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

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


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.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Autoimmune Diseases / drug therapy
  • Autoimmune Diseases / immunology*
  • B-Lymphocytes / immunology*
  • Double-Blind Method
  • Female
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Hypertension, Pulmonary / drug therapy
  • Hypertension, Pulmonary / immunology*
  • Immune Reconstitution / immunology
  • Immunoglobulin Heavy Chains / genetics
  • Immunoglobulin Heavy Chains / immunology
  • Immunologic Factors / therapeutic use*
  • Longitudinal Studies
  • Lymphocyte Depletion*
  • Middle Aged
  • Placebos
  • Plasma Cells / immunology
  • Rituximab / therapeutic use
  • Scleroderma, Systemic / drug therapy
  • Scleroderma, Systemic / immunology*
  • Sequence Analysis, DNA
  • Time Factors
  • V(D)J Recombination / immunology


  • Immunoglobulin Heavy Chains
  • Immunologic Factors
  • Placebos
  • Rituximab

Associated data

  • ClinicalTrials.gov/NCT01086540
  • ClinicalTrials.gov/NCT02133781
  • ClinicalTrials.gov/NCT03020498
  • ClinicalTrials.gov/NCT03022396
  • ClinicalTrials.gov/NCT03022422