Cochlin-Expressing Memory B (COMB) Cells Are Enriched in Autoimmune Diseases and Display a Distinct Activation Profile

Abstract

Rheumatoid arthritis (RA) is the most common chronic autoimmune arthritis, causing joint damage and affecting multiple organs over time. B cells play a key role in driving the disease by producing autoantibodies, releasing cytokines, and presenting antigens to T cells. While B cell depletion therapies can help reduce inflammation, they remove all CD20+B cells indiscriminately, which can increase infection risk and interfere with important regulatory immune functions. To better define pathogenic B cell subsets, we performed single-cell RNA and ATAC sequencing on circulating and synovial B cells from patients with early, untreated RA. We identified a novel population of memory B cells expressing cochlin (COCH), termed cochlin - expressing memory B (COMB) cells. While detectable at low levels in healthy controls, COMB cells are significantly expanded in RA and exhibit a distinct transcriptional profile indicative of immune activation. Epigenetic analysis showed that COMB cells have more open chromatin at key immune regulatory regions, including sites bound by NF-{kappa}B family transcription factors like RELA and REL. This suggests that these cells are primed to respond to inflammatory signals. We also looked at publicly available datasets and found COMB-like cells in the blood of people with systemic lupus erythematosus (SLE) and Sjogrens syndrome (SjS), as well as in inflamed kidney tissue from patients with SLE. COMB cells across these diseases share a conserved gene expression signature, pointing to a common memory B cell programme associated with autoimmunity. These findings define COMB cells as a previously unrecognised, transcriptionally and epigenetically distinct memory B cell subset enriched across autoimmune diseases, offering new insights into B cell-mediated pathology and potential therapeutic targets.