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Publisher: Elsevier   (Total: 3160 journals)

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Showing 1401 - 1600 of 3160 Journals sorted alphabetically
Intl. J. of Adhesion and Adhesives     Hybrid Journal   (Followers: 19, 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: 36, 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: 7, 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: 17, 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: 19, SJR: 0.769, CiteScore: 2)
Intl. J. of Drug Policy     Hybrid Journal   (Followers: 463, 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: 28, SJR: 0.617, CiteScore: 1)
Intl. J. of Electrical Power & Energy Systems     Open Access   (Followers: 26, SJR: 1.276, CiteScore: 5)
Intl. J. of Engineering Science     Hybrid Journal   (Followers: 5, SJR: 2.82, CiteScore: 6)
Intl. J. of Fatigue     Hybrid Journal   (Followers: 38, SJR: 1.402, CiteScore: 3)
Intl. J. of Food Microbiology     Hybrid Journal   (Followers: 16, SJR: 1.366, CiteScore: 4)
Intl. J. of Forecasting     Hybrid Journal   (Followers: 30, 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: 6, 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: 294, 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: 22, 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: 25, 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: 325, SJR: 1.373, CiteScore: 6)
Intl. J. of Intercultural Relations     Hybrid Journal   (Followers: 14, SJR: 0.732, CiteScore: 2)
Intl. J. of Law and Psychiatry     Hybrid Journal   (Followers: 9, SJR: 0.546, CiteScore: 1)
Intl. J. of Law, Crime and Justice     Hybrid Journal   (Followers: 57, 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: 10, SJR: 1.247, CiteScore: 4)
Intl. J. of Medical Microbiology     Hybrid Journal   (Followers: 9, 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: 9, 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: 2, 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: 11, 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: 2, SJR: 0.144, CiteScore: 1)
Intl. J. of Pharmaceutics     Hybrid Journal   (Followers: 37, 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: 28, SJR: 0.981, CiteScore: 2)
Intl. J. of Production Economics     Hybrid Journal   (Followers: 17, SJR: 2.401, CiteScore: 5)
Intl. J. of Project Management     Hybrid Journal   (Followers: 50, SJR: 1.463, CiteScore: 5)
Intl. J. of Psychophysiology     Hybrid Journal   (Followers: 6, 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: 9, 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   (Followers: 1, 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: 7)
Intl. Review of Cell and Molecular Biology     Full-text available via subscription   (Followers: 7, SJR: 1.973, CiteScore: 4)
Intl. Review of Cytology     Full-text available via subscription  
Intl. Review of Economics & Finance     Hybrid Journal   (Followers: 27, 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: 22, 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: 5)
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: 71, 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: 1063, SJR: 1.224, CiteScore: 2)
J. of Accounting and Economics     Hybrid Journal   (Followers: 39, 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: 15, SJR: 1.01, CiteScore: 2)
J. of Adolescent Health     Hybrid Journal   (Followers: 24, 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: 31, SJR: 5.049, CiteScore: 7)
J. of Allergy and Clinical Immunology : In Practice     Full-text available via subscription   (Followers: 13, SJR: 1.461, CiteScore: 3)
J. of Alloys and Compounds     Hybrid Journal   (Followers: 13, 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: 78, 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: 14, SJR: 1.339, CiteScore: 3)
J. of Applied Economics     Full-text available via subscription   (Followers: 10, 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: 50, 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: 3, SJR: 0.419, CiteScore: 1)
J. of Atmospheric and Solar-Terrestrial Physics     Hybrid Journal   (Followers: 162, SJR: 0.696, CiteScore: 2)
J. of Autoimmunity     Hybrid Journal   (Followers: 16, 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: 182)
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: 4, SJR: 0.475, CiteScore: 1)
J. of Biochemical and Biophysical Methods     Hybrid Journal   (Followers: 5)
J. of Biomechanics     Hybrid Journal   (Followers: 37, SJR: 1.147, CiteScore: 3)
J. of Biomedical Informatics     Partially Free   (Followers: 16, 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: 62, 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: 3, 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)
J. of Business Venturing Insights     Hybrid Journal   (Followers: 1, SJR: 1.162, CiteScore: 2)

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Similar Journals
Journal Cover
Journal of Autoimmunity
Journal Prestige (SJR): 2.046
Citation Impact (citeScore): 7
Number of Followers: 16  
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0896-8411 - ISSN (Online) 1095-9157
Published by Elsevier Homepage  [3160 journals]
  • Transcriptomic and proteomic analysis of iris tissue and aqueous humor in
           juvenile idiopathic arthritis-associated uveitis
    • Abstract: Publication date: Available online 15 March 2019Source: Journal of AutoimmunityAuthor(s): Lena Wildschütz, Doreen Ackermann, Anika Witten, Maren Kasper, Martin Busch, Shirin Glander, Harutyun Melkonyan, Karoline Walscheid, Christoph Tappeiner, Solon Thanos, Andrei Barysenka, Jörg Koch, Carsten Heinz, Björn Laffer, Dirk Bauer, Monika Stoll, Simone König, Arnd Heiligenhaus Gene and protein expression profiles of iris biopsies, aqueous humor (AqH), and sera in patients with juvenile idiopathic arthritis-associated uveitis (JIAU) in comparison to control patients with primary open-angle glaucoma (POAG) and HLA-B27-positive acute anterior uveitis (AAU) were investigated. Via RNA Sequencing (RNA-Seq) and mass spectrometry-based protein expression analyses 136 genes and 56 proteins could be identified as being significantly differentially expressed (DE) between the JIAU and POAG group. Gene expression of different immunoglobulin (Ig) components as well as of the B cell-associated factors ID3, ID1, and EBF1 was significantly upregulated in the JIAU group as compared to POAG patients. qRT-PCR analysis showed a significantly higher gene expression of the B cell-related genes CD19, CD20, CD27, CD138, and MZB1 in the JIAU group. At the protein level, a significantly higher expression of Ig components in JIAU than in POAG was confirmed. The B cell-associated protein MZB1 showed a higher expression in JIAU patients than in POAG which was confirmed by western blot analysis. Using bead-based immunoassay analysis we were able to detect a significantly higher concentration of the B cell-activating and survival factors BAFF, APRIL, and IL-6 in the AqH of JIAU and AAU patients than in POAG patients. The intraocularly upregulated B cell-specific genes and proteins in iris tissue suggest that B cells participate in the immunopathology of JIAU. The intracameral environment in JIAU may facilitate local effector and survival functions of B cells, leading to disease course typical for anterior uveitis.
  • Plcγ2/Tmem178 dependent pathway in myeloid cells modulates the
           pathogenesis of cytokine storm syndrome
    • Abstract: Publication date: Available online 15 March 2019Source: Journal of AutoimmunityAuthor(s): Sahil Mahajan, Corinne E. Decker, Zhengfeng Yang, Deborah Veis, Elizabeth D. Mellins, Roberta Faccio Cytokine storm syndrome (CSS) is a life-threatening condition characterized by excessive activation of T cells and uncontrolled inflammation, mostly described in patients with familial hemophagocytic lymphohistiocytosis and certain systemic auto-inflammatory diseases, such as systemic juvenile idiopathic arthritis (sJIA). Defects in T cell cytotoxicity as a mechanism for uncontrolled inflammation following viral infections fail to represent the whole spectrum of CSS. Evidence implicates dysregulated innate immune responses, especially activation of monocytes and macrophages, in patients with CSS. However, the direct contribution of monocytes/macrophages to CSS development and the signaling pathways involved in their activation have not been formally investigated. We find that depletion of monocytes/macrophages during early stages of CSS development, by clodronate-liposomes or neutralizing anti-CSF1 antibody, reduces mortality and inflammatory cytokine levels in two CSS mouse models, one dependent on T cells and the second induced by repeated TLR9 stimulation. We further demonstrate that activation of Plcγ2 in myeloid cells controls CSS development by driving macrophage pro-inflammatory responses. Intriguingly, the Plcγ2 downstream effector Tmem178, a negative modulator of calcium levels, acts in a negative feedback loop to restrain inflammatory cytokine production. Genetic deletion of Tmem178 leads to pro-inflammatory macrophage polarization in vitro and more severe CSS in vivo. Importantly, Tmem178 levels are reduced in macrophages from mice with CSS and after exposure to plasma from sJIA patients with active disease. Our data identify a novel Plcγ2/Tmem178 axis as a modulator of inflammatory cytokine production by monocytes/macrophages. We also find that loss of Tmem178 accentuates the pro-inflammatory responses in CSS.
