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.

Autoimmunity to stromal-derived autoantigens in rheumatoid ectopic germinal centers exacerbates arthritis and affects clinical response / Corsiero, Elisa; Caliste, Mattia; Jagemann, Lucas; Fossati-Jimack, Liliane; Goldmann, Katriona; Cubuk, Cankut; Ghirardi, Giulia M.; Prediletto, Edoardo; Rivellese, Felice; Alessandri, Cristiano; Hopkinson, Mark; Javaheri, Behzad; Pitsillides, Andrew A.; Lewis, Myles J.; Pitzalis, Costantino; Bombardieri, Michele. - In: THE JOURNAL OF CLINICAL INVESTIGATION. - ISSN 1558-8238. - 134:12(2024). [10.1172/jci169754]

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

Caliste, Mattia;Alessandri, Cristiano;Bombardieri, Michele
2024

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.
2024
autoimmune diseases; autoimmunity; immunoglobulins; rheumatology
01 Pubblicazione su rivista::01a Articolo in rivista
Autoimmunity to stromal-derived autoantigens in rheumatoid ectopic germinal centers exacerbates arthritis and affects clinical response / Corsiero, Elisa; Caliste, Mattia; Jagemann, Lucas; Fossati-Jimack, Liliane; Goldmann, Katriona; Cubuk, Cankut; Ghirardi, Giulia M.; Prediletto, Edoardo; Rivellese, Felice; Alessandri, Cristiano; Hopkinson, Mark; Javaheri, Behzad; Pitsillides, Andrew A.; Lewis, Myles J.; Pitzalis, Costantino; Bombardieri, Michele. - In: THE JOURNAL OF CLINICAL INVESTIGATION. - ISSN 1558-8238. - 134:12(2024). [10.1172/jci169754]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1715832
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