B cell receptor repertoire analysis in six immune-mediated diseases

B cells are important in the pathogenesis of many, and perhaps all, immune-mediated diseases (IMDs). Each B cell expresses a single B cell receptor (BCR)(1), with the diverse range of BCRs expressed by an individual’s total B cell population being termed the “BCR repertoire”. Our understanding of the BCR repertoire in the context of IMDs is incomplete, and defining this could reveal new insights into pathogenesis and therapy. We therefore compared the BCR repertoire in systemic lupus erythematosus (SLE), ANCA-associated vasculitis (AAV), Crohn’s disease (CD), Behçet’s disease (BD), eosinophilic granulomatosis with polyangiitis (EGPA) and IgA vasculitis (IgAV), analysing BCR clonality, and immunoglobulin heavy chain gene (IGHV) and, in particular, isotype usage. An IgA-dominated increased clonality in SLE and CD, together with skewed IGHV gene usage in these and other diseases, suggested a microbial contribution to pathogenesis. Different immunosuppressive treatment had specific and distinct impacts on the repertoire; B cells persisting after rituximab were predominately isotype-switched and clonally expanded, the inverse of those persisting after mycophenolate mofetil. A comparative analysis of the BCR repertoire in immune-mediated disease reveals a complex B cell architecture, providing a platform for understanding pathological mechanisms and designing treatment strategies.