies were analyzed. Primary and probably secondary rearrangements led to altered VDJ usage and an extended complementarity determining region 3 (CDR3) of IGHV clones from GPA tissue. Selection against amino acid exchanges was prominent in the framework region of IGHV clones from GPA tissue. The comparison of V(D)J rearrangements and deduced amino acid sequences of the CDR3 yielded no identities and few similarities between clones derived from respiratory tissue of GPA and anti-PR3 antibodies, arguing against a presence of B cells that carry PR3-ANCA-prone Ig genes among the clones. In line with the scarcity of 5/7 Id+ B lymphocytes in GPA tissue, the results suggest that with respect to a local anti-PR3 response, methods detecting rare clones are required.
  • Protein tyrosine phosphatase PTPN22 regulates LFA-1 dependent Th1
    • Abstract: Publication date: Available online 24 July 2018Source: Journal of AutoimmunityAuthor(s): Cristina Sanchez-Blanco, Fiona Clarke, Georgina H. Cornish, David Depoil, Stephen J. Thompson, Xuezhi Dai, David J. Rawlings, Michael L. Dustin, Rose Zamoyska, Andrew P. Cope, Harriet A. Purvis A missense C1858T single nucleotide polymorphism within PTPN22 is a strong genetic risk factor for the development of multiple autoimmune diseases. PTPN22 encodes a protein tyrosine phosphatase that negatively regulates immuno-receptor proximal Src and Syk family kinases. Notably, PTPN22 negatively regulates kinases downstream of T-cell receptor (TCR) and LFA-1, thereby setting thresholds for T-cell activation. Alterations to the quality of TCR and LFA-1 engagement at the immune synapse and the regulation of downstream signals can have profound effects on the type of effector T-cell response induced. Here we describe how IFNγ+ Th1 responses are potentiated in Ptpn22−/− T-cells and in T-cells from mice expressing Ptpn22R619W (the mouse orthologue of the human genetic variant) as they age, or following repeated immune challenge, and explore the mechanisms contributing to the expansion of Th1 cells. Specifically, we uncover two LFA-1-ICAM dependent mechanisms; one T-cell intrinsic, and one T-cell extrinsic. Firstly, we found that in vitro anti-CD3/LFA-1 induced Th1 responses were enhanced in Ptpn22−/− T-cells compared to WT, whereas anti-CD3/anti-CD28 induced IFNy responses were similar. These data were associated with an enhanced ability of Ptpn22−/− T-cells to engage ICAM-1 at the immune synapse when incubated on planar lipid bilayers, and to form conjugates with dendritic cells. Secondly, we observed a T-cell extrinsic mechanism whereby repeated stimulation of WT OT-II T-cells with LPS and OVA323-339 pulsed Ptpn22−/− bone marrow derived dendritic cells (BMDCs) was sufficient to enhance Th1 cell development compared to WT BMDCs. Furthermore, this response could be reversed by LFA-1 blockade. Our data point to two related but distinct mechanisms by which PTPN22 regulates LFA-1 dependent signals to enhance Th1 development, highlighting how perturbations to PTPN22 function over time to regulate the balance of the immune response.
  • Molecular profiling of regulatory T cells in pulmonary sarcoidosis
    • Abstract: Publication date: Available online 23 July 2018Source: Journal of AutoimmunityAuthor(s): Neli Kachamakova-Trojanowska, Agnieszka Jazwa-Kusior, Krzysztof Szade, Lukasz Kasper, Jerzy Soja, Anna Andrychiewicz, Bogdan Jakiela, Hanna Plutecka, Marek Sanak, Alicja Jozkowicz, Krzysztof Sladek, Jozef Dulak BackgroundSarcoidosis is characterized by exaggerated immune response to unknown agent and can affect different organs. One of the main players in the pathology of the disease are regulatory T cells (Tregs), however, up to date the mechanisms of the possible molecular alterations of this particular cell subset are not known.MethodsIn the current study we looked for the global transcriptomic changes of miRNAs, using predefined array, and mRNAs (RNA seq analysis) of Tregs of patients with the most predominant form of the disease - acute pulmonary sarcoidosis (PS). For this purpose sorted CD4+/CD25+/CD127- Tregs from peripheral blood (PB) and CD4+/CD25 + Tregs from bronchoalveolar lavage (BAL) were used.ResultsMiRNA analysis revealed that Tregs isolated from PB and BAL display significantly different miRNA profile, suggesting an important role of the pulmonary microenvironment in creating these changes. Among disease-related miRNAs of PB Tregs we identified miR-155 and miR-223. Moreover, looking at the global transcriptome of PB Tregs, we recognized alterations in TLR-2 signaling pathway and in the downstream of NF-κB apoptosis and proliferation signals. However, induction of TLR-2 expression was found not only in Tregs, but also in the heterogeneous population of peripheral blood mononuclear cells (PBMC) as well as two PBMC subpopulations (CD4+/CD25-and CD4-/CD25-) of patients with PS. This indicates that activation of TLR signaling pathway in sarcoidosis does not occur only in Tregs.ConclusionOur findings offer a deeper insight into the molecular mechanisms of Tregs reduced suppression and increased apoptosis in patients with PS. Based on the current results, future studies should focus on possible therapeutic effect of TLR-2 signaling inhibition.
