IPEX syndrome

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IPEX syndrome
Other namesAutoimmune enteropathy type 1 [1]
X-linked recessive.svg
IPEX syndrome is inherited via X-linked recessive
Specialty Immunology   OOjs UI icon edit-ltr-progressive.svg
Symptoms Lymphadenopathy [2]
CausesFOXP3 gene mutation [1]
Diagnostic method Family history, Genetic test [1]
TreatmentTPN(nutritional purpose), Cyclosporin A and FK506, Bone marrow transplant [3] [4]

Immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX syndrome) is a rare autoimmune disease. It is one of the autoimmune polyendocrine syndromes. Most often, IPEX presents with autoimmune enteropathy, dermatitis (eczema), and autoimmune endocrinopathy (most often Type 1 diabetes), but other presentations exist. [5]

Contents

IPEX is caused by mutations in the gene FOXP3, which encodes transcription factor forkhead box P3 (FOXP3). FOXP3 is widely considered to be the master regulator of the regulatory T cell (Treg) lineage. [6] [7] FOXP3 mutation can lead to the dysfunction of CD4+ Tregs. In healthy people, Tregs maintain immune homeostasis. [8] When there is a deleterious FOXP3 mutation, Tregs do not function properly and cause autoimmunity. [8] [9]

IPEX onset usually happens in infancy. If left untreated, it is often fatal by the age of 2 or 3. [10] [11] A bone marrow transplant is generally considered the best treatment option. [11] IPEX exclusively affects males and is inherited in an X-linked recessive manner; [1] [2] female carriers of pathogenic FOXP3 mutations do not have symptoms and no female cases are known. [4]

Presentation

Classical triad

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]

Endocrinopathy

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]

Enteropathy

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 520 Eczema.jpg
Eczema
Skin manifestations

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]

Early life

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]

Genetics

Mutations in FOXP3 gene causing IPEX syndrome - known in the year 2012. IPEX Mutations.png
Mutations in FOXP3 gene causing IPEX syndrome - known in the year 2012.

FOXP3 gene

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]

FOXP3 mutations

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 pathways

FOXP3 can function as both a repressor and a trans‐activator of Treg 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 Treg 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 Treg cells. FOXP3 forms complexes with histone deacetylase (HDAC)7, HDAC9, and the histone acetyl transferase TIP60, which alters epigenetic activity of Treg 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 Treg cells. [17]

Diagnosis

Early detection of the disease is crucial because IPEX has a high mortality level if left untreated. [20] IPEX is usually diagnosed based on the following criteria: [1] [4]

Treatment

Tacrolimus Tacrolimus3Dan.gif
Tacrolimus

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]

Research

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 mouse

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]

See also

Related Research Articles

Immunodeficiency, also known as immunocompromisation, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that affect the patient's immune system. Examples of these extrinsic factors include HIV infection and environmental factors, such as nutrition. Immunocompromisation may also be due to genetic diseases/flaws such as SCID.

<span class="mw-page-title-main">Autoimmune polyendocrine syndrome</span> Medical condition

Autoimmune polyendocrine syndromes (APSs), also called polyglandular autoimmune syndromes (PGASs) or polyendocrine autoimmune syndromes (PASs), are a heterogeneous group of rare diseases characterized by autoimmune activity against more than one endocrine organ, although non-endocrine organs can be affected. There are three types of APS, and there are a number of other diseases which involve endocrine autoimmunity.

The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells. Treg cells express the biomarkers CD4, FOXP3, and CD25 and are thought to be derived from the same lineage as naïve CD4+ cells. Because effector T cells also express CD4 and CD25, Treg cells are very difficult to effectively discern from effector CD4+, making them difficult to study. Research has found that the cytokine transforming growth factor beta (TGF-β) is essential for Treg cells to differentiate from naïve CD4+ cells and is important in maintaining Treg cell homeostasis.

<span class="mw-page-title-main">Wiskott–Aldrich syndrome</span> Medical condition

Wiskott–Aldrich syndrome (WAS) is a rare X-linked recessive disease characterized by eczema, thrombocytopenia, immune deficiency, and bloody diarrhea. It is also sometimes called the eczema-thrombocytopenia-immunodeficiency syndrome in keeping with Aldrich's original description in 1954. The WAS-related disorders of X-linked thrombocytopenia (XLT) and X-linked congenital neutropenia (XLN) may present with similar but less severe symptoms and are caused by mutations of the same gene.

