Frontiers in Celiac Disease: Where Autoimmunity and Environment Meet.

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Celiac disease is a chronic, immune-mediated enteropathy driven by dietary gluten found in genetically susceptible hosts. It has a worldwide distribution, is one of the most common autoimmune disorders globally, and is the only autoimmune condition for which the trigger is known. Despite advances in characterizing mechanisms of disease, gaps in understanding of celiac disease pathogenesis remain. A "frontier" concept is considering what moves an HLA-DQ2 or DQ8-positive individual from asymptomatic gluten tolerance to celiac disease manifestation. In this arena, environmental triggers, including age at the time of initial gluten exposure, the occurrence of usual childhood viral infections, and microbiome alterations have emerged as key events in triggering the symptomatic disease. Pathologists play a major role in frontier aspects of celiac disease. This includes the discovery that duodenal mucosal histology in follow-up biopsies does not correlate with ongoing patient symptoms, antitissue transglutaminase antibody titers and diet adherence in celiac disease patients. Further, in light of recent evidence that the detection of monoclonal T-cell populations in formalin-fixed biopsies is not specific for type II refractory celiac disease, pathologists should resist performing such analyses until common causes of "apparent" refractoriness are excluded. The promise of therapies in celiac disease has led to clinical trials targeting many steps in the inflammatory cascade, which depend upon a pathologist's confirmation of the initial diagnosis and evaluation of responses to therapies. As pathologists continue to be active participants in celiac disease research, partnering with other stakeholders, we will continue to impact this important autoimmune disease.