Both genetic susceptibility and environmental factors contribute to autoimmunity. Of the genetic factors, HLA has the strongest effect. However, a number of disease-associated genetic variants that are shared between several autoimmune diseases or fall within biological pathways have recently been identified in humans. Several of these genes encode proteins that are in cytokine signaling pathways. Cytokines are small molecules that act like local hormones. These cytokines can impact the type, duration and magnitude of an immune response making them a source of immune dysregulation when their expression or response is altered. In the Long Laboratory, we are studying how dysregulation of cytokine pathways in autoimmunity contribute to disease. Gaining a better understanding of the disease-related causes and consequences of defective cytokine signaling may lead to development of targeted therapies and more sensitive biomarkers.
Currently, we are focusing on the IL-2 and IL-15 signaling pathways in Type 1 diabetes (T1D). Both IL-2 and IL-15 support regulatory T cells, CD8 memory T cells and NK cells. Genetic variation in CD25 (the high affinity receptor for IL-2) and PTPN2 (a negative regulator of cytokine signaling) is associated with autoimmune diseases including T1D. Using genotype-phenotype and functional studies we are discovering the underlying molecular mechanisms of defective IL-2R signaling in T1D and the physiological impact of IL-2 dysregulation on lymphocytes.