From IPEX syndrome to FOXP3 mutation: a lesson on immune dysregulation

Abstract

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare disorder that increasingly has gained attention as a model of genetic autoimmunity. Numerous papers documenting the key clinical and molecular characteristics of IPEX have provided a detailed understanding of this devastating disease. IPEX is a primary immunodeficiency caused by mutations in the gene FOXP3, which encodes an essential transcription factor required for maintenance of thymus-derived regulatory T (tT reg ) cells. tT reg cell dysfunction is the main pathogenic event leading to multiorgan autoimmunity in IPEX. In addition to the traditional clinical presentation (i.e., severe enteropathy, type 1 diabetes, and eczema), IPEX may encompass other variable and distinct clinical manifestations. As IPEX awareness and characterization have increased, so has identification of FOXP3 mutations, with at least 70 to date. Thus, while FOXP3 is the unifying gene, IPEX is a complex and diverse clinical continuum of disorders. Despite understanding IPEX pathogenesis, new treatment options have remained elusive, although early diagnosis led to hematopoietic stem cell transplantation (HSCT) and immunosuppression treatment and improved patient outcomes. Here, we review current knowledge about IPEX syndrome and highlight findings that could lead to novel targeted treatments.

DOCK8 enforces immunological tolerance by promoting IL-2 signaling and immune synapse formation in Tregs

“…TCR signaling is also important for the induction of Foxp3 gene transcription and Treg function (10). FOXP3 is dispensable for Treg development but is crucial for Treg function, as evidenced by the development of severe autoimmunity in patients and mice deficient in FOXP3 (11). Thus, both IL-2 signaling and TCR signaling are important for Treg function.…”

EXPRESSION OF FoxP3 TRANSCRIPTION FACTOR IN BRONCHIAL ASTHMA

“…На сегодняшний день не подвергается сомнению важнейшая роль FoxP3 в патогенезе раковых [6] и аутоим-мунных [3] заболеваний в качестве основного транскрипционного фактора Treg (регуляторная Т-клетка), а значит, и ключевого фактора сохра-нения иммунологического гомеостаза посред-ством реализации супрессивных функций [11].…”

Loss of microbiota depletes cross-reactive Foxp3+ Tregs leading to selective immunopathologies

“…A subset of autoimmune diseases likely has a purely genetic basis independent of failure of self-nonself discrimination, such as seen in AIRE or Foxp3 gene hypomorphisms (Bacchetta et al, 2016) and such genetic malfunctions would equally affect both self and nonself immune responses.…”