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

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Thompson, WS 
Pekalski, ML 
Simons, HZ 
Smyth, DJ 
Castro-Dopico, X 


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.



B lymphocytes, IL-2, IL-21, PTPN22, human immunology, immunophenotyping, type 1 diabetes, Adolescent, Adult, Age Factors, Autoantibodies, B-Lymphocyte Subsets, Case-Control Studies, Child, Cytokines, Diabetes Mellitus, Type 1, Female, Flow Cytometry, Gene Expression Regulation, Genetic Association Studies, Humans, Immunophenotyping, Male, Phenotype, Protein Tyrosine Phosphatase, Non-Receptor Type 22, Signal Transduction, Young Adult

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Clin Exp Immunol

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Oxford University Press (OUP)
Wellcome Trust (083650/Z/07/Z)
Wellcome Trust (089989/Z/09/Z)
Wellcome Trust (100140/Z/12/Z)
Wellcome Trust (091157/Z/10/B)