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- W2615366920 abstract "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. Here we study the clonal structure of the B-cell repertoire in SSc-PAH using immunoglobulin heavy-chain 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 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 shed light on the humoral immune basis of SSc-PAH and provide insights into the effect of B-cell depletion on the antibody repertoire. Abbreviations SSc-PAH Systemic sclerosis with pulmonary arterial hypertension IGH immunoglobulin heavy-chain BCR B-cell receptor CDR3 complementarity-determining region 3 Ig immunoglobulin AA amino acid" @default.
- W2615366920 created "2017-05-26" @default.
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- W2615366920 date "2017-05-18" @default.
- W2615366920 modified "2023-10-17" @default.
- W2615366920 title "Dynamics of the Human Antibody Repertoire following B-cell Depletion in Systemic Sclerosis" @default.
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- W2615366920 doi "https://doi.org/10.1101/139758" @default.
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