Neutralizing Anti-Interleukin-1 Receptor-Antagonist Autoantibodies Induce Inflammatory and Fibrotic Mediators in IgG4-Related Disease. The Journal of allergy and clinical immunology Jarrell, J. A., Baker, M. C., Perugino, C. A., Liu, H., Bloom, M. S., Maehara, T., Wong, H. H., Lanz, T., Adamska, J. Z., Kongpachith, S., Sokolove, J., Stone, J. H., Pillai, S. S., Robinson, W. H. 2021


BACKGROUND: IgG4-related disease (IgG4-RD) is a fibro-inflammatory 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: 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 monoclonal antibodies (mAb) were expressed and their specificities characterized using cytokine microarrays. The role of anti-interleukin-1 receptor-antagonist (IL-1RA) autoantibodies was investigated using in vitro assays.RESULTS: We identified strong reactivity against human IL-1RA using a clonally-expanded plasmablast-derived mAb from a patient with IgG4-RD. IgG4-RD patient plasma exhibited elevated levels of reactivity against IL-1RA compared to controls and neutralized IL-1RA activity, resulting in inflammatory and fibrotic mediator production in vitro. IL-1RA was detected in lesional tissues from IgG4-RD patients. Patients with anti-IL-1RA autoantibodies of the IgG4 subclass had greater numbers of organs affected than 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 to controls.CONCLUSION: A subset of patients with IgG4-RD have anti-IL-1RA autoantibodies, which promote pro-inflammatory and pro-fibrotic meditator production via IL-1RA neutralization. These findings support a novel immunological 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.

View details for DOI 10.1016/j.jaci.2021.05.002

View details for PubMedID 33974929