  • Elevated autoimmunity in residents living near abandoned uranium mine
           sites on the Navajo Nation
    • Abstract: Publication date: Available online 14 March 2019Source: Journal of AutoimmunityAuthor(s): Esther Erdei, Chris Shuey, Curtis Miller, Bernadette Pacheco, Miranda Cajero, Johnnye Lewis, Robert L. Rubin Specific autoantibodies were assessed among residents of the Navajo Nation in New Mexico chronically exposed to metal mixtures from uranium mine wastes and in drinking water supplies. Age and the extent of exposure to legacy waste from 100 abandoned uranium mine and mill sites were associated with antibodies to denatured DNA, previously known to be an early indicator of medication-induced autoimmunity. Surprisingly, autoantibodies to native DNA and/or chromatin were also linked to environmental exposure, specifically uranium consumption through drinking water for both men and women, while urinary arsenic was negatively associated with these autoantibodies in women. These findings suggest that contaminants derived from uranium mine waste enhanced development of autoantibodies in some individuals, while arsenic may be globally immunosuppressive with gender-specific effects. Specific autoantibodies may be a sensitive indicator of immune perturbation by environmental toxicants, an adverse effect not considered in current drinking water standards or regulatory risk assessment evaluations.
  • Expansion of circulating extrafollicular helper T-like cells in patients
           with chronic graft-versus-host disease
    • Abstract: Publication date: Available online 13 March 2019Source: Journal of AutoimmunityAuthor(s): Hua Jin, Kaibo Yang, Haiyan Zhang, Yanqiu Chen, Hanzhou Qi, Zhiping Fan, Fen Huang, Li Xuan, Ren Lin, Ke Zhao, Qifa Liu Chronic graft-versus-host disease (cGVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Previous studies have shown that T follicular helper cells (Tfh) contribute to immune pathology in cGVHD, but the function of extrafollicular helper T cells during cGVHD pathogenesis remains largely unknown. In the current study, we identified circulating extrafollicular helper T-like cells (CD44hiCD62LloPSGL-1loCD4+, c-extrafollicular Th-like) in human peripheral blood. We performed phenotypic and functional analyses of c-extrafollicular Th-like cells from 80 patients after allo-HSCT to explore the role of these cells in the development of human cGVHD. Patients with active cGVHD had significantly higher frequencies and counts of c-extrafollicular Th-like cells than those of patients without cGVHD. The expansion of c-extrafollicular Th-like cells was more significant in patients with moderate/severe cGVHD than that of patients with mild cGVHD. C-extrafollicular Th-like cells from patients with active cGVHD exhibited increased functional abilities to induce plasmablast differentiation and IgG1 secretion compared to those of patients without cGVHD. Moreover, c-extrafollicular Th-like cell levels were highly correlated with the generation of autoreactive B cells, plasmablasts and IgG1 antibodies. Our studies provide new insights into human cGVHD pathogenesis and identify c-extrafollicular Th-like cells as a key element in the development of human cGVHD.
  • cGAS activation causes lupus-like autoimmune disorders in a TREX1 mutant
           mouse model
    • Abstract: Publication date: Available online 11 March 2019Source: Journal of AutoimmunityAuthor(s): Nanyang Xiao, Jingjing Wei, Shan Xu, Hekang Du, Miaohui Huang, Sitong Zhang, Weiwei Ye, Lijun Sun, Qi Chen TREX1 encodes a major cellular DNA exonuclease. Mutations of this gene in human cause cellular accumulation of DNA that triggers autoimmune diseases including Aicardi–Goutieres Syndrome (AGS) and systemic lupus erythematosus (SLE). We created a lupus mouse model by engineering a D18 N mutation in the Trex1 gene which inactivates the enzyme and has been found in human patients with lupus-like disorders. The Trex1D18N/D18N mice exhibited systemic inflammation that consistently recapitulates many characteristics of human AGS and SLE. Importantly, ablation of cGas gene in the Trex1D18N/D18N mice rescued the lethality and all detectable pathological phenotypes, including multi-organ inflammation, interferon stimulated gene induction, autoantibody production and aberrant T-cell activation. These results indicate that cGAS is a key mediator in the autoimmune disease associated with defective TREX1 function, providing additional insights into disease pathogenesis and guidance to the development of therapeutics for human systemic autoimmune disorders.
  • Inflammatory myopathy associated with PD-1 inhibitors
    • Abstract: Publication date: Available online 10 March 2019Source: Journal of AutoimmunityAuthor(s): Morinobu Seki, Akinori Uruha, Yuko Ohnuki, Sachiko Kamada, Tomoko Noda, Asako Onda, Masayuki Ohira, Aiko Isami, Sumie Hiramatsu, Makoto Hibino, Shunya Nakane, Seiya Noda, Sachiko Yutani, Akira Hanazono, Hiroshi Yaguchi, Masaki Takao, Takashi Shiina, Masahisa Katsuno, Jin Nakahara, Shiro Matsubara ObjectiveTo characterize the inflammatory myopathy associated with programmed cell death 1 inhibitors (PD-1 myopathy).MethodsWe studied 19 Japanese patients with PD-1 myopathy (13 men and 6 women, mean age 70 years), who were referred to Keio University. As control groups, we used 68 patients with anti-signal recognition particle antibodies, 51 patients with anti-aminoacyl transfer RNA synthetase antibodies and 460 healthy subjects.ResultsIn regard to muscle-disease severity, 10 patients showed a mild form of disease and 9 patients showed a severe form. Non-small cell lung cancer was the most common underlying cancer. PD-1 inhibitor consisted of 11 nivolumab and 8 pembrolizumab. PD-1 myopathy occurred 29 days on average after the first administration of PD-1 inhibitor. The initial manifestation of muscle weakness was ptosis in 10 patients, 15 patients had ptosis, 13 diplopia, 8 facial muscle weakness, 10 bulbar symptoms, 13 limb weakness, 14 neck weakness, 4 cardiac involvement, 6 respiratory involvement and 16 myalgia. Ocular, facial, cardiac and respiratory involvement and myalgia were more frequently observed than controls. Serum creatine kinase was increased to 5247 IU/L on average. Autoantibodies related to inflammatory myopathy were negative, while anti-striational antibodies were found in 13 (68%) patients. HLA-C*12:02 alleles were more frequently detected than healthy controls. Muscle pathology was characterized by multifocal necrotic myofibers with endomysial inflammation and expression of MHC class I. Immunosuppressive therapy with corticosteroids was generally effective for muscle weakness.ConclusionsBased on our clinical, histological and immunological findings, PD-1 myopathy is a discrete subset of inflammatory myopathy.
  • Successful treatment of extensive calcifications and acute pulmonary
           involvement in dermatomyositis with the Janus-Kinase inhibitor tofacitinib
           – A report of two cases
    • Abstract: Publication date: Available online 9 March 2019Source: Journal of AutoimmunityAuthor(s): Sarah Wendel, Nils Venhoff, Bjoern C. Frye, Annette M. May, Prerana Agarwal, Marta Rizzi, Reinhard E. Voll, Jens Thiel IntroductionDermatomyositis (DM) can be complicated by calcinosis and interstitial lung disease (ILD). Calcinosis can be severely debilitating or life-threatening and to date there is no treatment with proven efficacy. In DM type I interferon contributes to pathophysiology by inducing the expression of proinflammatory cytokines and the JAK-STAT (signal transducer and activator of transcription) pathway may be involved in the regulation of mitochondrial calcium store release, a process potentially important for calcification in DM. JAK-inhibition may therefore be an attractive therapy in DM complicated by calcifications.Methods and resultsWe report on the fast and persistent response of extensive and rapidly progressive DM-associated calcifications in two patients treated with the JAK-inhibitor tofacitinib. During the 28-week observation period in both patients no new calcifications formed and existing calcifications were either regressive or stable. Furthermore, concomitant life-threatening DM-associated ILD (acute fibrinous and organizing pneumonia; AFOP) in one patient rapidly responded to tofacitinib monotherapy. Both patients were able to taper concomitant glucocorticoids. Tofacitinib was well tolerated and safe.ConclusionsThe results of our study support the role of JAK/STAT signaling in the development of calcinosis and ILD in DM. Tofacitinib may be an effective and safe treatment for calcinosis in DM and potentially for other connective tissue disease complicated by calcinosis.
