Etiology of autoimmune (type 1) diabetes

The purpose is to clarify the etiological mechanisms by which beta cells are attacked by virus causing an autoimmune reaction or spontaneously attacked in the BB rat.

Specific aim 1:  to investigate if prolonged enterovirus shedding in children with a first autoantibody results in a persistent infection.

Specifically, we will determine if the appearance of either IAA-first or GADA-first is related to the presence of enterovirus in sorted peripheral blood cells in 11-15-year-old TEDDY children. The hypothesis is that these children have a persistent virus infection.

Specifically, we will determine enterovirus RNA in neutrophils, macrophages, CD4+ and CD8+ T cells as well as in B cells sorted from children without or with beta cell autoantibodies at their last visits to TEDDY.

During these last years of TEDDY (2021-2023), we will uncover if children with IAA-first or GADA-first since early life carry more chronic infections.

Specific aim 2: to determine in the spontaneously diabetic BB rat, plasma levels of IgE as a novel biomarker to dissect initiation of  insulitis and diabetes. Using IgE levels as a biomarker preceding insulitis we will predict onset of insulitis.

We test the hypothesis that a signal generated by the absence of the Gimap5 protein results in accumulation of HA, followed by CD68 cell-CD4+ and CD8+ T cells.

Prediction of the genetically controlled rapid insulitis allow dissection of MHC controlled beta-cell killing in a way not possible in humans.