| Title: |
Autoimmunity to stromal-derived autoantigens in rheumatoid ectopic germinal centers exacerbates arthritis and affects clinical response |
| Authors: |
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 |
| Contributors: |
Corsiero, Elisa; Caliste, Mattia; Jagemann, Luca; 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 |
| Publisher Information: |
American Society for Clinical Investigation |
| Publication Year: |
2024 |
| Collection: |
Sapienza Università di Roma: CINECA IRIS |
| Subject Terms: |
autoimmune disease; autoimmunity; immunoglobulin; rheumatology |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/38950333; info:eu-repo/semantics/altIdentifier/wos/WOS:001250253600003; volume:134; issue:12; numberofpages:12; journal:THE JOURNAL OF CLINICAL INVESTIGATION; https://hdl.handle.net/11573/1715832 |
| DOI: |
10.1172/jci169754 |
| Availability: |
https://hdl.handle.net/11573/1715832; https://doi.org/10.1172/jci169754 |
| Rights: |
info:eu-repo/semantics/openAccess |
| Accession Number: |
edsbas.1E07494D |
| Database: |
BASE |