Collagen epitope expression on B cells is sufficient to confer tolerance to collagen-induced arthritis.

Sofia E M Andersson,Kenth Gustafsson,Jan Kihlberg,Anna Stern,Bibo Liang,Katrin Thorarinsdottir,Inger Gjertsson,Tove Eneljung,Sara Tengvall,Inga-Lill Mårtensson,Pernilla Jirholt,Rikard Holmdahl,Louise Henningsson

doi:10.1186/s13075-016-1037-7

Abstract

BackgroundThe mechanisms underlying tolerance induction and maintenance in autoimmune arthritis remain elusive. In a mouse model of rheumatoid arthritis, collagen type II (CII)-induced arthritis, we explore the contribution of B cells to antigen-specific tolerance.MethodsTo generate expression of the CII-peptide specifically on B-cell major histocompatibility complex type II, lentiviral-based gene therapy including a B-cell-specific Igk promoter was used.ResultsPresentation of the CII-peptide on B cells significantly reduced the frequency and severity of arthritis as well as the serum levels of CII -specific IgG antibodies. Further, both frequency and suppressive function of regulatory T cells were increased in tolerized mice. Adoptive transfer of regulatory T cells from tolerized mice to naïve mice ameliorated the development of CII-induced arthritis.ConclusionOur data suggest that endogenous presentation of the CII-peptide on B cells is one of the key contributors to arthritis tolerance induction and maintenance.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1037-7) contains supplementary material, which is available to authorized users.

Highlights

The mechanisms underlying tolerance induction and maintenance in autoimmune arthritis remain elusive
Frequency and suppressive function of Tregs are enhanced in LNT-Igk-collagen type II (CII) mice We have shown previously that tolerance induced by presentation of the CII-peptide on Aq, driven by a general promoter, is associated with an increased proportion of Tregs [18, 19], which is consistent with Tregs as key mediators of peripheral tolerance and their ability to prevent the development of collagen-induced arthritis (CIA) [31]
The LNT-Igk-CII B cells will most likely induce tolerance in heteroreactive T cells (i.e. T cells recognizing the rat CII-peptide), which will prevent the T-cell response to CII immunization and the cross-reactivity leading to an autoreactive response

Summary

Introduction

The mechanisms underlying tolerance induction and maintenance in autoimmune arthritis remain elusive. In a mouse model of rheumatoid arthritis, collagen type II (CII)-induced arthritis, we explore the contribution of B cells to antigen-specific tolerance. The pathogenesis of rheumatoid arthritis (RA) is complex and not fully understood. A hallmark of RA is the production of autoantibodies to citrullinated proteins and to IgG (rheumatoid factor). These are present in serum and produced in the joints [1,2,3]. Antibodies are produced by B cells, and during the last decade this cell type has regained interest as a pathogenic cell because autoantibody production precedes the onset of RA [4].

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