IPEX syndrome

The classical triad describes the most common symptoms of IPEX: intractable diarrhea, type 1 diabetes, and eczema. 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 common endocrinopathy associated with IPEX is type 1 diabetes, especially neonatal diabetes. In this type of diabetes, the immune system attacks insulin-producing cells. This makes the pancreas unable to produce insulin. Diabetes can permanently damage the pancreas.[13]

Thyroid disorders are also common.[14]

The most common enteropathy associated with IPEX is intractable diarrhea. Vomiting and gastritis are also common. Other manifestations include Celiac disease, ulcerative colitis, and ileus.[14]

Eczema

The most common form of skin involvement is dermatitis. It can occur in three forms: eczematiform (mainly atopic dermatitis), ichthyosiform, psoriasiform, or a combination. Other skin manifestations can include cheilitis, onychodystrophy, and alopecia.[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 with intrauterine growth restriction and evidence of meconium in the amniotic fluid.[16]

IPEX syndrome is inherited in males in an X-linked recessive pattern through the FOXP3 gene. FOXP3's cytogenetic location is Xp11.23.[6][7] The FOXP3 gene has 12 exons and its full reading open frame encodes 431 amino acids. FOXP3 is a member of the FKH family of transcription factors and contains a proline‐rich (PRR) amino‐terminal domain, central zinc finger (ZF) and leucine zipper (LZ) domains important for protein–protein interactions. It also has a carboxyl‐terminal FKH domain required for nuclear localization and DNA‐binding activity. In humans, exons 2 and 7 may be spliced and excluded from the protein.[17]

A large variety of mutations have been found, including single base substitutions, deletions, and splicing mutations. Data from 2018 describes over 70 mutations in the FOXP3 gene leading to IPEX syndrome. This number has grown dramatically in the past decade.[18] In 2010 there were only 20 mutations of FOXP3 known in the literature.[19] Some mutations cause FOXP3 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 the neonatal period or later in life. Other individuals express no FOXP3 protein.[20] A common location for mutation of FOXP3 leading to expression of malfunctioning protein is the DNA-binding domain called the forkhead domain. The mutation makes the truncated protein unable to bind to its DNA binding site. This impairs its function concerning Treg development and functioning. The absence or dysfunction of Tregs causes autoimmune symptoms.[19]

FOXP3 can function as both a repressor and a trans‐activator of T_reg cells depending on its interactions with other proteins. FOXP3 expression is characterised by controlling transcription, influencing epigenetic changes and post-transcriptional modifications. The N‐terminal repressor domain of FOXP3 can change transcription or epigenetic regulation of T_reg cells. Transcriptional activity is altered through interactions between the N-terminal domain and Eos - which associates with CtBP1 and forms a corepressor complex. This complex binds the IL2 promoter and enables FOXP3 to repress IL2 transcription in T_reg cells. FOXP3 forms complexes with histone deacetylase (HDAC)7, HDAC9, and the histone acetyl transferase TIP60, which alters epigenetic activity of T_reg cells. The N‐terminal domain of FOXP3 can also antagonize the transcription factors RORγ and RORα, thereby inhibiting TH17 cell 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 T_reg cells.[17]

Scurfy is a type of model mouse used for immunology research. Scurfy mice have had 2 base pairs inserted within the FOXP3 gene. This leads to a frameshift 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 enlarged spleen and lymph 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 of scurfy mice and that the FOXP3 gene is responsible.[10]