Abstract
Aims/hypothesisIslet-specific autoantibodies can predict the development of type 1 diabetes. However, it remains unclear if B cells, per se, contribute to the causal pancreatic immunopathology. We aimed to identify phenotypic signatures of disease progression among naive and memory B cell subsets in the peripheral blood of individuals with type 1 diabetes.MethodsA total of 69 participants were recruited across two separate cohorts, one for discovery purposes and the other for validation purposes. Each cohort comprised two groups of individuals with type 1 diabetes (one with newly diagnosed type 1 diabetes and the other with long-standing type 1 diabetes) and one group of age- and sex-matched healthy donors. The phenotypic characteristics of circulating naive and memory B cells were investigated using polychromatic flow cytometry, and serum concentrations of various chemokines and cytokines were measured using immunoassays.ResultsA disease-linked phenotype was detected in individuals with long-standing type 1 diabetes, characterised by reduced C-X-C motif chemokine receptor 3 (CXCR3) expression on switched (CD27+IgD−) and unswitched (CD27intermediateIgD+) memory B cells. These changes were associated with raised serum concentrations of B cell activating factor and of the CXCR3 ligands, chemokine (C-X-C motif) ligand (CXCL)10 and CXCL11. A concomitant reduction in CXCR3 expression was also identified on T cells.Conclusions/interpretationOur data reveal a statistically robust set of abnormalities that indicate an association between type 1 diabetes and long-term dysregulation of a chemokine ligand/receptor system that controls B cell migration.
Highlights
Type 1 diabetes is a multifactorial autoimmune disorder triggered by islet antigen-specific CD4+ and CD8+ T cellmediated destruction of insulin-producing cells in the pancreas
CXCR3 expression is reduced on memory B cells in individuals with type 1 diabetes To evaluate the phenotypic characteristics of naive and memory B cells in individuals with type 1 diabetes, we developed a polychromatic flow cytometry panel incorporating a viability dye and monoclonal antibodies specific for CD3, CD19, CD21, CD24, CD27, CD38, CD45R/ B220, CD95, CXCR3 and IgD
The spanning-tree progression analysis of density-normalised events (SPADE) analysis first identified two areas of naive cells (CD27−IgD+), each of which had distinct expression of other markers: area 1 cells were CD19+CD21−CD24++CD38++, and area 4 cells were CD19++CD21+CD24+CD38+
Summary
Type 1 diabetes is a multifactorial autoimmune disorder triggered by islet antigen-specific CD4+ and CD8+ T cellmediated destruction of insulin-producing cells in the pancreas. A previous study identified transitional CD27−IgD+IgM− B cell expansions in individuals with type 1 diabetes and healthy carriers of the PTPN22 genetic variant 1858T, which predisposes to a variety of autoimmune disorders [4]. No disease-specific alterations in the B cell compartment were detected in another study, designed to quantify the expression levels of CD19, CD24, CD27, CD38, IgD and IgM in individuals with type 1 diabetes and age- and sex-matched healthy donors [5]. Decreased frequencies of CD40+ and interleukin (IL)-10+ B cells were detected in another cohort of individuals with type 1 diabetes relative to healthy donors [8]. Whilst differences are present in those with type 1 diabetes compared with healthy individuals, a consistent disease-relevant phenotype in the circulating B cell pool has not been delineated
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