Justin A Jarrell1, Matthew C Baker2, Cory A Perugino3, Hang Liu3, Michelle S Bloom1, Takashi Maehara3, Heidi H Wong1, Tobias V Lanz4, Julia Z Adamska1, Sarah Kongpachith1, Jeremy Sokolove1, John H Stone3, Shiv S Pillai3, William H Robinson5. 1. Department of Medicine, Division of Immunology and Rheumatology, Stanford University, Stanford, Calif; Institute for Immunity, Transplant and Infection, Stanford University, Stanford, Calif; VA Palo Alto Health Care System, Palo Alto, Calif. 2. Department of Medicine, Division of Immunology and Rheumatology, Stanford University, Stanford, Calif. 3. Massachusetts General Hospital, Harvard Medical School, Boston, Mass. 4. Department of Medicine, Division of Immunology and Rheumatology, Stanford University, Stanford, Calif; Institute for Immunity, Transplant and Infection, Stanford University, Stanford, Calif; VA Palo Alto Health Care System, Palo Alto, Calif; Department of Neurology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. 5. Department of Medicine, Division of Immunology and Rheumatology, Stanford University, Stanford, Calif; Institute for Immunity, Transplant and Infection, Stanford University, Stanford, Calif; VA Palo Alto Health Care System, Palo Alto, Calif. Electronic address: w.robinson@stanford.edu.
Abstract
BACKGROUND: IgG4-related disease (IgG4-RD) is a fibroinflammatory condition involving loss of B-cell tolerance and production of autoantibodies. However, the relevant targets and role of these aberrant humoral immune responses are not defined. OBJECTIVE: Our aim was to identify novel autoantibodies and autoantigen targets that promote pathogenic responses in IgG4-RD. METHODS: We sequenced plasmablast antibody repertoires in patients with IgG4-RD. Representative mAbs were expressed and their specificities characterized by using cytokine microarrays. The role of anti-IL-1 receptor antagonist (IL-1RA) autoantibodies was investigated by using in vitro assays. RESULTS: We identified strong reactivity against human IL-1RA by using a clonally expanded plasmablast-derived mAb from a patient with IgG4-RD. Plasma from patients with IgG4-RD exhibited elevated levels of reactivity against IL-1RA compared with plasma from the controls and neutralized IL-1RA activity, resulting in inflammatory and fibrotic mediator production in vitro. IL-1RA was detected in lesional tissues from patients with IgG4-RD. Patients with anti-IL-1RA autoantibodies of the IgG4 subclass had greater numbers of organs affected than did those without anti-IL-1RA autoantibodies. Peptide analyses identified IL-1RA epitopes targeted by anti-IL-1RA antibodies at sites near the IL-1RA/IL-1R interface. Serum from patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) also had elevated levels of anti-IL-1RA autoantibodies compared with those of the controls. CONCLUSION: A subset of patients with IgG4-RD have anti-IL-1RA autoantibodies, which promote proinflammatory and profibrotic meditator production via IL-1RA neutralization. These findings support a novel immunologic mechanism underlying the pathogenesis of IgG4-RD. Anti-IL-1RA autoantibodies are also present in a subset of patients with SLE and RA, suggesting a potential common pathway in multiple autoimmune diseases.
BACKGROUND: IgG4-related disease (IgG4-RD) is a fibroinflammatory condition involving loss of B-cell tolerance and production of autoantibodies. However, the relevant targets and role of these aberrant humoral immune responses are not defined. OBJECTIVE: Our aim was to identify novel autoantibodies and autoantigen targets that promote pathogenic responses in IgG4-RD. METHODS: We sequenced plasmablast antibody repertoires in patients with IgG4-RD. Representative mAbs were expressed and their specificities characterized by using cytokine microarrays. The role of anti-IL-1 receptor antagonist (IL-1RA) autoantibodies was investigated by using in vitro assays. RESULTS: We identified strong reactivity against human IL-1RA by using a clonally expanded plasmablast-derived mAb from a patient with IgG4-RD. Plasma from patients with IgG4-RD exhibited elevated levels of reactivity against IL-1RA compared with plasma from the controls and neutralized IL-1RA activity, resulting in inflammatory and fibrotic mediator production in vitro. IL-1RA was detected in lesional tissues from patients with IgG4-RD. Patients with anti-IL-1RA autoantibodies of the IgG4 subclass had greater numbers of organs affected than did those without anti-IL-1RA autoantibodies. Peptide analyses identified IL-1RA epitopes targeted by anti-IL-1RA antibodies at sites near the IL-1RA/IL-1R interface. Serum from patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) also had elevated levels of anti-IL-1RA autoantibodies compared with those of the controls. CONCLUSION: A subset of patients with IgG4-RD have anti-IL-1RA autoantibodies, which promote proinflammatory and profibrotic meditator production via IL-1RA neutralization. These findings support a novel immunologic mechanism underlying the pathogenesis of IgG4-RD. Anti-IL-1RA autoantibodies are also present in a subset of patients with SLE and RA, suggesting a potential common pathway in multiple autoimmune diseases.
Authors: Stan F J van de Graaf; Ulrich Beuers; Lowiek M Hubers; Harmjan Vos; Alex R Schuurman; Robin Erken; Ronald P Oude Elferink; Boudewijn Burgering Journal: Gut Date: 2017-08-01 Impact factor: 23.059
Authors: Jiachen Liu; Wei Yin; Lisa S Westerberg; Pamela Lee; Quan Gong; Yan Chen; Lingli Dong; Chaohong Liu Journal: Front Immunol Date: 2021-09-01 Impact factor: 7.561
Authors: Jochen Pfeifer; Bernhard Thurner; Christoph Kessel; Natalie Fadle; Parastoo Kheiroddin; Evi Regitz; Marie-Christin Hoffmann; Igor Age Kos; Klaus-Dieter Preuss; Yvan Fischer; Klaus Roemer; Stefan Lohse; Kristina Heyne; Marie-Claire Detemple; Michael Fedlmeier; Hendrik Juenger; Harald Sauer; Sascha Meyer; Tilman Rohrer; Helmut Wittkowski; Sören L Becker; Katja Masjosthusmann; Robert Bals; Stephan Gerling; Sigrun Smola; Moritz Bewarder; Einat Birk; Andre Keren; Michael Böhm; André Jakob; Hashim Abdul-Khaliq; Jordi Anton; Michael Kabesch; Rosa Maria Pino-Ramirez; Dirk Foell; Lorenz Thurner Journal: Lancet Rheumatol Date: 2022-03-29