Journal
CLINICAL AND EXPERIMENTAL IMMUNOLOGY
Volume 177, Issue 3, Pages 571-585Publisher
WILEY
DOI: 10.1111/cei.12362
Keywords
B lymphocytes; human immunology; IL-2; IL-21; immunophenotyping; PTPN22; type 1 diabetes
Categories
Funding
- NIHR Cambridge Biomedical Research Centre
- JDRF UK Centre for Diabetes Genes, Autoimmunity and Prevention (D-GAP) [4-2007-1003]
- JDRF
- Wellcome Trust (WT) [WT061858/091157, 083650/Z/07/Z]
- National Institute for Health Research Cambridge Biomedical Research Centre (CBRC)
- Wellcome Trust Strategic Award [100140]
- JDRF post-doctoral fellowship [3-2011-374]
- Wellcome Trust [088998]
- UK Department of Health via the National Institute for Health Research (NIHR) Biomedical Research Centre
- King's College London
- Medical Research Council [MR/J006742/1] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0513-10143, NF-SI-0508-10275, NF-SI-0508-10274, NF-SI-0513-10012] Funding Source: researchfish
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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 x 10(-4)) and islet-specific CD4(+) T cells (P = 2 9 x 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.
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