  • Altered distribution and function of splenic innate lymphoid cells in
           adult chronic immune thrombocytopenia.
    • Abstract: Publication date: Available online 23 July 2018Source: Journal of AutoimmunityAuthor(s): Sylvain Audia, Thomas Moulinet, Marion Ciudad-Bonté, Maxime Samson, Olivier Facy, Pablo Ortega-Deballon, Philippe Saas, Bernard Bonnotte Innate lymphoid cells (ILCs) have been characterized as innate immune cells capable to modulate the immune response in the mucosae. Human ILCs have been rarely described in secondary lymphoid organs except in tonsils. Moreover, their function and phenotype in human secondary lymphoid organs during autoimmune diseases have never been studied. We took advantage of splenectomy as a treatment of immune thrombocytopenia (ITP) to describe and compare splenic ILC from 18 ITP patients to 11 controls. We first confirmed that ILC3 represented the most abundant ILC subset in human non-inflamed spleens, accounting for 90% of total ILC, and that they were mostly constituted of NKp44- cells. On the contrary, proportions of ILC1 and ILC2 in spleens were lower than in blood. Splenic IL-2- and IFN-γ-producing ILC1 were increased in ITP. While the frequencies of total splenic ILC3 were similar in the two groups, splenic GM-CSF-producing ILC3 were increased in ITP.This is the first description of human ILC in a major secondary lymphoid organ during an autoimmune disease, ITP. We observed an expansion of splenic ILC1 that could participate to the Th1 skewing, while the increased production of GM-CSF by splenic ILC3 could stimulate splenic macrophages which play a key role in ITP pathophysiology.
  • Gene expression profiling identifies distinct molecular signatures in
           thrombotic and obstetric antiphospholipid syndrome
    • Abstract: Publication date: Available online 19 July 2018Source: Journal of AutoimmunityAuthor(s): Vera M. Ripoll, Francesca Pregnolato, Simona Mazza, Caterina Bodio, Claudia Grossi, Thomas McDonnell, Charis Pericleous, Pier Luigi Meroni, David A. Isenberg, Anisur Rahman, Ian P. Giles Antiphospholipid antibodies (aPL) cause vascular thrombosis (VT) and/or pregnancy morbidity (PM). Differential mechanisms however, underlying the pathogenesis of these different manifestations of antiphospholipid syndrome (APS) are not fully understood. Therefore, we compared the effects of aPL from patients with thrombotic or obstetric APS on monocytes to identify different molecular pathways involved in the pathogenesis of APS subtypes. VT or PM IgG induced similar numbers of differentially expressed (DE) genes in monocytes. However, gene ontology (GO) analysis of DE genes revealed disease-specific genome signatures. Compared to PM, VT-IgG showed specific up regulation of genes associated with cell response to stress, regulation of MAPK signalling pathway and cell communication. In contrast, PM-IgG regulated genes involved in cell adhesion, extracellular matrix and embryonic and skeletal development. A novel gene expression analysis based on differential variability (DV) was also applied. This analysis identified similar GO categories compared to DE analysis but also uncovered novel pathways modulated solely by PM or VT-IgG. Gene expression analysis distinguished a differential effect of VT or PM-IgG upon monocytes supporting the hypothesis that they trigger distinctive physiological mechanisms. This finding contributes to our understanding of the pathology of APS and may lead to the development of different targeted therapies for VT or PM APS.
