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“B”-fing up immune-mediated diseases

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Science Immunology  03 Jan 2020:
Vol. 5, Issue 43, eaba7108
DOI: 10.1126/sciimmunol.aba7108

Abstract

Extensive characterization of B cell receptor repertoires across six immune-mediated diseases reveals novel insights into disease pathogenesis.

B lymphocytes generate a remarkable degree of sequence diversity within their immunoglobulin loci, resulting in a broad array of B cell receptor (BCR) specificities for foreign and self-antigens. This BCR repertoire is composed of both naive and antigen-experienced B cells, which are subject to additional diversification via class-switch recombination (CSR) and/or somatic hypermutation.

Massively-parallel sequencing technologies has enabled researchers to capture BCR diversity on an unprecedented scale, yet challenges still exist in establishing relationships between a given BCR sequence, its target antigen, and specific functions. One example pertains to antibody isotypes that are encoded within the immunoglobulin heavy-chain constant (CH) region (e.g., IgA1, IgE, IgG4, etc.). These isotypes have unique effector functions in host defense and/or immunopathology, yet most BCR sequencing strategies do not detect these regions in conjunction with the upstream variable region sequences. To address these limitations, Bashford-Rogers et al. developed a sequencing strategy to resolve the variable and CH isotype sequence of individual BCR mRNA molecules. The authors applied this method to compare the blood BCR repertoire of 209 patients with one of six immune-mediated diseases (IMD): Behçet’s disease (BD), Crohn’s disease (CD), anti-neutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV), systemic lupus erythematosus (SLE), immunoglobulin A vasculitis (IgAV), and eosinophilic granulomatosis with polyangiitis (EGPA).

Notably, the authors found an overrepresentation of IgA isotypes in all IMDs except for AAV and EGPA. The enrichment for IgA was particularly strong in CD and SLE, suggesting a shared etiology between these entities with regard to recognition of microbiota at mucosal barrier surfaces. Further, the authors found expanded IgG3 isotypes in EGPA, which exhibited disproportionate IgE CSR. In BD, the authors also found a strong increase in the expression of three specific IGHV genes—namely, IGHV1-46, IGHV1-69, and IGHV1-3—all of which can recognize both microbial and self-antigens, also suggesting a microbial component to disease pathogenesis. Finally, the authors studied BCR sequences pre- and post-therapy in SLE and AAV patients who had received either rituximab or mycophenolate mofetil (MMF). Interestingly, the residual BCR repertoire with MMF showed a reduction in both clonally-expanded and isotype-switched BCRs, whereas rituximab led to an overall reduction in B cell numbers but relative preservation of isotype-switched and clonally-expanded BCRs.

Although the authors do not confirm the antigenic specificity or functionality of any of the novel BCR sequences highlighted in their study, their findings do represent a remarkable and well-executed compendium of B cell diversity in IMDs. As such, this study provides a strong foundation for further functional characterization and therapeutic targeting of the B cell repertoire in IMDs.

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