  • The immune milieu of cholangiocarcinoma: From molecular pathogenesis to
           precision medicine
    • Abstract: Publication date: Available online 9 March 2019Source: Journal of AutoimmunityAuthor(s): Lorenza Rimassa, Nicola Personeni, Alessio Aghemo, Ana Lleo Cholangiocarcinoma (CCA) is a deadly cancer of the biliary epithelium with limited therapeutic options. It is a heterogeneous group of cancer that could develop at any level from the biliary tree and is currently classified into intrahepatic, perihilar and distal based on its anatomical location. With incidence and mortality rates currently increasing, it is now the second most common type of primary liver cancer and represents up to 3% of all gastrointestinal malignancies. High-throughput genomics and epigenomics have greatly increased our understanding of CCA underlying biology, however its pathogenesis remains largely unknown. CCA is characterized by a highly desmoplastic microenvironment containing stromal cells, mainly cancer-associated fibroblasts, infiltrating tumor epithelium. Tumor microenvironment in CCA is a highly dynamic environment that, besides stromal and endothelial cells, encompass also an abundance of immune cells, of both the innate and adaptive immune system (including tumor-associated macrophages, neutrophils, natural killer cells, and T and B lymphocytes) and abundant proliferative factors. It is orchestrated by multiple soluble factors and signals, that eventually define a tumor growth-permissive microenvironment. Through complicate interactions with CCA cells, tumor microenvironment profoundly affects the proliferative and invasive abilities of epithelial cancer cells and plays an important role in accelerating neovascularization and preventing apoptosis of neoplastic cells. In this review, we discuss recent developments regarding the characteristics of the tumor microenvironment, the role of each cellular population, and their multiarticulate interaction with the malignant population. Further we discuss innovative treatment approaches, including immunotherapy, and how identification of CCA secreted factors by both the stromal component and immune cell subsets are leading towards a precision medicine in CCA.
  • Immunological effects of vitamin D and their relations to autoimmunity
    • Abstract: Publication date: Available online 8 March 2019Source: Journal of AutoimmunityAuthor(s): Erin Yamamoto, Trine N. Jørgensen Vitamin D deficiency is an established risk factor for many autoimmune diseases and the anti-inflammatory properties of vitamin D underscore its potential therapeutic value for these diseases. However, results of vitamin D3 supplementation clinical trials have been varied. To understand the clinical heterogeneity, we reviewed the pre-clinical data on vitamin D activity in four common autoimmune diseases: multiple sclerosis (MS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and inflammatory bowel disease (IBD), in which patients are commonly maintained on oral vitamin D3 supplementation. In contrast, many pre-clinical studies utilize other methods of manipulation (i.e. genetic, injection). Given the many actions of vitamin D3 and data supporting a vitamin D-independent role of the Vitamin D receptor (VDR), a more detailed mechanistic understanding of vitamin D3 activity is needed to properly translate pre-clinical findings into the clinic. Therefore, we assessed studies based on route of vitamin D3 administration, and identified where discrepancies in results exist and where more research is needed to establish the benefit of vitamin D supplementation.
  • AS101 ameliorates experimental autoimmune uveitis by regulating Th1 and
           Th17 responses and inducing Treg cells
    • Abstract: Publication date: Available online 8 March 2019Source: Journal of AutoimmunityAuthor(s): So Jin Bing, Itay Shemesh, Wai Po Chong, Reiko Horai, Yingyos Jittayasothorn, Phyllis B. Silver, Benjamin Sredni, Rachel R. Caspi AS101 is an organotellurium compound with multifaceted immunoregulatory properties that is remarkable for its lack of toxicity. We tested the therapeutic effect of AS101 in experimental autoimmune uveitis (EAU), a model for human autoimmune uveitis. Unexpectedly, treatment with AS101 elicited Treg generation in vivo in otherwise unmanipulated mice. Mice immunized for EAU with the retinal antigen IRBP and treated with AS101 developed attenuated disease, as did AS101-treated recipients of retina-specific T cells activated in vitro. In both settings, eye-infiltrating effector T cells were decreased, whereas regulatory T (Treg) cells in the spleen were increased. Mechanistic studies in vitro revealed that AS101 restricted polarization of retina-specific T cells towards Th1 or Th17 lineage by repressing activation of their respective lineage-specific transcription factors and downstream signals. Retina-specific T cells polarized in vitro towards Th1 or Th17 in the presence of AS101 had impaired ability to induce EAU in naïve recipients. Finally, AS101 promoted differentiation of retina-specific T cells to Tregs in vitro independently of TGF-β. We conclude that AS101 modulates autoimmune T cells by inhibiting acquisition and expression of effector function and by promoting Treg generation, and suggest that AS101 could be useful as a therapeutic approach for autoimmune uveitis.
  • ‘RA and the microbiome: do host genetic factors provide the
    • Abstract: Publication date: Available online 5 March 2019Source: Journal of AutoimmunityAuthor(s): Philippa M. Wells, Frances M.K. Williams, M.L. Matey-Hernandez, Cristina Menni, Claire J. Steves Rheumatoid arthritis (RA) is a chronic autoimmune disease, characterised by painful synovium inflammation, bony erosions, immune activation and the circulation of autoantibodies. Despite recent advances in therapeutics enabling disease suppression, there is a considerable demand for alternative therapeutic strategies as well as optimising those available at present. The relatively low concordance rate between monozygotic twins, 20–30% contrasts with heritability estimates of ∼65%, indicating a substantive role of other risk factors in RA pathogenesis. There is established evidence that RA has an infective component to its aetiology. More recently, differences in the commensal microbiota in RA compared to controls have been identified. Studies have shown that the gut, oral and lung microbiota is different in new onset treatment naïve, and established RA patients, compared to controls. Key taxonomic associations are an increase in abundance of Porphyromonas gingivalis and Prevotella copri in RA patients, compared to healthy controls. Host genetics may provide the link between disease and the microbiome. Genetic influence may be mediated by the host immune system; a differential response to RA associated taxa is suggested. The gut microbiome contains elements which are as much as 30% heritable. A better understanding of the influence of host genetics will shed light onto the role of the microbiome in RA. Here we review the role of the microbiome in RA through the lens of host genetics, and consider future research areas addressing microbiome study design and bioinformatics approaches.Graphical abstractPutative interactions mediating the link between host genetic factors, the gut and oral microbiome and rheumatoid arthritis.Image 1
  • Endogenous double-stranded Alu RNA elements stimulate IFN-responses in
           relapsing remitting multiple sclerosis
    • Abstract: Publication date: Available online 28 February 2019Source: Journal of AutoimmunityAuthor(s): Maxwell J. Heinrich, Caroline A. Purcell, Andrea J. Pruijssers, Yang Zhao, Charles F. Spurlock, Subramaniam Sriram, Kristen M. Ogden, Terence S. Dermody, Matthew B. Scholz, Philip S. Crooke, John Karijolich, Thomas M. Aune Various sensors that detect double-stranded RNA, presumably of viral origin, exist in eukaryotic cells and induce IFN-responses. Ongoing IFN-responses have also been documented in a variety of human autoimmune diseases including relapsing-remitting multiple sclerosis (RRMS) but their origins remain obscure. We find increased IFN-responses in leukocytes in relapsing-remitting multiple sclerosis at distinct stages of disease. Moreover, endogenous RNAs isolated from blood cells of these same patients recapitulate this IFN-response if transfected into naïve cells. These endogenous RNAs are double-stranded RNAs, contain Alu and Line elements and are transcribed from leukocyte transcriptional enhancers. Thus, transcribed endogenous retrotransposon elements can co-opt pattern recognition sensors to induce IFN-responses in RRMS.
  • Primary immunodeficiency and autoimmunity: A comprehensive review
    • Abstract: Publication date: Available online 20 February 2019Source: Journal of AutoimmunityAuthor(s): Laura Amaya-Uribe, Manuel Rojas, Gholamreza Azizi, Juan-Manuel Anaya, M. Eric Gershwin The primary immunodeficiency diseases (PIDs) include many genetic disorders that affect different components of the innate and adaptive responses. The number of distinct genetic PIDs has increased exponentially with improved methods of detection and advanced laboratory methodology. Patients with PIDs have an increased susceptibility to infectious diseases and non-infectious complications including allergies, malignancies and autoimmune diseases (ADs), the latter being the first manifestation of PIDs in several cases. There are two types of PIDS. Monogenic immunodeficiencies due to mutations in genes involved in immunological tolerance that increase the predisposition to develop autoimmunity including polyautoimmunity, and polygenic immunodeficiencies characterized by a heterogeneous clinical presentation that can be explained by a complex pathophysiology and which may have a multifactorial etiology. The high prevalence of ADs in PIDs demonstrates the intricate relationships between the mechanisms of these two conditions. Defects in central and peripheral tolerance, including mutations in AIRE and T regulatory cells respectively, are thought to be crucial in the development of ADs in these patients. In fact, pathology that leads to PID often also impacts the Treg/Th17 balance that may ease the appearance of a proinflammatory environment, increasing the odds for the development of autoimmunity. Furthermore, the influence of chronic and recurrent infections through molecular mimicry, bystander activation and super antigens activation are supposed to be pivotal for the development of autoimmunity. These multiple mechanisms are associated with diverse clinical subphenotypes that hinders an accurate diagnosis in clinical settings, and in some cases, may delay the selection of suitable pharmacological therapies. Herein, a comprehensively appraisal of the common mechanisms among these conditions, together with clinical pearls for treatment and diagnosis is presented.
