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.