Question

How was the Immune dysregulation disease, polndocrinopathy, X-linked enteropathy (IPEX) discovered, how it initially diagnosed as compared to now? What is the relevance of this disease in modern medicine, what can we learn from it? Give resources.

Answer 1

IMMUNE DYSREGULATION POLYENDOCRINOPATHY ENTEROPATHY X LINKED

Immunodysregulation polyendocrinopathy enteropathy X-linked (or IPEX) syndrome is a rare disease linked to the dysfunction of the transcription factor FOXP3, widely considered to be the master regulator of the regulatory T cell lineage. It leads to the dysfunction of regulatory T-cells and the subsequent autoimmunity. The disorder is one of the autoimmune polyendocrine syndromes and manifests with autoimmune enteropathy, psoriasiform or eczematous dermatitis, nail dystrophy, autoimmune endocrinopathies, and autoimmune skin conditions such as alopecia universalis and bullous pemphigoid.Management for IPEX has seen limited success in treating the syndrome by bone marrow transplantation.

syndrome is inherited in males via an x-linked recessive manner, as the FOXP3 gene, whose cytogenetic location is Xp11.23, is involved in the mechanism of this condition.

Mutation of FOXP3 leading to expression of malfunctioning protein is often localised in DNA-binding domain called the forkhead domain. The truncated protein can not bind to its binding-spot on the DNA and thus its function concerning T regulatory lymphocytes development and functioning is impaired. The absence or dysfunction of regulatory T cells is the cause of autoimmune symptoms.

Data from 2018 describes over 70 mutations in FOXP3 gene leading to IPEX syndrome. Nonetheless, this number is still changing with new cases and discoveries coming.For example in 2010 there were only 20 mutations of FOXP3 known in the literature.

DIAGNOSIS

The diagnosis of immunodysregulation polyendocrinopathy enteropathy X-linked syndrome is consistent with the following criteria

• Clinical examination
• Family history
• Laboratory findings
• Genetic testing TREATMENTS     

• FK506(Tacrolimus)

  In terms of treatment the following are done to manage the IPEX syndrome in those affected individuals (corticosteroids are the first treatment that is used):[4][3]

• TPN (nutritional purpose)
• Cyclosporin A and FK506
• Sirolimus (should FK506 prove non-effective)
• Granulocyte colony stimulating factor
• Bone marrow transplant
• Rituximab   

RESEARCH  

There is as well a special mouse model simulating the development and progression of the IPEX syndrome. The model mice are called "scurfy mice" and they have had 2 base pairs inserted within the Foxp3 gene. Consequently, this leads to a frameshift and the expressed protein is truncated, causing the same effects as FOXP3 mutation in humans. The mice suffer from enlarged spleen and lymph nodes, redness in eyes and skin abnormalities. The mice as well suffer from immunity problems and after approximately 3 weeks they die  

REFERENCE'S

1) RESERVED, INSERM US14 -- ALL RIGHTS. "Orphanet: Immune dysregulation polyendocrinopathy enteropathy X linked syndrome". www.orpha.net. Retrieved 2017-04-18.

2)  Wildin RS, Smyk-Pearson S, Filipovich AH (August 2002). "Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome". J Med Genet. 39 (8): 537–45. doi:10.1136/jmg.39.8.537. PMC 1735203. PMID 12161590.

3) ^ Verbsky, James W.; Chatila, Talal A. (2017-04-18). "Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) and IPEX-Related Disorders: an Evolving Web of Heritable Autoimmune Diseases". Current Opinion in Pediatrics. 25 (6): 708–714. doi:10.1097/MOP.0000000000000029. ISSN 1040-8703. PMC 4047515. PMID 24240290.