Multimodal repertoire analysis unveils B cell biology in immune-mediated diseases

Abstract

AbstractObjectivesDespite the involvement of B cells in the pathogenesis of immune-mediated diseases, biological mechanisms underlying their function are scarcely understood. To overcome this gap, here we constructed and investigated a large-scale repertoire catalog of five B cell subsets of immune-mediated disease patients.MethodsWe mapped B cell receptor regions from RNA sequencing data of sorted B cell subsets. Our dataset consisted of 595 donors under immune-mediated diseases and health. We characterized the repertoire features from various aspects, including their association with immune cell transcriptomes and clinical features and their response to belimumab treatment.ResultsHeavy-chain complementarity-determining region 3 (CDR-H3) length among naïve B cells was shortened among autoimmune diseases. Strong negative correlation between interferon signature strength and CDR-H3 length was observed only in naïve B cells and suggested the role for interferon in pre-mature B cell development. VDJ gene usage was skewed especially in plasmablasts and unswitched-memory B cells of systemic lupus erythematosus (SLE) patients. We developed a scoring system for this skewing, and it positively correlated with peripheral helper T cell transcriptomic signatures and negatively correlated with the amount of somatic hyper mutations in plasmablasts, suggesting the association of extra-follicular pathway. Further, this skewing led to high usage of IGHV4-34 gene in unswitched-memory B cells, whose usage showed prominent positive correlation with disease activity in SLE. Gene usage skewing in unswitched-memory B cells was ameliorated after belimumab treatment.ConclusionsOur multimodal repertoire analysis enabled us the system-level understanding of B cell abnormality in diseases.