<span class="mw-page-title-main">FOXP3</span> Immune response protein

FOXP3, also known as scurfin, is a protein involved in immune system responses. A member of the FOX protein family, FOXP3 appears to function as a master regulator of the regulatory pathway in the development and function of regulatory T cells. Regulatory T cells generally turn the immune response down. In cancer, an excess of regulatory T cell activity can prevent the immune system from destroying cancer cells. In autoimmune disease, a deficiency of regulatory T cell activity can allow other autoimmune cells to attack the body's own tissues.

<span class="mw-page-title-main">Cytotoxic T-lymphocyte associated protein 4</span> Mammalian protein found in humans

Cytotoxic T-lymphocyte associated protein 4, (CTLA-4) also known as CD152, is a protein receptor that functions as an immune checkpoint and downregulates immune responses. CTLA-4 is constitutively expressed in regulatory T cells but only upregulated in conventional T cells after activation – a phenomenon which is particularly notable in cancers. It acts as an "off" switch when bound to CD80 or CD86 on the surface of antigen-presenting cells. It is encoded by the gene CTLA4 in humans.

Enteropathy refers to any pathology of the intestine. Although enteritis specifically refers to an inflammation of the intestine, and is thus a more specific term than "enteropathy", the two terms are sometimes used interchangeably.

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Immune dysregulation is any proposed or confirmed breakdown or maladaptive change in molecular control of immune system processes. For example, dysregulation is a component in the pathogenesis of autoimmune diseases and some cancers. Immune system dysfunction, as seen in IPEX syndrome leads to immune dysfunction, polyendocrinopathy, enteropathy, X-linked (IPEX). IPEX typically presents during the first few months of life with diabetes mellitus, intractable diarrhea, failure to thrive, eczema, and hemolytic anemia. unrestrained or unregulated immune response.

<span class="mw-page-title-main">Autoimmune regulator</span> Immune system protein

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<span class="mw-page-title-main">PTPN22</span> Protein-coding gene in the species Homo sapiens

Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is a cytoplasmatic protein encoded by gene PTPN22 and a member of PEST family of protein tyrosine phosphatases. This protein is also called "PEST-domain Enriched Phosphatase" ("PEP") or "Lymphoid phosphatase" ("LYP"). The name LYP is used strictly for the human protein encoded by PTPN22, but the name PEP is used only for its mouse homolog. However, both proteins have similar biological functions and show 70% identity in amino acid sequence. PTPN22 functions as a negative regulator of T cell receptor (TCR) signaling, which maintains homeostasis of T cell compartment.

<span class="mw-page-title-main">IL2RA</span> Mammalian protein found in Homo sapiens

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<span class="mw-page-title-main">Autoimmune polyendocrine syndrome type 1</span> Autoimmune condition causing dysfunction of endocrine glands

Autoimmune polyendocrine syndrome type 1 (APS-1), is a subtype of autoimmune polyendocrine syndrome. It causes the dysfunction of multiple endocrine glands due to autoimmunity. It is a genetic disorder, inherited in autosomal recessive fashion due to a defect in the AIRE gene , which is located on chromosome 21 and normally confers immune tolerance.

<span class="mw-page-title-main">CD25 deficiency</span> Medical condition

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<span class="mw-page-title-main">Autoimmune enteropathy</span> Medical condition

Autoimmune enteropathy is a rare autoimmune disorder characterized by weight loss from malabsorption, severe and protracted diarrhea, and autoimmune damage to the intestinal mucosa. Autoimmune enteropathy typically occurs in infants and younger children however, adult cases have been reported in literature. Autoimmune enteropathy was first described by Walker-Smith et al. in 1982.

