Genetic Disorders of Immune Tolerance: The Flip Side of Immune Deficiency Where Autoimmunity Trumps Infection

Primary Immune Regulatory Disorders (PIRD) are group of congenital Immunodeficiencies that present primarily with autoimmunity and less frequently with infections. The paradigm for these disorders is the syndrome of Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX), a disorder caused by a lack of functional regulatory T cells due defects in the lineage-specifying transcription factor, FOXP3. We have collected and evaluated a large cohort of patients with clinical manifestations suggestive of IPEX and have found FOXP3 mutations in more than 90 patients. This has informed our further investigation into the structure and function of the FOXP3 transcription factor. In patients that have IPEX-like clinical features but lack FOXP3 mutations, we have identified defects in several other genes now associated with an IPEX-like clinical phenotype, including germline STAT1 and STAT3 gain-of-function (GOF) mutations, CTLA4 haploinsufficiency, LRBA deficiency and others. We have shown that within this cohort, all have IPEX-like clinical features but there are some clinical and laboratory features that can help with differentiating between the different genetic syndromes. To determine the best approach to treatment of these disorders, we have also collected data on the international experience with bone marrow transplant for some of these disorders including IPEX, CTLA4 haploinsufficiency, STAT1-GOF, and STAT3-GOF disease. We have demonstrated that bone marrow transplant can be curative for each of these disorders but that patients with autosomal dominant gain-of-function mutations in STAT1 and STAT3 may pose unique challenges for transplant that will be discussed. These data will be presented along with preliminary data suggesting non-transplant approaches to management using targeted therapies.