Multi-parametric flow cytometric and genetic investigation of the peripheral B cell compartment in human type 1 diabetes. (24th July 2014)

• Record Type: Journal Article
• 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
• Is Part Of: Clinical and experimental immunology. Volume 177:Number 3(2014:Sep.)
• Page Start: 571
• Page End: 585
• Publication Date: 2014-07-24
• Subjects: B lymphocytes -- human immunology -- IL-2 -- IL-21 -- immunophenotyping -- PTPN22 -- type 1 diabetes; Immunopathology -- Periodicals; 616.079
• DOI: 10.1111/cei.12362
• Languages: English
• ISSNs: 0009-9104

Abstract

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 − 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.