Phenotypic changes in B and T cells of people with type 1 diabetes and people who are autoantibody positive but do not progress to type 1 diabetes.

Background

Islet-specific autoantibodies can predict the development of type 1 diabetes. However, it remains unclear how B cells contribute to the causal pancreatic immunopathology. Furthermore, up to 30% of people positive for multiple autoantibodies will not progress to type 1 diabetes within 10 years (slow progressors/SPs). We aimed to identify phenotypic signatures of disease progression among B cell subsets in the peripheral blood of individuals with type 1 diabetes and to characterise the B and T cell phenotypes of SPs.

Methods

Individuals with type 1 diabetes were compared to age- and sex-matched healthy donors. SPs from the Bart’s Oxford study, seropositive for at least two islet-specific autoantibodies for 14+ years and still free of type 1 diabetes, were compared to a separate group of matched healthy donors.

The phenotypic characteristics of circulating B and T cells were investigated using polychromatic flow cytometry, tetramer staining and ELISpots, and serum concentrations of chemokines and cytokines were measured. 

Results

A disease-linked phenotype was detected in individuals with long-standing type 1 diabetes, characterised by reduced CXCR3 expression on memory B cells. These changes were associated with raised serum concentrations of BAFF and of the CXCR3 ligands, CXCL10 and CXCL11. CD24 and CD95 (FasR) expression were also reduced on the B cells of people with long-standing type 1 diabetes. In contrast, B cells from SPs had increased levels of CD95 expression and a trend towards increased DcR3 (decoy FasL receptor) levels in the serum. There was also an expansion of a CD127⁺CD27^intermediateCD95^intermediate memory T cell subset in SPs.

Conclusion

Our findings indicated an association between type 1 diabetes and long-term dysregulation of a chemokine ligand/receptor system that controls B cell migration. In addition, changes in CD95 suggested a pathway by which progression to type 1 diabetes could be modulated by B cell susceptibility to apoptosis.