Underlying IPEX Syndrome in a Patient With Idiopathic Juvenile Arthritis and Vitiligo

IPEX syndrome (MIM #304790) also known as immune dysregulation, polyendocrinopathy, enteropathy, X-linked is a monogenic inborn error of immunity due to loss-of-function mutations in the forkhead box 3 (FOXP3) gene. This gene is crucial for the development, maturation and maintenance of CD4+ regulatory T (T-reg) cells. Various phenomenon mainly of autoimmune origin are characteristics of the syndrome such as enteropathy, endocrinopathies, cytopenias, renal disorders and skin manifestations (1).

Gastric Adenocarcinoma in the Setting of IPEX Syndrome

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare X-linked disorder caused by a loss of function mutation in the FOXP3 gene. It manifests early in infancy with clinical symptoms including autoimmune enteropathy, type 1 diabetes mellitus, and eczema. While aberrant FOXP3 expression has been associated with several types of cancer, little is known regarding the risk of cancer in patients with IPEX harboring the characteristic FOXP3 mutation. Here, we present a unique case of a primary signet ring gastric adenocarcinoma in a pediatric patient with IPEX syndrome.

IL-4 inhibits regulatory T cells differentiation by HDAC9-mediated epigenetic regulation

Regulatory T cells play a crucial role in orchestrating immune response and maintaining immune tolerance, and the expression of the Foxp3 gene is indispensable to the differentiation of regulatory T cells. IL-4 shows strong inhibitory effects on Foxp3 expression and regulatory T cells differentiation, but the detailed mechanisms are still unclear. Here, we revealed that epigenetic modulations are key to this process. Specifically, the inhibition was found to be STAT6 dependent, and HDAC9 was involved with the process of histone deacetylation at the Foxp3 locus, subsequently decreasing chromatin accessibility and Foxp3 gene transcription. Pan-histone deacetylation inhibitors, especially sodium butyrate, notably abolished the inhibitory effects of IL-4 and ameliorated allergic airway inflammation in mouse models. Our research provides important mechanistic insights into how IL-4 inhibits regulatory T cells differentiation and suggests the therapeutic potential of the sodium butyrate in allergic airway disease.