  • Nrf2-mediated metabolic reprogramming of tolerogenic dendritic cells is
           protective against aplastic anemia
    • Abstract: Publication date: Available online 17 July 2018Source: Journal of AutoimmunityAuthor(s): Hsi-Ju Wei, Ashish Gupta, Wei-Ming Kao, Omar Almudallal, John J. Letterio, Tej K. Pareek Aplastic anemia (AA) is a rare disease characterized by immune-mediated suppression of bone marrow (BM) function resulting in progressive pancytopenia. Stem cell transplant and immunosuppressive therapies remain the major treatment choices for AA patients with limited benefit and undesired side effects. Here, we report for the first time the therapeutic utility of Nrf2-induced metabolically reprogrammed tolerogenic dendritic cells (TolDCs) in the suppression of AA in mice. CDDO-DFPA-induced Nrf2 activation resulted in a TolDC phenotype as evidenced by induction of IL-4, IL-10, and TGF-β and suppression of TNFα, IFN-γ, and IL-12 levels in Nrf2+/+ but not Nrf2−/− DCs. Cellular metabolism holds the key to determining DC immunogenic or tolerogenic cell fate. Although immature and LPS-induced (mature) Nrf2+/+ and Nrf2−/− DCs exhibited similar patterns of oxidative phosphorylation (OXPHOS) and glycolysis, only Nrf2+/+ DCs partially restored OXPHOS and reduced glycolysis during CDDO-DFPA-induced Nrf2 activation. These results were further confirmed by altered glucose uptake and lactate production. We observed significantly enhanced HO-1 and reduced iNOS/NO production in Nrf2+/+ compared to Nrf2−/− DCs, suggesting Nrf2-dependent TolDC induction is linked to suppression of the inhibitory effect of NO on OXPHOS. Furthermore, Nrf2−/− DCs demonstrated higher antigen-specific T cell proliferation. Lastly, TolDC administration improved hematopoiesis and survival in AA murine model, with decreased Th17 and increased Treg cells. Concomitantly, immunohistochemical analysis of AA patient BM biopsies displayed higher DCs, T cells, and iNOS expression accompanied with lower Nrf2 and HO-1 expression when compared to normal subjects. These results provide new insight into the therapeutic utility of metabolically reprogrammed TolDCs by CDDO-DFPA induced Nrf2 signaling in the treatment of AA.
  • Soluble antigen arrays disarm antigen-specific B cells to promote lasting
           immune tolerance in experimental autoimmune encephalomyelitis
    • Abstract: Publication date: Available online 12 July 2018Source: Journal of AutoimmunityAuthor(s): Brittany L. Hartwell, Chad J. Pickens, Martin Leon, Laura Northrup, Matthew A. Christopher, J. Daniel Griffin, Francisco Martinez-Becerra, Cory Berkland Autoreactive lymphocytes that escape central immune tolerance may be silenced via an endogenous peripheral tolerance mechanism known as anergy. Antigen-specific therapies capable of inducing anergy may restore patients with autoimmune diseases to a healthy phenotype while avoiding deleterious side effects associated with global immunosuppression. Inducing anergy in B cells may be a particularly potent intervention, as B cells can contribute to autoimmune diseases through multiple mechanisms and offer the potential for direct antigen-specific targeting through the B cell receptor (BCR). Our previous results suggested autoreactive B cells may be silenced by multivalent ‘soluble antigen arrays’ (SAgAs), which are polymer conjugates displaying multiple copies of autoantigen with or without a secondary peptide that blocks intracellular cell-adhesion molecule-1 (ICAM-1). Here, key therapeutic molecular properties of SAgAs were identified and linked to the immunological mechanism through comprehensive cellular and in vivo analyses. We determined non-hydrolyzable ‘cSAgAs’ displaying multivalent ‘click’-conjugated antigen more potently suppressed experimental autoimmune encephalomyelitis (EAE) compared to hydrolyzable SAgAs capable of releasing conjugated antigen. cSAgAs restored a healthy phenotype in disease-specific antigen presenting cells (APCs) by inducing an anergic response in B cells and a subset of B cells called autoimmune-associated B cells (ABCs) that act as potent APCs in autoimmune disease. Accompanied by a cytokine response skewed towards a Th2/regulatory phenotype, this generated an environment of autoantigenic tolerance. By identifying key therapeutic molecular properties and an immunological mechanism that drives SAgA efficacy, this work guides the design of antigen-specific immunotherapies capable of inducing anergy.
