Objectives Mast cells (MCs) are involved in the pathogenesis of rheumatoid arthritis (RA). However, their contribution remains controversial. To establish their role in RA, we analysed their presence in the synovium of treatment-naïve patients with early RA and their association and functional relationship with histological features of synovitis.
Methods Synovial tissue was obtained by ultrasound-guided biopsy from treatment-naïve patients with early RA (n=99). Immune cells (CD3/CD20/CD138/CD68) and their relationship with CD117+MCs in synovial tissue were analysed by immunohistochemistry (IHC) and immunofluorescence (IF). The functional involvement of MCs in ectopic lymphoid structures (ELS) was investigated in vitro, by coculturing MCs with naïve B cells and anticitrullinated protein antibodies (ACPA)-producing B cell clones, and in vivo in interleukin-27 receptor alpha (IL27ra)-deficient and control mice during antigen-induced arthritis (AIA).
Results High synovial MC counts are associated with local and systemic inflammation, autoantibody positivity and high disease activity. IHC/IF showed that MCs reside at the outer border of lymphoid aggregates. Furthermore, human MCs promote the activation and differentiation of naïve B cells and induce the production of ACPA, mainly via contact-dependent interactions. In AIA, synovial MC numbers increase in IL27ra deficient mice, in association with ELS and worse disease activity.
Conclusions Synovial MCs identify early RA patients with a severe clinical form of synovitis characterised by the presence of ELS.
- early rheumatoid arthritis
- B cells
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Handling editor Josef S Smolen
Contributors FR: study design, experiments, data acquisition, data analysis, manuscript preparation and revision; DM: study design, experiments, data acquisition and data analysis; LF-J and GWJ: experiments, data acquisition and data analysis (animal data); SP and TM: experiments and data acquisition; AN and FH: data acquisition and data analysis (clinical data); AR, SR, FASK, REMT, GS, SAJ , FWR, AdP, GM and MEMES: interpretation of experimental results and manuscript revision; CP: study design, interpretation of experimental results, manuscript preparation and revision. FR wrote the manuscript, and all authors critically revised its final preparation and approved its submission.
Funding The research leading to these results has received funding from the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007 2013) under REA grant agreement n° 608765. This work was supported in part by grants from the Ministero dell’Istruzione, Università e Ricerca (MIUR) and Regione Campania CISILab Project, CRÈME Project, and TIMING Project. The Pathobiology of Early Arthritis Cohort (PEAC) was funded by the MRC grant 36661. Additional funding from MRC funded Maximising Therapeutic Utility for Rheumatoid Arthritis using genetic and genomic tissue responses to stratify medicines (MATURA) Grant Ref: MR/K015346/1 and ARUK funded Experimental Arthritis Treatment Centre (EATC) Grant Ref: 20022. The animal work was supported by Arthritis Research UK Grants Reference 20305 and 20770.
Competing interests None declared.
Patient consent Not required.
Ethics approval All procedures were performed following written informed consent and were approved by the Research Ethics Committee – Queen Mary University – REC 05/Q0703/198.
Provenance and peer review Not commissioned; externally peer reviewed.
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