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

Summary 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,...

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Published in:	Clinical and experimental immunology Vol. 177; no. 3; pp. 571 - 585
Main Authors:	Thompson, W. S., Pekalski, M. L., Simons, H. Z., Smyth, D. J., Castro‐Dopico, X., Guo, H., Guy, C., Dunger, D. B., Arif, S., Peakman, M., Wallace, C., Wicker, L. S., Todd, J. A, Ferreira, R. C.
Format:	Journal Article
Language:	English
Published:	England Oxford University Press 01-09-2014 Blackwell Science Inc
Subjects:	Adolescent Adult Age Factors Autoantibodies - immunology B lymphocytes 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 human immunology Humans IL‐2 IL‐21 Immunophenotyping Male Original Phenotype Protein Tyrosine Phosphatase, Non-Receptor Type 22 - genetics PTPN22 Signal Transduction type 1 diabetes Young Adult type 1 diabetes B lymphocytes immunophenotyping IL-2 PTPN22 human immunology IL-21
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Summary:	Summary 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−CD24hiCD38hi 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 Trp620 T1D risk allele (rs2476601; Arg620Trp). 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors co-directed the project.
ISSN:	0009-9104 1365-2249
DOI:	10.1111/cei.12362