  • A Comprehensive Review of Immune-Mediated Dermatopathology in Systemic
           Lupus Erythematosus
    • Abstract: Publication date: Available online 11 July 2018Source: Journal of AutoimmunityAuthor(s): Qianwen Li, Haijing Wu, Wei Liao, Ming Zhao, Vera Chan, Linfeng Li, Min Zheng, Genhui Chen, Jianzhong Zhang, Chak-Sing Lau, Qianjin Lu Lupus erythematosus (LE) is an autoimmune disease with a broad clinical spectrum ranging from cutaneous lesions to severe systemic manifestations. The pathogenesis of the disease and the immunological mechanisms for the heterogeneities in lupus remain unclear. The LE-specific cutaneous manifestations are generally divided into three categories: acute cutaneous LE (ACLE), subacute cutaneous LE (SCLE) and chronic cutaneous lupus erythematosus (CCLE). Clinically, lupus patients with skin lesions can be divided into two subsets based on the organs involved: cutaneous LE, such as DLE and SCLE, which appears only as a skin manifestation, and systemic lupus erythematosus (SLE), e.g., ACLE, which involves other organs, such as kidneys, joints, and the hematopoietic system. However, lupus is an aggressive disease, and cutaneous lupus and systemic lupus partially overlap. Fewer than 5% of DLE patients and approximately 50% of SCLE patients might develop major organ damage and then develop SLE in subsequent years. Furthermore, there are no predictive biomarkers in clinical use. To the best of our knowledge, increasing evidence from clinical trials has revealed that early intervention can either reduce or delay the onset of severe manifestations. Therefore, identification of certain biomarkers in skin lesions or circulation from patients with skin lesions to predict future flares and advise treatment is an unmet need. In this review, we comprehensively describe the subtypes of LE with pathological criteria and clinical manifestations; summarize the up-to-date evidence on certain cell distributions, such as keratinocytes, neutrophils, dendritic cells, T cells and B cells, in skin and peripheral blood; and discuss their pathogenic roles and their potential roles in predictive diagnosis and as therapeutic targets.
  • Commensal bacteria aggravate allergic asthma via NLRP3/IL-1β signaling in
           post-weaning mice
    • Abstract: Publication date: Available online 7 July 2018Source: Journal of AutoimmunityAuthor(s): Chao Huang, Jian Wang, Xiaodong Zheng, Yongyan Chen, Rongbin Zhou, Haiming Wei, Rui Sun, Zhigang Tian Perturbation of commensal bacteria by antibiotic exposure aggravates ovalbumin (OVA)-induced allergic asthma in pre-weaning mice. However, the influence of dysbiosis of commensal bacteria on asthma development in post-weaning mice is still limited. Here, we treated 3-week-old post-weaning mice with antibiotics to disrupt commensal bacteria and then established OVA-induced allergic asthma by peritoneal sensitization using OVA/alum and intranasal challenge with OVA. Contrary to the protective function in pre-weaning mice, commensal bacteria in post-weaning mice aggravated OVA-induced asthma. Commensal bacteria in post-weaning mice promoted OVA-induced allergic asthma through maintenance of NLRP3/IL-1β expression in peritoneal macrophages (pMφ), which promoted recruitment of inflammatory cells, especially inflammatory monocytes, into the peritoneal cavity after OVA/alum sensitization. Further study showed that metronidazole- and vancomycin-sensitive bacteria are involved in maintenance of NLRP3/IL-1β signal in pMφ. Our results suggest that certain species of commensal bacteria in post-weaning mice aggravate OVA-induced allergic asthma through NLRP3/IL-1β signal pathway.Graphical abstractImage 1
  • Autoimmune liver disease serology in acute hepatitis E virus infection
    • Abstract: Publication date: Available online 7 July 2018Source: Journal of AutoimmunityAuthor(s): Benedetta Terziroli Beretta-Piccoli, Paolo Ripellino, Claudio Gobbi, Andreas Cerny, Adriana Baserga, Claudia Di Bartolomeo, Florian Bihl, Gaia Deleonardi, Laura Melidona, Ana Gabriela Grondona, Giorgina Mieli-Vergani, Diego Vergani, Luigi Muratori, Swiss Autoimmune Hepatitis Cohort Study Group The etiology of autoimmune hepatitis (AIH) is unknown, though hepatotropic viruses may be potential triggers. Hepatitis E virus (HEV) infection, an increasingly recognized cause of acute hepatitis, has been misdiagnosed as AIH due to the occurrence of autoantibodies during its acute phase. It has also been suggested that HEV infection may lead to or unmask AIH. The HEV seroprevalence has been ascertained in patients with AIH, but the prevalence of AIH-related autoantibodies in patients with HEV infection has not been systematically tested. We aimed to investigate whether acute HEV infection is associated with the presence of AIH-relevant autoantibodies, following the liver autoimmune serology guidelines of the International AIH Group. We tested 48 patients with acute HEV infection. Half of them had at least one autoantibody, 17% two autoantibodies. Anti-nuclear antibody (ANA) were detected in 16 (33%), anti-smooth muscle antibody (SMA) in 10 (21%), and