Rheumatoid arthritis patients express a skewed repertoire of polyclonal, hypomutated B-cell receptors

Objectives The success of B cell depletion therapy in rheumatoid arthritis (RA) therapy testifies to their importance in disease pathogenesis, but the precise B cells mediating this are unclear. For example, it is unknown if RA patients predominantly express a limited number of circulating clonally expanded populations of B cells with highly mutated B cell antigen receptors (BCRs) that would constitute a shared antigen driven response.Methods To address this, we have undertaken the largest study to date utilising next generation sequencing (NGS), to identify the full length of the peripheral blood BCR sequences from the antigen-binding heavy chain. Between 25,000 to 200,000 BCR sequences per patient were analysed from 127 newly diagnosed RA patients, 16 heathy controls, 16 RA patients with established disease and 8 paired blood and synovial samples. This was complemented with B cell subset analysis from an additional 64 RA patients and 22 healthy controls.Results RA patients expressed a significantly higher percentage of circulating poorly mutated polyclonal IgG+ve variable heavy (IgG-Vh) BCR sequences, both at the time of diagnosis and following treatment. These sequences resided predominantly within TNF-alpha secreting IgG+veCD27−ve B cells, that were expanded in RA peripheral blood and enriched in the rheumatoid synovium. Surprisingly, peripheral and synovial B cell repertoires of RA patients are quite distinct, sharing very few IgG sequences.Conclusions This is the first report to conclusively establish that a substantial component of the peripheral B cell repertoire in RA consists of polyclonal hypomutated IgG+ve BCRs that may play a critical role in driving an autoimmune mediated inflammation.* BCR : B cell receptor DMARD : Disease modifying anti-rheumatic drug VH : variable portion of the heavy chain BCDT : B cell depletion therapy ACPA : anti citrullinated protein antibodies RF-rheumatoid factor NGS : next generation sequencing PBMC : peripheral blood mononuclear cells ERA : early rheumatoid arthritis ESRA : established RA CDR : complementarity determining region SHM : somatic hypermutation AID : activation-induced cytidine deaminase GC : germinal centre FR : framework region CS : class-switching