Clinical and immunological features of adult-onset generalized autoimmune gut disorder

OBJECTIVES: Autoimmune enteropathy is a rare disorder of unknown pathogenesis, characterized by protracted diarrhea, villous atrophy, and enterocyte autoantibodies. Its association with extended inflammation of the whole gastrointestinal tract is termed as generalized autoimmune gut disorder (GAGD), generally a pediatric disease of difficult management due to its association with immunodeficiency. The aim of our work is to describe the mucosal immunological basis of an adult-onset case of GAGD. METHODS: We studied an adult female with a severe inflammatory involvement of the gastrointestinal tract (stomach, small and large bowel, and liver) and antienterocyte autoantibodies. She had antibody deficiency and a predisposition to systemic autoimmunity. We analyzed, by immunohistochemistry and flow cytometry, the phenotypic and functional characteristics of her intestinal intraepithelial and lamina propria (LP) lymphocytes. RESULTS: We observed the prominent and constant presence of an unusual CD4+alphaE/beta7- Tc subset in the jejunal epithelium. Signs of the lymphocyte activation as well as the prominent lymphoid TNF-alpha production observed in the rectal mucosa support the involvement of a cell-mediated pro-inflammatory response in the pathogenesis of GAGD. CONCLUSIONS: We report the second case of an adult fulfilling all diagnostic criteria for GAGD. We propose that the activated LP CD4+ T lymphocytes, as well as those atypically located in the epithelium, may play a pathogenic role. The alphaE/beta7- IEL could constitute a diagnostic marker of intestinal autoimmunity in the cases when autoantibodies are not evidenced, and mucosal TNF-alpha might represent a novel therapeutic target in this severe disease.