anti-neutrophil cytoplasmic antibody (ANCA) in 7 (14.6%). Of note, two patients showed SMA with VG or VGT patterns and five had ANA with homogeneous appearance, both being typical of AIH type 1. Other AIH-specific autoantibodies were negative. Atypical anti-mitochondrial antibody, without evidence of primary biliary cholangitis, was positive in one patient, disappearing at follow-up. Follow-up (median 12 months) serum was available from seven autoantibody positive patients: two became negative, while five remained positive, although no patient developed AIH to date. In conclusion, autoantibodies are frequently present during acute HEV infection, indicating that HEV should always be excluded before diagnosing AIH. Importantly, a minority of patients with acute hepatitis E develops AIH-specific autoantibodies, and, though they did not progress to autoimmune liver disease in the short-term, they warrant long-term monitoring.
  • Identification of loci where DNA methylation potentially mediates genetic
           risk of type 1 diabetes
    • Abstract: Publication date: Available online 29 June 2018Source: Journal of AutoimmunityAuthor(s): Jody Ye, Tom G. Richardson, Wendy L. McArdle, Caroline L. Relton, Kathleen M. Gillespie, Matthew Suderman, Gibran Hemani The risk of Type 1 Diabetes (T1D) comprises both genetic and environmental components. We investigated whether genetic susceptibility to T1D could be mediated by changes in DNA methylation, an epigenetic mechanism that potentially plays a role in autoimmune diabetes. From enrichment analysis, we found that there was a common genetic influence for both DNA methylation and T1D across the genome, implying that methylation could be either on the causal pathway to T1D or a non-causal biomarker of T1D genetic risk. Using data from a general population comprising blood samples taken at birth (n = 844), childhood (n = 846) and adolescence (n = 907), we then evaluated the associations between 64 top GWAS single nucleotide polymorphisms (SNPs) and DNA methylation levels at 55 non-HLA loci. We identified 95 proximal SNP-cytosine phosphate guanine (CpG) pairs (cis) and 1 distal SNP-CpG association (trans) consistently at birth, childhood, and adolescence. Combining genetic co-localization and Mendelian Randomization analysis, we provided evidence that at 5 loci, ITGB3BP, AFF3, PTPN2, CTSH and CTLA4, DNA methylation is potentially mediating the genetic risk of T1D mainly by influencing local gene expression.
  • TRIF deficiency protects non-obese diabetic mice from type 1 diabetes by
           modulating the gut microbiota and dendritic cells
    • Abstract: Publication date: Available online 28 June 2018Source: Journal of AutoimmunityAuthor(s): Elke Gülden, Chen Chao, Ningwen Tai, James A. Pearson, Jian Peng, Monika Majewska-Szczepanik, Zhiguang Zhou, F. Susan Wong, Li Wen The incidence of type 1 diabetes (T1D) is determined by both genetic and environmental factors. In recent years, the gut microbiota have been identified to be an important environmental factor that could modify diabetes susceptibility. We have previously shown that Myeloid differentiation primary response gene 88 (MyD88), a major adaptor protein downstream of most innate immune Toll-like receptor (TLR) signaling, is important for mediating diabetes susceptibility in the non-obese diabetic (NOD) mouse model of human T1D. Here we report the role of TIR-domain-containing adapter-inducing interferon-β (TRIF) in T1D development, as TRIF is an important adaptor protein downstream of TLR3 and TLR4 signaling. We found that TRIF-deficient (TRIF−/-) NOD mice were protected from development of diabetes, but only when housed with TRIF-deficient (TRIF−/-) NOD mice. When housed with TRIF-sufficient wild type (WT, i.e., TRIF+/+) NOD mice, the mice developed diabetes. We further investigated the gut microbiota as a potential cause for the altered diabetes development. Interestingly, TRIF−/−NOD mice had a different microbiota composition compared to WT NOD mice, only if they were housed with TRIF−/−NOD mice. However, the composition of gut microbiota in the TRIF−/−NOD mice was indistinguishable from WT NOD mice, if they were housed with WT NOD mice. The difference in the gut microbiota in TRIF−/−NOD mice, due to cohousing, accorded with the diabetes development in TRIF−/−NOD mice. Comparing the gut microbiota in TRIF−/- and WT NOD mice, we identified changes in percentage of Sutterella, Rikenella and Turicibacter species. Moreover, bacteria from WT NOD mice induced significantly stronger inflammatory immune responses in vitro compared to those from TRIF−/−NOD mice. Further immunological analysis revealed impaired function of dendritic cells and reduced T cell activation and proliferation in TRIF−/−NOD mice. Our data show that TRIF-deficiency protects NOD mice from diabetes development through alteration of the gut microbiota and reduced immune cell activation; however, that protection is over-ridden upon exposure to WT NOD bacteria. Therefore exposure to different microbiota can modify disease susceptibility determined by genetic factors related to innate immunity.
