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

作者：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^*

来源：Clinical and Experimental Immunology, 2014, 177(3): 571-585.

DOI：10.1111/cei.12362

• B lymphocytes
• human immunology
• IL-2
• IL-21
• immunophenotyping
• PTPN22
• type 1 diabetes

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.

• 出版日期2014-9
• 单位河北医科大学