Multi-parametric flow cytometric and genetic investigation of the peripheral B cell compartment in human 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 × 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.
JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
W S
WS
Thompson
M L
ML
Pekalski
H Z
HZ
Simons
D J
DJ
Smyth
X
X
Castro-Dopico
H
H
Guo
C
C
Guy
D B
DB
Dunger
S
S
Arif
M
M
Peakman
C
C
Wallace
L S
LS
Wicker
J A
JA
Todd
R C
RC
Ferreira
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D001323:Autoantibodies / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D016022:Case-Control Studies; D002648:Child; D016207:Cytokines / Q000096:biosynthesis; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D006801:Humans; D016130:Immunophenotyping; D008297:Male; D010641:Phenotype; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics; D015398:Signal Transduction; D055815:Young Adult
D001323:Autoantibodies; D016207:Cytokines; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22
B lymphocytes; IL-2; IL-21; PTPN22; human immunology; immunophenotyping; type 1 diabetes