Altered Systemic and Intestinal IgA Immune Responses in Individuals With Type 1 Diabetes

Objective Increasing evidence supports the observation that immunoglobulin A (IgA) exerts a critical effect on the susceptibility to autoimmunity by modulating gut homeostasis and subsequent host immunity. We hypothesized that the IgA immunity is altered in individuals with type 1 diabetes. To test our hypothesis, we investigated intestinal, oral, and peripheral IgA immune responses in individuals with type 1 diabetes. Methods We collected stool, oral cavity, and blood samples from participants diagnosed with type 1 diabetes (within 1 year and more than 1 year) and healthy control individuals. Serum islet autoantibody titers were detected by radioligand assays. IgA-bound bacteria and IgA-expressing B cells were studied by flow cytometry. Oral free IgA level was measured by enzyme-linked immunosorbent assay. Serum and stool free IgA concentrations were determined by immune-turbidimetry method. Results Individuals diagnosed with type 1 diabetes within 1 year had an increased proportion of stool IgA-bound bacteria compared with healthy control individuals. The proportion of stool IgA-bound bacteria was positively associated with glutamic acid decarboxylase autoantibody titer. Moreover, individuals with a longer disease duration displayed a higher level of IgA-bound bacteria than those diagnosed within 1 year. In contrast to healthy control individuals, type 1 diabetes patients had increased serum IgA concentrations. Conclusions Individuals with type 1 diabetes display altered IgA immunity, especially increased stool IgA-bound bacteria, which is likely to contribute to β-cell autoimmunity and the disease development, and thus, might be considered as a novel therapeutic target for the treatment of type 1 diabetes.

Islet Autoantibody Standardization Program 2018 Workshop: Interlaboratory Comparison of Glutamic Acid Decarboxylase Autoantibody Assay Performance

BACKGROUND The Islet Autoantibody Standardization Program (IASP) aims to improve the performance of immunoassays measuring type 1 diabetes (T1D)-associated autoantibodies and the concordance of results among laboratories. IASP organizes international interlaboratory assay comparison studies in which blinded serum samples are distributed to participating laboratories, followed by centralized collection and analysis of results, providing participants with an unbiased comparative assessment. In this report, we describe the results of glutamic acid decarboxylase autoantibody (GADA) assays presented in the IASP 2018 workshop. METHODS In May 2018, IASP distributed to participants uniquely coded sera from 43 new-onset T1D patients, 7 multiple autoantibody-positive nondiabetic individuals, and 90 blood donors. Results were analyzed for the following metrics: sensitivity, specificity, accuracy, area under the ROC curve (ROC-AUC), partial ROC-AUC at 95% specificity (pAUC95), and concordance of qualitative and quantitative results. RESULTS Thirty-seven laboratories submitted results from a total of 48 different GADA assays adopting 9 different formats. The median ROC-AUC and pAUC95 of all assays were 0.87 [interquartile range (IQR), 0.83–0.89] and 0.036 (IQR, 0.032–0.039), respectively. Large differences in pAUC95 (range, 0.001–0.0411) were observed across assays. Of formats widely adopted, bridge ELISAs showed the best median pAUC95 (0.039; range, 0.036–0.041). CONCLUSIONS Several novel assay formats submitted to this study showed heterogeneous performance. In 2018, the majority of the best performing GADA immunoassays consisted of novel or established nonradioactive tests that proved on a par or superior to the radiobinding assay, the previous gold standard assay format for GADA measurement.

Follicular Regulatory T Cells Are Associated With β-Cell Autoimmunity and the Development of Type 1 Diabetes

Objective Impaired follicular regulatory T (Tfr) cells enhance T follicular helper cells activity, resulting in the expansion of autoreactive B cells and autoantibody production. However, the role of Tfr cells in the pathogenesis of type 1 diabetes (T1D) is unclear. Design We evaluated the expression and changes in function of circulating Tfr cells by studying patients with T1D alongside those with type 2 diabetes (T2D), first-degree relatives of T1D patients, and healthy controls. We also investigated the effects of Tfr cells on disease development in nonobese diabetic (NOD) mice and in an adoptive transfer model. Results Tfr cells were significantly decreased in both patient groups. However, they showed different correlations with fasting C-peptide (C-P) and the area under the curve of blood C-P in patients with T1D and T2D. The frequency of Tfr cells was associated with the number of positive autoantibodies and the titer of glutamic acid decarboxylase autoantibody in T1D patients. Furthermore, Tfr cells decreased significantly after 1 year of follow-up. We also observed Tfr cells in four T1D patients treated with rituximab. After rituximab therapy, the frequency of C-X-C motif chemokine receptor 5 (CXCR5)+ programmed death 1+ Tfr cells was decreased and of CXCR5+ inducible costimulator+ Tfr cells was increased in three patients. We also found that Tfr cells were associated with the development of diabetes in NOD mice and an adoptive transfer model. Conclusions Tfr cell deficiency could be involved in the pathogenesis of T1D. Therapy with Tfr cells has potential value for T1D. Modulation of these cells may enhance protective immunity to inhibit autoimmune diabetes.