Research ArticleAUTOIMMUNITY

Dynamics of the human antibody repertoire after B cell depletion in systemic sclerosis

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Science Immunology  29 Sep 2017:
Vol. 2, Issue 15, eaan8289
DOI: 10.1126/sciimmunol.aan8289

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A revealing repertoire for systemic sclerosis

Systemic sclerosis (SSc) is an autoimmune disease associated with fibrosis and serious complications, including pulmonary arterial hypertension (PAH). Abnormal B cell responses have been associated with SSc pathogenesis, and de Bourcy et al. analyzed immunoglobulin heavy chain (IGH) transcripts of SSc-PAH patients enrolled in a B cell depletion clinical study. SSc-PAH was associated with several B cell development anomalies, particularly underuse of the IGHV2-5 segment and B cell homeostasis abnormalities. Depletion temporarily reversed these anomalous SSc-PAH disease signatures, and the data suggest that the rate of naïve B cell replenishment could be estimated from baseline measurements. These results define antibody signatures associated with SSc-PAH and reveal how B cell depletion shapes the antibody repertoire during reconstitution.

Abstract

Systemic sclerosis with pulmonary arterial hypertension (SSc-PAH) is a debilitating and frequently lethal disease of unknown cause lacking effective treatment options. Lymphocyte anomalies and autoantibodies observed in systemic sclerosis have suggested an autoimmune character. We study the clonal structure of the B cell repertoire in SSc-PAH using immunoglobulin heavy chain (IGH) sequencing before and after B cell depletion. We found SSc-PAH to be associated with anomalies in B cell development, namely, altered VDJ rearrangement frequencies (reduced IGHV2-5 segment usage) and an increased somatic mutation–fixation probability in expanded B cell lineages. SSc-PAH was also characterized by anomalies in B cell homeostasis, namely, an expanded immunoglobulin D–positive (IgD+) proportion with reduced mutation loads and an expanded proportion of highly antibody-secreting cells. Disease signatures pertaining to IGHV2-5 segment usage, IgD proportions, and mutation loads were temporarily reversed after B cell depletion. Analyzing the time course of B cell depletion, we find that the kinetics of naïve replenishment are predictable from baseline measurements alone, that release of plasma cells into the periphery can precede naïve replenishment, and that modes of B cell receptor diversity are highly elastic. Our findings reveal humoral immune signatures of SSc-PAH and uncover determinism in the effects of B cell depletion on the antibody repertoire.

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