| IPEX syndrome | |
|---|---|
| Other names | Autoimmune enteropathy type 1[1] |
 | |
| IPEX syndrome is inherited via X-linked recessive | |
| Specialty | Immunology  |
| Symptoms | Lymphadenopathy[2] |
| Causes | FOXP3 gene mutation[1] |
| Diagnostic method | Family history, Genetic test[1] |
| Treatment | TPN(nutritional purpose), Cyclosporin A and FK506, Bone marrow transplant[3][4] |
Immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX syndrome) is a rareautoimmune disease. It is one of theautoimmune polyendocrine syndromes. Most often, IPEX presents withautoimmune enteropathy,dermatitis (eczema), and autoimmuneendocrinopathy (most oftenType 1 diabetes), but other presentations exist.[5]
IPEX is caused by mutations in the geneFOXP3, which encodes transcription factor forkhead box P3 (FOXP3). FOXP3 is widely considered to be themaster regulator of theregulatory T cell (Treg) lineage.[6][7]FOXP3 mutation can lead to the dysfunction of CD4+ Tregs. In healthy people, Tregs maintain immunehomeostasis.[8] When there is a deleteriousFOXP3 mutation, Tregs do not function properly and causeautoimmunity.[8][9]
IPEX onset usually happens ininfancy. If left untreated, it is often fatal by the age of 2 or 3.[10][11] Abone marrow transplant is generally considered the best treatment option.[11] IPEX exclusively affects males and is inherited in anX-linked recessive manner;[1][2] female carriers of pathogenicFOXP3 mutations do not have symptoms and no female cases are known.[4]
The classical triad describes the most common symptoms of IPEX: intractablediarrhea,type 1 diabetes, andeczema. Symptoms usually begin shortly after birth.[12]
Other symptoms include:thyroid disease,kidney dysfunction,blood disorders, frequent infections,autoimmune hemolytic anemia, and food allergies, among others.[10]
The most commonendocrinopathy associated with IPEX istype 1 diabetes, especiallyneonatal diabetes. In this type of diabetes, the immune system attacksinsulin-producing cells. This makes the pancreas unable to produceinsulin. Diabetes can permanently damage thepancreas.[13]
Thyroid disorders are also common.[14]
The most commonenteropathy associated with IPEX is intractablediarrhea. Vomiting andgastritis are also common. Other manifestations includeCeliac disease,ulcerative colitis, andileus.[14]
The most common form of skin involvement isdermatitis. It can occur in three forms: eczematiform (mainlyatopic dermatitis), ichthyosiform, psoriasiform, or a combination. Other skin manifestations can includecheilitis,onychodystrophy, andalopecia.[14]
IPEX patients are usually born with normal weight and length at term. Nevertheless, the first symptoms may present in the first days of life,[15] and some reported cases labeled newborns withintrauterine growth restriction and evidence ofmeconium in theamniotic fluid.[16]
IPEX syndrome is inherited in males in anX-linked recessive pattern through theFOXP3 gene.FOXP3'scytogenetic location is Xp11.23.[6][7] TheFOXP3 gene has 12exons and its full reading open frame encodes 431amino acids. FOXP3 is a member of the FKH family oftranscription factors and contains a proline‐rich (PRR)amino‐terminal domain, centralzinc finger (ZF) andleucine zipper (LZ) domains important for protein–protein interactions. It also has acarboxyl‐terminal FKH domain required for nuclear localization and DNA‐binding activity. In humans, exons 2 and 7 may be spliced and excluded from theprotein.[17]
A large variety ofmutations have been found, including single base substitutions, deletions, and splicing mutations. Data from 2018 describes over 70 mutations in theFOXP3 gene leading to IPEX syndrome. This number has grown dramatically in the past decade.[18] In 2010 there were only 20 mutations ofFOXP3 known in the literature.[19] Some mutations causeFOXP3 expression to malfunction, which leads to a defect in Treg production. Those individuals do not have circulating CD4+/CD25+/FOXP3+ Treg cells. Reduced expression of FOXP3 has been described, and these individuals may express normal levels of dysfunctional protein, which leads to mild symptoms during theneonatal period or later in life. Other individuals express no FOXP3 protein.[20] A common location for mutation ofFOXP3 leading to expression of malfunctioning protein is theDNA-binding domain called theforkhead domain. The mutation makes the truncated protein unable to bind to itsDNA binding site. This impairs its function concerning Treg development and functioning. The absence or dysfunction of Tregs causesautoimmune symptoms.[19]
FOXP3 can function as both arepressor and atrans‐activator of Treg cells depending on its interactions with other proteins. FOXP3 expression is characterised by controllingtranscription, influencingepigenetic changes andpost-transcriptional modifications. The N‐terminal repressor domain of FOXP3 can change transcription or epigenetic regulation of Treg cells. Transcriptional activity is altered through interactions between the N-terminal domain andEos - which associates withCtBP1 and forms acorepressor complex. This complex binds theIL2promoter and enables FOXP3 to repressIL2 transcription in Treg cells. FOXP3 forms complexes with histone deacetylase(HDAC)7,HDAC9, and thehistone acetyl transferaseTIP60, which alters epigenetic activity of Treg cells. The N‐terminal domain of FOXP3 can also antagonize the transcription factorsRORγ and RORα, thereby inhibitingTH17cell differentiation. FOXP3 is linked to TCR signaling by downstream transcription factors. All of these findings verify the importance of FOXP3 in the regulation of transcriptional activity and repression in Treg cells.[17]
Early detection of the disease is crucial because IPEX has a highmortality level if left untreated.[20] IPEX is usually diagnosed based on the following criteria:[1][4]
Individuals with IPEX will usually need supportive care in a hospital. Most common is nutritional treatment for enteropathy and insulin therapy for T1D. IPEX treatment tends to focus on managing symptoms, reducing autoimmunity, and/or treating secondary conditions. Usually, treatment will involve immunosuppression.[11]
Drugs used include:
Currently, the standard treatment for IPEX is a bone marrow transplant. If donor-recipient chimerism is achieved, individuals with IPEX can achieve complete remission.[11]
In 1982, Powel et al. published a case report of a family with 19 males who were affected by an X-linked syndrome with symptoms including polyendocrinopathy and diarrhea. The most common symptoms in this family were severe enteropathy, T1D, and dermatitis. Only 2 of the 19 affected males in the family survived past 3 years old. These individuals lived to 10 and 30 years old.[21] Powel's study is now widely considered the first documentation of IPEX.[citation needed]
Scurfy is a type of model mouse used forimmunology research.Scurfy mice have had 2base pairs inserted within the FOXP3 gene. This leads to aframeshift mutation in FOXP3 gene and the expressed protein is truncated, causing functional deficiency of Treg cells. Then, autoreactive CD4+T cells and inflammatory cells cause tissue damage.[22]Scurfy mice have an enlargedspleen andlymph nodes, squinted red eyes, and scaly or "ruffled" skin. The mice also have immunity problems and tend to die approximately 3 weeks after birth.[18] From 2000 - 2001, multiple studies confirmed that IPEX is the human equivalent ofscurfy mice and that the FOXP3 gene is responsible.[10]
