Despite affecting up to 15% of people in their lifetime the pathogenesis of human autoimmune diseases remains poorly understood. While different autoimmune diseases display a range of clinical presentations, they all share a common pathological process that involve “rogue” immune cells escaping tolerance checkpoint mechanisms and involving somatic mutations in immune and epigenetic regulator genes that may drive autoreactive lymphocytes to survive, proliferate and cause tissue and organ damage/dysfunction.Celiac disease (CeD), which is an autoimmune disorder of the small intestine affecting 1% of people, is an excellent model for studying the ground-breaking concept of rogue cells escaping tolerance mechanisms because the environmental trigger is known (gluten).
Using single cell technology we will investigate how Rogue lymphocytes in CeD escape tolerance by evading immuno-checkpoints and acquire effector functions causing autoimmune disease via the acquisition of somatic DNA mutations in key immune and epigenetic regulatory genes. We will determine the immune phenotype of rogue cells in CeD and identify the landscape of somatic mutations in rogue cells. This proposal challenges current paradigm on understanding the origin of autoimmune responses by directly identifying the small population of autoreactive clones that underpin immunopathogenesis in CeD.