Role of gut protists in celiac disease

项目总结

Project Summary Celiac disease (CeD) is mediated by abnormal immune responses to gluten antigens found in wheat, barley, and rye and has an estimated prevalence of 1% in the general US population. Normally, tolerogenic dendritic cells (DCs) sample dietary antigens from the intestinal lumen and are central in establishing and maintaining oral tolerance. In persons with CeD the suppression of gluten-specific immune responses is impaired (loss of oral tolerance (LOT)). LOT is characterized by dampened regulatory T cell (Treg) responses, resulting in inflammatory T helper 1 (Th1) immune responses against gluten in genetically susceptible individuals expressing the human leukocyte antigen (HLA) DQ2 or DQ8 alleles. The Th1 response against gluten is central to CeD pathogenesis and precedes the development of villous atrophy, the pathological hallmark of CeD. HLA DQ2 or DQ8 increases the risk of CeD and is required for CeD development, but neither is sufficient. Epidemiological and immunological observations support a role for additional genetic and environmental factors in CeD pathogenesis. In line with this hypothesis, we and others have discovered that both, interleukin-15 (IL-15) overexpression in the intestine and enteric virus infections promote LOT to gluten by inducing a proinflammatory program in otherwise tolerogenic DCs, which in turn triggers adverse inflammatory Th1 responses to gluten in CeD-relevant mouse models. One promising strategy to promote oral tolerance and to prevent or revert LOT in CeD is to use the immunoregulatory potential of commensal gut microbes. The planned research is based on a novel phenomenon that we just learned from host-protist interactions: commensal gut colonizing protists of the order Parabasalia promote tolerogenic mucosal immune responses to dietary antigens, resulting in the prevention of virus-induced LOT. We hypothesize that gut Parabasalia promote oral tolerance to dietary gluten, prevent LOT and revert LOT to gluten in CeD mouse models by directly modulating dietary-antigen presenting CD103+ DCs. We further posit that individuals colonized with Parabasalia have decreased risk of developing CeD. These are all original concepts in the field of CeD. The technical innovation in this proposal stems from: well-defined and highly relevant humanized CeD mouse models, new approaches to study human gut colonizing Parabasalia in oral tolerance, and cutting-edge next-generation sequencing tools to determine Parabasalia- induced functional changes in CD103+ DCs to delineate the mechanism of how Parabasalia promote oral tolerance and protect from LOT to gluten in CeD. Taken together, we will use conceptually and technically innovative studies to gain novel insights into how gut Parabasalia promote oral tolerance and prevent/revert LOT to gluten in CeD. Furthermore, this study will motivate the design of novel Parabasalia-based therapies to prevent LOT to gluten in individuals at-risk for developing CeD and to re-establish oral tolerance to gluten and thus ultimately has the potential to impact fields of immunology and cell biology fundamentally.