Project 466637

Type 1 Diabetes (T1D) is an autoimmune disease that involves the destruction of insulin-producing cells in the pancreas by autoreactive lymphocytes. Research has shown that abnormalities in the gut play a significant role in disease development. Two key features of a healthy gut include the presence of a community of microorganisms called the microbiota as well as secretions of Immunoglobulin A (IgA) into the gut. During infancy when the immune system is immature, breast milk provides copious amounts of IgAas well as a sampling of the maternal microbiota, both delivered directly to the infant gut. In both infants and adults, the IgA and microbiota work together to preserve the integrity of the gut barrier and regulate immune responses both in the gut and systemically. Interestingly, common T1D features include chronic gut inflammation, altered gut microbiota, loss of gut integrity and barrier function as well as an increased incidence of IgA deficiency. We hypothesized that IgA in the gut plays a protective role in the development of T1D and that a deficiency of IgA would enhance disease. We have addressed this using a non-obese diabetic mouse model (NOD), comparing disease onset and progression in IgA-deficient mice versus their IgA-sufficient littermates. Interestingly, the major contributing factor of disease incidence in our model is maternal IgA availability. Specifically, offspring of IgA-deficient dams show significantly lower disease incidence. Analysis of lymphocyte populations has shown differences in proportion, activation state and cytokine production in the bowels and associated draining lymph nodes. We aim to further characterize these population differences with links to IgA-mediated microbiome:immune crosstalk and to determine their role in disease.