Abstract
While B cells play a significant role in the onset of type-1 diabetes (T1D), little is know about their role in those early stages. Thus, to gain new insights into the role of B cells in T1D, we converted a physiological early pancreas-infiltrating B cell into a novel BCR mouse model using Somatic Cell Nuclear Transfer (SCNT). Strikingly, SCNT-derived B1411 model displayed neither developmental block nor anergy. Instead, B1411 underwent spontaneous germinal center reactions. Without T cell help, B1411-Rag1−/− was capable of forming peri-/intra-pancreatic lymph nodes, and undergoing class-switching. RNA-Seq analysis identified 93 differentially expressed genes in B1411 compared to WT B cells, including Irf7, Usp18, and Mda5 that had been linked to a potential viral etiology of T1D. We also found various members of the oligoadenylate synthase (OAS) family to be enriched in B1411, such as Oas1, which had recently also been linked to T1D. Strikingly, when challenged with glucose B1411-Rag1−/− mice displayed impaired glucose tolerance.
Highlights
Autoimmune Type-1 diabetes mellitus (T1D) is caused by the destruction of pancreatic insulinsecreting β-cells [1]
While the lymph nodes of WT non-obese diabetic (NOD) (Figures 1D,E) showed a wellpreserved normal germinal center reaction, B1411-Rag1−/− mice (Figures 1I,J) showed large bright structures in every of the examined lymph nodes independent of its location
In line with our germinal center (GC) B cell data, we found a significant increase in follicular helper T (TFH) cells in B1411-IgμhomIgκhom compared to WT NOD mice (Figure 5B) indicating that the cognate autoantigen is present in untreated NOD mice
Summary
Autoimmune Type-1 diabetes mellitus (T1D) is caused by the destruction of pancreatic insulinsecreting β-cells [1]. The autoimmune attack on pancreatic β-cells is executed by both innate and adaptive immune cells [12]. Among the adaptive immune cells, a major focus had been on CD4+ and CD8+ T cells This is probably due to reports in the non-obese diabetic (NOD) mouse model showing that disease can be induced in recipient mice only by adoptive transfer of CD4+ and CD8+ T cells isolated from diabetic mice [13,14,15,16]. While depletion of B cells by antibody injection or gene targeting lessened the T1D manifestation in NOD mice, B cells alone were not capable of inducing T1D upon adoptive transfer into recipient mice [19, 20]. Clinical studies further support an essential role of B cells in T1D based on the observation that B cell-depleting treatments lead to an improvement in pancreatic β-cell function [21]
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