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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 Article has an altmetric score of 1

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

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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 3

Effect of anti-FLS RA-rmAbs in CIA.

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Effect of anti-FLS RA-rmAbs in CIA.
(A) Graph shows the arthritis scores...
(A) Graph shows the arthritis scores for CIA DBA/1 mice treated i.p. with anti-FLS rmAbs (n = 20), PBS (controls, n = 40), and anti-histone rmAbs (n = 20). Anti-FLS rmAbs were administered on days 17, 28, 38, and 49. The anti-FLS rmAbs cocktail consisted of RA056/11.76.1, RA057/11.35.1, and RA057/11.89.1 antibodies. The anti-histone rmAbs cocktail consisted of RA015/11.58, RA015/11.88, and RA015/11.91 antibodies. Results are from 2 independent experiments. The scores are reported as the mean of the sum of the score ± SEM assessed for each paw of the mouse. The P values correspond to the treatment × time element from the ANOVA linear model between groups. (B) Representative IHC (top) and safranin-O (SO) (bottom) images of control- and anti-FLS–treated mice. Scale bars: 2.5 mm. Original magnification, ×1.5 (enlarged insets, control) and ×23 (anti-FLS). (C) Representative μCT scan of a hind paw from a CIA mouse and the scoring system used to evaluate bone erosion (erosion score). The score was given for each digit (color-coded area), with a maximum score of 24. 0 = normal; 1 = signs of pathological bone changes; 2 = heavy pathological bone changes. (D) Representative μCT scan images of control-treated, anti-FLS–treated (n = 5) and anti-histone–treated (n = 5) mice. (E) Graph shows the μCT erosion score for CIA DBA/1 mice treated with PBS, anti-FLS RA-rmAbs, or anti-histone RA-rmAbs. Five representative hind paws were used for each group. The scoring was done blindly by 3 independent evaluators and is reported as the mean of the sum ± SEM. *P < 0.05 and **P < 0.01, by 1-way ANOVA with multiple comparisons.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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