Shared recognition of citrullinated tenascin-C peptides by T and B cells in rheumatoid arthritis.

Jing Song,Alicia Wong,Virginia S Muir,Cliff Rims,Anja Schwenzer,Jane H Buckner,Vivianne Malmström,Kim S Midwood,David Arribas-Layton,Christina Gerstner,Sara Turcinov,Lorena Rodriguez Martinez,Eddie A James

doi:10.1172/jci.insight.145217

Abstract

Tenascin-C (TNC), an extracellular matrix protein that has proinflammatory properties, is a recently described antibody target in rheumatoid arthritis (RA). In this study, we utilized a systematic discovery process and identified 5 potentially novel citrullinated TNC (cit-TNC) T cell epitopes. CD4+ T cells specific for these epitopes were elevated in the peripheral blood of subjects with RA and showed signs of activation. Cit-TNC–specific T cells were also present among synovial fluid T cells and secreted IFN-γ. Two of these cit-TNC T cell epitopes were also recognized by antibodies within the serum and synovial fluid of individuals with RA. Detectable serum levels of cit-TNC–reactive antibodies were prevalent among subjects with RA and positively associated with cyclic citrullinated peptide (CCP) reactivity and the HLA shared epitope. Furthermore, cit-TNC–reactive antibodies were correlated with rheumatoid factor and elevated in subjects with a history of smoking. This work confirms cit-TNC as an autoantigen that is targeted by autoreactive CD4+ T cells and autoantibodies in patients with RA. Furthermore, our findings raise the possibility that coinciding epitopes recognized by both CD4+ T cells and B cells have the potential to amplify autoimmunity and promote the development and progression of RA.

Highlights

Rheumatoid arthritis (RA) is a chronic debilitating disease with a prevalence between 0.3% and 1% [1]
There is ample evidence to suggest that failure of both B cell and T cell tolerance contributes to the pathogenesis of seropositive rheumatoid arthritis (RA)
In light of the observation of intimate interactions between T cells and B calls in the synovium [12] and the fact that antigen-specific B cells can be uniquely potent antigenpresenting cells, these are likely to be mutually reinforcing phenomena

Summary

Introduction

Rheumatoid arthritis (RA) is a chronic debilitating disease with a prevalence between 0.3% and 1% [1]. A variety of CD4+ T cell specificities have been implicated in disease pathogenesis, including multiple citrullinated peptides from self-proteins that have been shown to be recognized by peripheral blood T cells, and by T cells from synovial fluid [8,9,10,11]. In spite of this knowledge, the immunologic factors that initiate and perpetuate RA are not completely understood. This overlap, coupled with the observation of compartmentalized T and B cell structures, could indicate that interactions between antigen-specific T cells and B cells play an important role in the etiology of RA [12]

Methods

Results

Conclusion