  • Protective role of commensal bacteria in Sjögren Syndrome
    • Abstract: Publication date: Available online 20 June 2018Source: Journal of AutoimmunityAuthor(s): Mahira Zaheer, Changjun Wang, Fang Bian, Zhiyuan Yu, Humberto Hernandez, Rodrigo G. de Souza, Ken T. Simmons, Deborah Schady, Alton G. Swennes, Stephen C. Pflugfelder, Robert A. Britton, Cintia S. de Paiva CD25 knock-out (CD25KO) mice spontaneously develop Sjögren Syndrome (SS)-like inflammation. We investigated the role of commensal bacteria by comparing CD25KO mice housed in conventional or germ-free conditions. Germ-free CD25KO mice have greater corneal barrier dysfunction, lower goblet cell density, increased total lymphocytic infiltration score, increased expression of IFN-γ, IL-12 and higher a frequency of CD4+IFN-γ+ cells than conventional mice. CD4+ T cells isolated from female germ-free CD25KO mice adoptively transferred to naive immunodeficient RAG1KO recipients caused more severe Sjögren-like disease than CD4+ T cells transferred from conventional CD25KO mice. Fecal transplant in germ-free CD25KO mice reversed the spontaneous dry eye phenotype and decreased the generation of pathogenic CD4+IFN-γ+ cells. Our studies indicate that lack of commensal bacteria accelerates the onset and severity of dacryoadenitis and generates autoreactive CD4+T cells with greater pathogenicity in the CD25KO model, suggesting that the commensal bacteria or their metabolites products have immunoregulatory properties that protect exocrine glands in the CD25KO SS model.
  • Targeted inhibition of Axl receptor tyrosine kinase ameliorates
           anti-GBM-induced lupus-like nephritis
    • Abstract: Publication date: Available online 9 June 2018Source: Journal of AutoimmunityAuthor(s): Yuxuan Zhen, Iris J. Lee, Fred D. Finkelman, Wen-Hai Shao Glomerulonephritis (GN) is a typical lesion in autoantibody and immune complex disorders, including SLE. Because the Gas6/Axl pathway has been implicated in the pathogenesis of many types of GN, targeting this pathway might ameliorate GN. Consequently, we have studied the efficacy and mechanism of R428, a potent selective Axl inhibitor, in the prevention of experimental anti-GBM nephritis. Axl upregulation was investigated with Sp1/3 siRNA in the SV40-transformed mesangial cells. For Axl inhibition, a daily dose of R428 (125 mg/kg) or vehicle was administered orally. GN was induced with anti-GBM sera. Renal disease development was followed by serial blood urine nitrogen (BUN) determinations and by evaluation of kidney histology at the time of sacrifice. Axl-associated signaling proteins were analyzed by Western blotting and inflammatory cytokine secretion was analyzed by Proteome array. SiRNA data revealed the transcription factor Sp1 to be an important regulator of mesangial Axl expression. Anti-GBM serum induced severe nephritis with azotemia, protein casts and necrotic cell death. R428 treatment diminished renal Axl expression and improved kidney function, with significantly decreased BUN and glomerular proliferation. R428 treatment inhibited Axl and significantly decreased Akt phosphorylation and renal inflammatory cytokine and chemokine expression; similar effects were observed in anti-GBM antiserum-treated Axl-KO mice. These studies support a role for Axl inhibition in glomerulonephritis.
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