Autoimmunity to stromal-derived autoantigens in rheumatoid ectopic germinal centers exacerbates arthritis and affects clinical response

Corsiero, E; Caliste, M; Jagemann, L; Fossati-Jimack, L; Goldmann, K; Cubuk, C; Ghirardi, GM; Prediletto, E; Rivellese, F; Alessandri, C; Hopkinson, M; Javaheri, B; Pitsillides, AA; Lewis, MJ; Pitzalis, C; Bombardieri, M

Abstract

Ectopic lymphoid structures (ELSs) in the rheumatoid synovial joints sustain autoreactivity against locally expressed autoantigens. We recently identified recombinant monoclonal antibodies (RA-rmAbs) derived from single, locally differentiated rheumatoid arthritis (RA) synovial B cells, which specifically recognize fibroblast -like synoviocytes (FLSs). Here, we aimed to identify the specificity of FLS-derived autoantigens fueling local autoimmunity and the functional role of anti-FLS antibodies in promoting chronic inflammation. A subset of anti-FLS RA-rmAbs reacting with a 60 kDa band from FLS extracts demonstrated specificity for HSP60 and partial cross -reactivity to other stromal autoantigens (i.e., calreticulin/ vimentin) but not to citrullinated fibrinogen. Anti-FLS RA-rmAbs, but not anti-neutrophil extracellular traps rmAbs, exhibited pathogenic properties in a mouse model of collagen -induced arthritis. In patients, anti-HSP60 antibodies were preferentially detected in RA versus osteoarthritis (OA) synovial fluid. Synovial HSPD1 and CALR gene expression analyzed using bulk RNA-Seq and GeoMx-DSP closely correlated with the lympho-myeloid RA pathotype, and HSP60 protein expression was predominantly observed around ELS. Moreover, we observed a significant reduction in synovial HSP60 gene expression followed B cell depletion with rituximab that was strongly associated with the treatment response. Overall, we report that synovial stromal-derived autoantigens are targeted by pathogenic autoantibodies and are associated with specific RA pathotypes, with potential value for patient stratification and as predictors of the response to B cell-depleting therapies.

Citation

Corsiero, E., Caliste, M., Jagemann, L., Fossati-Jimack, L., Goldmann, K., Cubuk, C., …Bombardieri, M. (2024). Autoimmunity to stromal-derived autoantigens in rheumatoid ectopic germinal centers exacerbates arthritis and affects clinical response. Journal of Clinical Investigation, 134(12), https://doi.org/10.1172/JCI169754

• Journal Article Type: Article
• Acceptance Date: Apr 23, 2024
• Online Publication Date: Jun 17, 2024
• Publication Date: 2024
• Deposit Date: Jul 25, 2024
• Publicly Available Date: Jul 25, 2024
• Print ISSN: 0021-9738
• Electronic ISSN: 1558-8238
• Publisher: American Society for Clinical Investigation
• Peer Reviewed: Peer Reviewed
• Volume: 134
• Issue: 12
• DOI: https://doi.org/10.1172/JCI169754
• Keywords: HEAT-SHOCK-PROTEIN; MONOCLONAL-ANTIBODIES; SYNOVIAL FIBROBLASTS; CELLS; EXPRESSION; COLOCALIZATION; PATHOGENESIS; RECOGNITION