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Sci Immunol. 2017 Sep 29;2(15). pii: eaan8289. doi: 10.1126/sciimmunol.aan8289.

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

Author information

1
Department of Applied Physics, Stanford University, Stanford, CA 94305, USA.
2
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.
3
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
4
Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA.
5
Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
6
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
7
Veterans Affairs Palo Alto Health Care System, Medical Service, Palo Alto, CA 94303, USA.
8
Department of Applied Physics, Stanford University, Stanford, CA 94305, USA. quake@stanford.edu.
9
Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
10
Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.

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.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT01086540 NCT02133781 NCT03020498 NCT03022396 NCT03022422.

PMID:
28963118
PMCID:
PMC5800854
DOI:
10.1126/sciimmunol.aan8289
[Indexed for MEDLINE]
Free PMC Article

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