  • Oral administration of Domain-I of beta-2glycoprotein-I induces
           immunological tolerance in experimental murine antiphospholipid syndrome
    • Abstract: Publication date: Available online 20 February 2019Source: Journal of AutoimmunityAuthor(s): Asaf Shemer, Rohan Willis, Emilio B. Gonzalez, Zurina Romay-Penabad, Ora Shovman, Yehuda Shoenfeld, Miri Blank, Howard Amital It is well established that the humoral immunity in antiphospholipid syndrome (APS) is presented by circulating pathogenic anti-β2GPI autoantibodies targeting mainly domain I of the β2GPI protein, playing a major role in the disease pathogenesis. Previously, we have demonstrated that treatment of experimental APS mice with tolerogenic dendritic cells loaded with domain-I was more efficient in tolerance induction than with the whole molecule or domain-V. In the current study we had orally administered a domain-I derivative of the β2GPI molecule, as a new therapeutic approach to induce oral tolerance in this mouse model of APS. BALB/c mice immunized with β2GPI, were fed with either domain-I, domain-V derivative or the complete β2GPI protein. β2GPI immunized mice developed experimental APS which were fed with domain-I significantly had decreased fetal loss (p 
  • Counter-regulation of regulatory T cells by autoreactive CD8+ T cells in
           rheumatoid arthritis
    • Abstract: Publication date: Available online 16 February 2019Source: Journal of AutoimmunityAuthor(s): Ilenia Cammarata, Carmela Martire, Alessandra Citro, Domenico Raimondo, Doriana Fruci, Ombretta Melaiu, Valentina D'Oria, Chiara Carone, Giovanna Peruzzi, Cristina Cerboni, Angela Santoni, John Sidney, Alessandro Sette, Marino Paroli, Rosalba Caccavale, Edoardo Milanetti, Mara Riminucci, Eleonora Timperi, Silvia Piconese, Antonio Manzo The mechanisms whereby autoreactive T cells escape peripheral tolerance establishing thus autoimmune diseases in humans remain an unresolved question. Here, we demonstrate that autoreactive polyfunctional CD8+ T cells recognizing self-antigens (i.e., vimentin, actin cytoplasmic 1, or non-muscle myosin heavy chain 9 epitopes) with high avidity, counter-regulate Tregs by killing them, in a consistent percentage of rheumatoid arthritis (RA) patients. Indeed, these CD8+ T cells express a phenotype and gene profile of effector (eff) cells and, upon antigen-specific activation, kill Tregs indirectly in an NKG2D-dependent bystander fashion in vitro. This data provides a mechanistic basis for the finding showing that AE-specific (CD107a+) CD8+ T killer cells correlate, directly with the disease activity score, and inversely with the percentage of activated Tregs, in both steady state and follow-up studies in vivo. In addition, multiplex immunofluorescence imaging analyses of inflamed synovial tissues in vivo show that a remarkable number of CD8+ T cells express granzyme-B and selectively contact FOXP3+ Tregs, some of which are in an apoptotic state, validating hence the possibility that CD8+ Teff cells can counteract neighboring Tregs within inflamed tissues, by killing them. Alternatively, the disease activity score of a different subset of patients is correlated with the expansion of a peculiar subpopulation of autoreactive low avidity, partially-activated (pa)CD8+ T cells that, despite they conserve the conventional naïve (N) phenotype, produce high levels of tumor necrosis factor (TNF)-α and exhibit a gene expression signature of a progressive activation state. Tregs directly correlate with the expansion of this autoreactive (low avidity) paCD8+ TN cell subset in vivo, and efficiently control their differentiation rather their proliferation in vitro. Interestingly, autoreactive high avidity CD8+ Teff cells or low avidity paCD8+ TN cells are significantly expanded in RA patients who would become non-responders or patients who would become responders to TNF-α inhibitor therapy, respectively. These data provide evidence of a previously undescribed role of such mechanisms in the progression and therapy of RA.
  • Clinical significance and immunobiology of IL-21 in autoimmunity
    • Abstract: Publication date: Available online 14 February 2019Source: Journal of AutoimmunityAuthor(s): Di Long, Yongjian Chen, Haijing Wu, Ming Zhao, Qianjin Lu Interleukin-21 (IL-21), an autocrine cytokine predominantly produced by follicular helper T (Tfh) and T helper 17 (Th17) cells, has been proven to play an important role in the immune system, for example, by promoting proliferation and the development of Tfh and Th17 cells, balancing helper T cell subsets, inducing B cell generation and differentiation into plasma cells, and enhancing the production of immunoglobulin. These effects are mainly mediated by activation of the JAK/STAT, MAPK and PI3K pathways. Some IL-21 target genes, such as B lymphocyte induced maturation protein-1 (Blimp-1), suppressor of cytokine signaling (SOCS), CXCR5 and Bcl-6, play important roles in the immune response. Therefore, IL-21 has been linked to autoimmune diseases. Indeed, IL-21 levels are increased in the peripheral blood and tissues of patients with systematic lupus erythematosus (SLE), rheumatoid arthritis (RA), type 1 diabetes (T1D), immune thrombocytopenia (ITP), primary Sjogren's syndrome (pSS), autoimmune thyroid disease (AITD) and psoriasis. This increased IL-21 even positively associates with Tfh cells, plasma cells, autoantibodies and disease activity in SLE and RA. Additionally, IL-21 has been utilized as a therapeutic target in SLE, RA, T1D and psoriatic mouse models. Profoundly, clinical trials have shown safety and improvement in RA patients. However, tolerance and long-term pharmacodynamics effects with low bioavailability have been found in SLE patients. Therefore, this review aims to summarize the latest progress on IL-21 function and its signaling pathway and discuss the role of IL-21 in the pathogenesis of and therapy for autoimmune diseases, with the hope of providing potential therapeutic and diagnostic strategies for clinical use.
  • Autophagy promotes aortic adventitial fibrosis via the IL-6/Jak1 signaling
           pathway in Takayasu's arteritis
    • Abstract: Publication date: Available online 11 February 2019Source: Journal of AutoimmunityAuthor(s): Rongyi Chen, Ying Sun, Xiaomeng Cui, Zongfei Ji, Xiufang Kong, Sifan Wu, Qingrong Huang, Xiaoming Dai, Si Zhang, Lili Ma, Lindi Jiang BackgroundAutophagy is a ubiquitous and evolutionarily conserved self-rescue process. Studies have shown that autophagy is involved in the pathogenesis of multiple diseases; however, whether autophagy is associated with the pathogenesis of Takayasu's arteritis (TA), a large vessel idiopathic inflammatory disease characterized by vascular fibrosis, remains unclear. Moreover, although IL-6 is believed to be a direct target for TA treatment, anti-IL-6 treatment could not block TA-associated fibrosis in some cases, which impairs the aortic function of patients and can result in death. Thus, identify the mechanisms associated with TA is extremely important. Based on the relationship between autophagy and IL-6, we investigated the role of autophagy in the vascular fibrosis of TA induced by IL-6.MethodsAutophagy proteins (LC3 and Atg3), IL-6, and markers of fibrosis (collagen 1 and α-SMA) were detected in tissues with TA lesions via immunochemistry, immunofluorescence, and Western blot, respectively. Different stages of autophagy were analyzed by the specific inhibitors, 3-methyladenosine (early stage), hydroxychloroquine sulfate (late stage), and bafilomycin A1 (late stage). Autophagosomes were detected using electron microscopy and a viral-vector transfection assay. The fibrosis profiles induced by IL-6-dependent autophagy was assessed with an ELISA.ResultsThe expression of autophagy, IL-6, and fibrosis markers were elevated and correlated with each other in the adventitia tissues of TA patients. Furthermore, exogenous IL-6/IL-6Rα could significantly increase autophagy and fibrosis in vitro. An autophagy inhibitor was found to significantly block both autophagy and fibrosis induced by IL-6. Finally, IL-6 was found to significantly promote autophagy-induced fibrosis through the activation of the Jak1 pathway.ConclusionsIL-6-induced autophagy plays an important role in vascular fibrosis of TA. Targeting autophagy pathways might represent a novel therapeutic option for the treatment of TA.
