In human autoimmunity, a substantial component of the B cell repertoire consists of polyclonal, barely mutated IgG +ve B cells

Cowan, G. J. M., Miles, K., Capitani, L., Giguere, S. S. B., Johnsson, H., Goodyear, C., McInnes, I. B. , Breusch, S., Gray, D. and Gray, M. (2020) In human autoimmunity, a substantial component of the B cell repertoire consists of polyclonal, barely mutated IgG +ve B cells. Frontiers in Immunology, 11, 395. (doi: 10.3389/fimmu.2020.00395) (PMID:32265907) (PMCID:PMC7099054)

Abstract

B cells are critical for promoting autoimmunity and the success of B cell depletion therapy in rheumatoid arthritis (RA) confirms their importance in driving chronic inflammation. Whilst disease specific autoantibodies are useful diagnostically, our understanding of the pathogenic B cell repertoire remains unclear. Defining it would lead to novel insights and curative treatments. To address this, we have undertaken the largest study to date of over 150 RA patients, utilizing next generation sequencing (NGS) to analyze up to 200,000 BCR sequences per patient. The full-length antigen-binding variable region of the heavy chain (IgGHV) of the IgG B cell receptor (BCR) were sequenced. Surprisingly, RA patients do not express particular clonal expansions of B cells at diagnosis. Rather they express a polyclonal IgG repertoire with a significant increase in BCRs that have barely mutated away from the germline sequence. This pattern remains even after commencing disease modifying therapy. These hypomutated BCRs are expressed by TNF-alpha secreting IgG+veCD27−ve B cells, that are expanded in RA peripheral blood and enriched in the rheumatoid synovium. A similar B cell repertoire is expressed by patients with Sjögren's syndrome. A rate limiting step in the initiation of autoimmunity is the activation of B cells and this data reveals that a sizeable component of the human autoimmune B cell repertoire consists of polyclonal, hypomutated IgG+ve B cells, that may play a critical role in driving chronic inflammation.

• Item Type: Articles
• Additional Information: Funding: This work was made possible by grants from the Wellcome Trust to MG (WT109705MA).
• Keywords: Immunology, B cells, BCR, autoimmunity, TNF, rheumatoid arthritis
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: McInnes, Professor Iain and Johnsson, Dr Hanna
• Authors: Cowan, G. J. M., Miles, K., Capitani, L., Giguere, S. S. B., Johnsson, H., Goodyear, C., McInnes, I. B., Breusch, S., Gray, D., and Gray, M.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Research Centre: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology
• Journal Name: Frontiers in Immunology
• Publisher: Frontiers Media S.A.
• ISSN: 1664-3224
• ISSN (Online): 1664-3224
• Copyright Holders: Copyright © 2020 Cowan, Miles, Capitani, Giguere, Johnsson, Goodyear, McInnes, Breusch, Gray and Gray
• First Published: First published in Frontiers in Immunology 11:395
• Publisher Policy: Reproduced under a Creative Commons Licence