Autoimmunity to stromal-derived autoantigens in rheumatoid ectopic germinal centers exacerbates arthritis and affects clinical response
Elisa Corsiero, … , Costantino Pitzalis, Michele Bombardieri
Elisa Corsiero, … , Costantino Pitzalis, Michele Bombardieri
Published June 17, 2024
Citation Information: J Clin Invest. 2024;134(12):e169754. https://doi.org/10.1172/JCI169754.
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Research Article Autoimmunity

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

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.

Authors

Elisa Corsiero, Mattia Caliste, Lucas Jagemann, Liliane Fossati-Jimack, Katriona Goldmann, Cankut Cubuk, Giulia M. Ghirardi, Edoardo Prediletto, Felice Rivellese, Cristiano Alessandri, Mark Hopkinson, Behzad Javaheri, Andrew A. Pitsillides, Myles J. Lewis, Costantino Pitzalis, Michele Bombardieri

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Figure 5

Expression of anti-HSP60 antibodies in serum and SF of patients with RA or OA.

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Expression of anti-HSP60 antibodies in serum and SF of patients with RA ...
(A) Graphs show the correlation of matching RA SF IgG, IgM, and IgA binding to HSP60 with RA sera IgG, IgM, and IgA binding to HSP60. (B) Box plots display the levels of IgG, IgM, and IgA anti-HSP60 antibodies in SF of RA (n = 20) versus OA (n = 11) patients. (C) Scattered dot plots show IgG, IgM, and IgA binding to HSP60 in SF and sera of ACPA+ versus ACPA– RA patients. For B and C, the results are expressed as absorbance at 450 nm, and each data point represents an individual patient. *P < 0.05, **P < 0.01, and ****P < 0.0001, by Mann-Whitney U test.