  • Recruitment of CXCR3+ T cells into injured tissues in adult IgA vasculitis
           patients correlates with disease activity
    • Abstract: Publication date: Available online 8 February 2019Source: Journal of AutoimmunityAuthor(s): Alexandra Audemard-Verger, Evangéline Pillebout, Agnès Jamin, Laureline Berthelot, Cédric Aufray, Bruno Martin, Aurélie Sannier, Eric Daugas, Julie Déchanet-Merville, Yolande Richard, Renato Monteiro, Bruno Lucas ObjectivesAdult immunoglobulin A vasculitis (IgAV) is an immune complex small vessel vasculitis. So far, the involvement of T cells in this pathology has been poorly studied. The aim of this study was to analyze T-cell homeostasis as well as cytokine and chemokine concentrations in the blood and tissues of IgAV patients.MethodsT cells, cytokine and chemokine concentrations were analyzed in peripheral blood using flow cytometry and multiplex assays. T-cell infiltrates in the kidney and the skin were characterized by immunohistochemistry. This study prospectively included 44 adult patients with biopsy-proven IgAV and 24 age- and sex-matched healthy controls.ResultsWe observed reduced proportions of circulating CXCR5-and CXCR3-expressing memory CD4 T cells at diagnosis but normal values at remission. The plasma levels of Th1-related cytokines (IL-12, IL-27 and IFNγ) and of the TFH-related cytokine, IL-21, were paradoxically not reduced in patients. We observed increased plasma concentrations of the CXCR5 ligand, CXCL13, and of the CXCR3 ligands, CXCL10/11, suggesting a potential relocation of the corresponding T cells into inflamed tissues. We then confirmed the recruitment of CXCR3-expressing T cells into the skin and kidneys. In the skin, T-cell infiltrates mainly co-localized with damaged dermal small vessels. Finally, patients with the largest kidney T-cell infiltrates were also those with the highest proteinuria.ConclusionAltogether, our results strongly suggest that, in IgAV patients, CXCL10/11 orchestrate the recruitment of CXCR3-expressing T cells in injured tissues, contributing to tissue damage and disease activity.
  • Ischemic stroke in giant-cell arteritis: French retrospective study
    • Abstract: Publication date: Available online 5 February 2019Source: Journal of AutoimmunityAuthor(s): Aaron Pariente, Alexis Guédon, Sonia Alamowitch, Sara Thietart, Fabrice Carrat, Stephen Delorme, Jean Capron, Carlotta Cacciatore, Michael Soussan, Azeddine Dellal, Olivier Fain, Arsene Mekinian Acute cerebrovascular ischemic events are a rare and severe complication of giant cell arteritis (GCA). We aimed to determine the prevalence of GCA-related stroke, the overall survival and the relapse-free survival in patients with GCA.A multicentric retrospective analysis was performed on 129 patients with GCA diagnosed between September 2010 and October 2018 in two University Hospitals. Among 129 GCA patients, 18 (16%) presented an acute ischemic cerebrovascular event. Patients with stroke were older (83 [67–96] years versus 76 [58–96]; p = 0.014) and more frequently males (61% versus 30%; p = 0.014) than those without stroke. The frequency of anterior ischemic optic neuropathy was higher in patients with stroke (n = 6, 33%) than patients without stroke (n = 12, 11%)(p = 0.02). Overall survival was significantly decreased in GCA patients with stroke (4.4 months), comparatively to patients without stroke (221.7 months; log rank test = 0.006). The 3-years relapse-free survival was decreased in patients with stroke (8.42 versus78.0 months; log rank = 0.0001), as well as the time with sustained remission (78 versus 139 months; log rank test = 0.0004). This study shows the prevalence and risk factors of ischemic stroke in GCA.
  • Histologically proven AMA positive primary biliary cholangitis but normal
           serum alkaline phosphatase: Is alkaline phosphatase truly a surrogate
    • Abstract: Publication date: Available online 30 January 2019Source: Journal of AutoimmunityAuthor(s): Chunyan Sun, Xiao Xiao, Li Yan, Li Sheng, Qixia Wang, Pan Jiang, Min Lian, Yanmei Li, Yiran Wei, Jun Zhang, Yong Chen, Bo Li, You Li, Binyuan Huang, Yikang Li, Yanshen Peng, Xiaoyu Chen, Jingyuan Fang, Dekai Qiu, Jing Hua Background and aimsThe most highly directed and specific autoantibody in human immunopathology is the serologic hallmark of primary biliary cholangitis (PBC), antimitochondrial antibodies (AMAs). However the clinical significance of finding a positive AMA, with normal alkaline phosphatase (ALP) remains enigmatic.MethodsWe took advantage of 169 consecutive outpatients who were identified as having a positive AMA, but normal ALP levels between January 2012 and January 2018. A liver biopsy was performed on 67/169 of these AMA positive normal ALP patients.ResultsIn all 169 patients we reconfirmed the AMA and also performed anti-gp210 and anti-sp100, liver stiffness (LSM) assessed by vibration-controlled transient elastography (VCTE), an abdominal computed tomography (CT) scan, and either a magnetic resonance imaging (MRI) or ultrasound. The liver biopsies were reviewed by two unbiased observers. 87.6% of the 169 patients were females with a mean age of 46; the median AMA titer 1:320; an elevated serum IgM was found in 53.3%. Importantly, in patients with a liver biopsy, 55(82.1%)out of 67 had varying degrees of cholangitis activity, diagnostic of PBC.ConclusionIn patients who were AMA-positive but had normal ALP levels, more than 80% were associated with histological classic PBC. These data emphasize the importance of a positive AMA, even with a normal ALP and also question the role of ALP as a sole surrogate marker of cholangitis.
  • Neutrophil extracellular traps exert both pro- and anti-inflammatory
           actions in rheumatoid arthritis that are modulated by C1q and LL-37
    • Abstract: Publication date: Available online 28 January 2019Source: Journal of AutoimmunityAuthor(s): Matthieu Ribon, Sarra Seninet, Julie Mussard, Mireille Sebbag, Cyril Clavel, Guy Serre, Marie-Christophe Boissier, Luca Semerano, Patrice Decker ObjectiveNeutrophil extracellular traps (NET), produced by activated polymorphonuclear neutrophils (PMN), are supposed to play a role in the pathogenesis of rheumatoid arthritis (RA), a chronic inflammatory autoimmune disease characterized by anti-citrullinated protein antibodies (ACPA). Indeed, NET contain citrullinated autoantigens and some RA autoantibodies recognize NET. However, the mechanisms by which NET trigger or perpetuate the inflammatory process in RA are hitherto not elucidated. We hypothesized that, in addition to citrullination, NET might also contain stimulatory proteins and directly activate inflammatory target cells, as PMN and macrophages.MethodsNET antigenic and inflammatory properties were analyzed in 157 healthy donors (HD) and RA patients, the largest analysis reported so far. Primary PMN and monocyte-derived macrophages were isolated and immunoglobulin G (IgG) purified. NET were induced (NETosis), isolated and quantified. NET antigenicity was analyzed by fluorescence microscopy. PMN and macrophages were stimulated with NET with/without ACPA, C1q, LL-37 or lipopolysaccharide (LPS) and cell activation was estimated by flow cytometry and ELISA.ResultsPMN from RA patients produced more NET than HD PMN. We next dissected how NET mechanistically affect inflammatory cells. Particularly, we show for the first time that RA and HD NET activated both resting macrophages and PMN, but importantly RA NET were more stimulatory, leading to secretion of inflammatory cytokines and up-regulation of HLA/CD86/CD11b. IgG from ACPA-positive RA patients specifically recognized RA and even HD NET. Nevertheless, NET-induced cell activation occurs independently of immune complex formation with ACPA. Likewise, endosomal acidification was not required. Notably, we also report that complement C1q increased the NET stimulatory activity on macrophages only, due to higher expression of C1q receptors, which was further supported by the LL-37 antimicrobial peptide. In contrast, NET specifically inhibited interleukin (IL)-6 secretion by LPS-activated macrophages and not PMN, especially with C1q/LL-37. This inhibition was not mediated by NET-derived proteases or LPS neutralization and was associated with the simultaneous induction of IL-10 secretion.ConclusionWe show that NET possess both pro- and anti-inflammatory properties depending on target cells, their activation levels and C1q/LL-37. Thus, independently of ACPA, NET modulate RA chronic inflammation via this new dual activity we identified. In addition, NET may trigger autoimmunity in RA as ACPA recognize NET antigens but not non-activated PMN. Therefore, we