Previous studies indicate that B-lymphocytes play a key role activating diabetogenic T-lymphocytes during the development of autoimmune diabetes. Recently, two transgenic NOD mouse models were generated: the NOD- PerIg and the 116C-NOD mice. In NOD- PerIg mice, B-lymphocytes acquire an activated proliferative phenotype and support accelerated autoimmune diabetes development. In contrast, in 116C-NOD mice, B-lymphocytes display an anergic-like phenotype delaying autoimmune diabetes onset and decreasing disease incidence. The present study further evaluates the T- and B-lymphocyte phenotype in both models. In islet-infiltrating B-lymphocytes (IIBLs) from 116C-NOD mice, the expression of H2-K d and H2-A g7 is decreased, whereas that of BAFF, BAFF-R, and TACI is increased. In contrast, IIBLs from NOD- PerIg show an increase in CD86 and FAS expression. In addition, islet-infiltrating T-lymphocytes (IITLs) from NOD- PerIg mice exhibit an increase in PD-1 expression. Moreover, proliferation assays indicate a high capacity of B-lymphocytes from NOD- PerIg mice to secrete high amounts of cytokines and induce T-lymphocyte activation compared to 116C B-lymphocytes. This functional variability between 116C and PerIg B-lymphocytes ultimately results in differences in the ability to shape T-lymphocyte phenotype. These results support the role of B-lymphocytes as key regulators of T-lymphocytes in autoimmune diabetes and provide essential information on the phenotypic characteristics of the T- and B-lymphocytes involved in the autoimmune response in autoimmune diabetes.

IntroductionDuring the development of Autoimmune Diabetes (AD) an autoimmune attack against the Peripheral Nervous System occurs. To gain insight into this topic, analyses of Dorsal Root Ganglia (DRG) from Non-Obese Diabetic (NOD) mice were carried out.MethodsHistopathological analysis by electron and optical microscopy in DRG samples, and mRNA expression analyzes by the microarray technique in DRG and blood leukocyte samples from NOD and C57BL/6 mice were performed.ResultsThe results showed the formation of cytoplasmic vacuoles in DRG cells early in life that could be related to a neurodegenerative process. In view of these results, mRNA expression analyses were conducted to determine the cause and/or the molecules involved in this suspected disorder. The results showed that DRG cells from NOD mice have alterations in the transcription of a wide range of genes, which explain the previously observed alterations. In addition, differences in the transcription genes in white blood cells were also detected.DiscussionTaken together, these results indicate that functional defects are not only seen in beta cells but also in DRG in NOD mice. These results also indicate that these defects are not a consequence of the autoimmune process that takes place in NOD mice and suggest that they may be involved as triggers for its development.

Objective Type 1 diabetes (T1D) has been associated with alterations of the gut microbiota. Here we investigate the cross-talk between the immune system and the intestinal microbiota in murine T1D. Design To evaluate the modulation of T1D by gut microbiota, non-obese diabetic (NOD) mice were cohoused with the 116C-NOD B-cell transgenic model. To further explore the influence of the adaptive immune system of NOD and 116C-NOD models on their fecal microbiota, we studied the immunodeficient variants NOD.RAG-2-/- and 116C-NOD.RAG-2-/-, as well as a non-T1D-prone mouse control. The role of B and T cells in modulating the gut microbiota composition was analyzed via intravenous injection of lymphocytes. Only female mice were studied. Results NOD cohoused with 116C-NOD exhibited a reduction of T1D incidence. This incidence decrease was associated with a shift from a Th1 to a Th17 immune response and was driven by intestinal microbiota changes. Moreover, T1D could be predicted by different gut bacterial signatures in each group of T1D-prone mice. The proliferation of segmented filamentous bacteria, known as immune modulatory organisms, was enabled by the absence of T lymphocytes in young NOD, 116C-NOD, and immunodeficient NOD.RAG-2-/- and 116C-NOD.RAG-2-/- at all ages. Conversely, Bifidobacterium colonization required the presence of lymphocytes and was boosted in a non-diabetogenic milieu. Finally, 116C-NOD B cells enriched the gut microbiota of 116C-NOD.RAG-2-/- in Adlercreutzia. Conclusion Together, these findings evidence the reciprocal modulation of gut microbiota and the immune system in rodent models of T1D.