Autoimmunity and chronic inflammatory diseases develop as a result of a complex interplay of genetic, environmental, and lifestyle factors that are unique to each individual. However, these diseases manifest in a common immunologic response defined by a persistent hyper-responsiveness to self-tissues, environmental antigens, or commensal microorganisms. Notably, recent genetic and experimental evidence demonstrate that IL-17 producing CD4 T helper (Th17) cells are a major pathogenic cell type involved in the pathogenesis of inflammatory bowel disease (IBD), multiple sclerosis (MS), and rheumatoid arthritis (RA). Despite these advances, it remains poorly understood how Th17 cells are induced and regulated in the context of autoimmunity. Recently my host laboratory defined that a related cell type of the innate immune system, termed group 3 innate lymphoid cells (ILC3), play an essential tolerogenic role in the intestine by restraining Th17 cell responses to commensal bacteria through antigen-presentation via major histocompatibility complex class II (MHCII+ ILC3). In new preliminary data generated for this proposal, I now define that MHCII+ ILC3 functionally impact the progression of experimental autoimmune encephalomyelitis (EAE), an animal model for T-cell mediated human multiple sclerosis (MS), and further test whether we can employ this tolerogenic pathway to prevent EAE. The fundamental focus of this research proposal is to better define how ILC3/T cell interactions occur and functionally impact the progression of autoimmunity to self-antigens. It is expected that results from the two aims of this proposal will crucially define the role and therapeutic potential of modulating interactions between ILC3s and CD4 T cells in the context of MS that could be extended to other forms of T cell mediated autoimmunity.
Considering all types of autoimmunity, the estimated incidence rate of autoimmune disease is at 4.5%, making these diseases a significant public health issue and economic burden. Currently, there are limited anti- inflammatory treatment options available for autoimmune diseases and chronic use of anti-inflammatory therapies often comes with severe side-effects including increased susceptibility to infection and neoplasia. This research proposal includes novel experiments to more precisely interrogate cellular interactions that underlie tissue-specific inflammation in autoimmunity, and also explores whether a subset of immune cells could be utilized to preventatively, or therapeutically, induce antigen-specific tolerance in autoimmunity.