conclude that excess of NETosis together with enhanced NET activity participate to RA pathogenesis at different levels.Graphical abstractDual activity of NET. Activated PMN enter NETosis in response to some stimuli. In RA, PMN are significantly more sensitive to NETosis triggering. These NET directly activate (pink arrows) steady state PMN (left) and macrophages (MΦ, right), leading to strong IL-8, TNF and IL-6 secretion (three important cytokines in RA) but low IL-10 induction, i.e. a pro-inflammatory profile. In addition, RA NET are significantly more stimulatory than normal NET. Although NET are recognized by ACPA, the resulting immune complexes do not clearly enhance PMN and MΦ response to NET. Likewise, endosomal TLR are probably not involved in NET sensing. Regarding MΦ, NET-induced activation is specifically increased in the presence of DNA-binding molecules like C1q and LL-37 (blue arrows). C1q in combination with LL-37 carry NET to PMN and MΦ which express surface C1q and LL-37 receptors (C1qR, LL-37-R). Because MΦ express much more C1qR than PMN, MΦ (and not PMN) activation by NET is enhanced by C1q or C1q/LL-37. On the contrary, NET induce an anti-inflammatory profile in strongly-activated MΦ but not PMN (green arrows). Indeed, NET specifically (partly) inhibit secretion of the pro-inflammatory cytokine IL-6 by MΦ in response to LPS, especially in the presence of both C1q and LL-37, and inversely enhance IL-10 secretion by those MΦ.Image 1
  • The microbiome and immunodeficiencies: Lessons from rare diseases
    • Abstract: Publication date: Available online 28 January 2019Source: Journal of AutoimmunityAuthor(s): Martina Pellicciotta, Rosita Rigoni, Emilia Liana Falcone, Steven M. Holland, Anna Villa, Barbara Cassani Primary immunodeficiencies (PIDs) are inherited disorders of the immune system, associated with a considerable increase in susceptibility to infections. PIDs can also predispose to malignancy, inflammation and autoimmunity. There is increasing awareness that some aspects of the immune dysregulation in PIDs may be linked to intestinal microbiota. Indeed, the gut microbiota and its metabolites have been shown to influence immune functions and immune homeostasis both locally and systemically. Recent studies have indicated that genetic defects causing PIDs lead to perturbations in the conventional mechanisms underlying homeostasis in the gut, resulting in poor immune surveillance at the intestinal barrier, which associates with altered intestinal permeability and bacterial translocation. Consistently, a substantial proportion of PID patients presents with clinically challenging IBD-like pathology. Here, we describe the current body of literature reporting on dysbiosis of the gut microbiota in different PIDs and how this can be either the result or cause of immune dysregulation. Further, we report how infections in PIDs enhance pathobionts colonization and speculate how, in turn, pathobionts may be responsible for increased disease susceptibility and secondary infections in these patients. The potential relationship between the microbial composition in the intestine and other sites, such as the oral cavity and skin, is also highlighted. Finally, we provide evidence, in preclinical models of PIDs, for the efficacy of microbiota manipulation to ameliorate disease complications, and suggest that the potential use of dietary intervention to correct dysbiotic flora in PID patients may hold promise.
  • PAM3 supports the generation of M2-like macrophages from lupus patient
           monocytes and improves disease outcome in murine lupus
    • Abstract: Publication date: Available online 22 January 2019Source: Journal of AutoimmunityAuthor(s): Begum Horuluoglu, Defne Bayik, Neslihan Kayraklioglu, Emilie Goguet, Mariana J. Kaplan, Dennis M. Klinman Systematic Lupus Erythematosus (SLE) is an autoimmune syndrome of unclear etiology. While T and B cell abnormalities contribute to disease pathogenesis, recent work suggests that inflammatory M1-like macrophages also play a role. Previous work showed that the TLR2/1 agonist PAM3CSK4 (PAM3) could stimulate normal human monocytes to preferentially differentiate into immunosuppressive M2-like rather than inflammatory M1-like macrophages. This raised the possibility of PAM3 being used to normalize the M1:M2 ratio in SLE. Consistent with that possibility, monocytes from lupus patients differentiated into M2-like macrophages when treated with PAM3 in vitro. Furthermore, lupus-prone NZB x NZW F1 mice responded similarly to weekly PAM3 treatment. Normalization of the M2 macrophage frequency was associated with delayed disease progression, decreased autoantibody and inflammatory cytokine synthesis, reduced proteinuria and prolonged survival in NZB x NZW F1 mice. The ability of PAM3 to bias monocyte differentiation in favor of immunosuppressive macrophages may represent a novel approach to the therapy of SLE.
  • The therapeutic potential of tuftsin-phosphorylcholine in giant cell
    • Abstract: Publication date: Available online 10 January 2019Source: Journal of AutoimmunityAuthor(s): Stefania Croci, Martina Bonacini, Francesco Muratore, Andrea Caruso, Antonio Fontana, Luigi Boiardi, Alessandra Soriano, Alberto Cavazza, Luca Cimino, Lucia Belloni, Ori Perry, Mati Fridkin, Maria Parmeggiani, Miri Blank, Yehuda Shoenfeld, Carlo Salvarani Tuftsin-PhosphorylCholine (TPC) is a novel bi-specific molecule which links tuftsin and phosphorylcholine. TPC has shown immunomodulatory activities in experimental mouse models of autoimmune diseases. We studied herein the effects of TPC ex vivo on both peripheral blood mononuclear cells (PBMCs) and temporal artery biopsies (TABs) obtained from patients with giant cell arteritis (GCA) and age-matched disease controls. GCA is an immune-mediated disease affecting large vessels. Levels of 18 cytokines in supernatants, PBMC viability, T helper (Th) cell differentiation of PBMCs and gene expression in TABs were analyzed. Treatment ex vivo with TPC decreased the production of IL-1β, IL-2, IL-5, IL-6, IL-9, IL-12(p70), IL-13, IL-17A, IL-18, IL-21, IL-22, IL-23, IFNγ, TNFα, GM-CSF by CD3/CD28 activated PBMCs whereas it negligibly affected cell viability. It reduced Th1 and Th17 differentiation while did not impact Th22 differentiation in PBMCs stimulated by phorbol 12-myristate 13-acetate plus ionomycin. In inflamed TABs, treatment with TPC down-regulated the production of IL-1β, IL-6, IL-13, IL-17A and CD68 gene expression. The effects of TPC were comparable to the effects of dexamethasone, included as the standard of care, with the exception of a greater reduction of IL-2, IL-18, IFNγ in CD3/CD28 activated PBMCs and CD68 gene in inflamed TABs. In conclusion our results warrant further investigations regarding TPC as an immunotherapeutic agent in GCA and potentially other autoimmune and inflammatory diseases.
  • Gut microbiota in children and altered profiles in juvenile idiopathic
    • Abstract: Publication date: Available online 9 January 2019Source: Journal of AutoimmunityAuthor(s): Carlotta De Filippo, Monica Di Paola, Teresa Giani, Francesca Tirelli, Rolando Cimaz Microbial diversity plays a key role in the maintenance of intestinal homeostasis and in the development of the immune system in the gut mucosa. Maybe one of the most important function of our gut microbiota is the immune system education, in particular the discrimination of friends from foes that occurs during childhood. In addition to bacterial antigens, several metabolites of microbial origin have a crucial role in training of the immune system, such as Short Chain Fatty Acids (SCFAs).There are many evidences on the role of the gut microbiota in rheumatic diseases, in particular modifications of microbiota composition causing dysbiosis that, in turn, can induce gut permeability, and thus immunological imbalance and trigger inflammation. In particular, immune cells can reach extra-intestinal sites, such as joints and trigger local inflammation. Childhood is a crucial period of life for development and evolution of the gut microbiota, especially for the acquisition of fundamental functions such as immunotolerance of commensal microorganisms. For this reason, gut dysbiosis is gaining interest as a potential pathogenetic factor for Juvenile Idiopathic Arthritis (JIA). Here we summarized the studies conducted on JIA patients in which a pro-arthritogenic microbial profiles has been observed; this, together with a depletion of microbial biodiversity, clearly distinguish patients' from healthy subjects' microbiota. Further studies are however needed to better clarify the role of microbiota in JIA pathogenesis.
