Autoimmune enteropathy: molecular concepts

Abstract

Enteropathies causing temporary or permanent intestinal failure are a big diagnostic and therapeutic challenge for pediatric gastroenterologists. A now well-recognized and distinct entity is in the form of "autoimmune enteropathy (AIE)". Recent advances in the molecular workup of AIE gave first insight into the pathophysiology of AIE. In this review, we discuss new molecular concepts of AIE resulting in new diagnostic and therapeutic possibilities. The identification of disease-causing mutations in the FOXP3 gene as a basic defect resulting in AIE points to a defect in regulatory T-cell homeostasis. FOXP3, primarily expressed by CD4+CD25+regulatory T cells, is a potent transcriptional suppressor and key modulator of T-cell functions. Nonfunctional FOXP3 leads to a tremendous hyperactivation of T cells, resulting in autoimmune aggression, such as seen in patients with immune dysregulation, polyendocrinopathy autoimmune enteropathy X-linked (IPEX) syndrome, a subgroup of AIE. There is recent evidence suggesting that a defect of regulatory factors other than FOXP3 might cause AIE. Anti-enterocyte autoantibodies, another main characteristic of AIE, seem to be of a secondary nature and can no more be considered as directly disease causing. Based on the profound immune dysregulation, new treatment strategies emerged for AIE. The use of T-cell immunosuppressive drugs, such as tacrolimus combined to steroids, seems to be beneficial in some patients; however, long-term remission is not always possible. Bone marrow transplantation might be the treatment of choice in those patients who do not respond to immunosuppression; however, the first encouraging results remain to be confirmed since to date long-term outcome remains mixed.