Multi-parametric flow cytometric and genetic investigation of the peripheral B cell compartment in human type 1 diabetes

Clin Exp Immunol. 2014 Sep;177(3):571-85. doi: 10.1111/cei.12362.


The appearance of circulating islet-specific autoantibodies before disease diagnosis is a hallmark of human type 1 diabetes (T1D), and suggests a role for B cells in the pathogenesis of the disease. Alterations in the peripheral B cell compartment have been reported in T1D patients; however, to date, such studies have produced conflicting results and have been limited by sample size. In this study, we have performed a detailed characterization of the B cell compartment in T1D patients (n = 45) and healthy controls (n = 46), and assessed the secretion of the anti-inflammatory cytokine interleukin (IL)-10 in purified B cells from the same donors. Overall, we found no evidence for a profound alteration of the B cell compartment or in the production of IL-10 in peripheral blood of T1D patients. We also investigated age-related changes in peripheral B cell subsets and confirmed the sharp decrease with age of transitional CD19(+) CD27(-) CD24(hi) CD38(hi) B cells, a subset that has recently been ascribed a putative regulatory function. Genetic analysis of the B cell compartment revealed evidence for association of the IL2-IL21 T1D locus with IL-10 production by both memory B cells (P = 6·4 × 10(-4) ) and islet-specific CD4(+) T cells (P = 2·9 × 10(-3) ). In contrast to previous reports, we found no evidence for an alteration of the B cell compartment in healthy individuals homozygous for the non-synonymous PTPN22 Trp(620) T1D risk allele (rs2476601; Arg(620) Trp). The IL2-IL21 association we have identified, if confirmed, suggests a novel role for B cells in T1D pathogenesis through the production of IL-10, and reinforces the importance of IL-10 production by autoreactive CD4(+) T cells.

Keywords: B lymphocytes; IL-2; IL-21; PTPN22; human immunology; immunophenotyping; type 1 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Age Factors
  • Autoantibodies / immunology
  • B-Lymphocyte Subsets / immunology*
  • B-Lymphocyte Subsets / metabolism*
  • Case-Control Studies
  • Child
  • Cytokines / biosynthesis
  • Diabetes Mellitus, Type 1 / genetics*
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / metabolism
  • Female
  • Flow Cytometry
  • Gene Expression Regulation
  • Genetic Association Studies
  • Humans
  • Immunophenotyping
  • Male
  • Phenotype
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22 / genetics
  • Signal Transduction
  • Young Adult


  • Autoantibodies
  • Cytokines
  • PTPN22 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22