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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.
Afiliación
  • Corsiero E; Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London (QMUL), London, United Kingdom.
  • Caliste M; Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London (QMUL), London, United Kingdom.
  • Jagemann L; Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London (QMUL), London, United Kingdom.
  • Fossati-Jimack L; Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London (QMUL), London, United Kingdom.
  • Goldmann K; Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London (QMUL), London, United Kingdom.
  • Cubuk C; Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London (QMUL), London, United Kingdom.
  • Ghirardi GM; Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London (QMUL), London, United Kingdom.
  • Prediletto E; Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London (QMUL), London, United Kingdom.
  • Rivellese F; Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London (QMUL), London, United Kingdom.
  • Alessandri C; Arthritis Center, Department of Clinical, Internal Medicine, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy.
  • Hopkinson M; Comparative Biomedical Sciences Centre, Royal Veterinary College, London, United Kingdom.
  • Javaheri B; Comparative Biomedical Sciences Centre, Royal Veterinary College, London, United Kingdom.
  • Pitsillides AA; Comparative Biomedical Sciences Centre, Royal Veterinary College, London, United Kingdom.
  • Lewis MJ; Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London (QMUL), London, United Kingdom.
  • Pitzalis C; Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London (QMUL), London, United Kingdom.
  • Bombardieri M; IRCCS Istituto Clinico Humanitas Via Manzoni, Rozzano (Milano), Italy.
J Clin Invest ; 134(12)2024 Apr 30.
Article en En | MEDLINE | ID: mdl-38950333
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Artritis Reumatoide / Autoantígenos / Chaperonina 60 / Centro Germinal Límite: Animals / Female / Humans / Male Idioma: En Revista: J Clin Invest Año: 2024 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Artritis Reumatoide / Autoantígenos / Chaperonina 60 / Centro Germinal Límite: Animals / Female / Humans / Male Idioma: En Revista: J Clin Invest Año: 2024 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Estados Unidos