Circulating T follicular helper cell and regulatory T cell frequencies are influenced by B cell depletion in patients with granulomatosis with polyangiitis.

OBJECTIVE: Granulomatosis with polyangiitis (GPA) is a rare and sometimes fatal systemic autoimmune disease. ANCAs specific for PR3 are associated with GPA. Remission in GPA can be achieved through B cell depletion (BCD) therapy. Our aim was to understand whether the frequencies of T cell subsets are influenced by BCD. METHODS: The frequencies of circulating T follicular helper cells (cTFHs) and regulatory T cells (Tregs) from 36 GPA patients including 11 rituximab-treated patients and 10 healthy controls were studied by flow cytometry. The functional capacity of Tregs was assessed by in vitro co-culture assays. RESULTS: We observed an increased frequency of cTFHs and a reduced frequency of antigen-experienced Tregs in peripheral blood from GPA patients on conventional therapies but not in those treated with rituximab compared with healthy controls. Furthermore, the ratio of cTFHs to Tregs was significantly higher in GPA patients on conventional therapies than in GPA patients treated with rituximab who were clinically improved or controls. Whereas Tregs were numerically reduced in GPA patients on conventional therapy, the suppressive capacity of Tregs on a per cell basis was not significantly altered in these individuals. CONCLUSION: Our study illustrated increased cTFHs with decreased antigen-experienced Tregs in GPA patients on conventional therapies, but in B cell-depleted patients the levels of cTFHs and Tregs were similar to healthy controls. The negative correlation between cTFHs and Tregs implies the balance between T cell subsets and its B cell dependence impact on disease activity in GPA.

Type 1 diabetes-associated IL2RA variation lowers IL-2 signaling and contributes to diminished CD4+CD25+ regulatory T cell function.

Numerous reports have demonstrated that CD4(+)CD25(+) regulatory T cells (Tregs) from individuals with a range of human autoimmune diseases, including type 1 diabetes, are deficient in their ability to control autologous proinflammatory responses when compared with nondiseased, control individuals. Treg dysfunction could be a primary, causal event or may result from perturbations in the immune system during disease development. Polymorphisms in genes associated with Treg function, such as IL2RA, confer a higher risk of autoimmune disease. Although this suggests a primary role for defective Tregs in autoimmunity, a link between IL2RA gene polymorphisms and Treg function has not been examined. We addressed this by examining the impact of an IL2RA haplotype associated with type 1 diabetes on Treg fitness and suppressive function. Studies were conducted using healthy human subjects to avoid any confounding effects of disease. We demonstrated that the presence of an autoimmune disease-associated IL2RA haplotype correlates with diminished IL-2 responsiveness in Ag-experienced CD4(+) T cells, as measured by phosphorylation of STAT5a, and is associated with lower levels of FOXP3 expression by Tregs and a reduction in their ability to suppress proliferation of autologous effector T cells. These data offer a rationale that contributes to the molecular and cellular mechanisms through which polymorphisms in the IL-2RA gene affect immune regulation, and consequently upon susceptibility to autoimmune and inflammatory diseases.