Characterizing the BCR repertoire in immune-mediated diseases

Abstract

B cells can assume protective or pathogenic roles in immune-mediated diseases (IMDs). Analysis of the B cell receptor (BCR) repertoires in six IMDs provides insights into the diversity of B cell repertoires across diseases as well as into potential pathological mechanisms and the effects of different treatments.

Fig. 1 |. Model for the role of B cells in immune-mediated diseases.

Healthy individuals possess B cell receptor (BCR) repertoires that are largely tolerant to self-antigens. Upon antigen exposure to infectious microbes or in response to commensal organisms, BCRs diversify by somatic hypermutation (SHM) and class-switch recombination (CSR). Production of protective, specific antibodies contributes to the prevention and/or resolution of microbial infections. Tolerance breaks can lead to the expansion of autoreactive pathogenic B cells, promoting disease. B cell depletion therapies such as rituximab (RTX) can reduce development of pathogenic B cells, promoting restoration of tolerance. However, a small subset of persistent, class-switched, somatically hypermutated clones might continue to expand, promoting relapse. Mycophenolate mofetil (MMF) inhibits the proliferation of somatically hypermutated and class-switched B cells but does not deplete them. Combination therapy (for example, with MMF and RTX) might promote more effective therapeutic outcomes.