  • Multi-faceted inhibition of dendritic cell function by CD4+Foxp3+
           regulatory T cells
    • Abstract: Publication date: Available online 5 January 2019Source: Journal of AutoimmunityAuthor(s): Christina Seitz, Sang Liu, Katrin Klocke, Anne-Laure Joly, Paulo V. Czarnewski, Christopher A. Tibbitt, Sara M. Parigi, Lisa S. Westerberg, Jonathan M. Coquet, Eduardo J. Villablanca, Kajsa Wing, John Andersson CTLA-4 is required for CD4+Foxp3+ regulatory T (Treg) cell function, but its mode of action remains incompletely defined. Herein we generated Ctla-4ex2fl/flFoxp3-Cre mice with Treg cells exclusively expressing a naturally occurring, ligand-independent isoform of CTLA-4 (liCTLA-4) that cannot interact with the costimulatory molecules CD80 and CD86. The mice did not exhibit any signs of effector T cell activation early in life, however, at 6 months of age they exhibited excessive T cell activation and inflammation in lungs. In contrast, mice with Treg cells completely lacking CTLA-4 developed lymphoproliferative disease characterized by multi-organ inflammation early in life. In vitro, Treg cells exclusively expressing liCTLA-4 inhibited CD80 and CD86 expression on dendritic cells (DC). Conversely, Treg cells required the extra-cellular part of CTLA-4 to up-regulate expression of the co-inhibitory molecule PD-L2 on DCs. Transcriptomic analysis of suppressed DCs revealed that Treg cells induced a specific immunosuppressive program in DCs.
  • NF-kB signaling in myeloid cells mediates the pathogenesis of
           immune-mediated nephritis
    • Abstract: Publication date: Available online 3 January 2019Source: Journal of AutoimmunityAuthor(s): Samantha A. Chalmers, Sayra J. Garcia, Joshua A. Reynolds, Leal Herlitz, Chaim Putterman Immune-mediated glomerulonephritis is a serious end organ pathology that commonly affects patients with systemic lupus erythematosus (SLE). A classic murine model used to study lupus nephritis (LN) is nephrotoxic serum nephritis (NTN), in which mice are passively transferred nephrotoxic antibodies. We have previously shown that macrophages are important in the pathogenesis of LN. To further investigate the mechanism by which macrophages contribute to the pathogenic process, and to determine if this contribution is mediated by NF-κB signaling, we created B6 mice which had RelA knocked out in myeloid cells, thus inhibiting classical NF-κB signaling in this cell lineage. We induced NTN in this strain to assess the importance of macrophage derived NF-κB signaling in contributing to disease progression.Myeloid cell RelA knock out (KO) mice injected with nephrotoxic serum had significantly attenuated proteinuria, lower BUN levels, and improved renal histopathology compared to control injected wildtype B6 mice (WT). Inhibiting myeloid NF-κB signaling also decreased inflammatory modulators within the kidneys. We found significant decreases of IL-1a, IFNg, and IL-6 in kidneys from KO mice, but higher IL-10 expression. Flow cytometry revealed decreased numbers of kidney infiltrating classically activated macrophages in KO mice as well.Our results indicate that macrophage NF-κB signaling is instrumental in the contribution of this cell type to the pathogenesis of NTN. While approaches which decrease macrophage numbers can be effective in immune mediated nephritis, more targeted treatments directed at modulating macrophage signaling and/or function could be beneficial, at least in the early stages of disease.
  • Role of NOD2 in antiphospholipid antibody-induced and bacterial MDP
           amplification of trophoblast inflammation
    • Abstract: Publication date: Available online 26 December 2018Source: Journal of AutoimmunityAuthor(s): Melissa J. Mulla, Monica C. Pasternak, Jane E. Salmon, Lawrence W. Chamley, Vikki M. Abrahams Women with antiphospholipid antibodies (aPL) are at high risk for pregnancy complications, such as preeclampsia. We previously demonstrated that aPL recognizing β2GPI promote an extravillous trophoblast pro-inflammatory, anti-migratory and anti-angiogenic profile similar to that seen in preeclampsia. Since preeclampsia in the absence of aPL may have an underlying infectious element, women with aPL may be at increased risk for preeclampsia or other adverse outcomes if an infection is present. Our objective was to determine the impact the common bacterial component, muramyl dipeptide (MDP), has on trophoblast responses to aPL. Herein, we report that bacterial MDP amplifies trophoblast IL-1β expression, processing, and secretion in the presence of aPL through activation of NOD2. In the absence of MDP, NOD2 also mediates anti- β2GPI antibody-induced trophoblast IL-1β and VEGF secretion. Additionally, we report a role for extravillous trophoblast vimentin as a novel danger signal that contributes to the aPL-induced trophoblast IL-1β production. Together our data indicate that NOD2 mediates trophoblast inflammatory and angiogenic responses to aPL alone, and mediates trophoblast inflammation in the presence of bacterial MDP. These findings suggest that a bacterial infection at the maternal-fetal interface may exacerbate the impact aPL have on trophoblast inflammation and, thus, on pregnancy outcome.Graphical abstractImage 1
  • Crosstalk between tumor necrosis factor-alpha signaling and aryl
           hydrocarbon receptor signaling in nuclear factor –kappa B activation: A
           possible molecular mechanism underlying the reduced efficacy of
           TNF-inhibitors in rheumatoid arthritis by smoking
    • Abstract: Publication date: Available online 25 December 2018Source: Journal of AutoimmunityAuthor(s): Takuro Nii, Kentaro Kuzuya, Daijiro Kabata, Toshihiro Matsui, Atsuko Murata, Takeshi Ohya, Hidetoshi Matsuoka, Takashi Shimizu, Eri Oguro, Yasutaka Okita, Chikako Udagawa, Maiko Yoshimura, Eriko Kudo-Tanaka, Satoru Teshigawara, Yoshinori Harada, Yuji Yoshida, Kentaro Isoda, So-Ichiro Tsuji, Shiro Ohshima, Jun Hashimoto ObjectivesTo examine the influence of smoking on biologics treatment against different therapeutic targets, such as TNFα, IL-6, and T cell, in rheumatoid arthritis (RA) and elucidate the underlying molecular mechanism.MethodsThe association between drug-discontinuation due to poor therapeutic response and smoking status was analyzed individually in biologics against different therapeutic targets by a multivariable logistic regression analysis using the “NinJa” Registry, one of the largest cohorts of Japanese RA patients. In vitro enhancement of TNFα-induced NF-κB activation and subsequent proinflammatory cytokine production by cigarette chemical components was examined by RT-PCR, qPCR, ELISA, and western blotting using an immortalized rheumatoid synovial cell line, MH7A.ResultsThe rate of drug-discontinuation due to poor therapeutic response was higher in the current smoking group than in the never- or ever-smoking groups (the odds ratio of current/never smoking: 2.189, 95%CI; 1.305–3.672,P = 0.003; current/ever: 1.580, 95%CI; 0.879–2.839,P = 0.126) in the TNF inhibitor (TNFi) treatment group. However, this tendency was not observed in either the IL-6 or T cell inhibitor treatment groups. Cigarette smoke chemical components, such as benzo[α]pyrene, known as aryl hydrocarbon receptor (AhR) ligands, themselves activated NF-κB and induced proinflammatory cytokines, IL-1β and IL-6. Furthermore, they also significantly enhanced TNFα-induced NF-κB activation and proinflammatory cytokine production. This enhancement was dominantly inhibited by Bay 11-7082, an NF-κB inhibitor.ConclusionsThese results suggest a crosstalk between TNFα signaling and AhR signaling in NF-κB activation which may constitute one of the molecular mechanisms underlying the higher incidence of drug-discontinuation in RA patients undergoing TNFi treatment with smoking habits.
  • Il-23/Th17 cell pathway: A promising target to alleviate thymic
           inflammation maintenance in myasthenia gravis
    • Abstract: Publication date: Available online 18 December 2018Source: Journal of AutoimmunityAuthor(s): José A. Villegas, Alexandra C. Bayer, Katia Ider, Jacky Bismuth, Frédérique Truffault, Régine Roussin, Nicola Santelmo, Rozen Le Panse, Sonia Berrih-Aknin, Nadine Dragin IL-23/Th17 pathway has been identified to sustain inflammatory condition in several autoimmune diseases and therefore being targeted in various therapeutic and effective approaches. Patients affected with autoimmune myasthenia gravis exhibit a disease effector tissue, the thymus, that harbors ectopic germinal centers that sustain production of auto-antibodies, targeting proteins located in the neuromuscular junction, cause of the organ-specific chronic autoimmune disease.The present study aims to investigate the IL-23/Th17 cell pathway in the thymic inflammatory and pathogenic events.We found that thymuses of MG patients displayed overexpression of Interleukin-17, signature cytokine of activated Th17 cells. This activation was sustained by a higher secretion of Interleukin-23 by TEC, in addition to the increased expression of cytokines involved in Th17 cell development. The overexpression of Interleukin-23 was due to a dysregulation of interferon type I pathway. Besides, Interleukin-17 secreted, and Th17 cells were localized around thymic ectopic germinal centers. These cells expressed podoplanin, a protein involved in B-cell maturation and antibody secretion. Finally, production of Interleukin-23 was also promoted by Interleukin-17 secreted itself by Th17 cells, highlighting a chronic loop of inflammation sustained by thymic cell interaction.Activation of the IL-23/Th17 pathway in the thymus of autoimmune myasthenia gravis patients creates an unstoppable loop of inflammation that may participate in ectopic germinal center maintenance. To alleviate the physio-pathological events in myasthenia gravis patients, this pathway may be considered as a new therapeutic target.
