Neutralizing anti–IL-1 receptor antagonist autoantibodies induce inflammatory and fibrotic mediators in IgG4-related disease - 05/01/22
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.
Le texte complet de cet article est disponible en PDF.Key words : IL-1 receptor antagonist, cytokine, IgG4-related disease, lupus, rheumatoid arthritis, autoimmune disease, autoantibodies, plasmablast, sequencing
Abbreviations used : G-CSF, HC, IgG4-RD, IL-1R, IL1-RA, MS, pAb, RA, SEAP, SLE
Plan
| Supported by grants from the Stanford Graduate Fellowship (to J.A.J.), the Rheumatology Research Foundation (to M.C.B. and C.A.P.), and the National Institutes of Health (grants T32AI07290 [to J.A.J.], 2T32AR050942-11 [to M.C.B.], T32AR007258 [to C.A.P.], UM1 AI1144295 [to J.H.S.], U19 AI110495 [to S.S.P.], and R01AR06367604 and U19AI11049103 [to W.H.R.]). |
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| Disclosure of potential conflict of interest: W. Robinson is a founder, member of the board of directors, and consultant to Atreca, Inc. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 149 - N° 1
P. 358-368 - janvier 2022 Retour au numéro
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