Analysis of the B cell receptor repertoire in six immune-mediated diseases.
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Bashford-Rogers, R., Bergamaschi, L., McKinney, E., Pombal, D., Mescia, F., Lee, J., Thomas, D., et al. (2019). Analysis of the B cell receptor repertoire in six immune-mediated diseases.. Nature, 574 122-126. https://doi.org/10.1038/s41586-019-1595-3
B cells are important in the pathogenesis of many, and perhaps all, immune-mediated diseases. Each B cell expresses a single B cell receptor (BCR)1, and the diverse range of BCRs expressed by the total B cell population of an individual is termed the 'BCR repertoire'. Our understanding of the BCR repertoire in the context of immune-mediated diseases is incomplete, and defining this could provide new insights into pathogenesis and therapy. Here, we compared the BCR repertoire in systemic lupus erythematosus, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, Crohn's disease, Behçet's disease, eosinophilic granulomatosis with polyangiitis, and immunoglobulin A (IgA) vasculitis by analysing BCR clonality, use of immunoglobulin heavy-chain variable region (IGHV) genes and-in particular-isotype use. An increase in clonality in systemic lupus erythematosus and Crohn's disease that was dominated by the IgA isotype, together with skewed use of the IGHV genes in these and other diseases, suggested a microbial contribution to pathogenesis. Different immunosuppressive treatments had specific and distinct effects on the repertoire; B cells that persisted after treatment with rituximab were predominately isotype-switched and clonally expanded, whereas the inverse was true for B cells that persisted after treatment with mycophenolate mofetil. Our 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.
This work was supported by the Wellcome Trust (grants WT106068AIA and 083650/Z/07/Z), the EU H2020 project SYSCID (grant 733100), the UK Medical Research Council (program grant MR/L019027) and the UK National Institute of Health Research (NIHR) Cambridge Biomedical Research Centre.
WELLCOME TRUST (106068/Z/14/Z)
Wellcome Trust (083650/Z/07/Z)
European Commission Horizon 2020 (H2020) Societal Challenges (733100)
WELLCOME TRUST (104064/Z/14/Z)
External DOI: https://doi.org/10.1038/s41586-019-1595-3
This record's URL: https://www.repository.cam.ac.uk/handle/1810/297601
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