  • Alopecia areata: A multifactorial autoimmune condition
    • Abstract: Publication date: Available online 15 December 2018Source: Journal of AutoimmunityAuthor(s): Teontor Simakou, John P. Butcher, Stuart Reid, Fiona L. Henriquez Alopecia areata is an autoimmune disease that results in non-scarring hair loss, and it is clinically characterised by small patches of baldness on the scalp and/or around the body. It can later progress to total loss of scalp hair (Alopecia totalis) and/or total loss of all body hair (Alopecia universalis). The rapid rate of hair loss and disfiguration caused by the condition causes anxiety on patients and increases the risks of developing psychological and psychiatric complications. Hair loss in alopecia areata is caused by lymphocytic infiltrations around the hair follicles and IFN-γ. IgG antibodies against the hair follicle cells are also found in alopecia areata sufferers. In addition, the disease coexists with other autoimmune disorders and can come secondary to infections or inflammation. However, despite the growing knowledge about alopecia areata, the aetiology and pathophysiology of disease are not well defined. In this review we discuss various genetic and environmental factors that cause autoimmunity and describe the immune mechanisms that lead to hair loss in alopecia areata patients.
  • Germinal center humoral autoimmunity independently mediates progression of
           allograft vasculopathy
    • Abstract: Publication date: Available online 7 December 2018Source: Journal of AutoimmunityAuthor(s): M. Saeed Qureshi, Jawaher Alsughayyir, Manu Chhabra, Jason M. Ali, Martin J. Goddard, Chris Devine, Thomas M. Conlon, Michelle A. Linterman, Reza Motallebzadeh, Gavin J. Pettigrew The development of humoral autoimmunity following organ transplantation is increasingly recognised, but of uncertain significance. We examine whether autoimmunity contributes independently to allograft rejection.In a MHC class II-mismatched murine model of chronic humoral rejection, we report that effector antinuclear autoantibody responses were initiated upon graft-versus-host allorecognition of recipient B cells by donor CD4 T-cells transferred within heart allografts. Consequently, grafts were rejected more rapidly, and with markedly augmented autoantibody responses, upon transplantation of hearts from donors previously primed against recipient. Nevertheless, rejection was dependent upon recipient T follicular helper (TFH) cell differentiation and provision of cognate (peptide-specific) help for maintenance as long-lived GC reactions, which diversified to encompass responses against vimentin autoantigen. Heart grafts transplanted into stable donor/recipient mixed haematopoietic chimeras, or from parental strain donors into F1 recipients (neither of which can trigger host adaptive alloimmune responses), nevertheless provoked GC autoimmunity and were rejected chronically, with rejection similarly dependent upon host TFH cell differentiation.Thus, autoantibody responses contribute independently of host adaptive alloimmunity to graft rejection, but require host TFH cell differentiation to maintain long-lived GC responses. The demonstration that one population of helper CD4 T-cells initiates humoral autoimmunity, but that a second population of TFH cells is required for its maintenance as a GC reaction, has important implications for how autoimmune-related phenomena manifest.
  • Targeting interferon activity to dendritic cells enables in vivo
           tolerization and protection against EAE in mice
    • Abstract: Publication date: Available online 19 November 2018Source: Journal of AutoimmunityAuthor(s): Anje Cauwels, Sandra Van Lint, Dominiek Catteeuw, Shengru Pang, Franciane Paul, Elke Rogge, Annick Verhee, Marco Prinz, Niko Kley, Gilles Uzé, Jan Tavernier Type I Interferon (IFN) is widely used for multiple sclerosis (MS) treatment, but its side effects are limiting and its mechanism of action still unknown. Furthermore, 30–50% of MS patients are unresponsive, and IFN can even induce relapses. Fundamental understanding of the cellular target(s) of IFN will help to optimize treatments by reducing side effects and separating beneficial from detrimental effects. To improve clinical systemic IFN usage, we are developing AcTaferons (Activity-on-Target IFNs = AFNs), optimized IFN-based immunocytokines that allow cell-specific targeting.In experimental autoimmune encephalitis (EAE) in mice, high dose WT mIFNα could delay disease, but caused mortality and severe hematological deficits. In contrast, AFN targeted to dendritic cells (DC, via Clec9A) protected without mortality or hematological consequences. Conversely, CD8-targeted AFN did not protect and exacerbated weight loss, indicating the presence of both protective and unfavorable IFN effects in EAE. Comparing Clec9A-, XCR1-and SiglecH-targeting, we found that targeting AFN to plasmacytoid (p) and conventional (c) DC is superior and non-toxic compared to WT mIFN. DC-targeted AFN increased pDC numbers and their tolerogenic potential, evidenced by increased TGFβ and IDO synthesis and regulatory T cell induction. In addition, both regulatory T and B cells produced significantly more immunosuppressive TGFβ and IL-10.In conclusion, specific DC-targeting of IFN activity induces a robust in vivo tolerization, efficiently protecting against EAE, without noticeable side effects. Thus, dissecting positive and negative IFN effects via cell-specific targeting may result in better and safer MS therapy and response rates.
  • Cluster analysis of autoimmune rheumatic diseases based on autoantibodies.
           New insights for polyautoimmunity
    • Abstract: Publication date: Available online 17 November 2018Source: Journal of AutoimmunityAuthor(s): Nicolás Molano-González, Manuel Rojas, Diana M. Monsalve, Yovana Pacheco, Yeny Acosta-Ampudia, Yhojan Rodríguez, Monica Rodríguez-Jimenez, Carolina Ramírez-Santana, Juan-Manuel Anaya Autoimmune diseases (ADs) are a chronic and clinically heterogeneous group of diseases characterized by share common immunopathogenic mechanisms and risk factors (i.e., the autoimmune tautology), which explain the fact that one AD may coexist with others (i.e., polyautoimmunity - PolyA). In the present exploratory study, a mixed-cluster analysis of the most common autoimmune rheumatic diseases (ARDs) was done. A total of 187 consecutive women with established systemic lupus erythematosus (n = 70), rheumatoid arthritis (n = 51), systemic sclerosis (n = 35) and Sjögren's syndrome (n = 31) were included. A comprehensive clinical, autoantibody and cytokine assessment was simultaneously done. Total PolyA was registered in 142 (75.9%) patients. Six clusters were obtained, built mainly on autoantibodies: PolyA-I to -VI. The PolyA-III cluster showed the highest frequency of overt PolyA (p = 0.01), and the PolyA-I, -III, and -IV clusters exhibited the highest positivity for IL-12/23p40 (p = 0.015). These results provide new insights into the pathophysiology of PolyA and warrant prospective validation to enable development of a more accurate taxonomy of ARDs.
  • A multi-epitope DNA vaccine enables a broad engagement of diabetogenic T
           cells for tolerance in Type 1 diabetes
    • Abstract: Publication date: Available online 17 November 2018Source: Journal of AutoimmunityAuthor(s): Jorge Postigo-Fernandez, Rémi J. Creusot Type 1 diabetes (T1D) is caused by diabetogenic T cells that evaded tolerance mechanisms and react against multiple β-cell antigens. Antigen-specific therapy to reinstate tolerance (typically using a single β-cell antigen) has so far proved unsuccessful in T1D patients. Plasmid DNA (pDNA)-mediated expression of proinsulin has demonstrated transient protection in clinical trials, but long-lasting tolerance is yet to be achieved. We aimed to address whether pDNA delivery of multiple epitopes/mimotopes from several β-cell antigens efficiently presented to CD4+ and CD8+ T cells could also induce tolerance. This approach significantly delayed T1D development, while co-delivery of pDNA vectors expressing four full antigens protected more mice. Delivery of multiple epitopes resulted in a broad engagement of specific T cells, eliciting a response distinct from endogenous epitopes draining from islets. T-cell phenotypes also varied with antigen specificity. Unexpectedly, the repertoire of T cells reactive to the same epitope was highly polyclonal. Despite induction of some CD25+ Foxp3+ regulatory T cells, protection from disease did not persist after treatment discontinuation. These data demonstrate that epitope-based tolerogenic DNA vaccines constitute effective precision medicine tools to target a broad range of specific CD4+ and CD8+ diabetogenic T-cell populations for prevention or treatment of T1D.
  • 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.
  • 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.
  • 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 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.
  • 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
  • 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.
  • 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.
  • 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
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
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