Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) and IPEX-related disorders: an evolving web of heritable autoimmune diseases.
OBJECTIVE
To summarize recent progress in our understanding of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) and IPEX-related disorders.


RESULTS
A number of Mendelian disorders of immune dysregulation and autoimmunity have been noted to result from defects in T regulatory cell, development and function. The best characterized of these is IPEX, resulting from mutations affecting FOXP3. A number of other gene defects that affect T regulatory cell function also give rise to IPEX-related phenotypes, including loss-of-function mutations in CD25, STAT5b and ITCH. Recent progress includes the identification of gain-of-function mutations in STAT1 as a cause of an IPEX-like disease, emerging FOXP3 genotype/phenotype relationships in IPEX, and the elucidation of a role for the microbiota in the immune dysregulation associated with regulatory T cell deficiency.


CONCLUSIONS
An expanding spectrum of genetic defects that compromise T regulatory cell function underlies human disorders of immune dysregulation and autoimmunity. Collectively, these disorders offer novel insights into pathways of peripheral tolerance and their disruption in autoimmunity.
aDepartment of Pediatrics, Division of Rheumatology, Medical College of Wisconsin, Milwaukee, Wisconsin bDepartment of Pediatrics, Division of Immunology, The Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
James W
JW
Verbsky
Talal A
TA
Chatila
D001323:Autoantibodies / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000151:congenital; D003967:Diarrhea / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology*; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D020022:Genetic Predisposition to Disease; D006801:Humans; D007154:Immune System Diseases / Q000151:congenital; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology*; D007410:Intestinal Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008297:Male; D009154:Mutation / Q000235:genetics; D016884:Polyendocrinopathies, Autoimmune / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology*; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000276:immunology*
D001323:Autoantibodies; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit; D012097:Repressor Proteins; D050799:STAT5 Transcription Factor; C494095:STAT5B protein, human; C432966:ITCH protein, human; D044767:Ubiquitin-Protein Ligases