Type 1 diabetes (T1D) is an autoimmune disease that occurs due to a complex interplay between genetic and environmental factors and is mediated by T cell responses against the insulin-producing beta cells. Despite the significant advancements in our understanding of T1D pathogenesis, there is still no cure for this chronic, life-long disease. The precise genetic drivers that lead to the disease and their environmental triggers remain poorly understood, and this knowledge gap hinders our ability to identify causative targets and hence preventative strategies and effective cure.
T1D is one of the most widely studied complex genetic disorders, with polymorphisms in the HLA genes as well as other genes associated with T cell functions to account for ~50% of T1D genetic risk 1,2. Despite these associations, it remains unknown why only some children develop T1D despite high genetic risk. Furthermore, about 7% of children with T1D also develop Coeliac Disease (CeD), an autoimmune disease that further increases life threatening risks and poor quality of life.
In this proposal we seek to utilize cutting edge single cell multi-omics techniques to test the novel hypothesis that the onset of autoimmunity is associated with clonal expansion of pathogenic T cells driven by genomic alterations specific to individual clones that break beta-cell specific tolerance. This proposal aims to generate a comprehensive single cell multi-omics profile of lymphocytes in children with T1D and CeD, identify aberrant T cell clones, and quantify their contribution to risk of disease.