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<span class="mw-page-title-main">LRBA deficiency</span> Medical condition

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References

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  2. 1 2 "Immunodysregulation, polyendocrinopathy and enteropathy X-linked | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Archived from the original on 2019-01-09. Retrieved 2017-04-16.
  3. ↑ Eisenbarth GS (2010-12-13). Immunoendocrinology: Scientific and Clinical Aspects. Springer Science & Business Media. pp. 129–138. ISBN   9781603274784.
  4. 1 2 3 Hannibal M, Torgerson T (1993-01-01). "IPEX Syndrome". In RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJ, Bird TD, Ledbetter N, Mefford H (eds.). GeneReviews. Seattle (WA): University of Washington, Seattle. PMID   20301297.update 2011
  5. ↑ "Embase". www.embase.com. Retrieved 2023-04-04.
  6. 1 2 "IPEX syndrome". Genetics Home Reference. Retrieved 2017-04-16.
  7. 1 2 "FOXP3 gene". Genetics Home Reference. Retrieved 2017-04-16.
  8. 1 2 Huang, Qianru; Liu, Xu; Zhang, Yujia; Huang, Jingyao; Li, Dan; Li, Bin (2020-01-20). "Molecular feature and therapeutic perspectives of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome". Journal of Genetics and Genomics. 47 (1): 17–26. doi: 10.1016/j.jgg.2019.11.011 . ISSN   1673-8527. PMID   32081609. S2CID   211231953.
  9. ↑ Bacchetta, Rosa; Barzaghi, Federica; Roncarolo, Maria-Grazia (April 2018). "From IPEX syndrome to FOXP3 mutation: a lesson on immune dysregulation: IPEX syndrome and FOXP3". Annals of the New York Academy of Sciences. 1417 (1): 5–22. Bibcode:2018NYASA1417....5B. doi: 10.1111/nyas.13011 . PMID   26918796. S2CID   11149833.
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  11. 1 2 3 4 Ben-Skowronek, Iwona (2021). "IPEX Syndrome: Genetics and Treatment Options". Genes. 12 (3): 323. doi: 10.3390/genes12030323 . ISSN   2073-4425. PMC   7995986 . PMID   33668198.
  12. ↑ Park JH, Lee KH, Jeon B, Ochs HD, Lee JS, Gee HY, et al. (June 2020). "Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome: A systematic review". Autoimmunity Reviews. 19 (6): 102526. doi:10.1016/j.autrev.2020.102526. PMID   32234571. S2CID   214768010.
  13. ↑ CDC (2022-03-11). "What Is Type 1 Diabetes?". Centers for Disease Control and Prevention. Retrieved 2023-04-16.
  14. 1 2 3 Park, Jae Hyon; Lee, Keum Hwa; Jeon, Bokyoung; Ochs, Hans D.; Lee, Joon Suk; Gee, Heon Yung; Seo, Seeun; Geum, Dongil; Piccirillo, Ciriaco A.; Eisenhut, Michael; van der Vliet, Hans J.; Lee, Jiwon M.; Kronbichler, Andreas; Ko, Younhee; Shin, Jae Il (2020-06-01). "Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome: A systematic review". Autoimmunity Reviews. 19 (6): 102526. doi:10.1016/j.autrev.2020.102526. ISSN   1568-9972. PMID   32234571. S2CID   214768010.
  15. ↑ Barzaghi F, Passerini L, Bacchetta R (2012). "Immune dysregulation, polyendocrinopathy, enteropathy, x-linked syndrome: a paradigm of immunodeficiency with autoimmunity". Frontiers in Immunology. 3: 211. doi: 10.3389/fimmu.2012.00211 . PMC   3459184 . PMID   23060872.
  16. ↑ Xavier-da-Silva MM, Moreira-Filho CA, Suzuki E, Patricio F, Coutinho A, Carneiro-Sampaio M (February 2015). "Fetal-onset IPEX: report of two families and review of literature". Clinical Immunology. 156 (2): 131–40. doi:10.1016/j.clim.2014.12.007. PMID   25546394.
  17. 1 2 Bacchetta, Rosa; Barzaghi, Federica; Roncarolo, Maria-Grazia (2018). "From IPEX syndrome to FOXP3 mutation: a lesson on immune dysregulation". Annals of the New York Academy of Sciences. 1417 (1): 5–22. Bibcode:2018NYASA1417....5B. doi: 10.1111/nyas.13011 . ISSN   1749-6632. PMID   26918796.
  18. 1 2 Bacchetta R, Barzaghi F, Roncarolo MG (April 2018). "From IPEX syndrome to FOXP3 mutation: a lesson on immune dysregulation". Annals of the New York Academy of Sciences. 1417 (1): 5–22. Bibcode:2018NYASA1417....5B. doi: 10.1111/nyas.13011 . PMID   26918796.
  19. 1 2 Michels AW, Gottlieb PA (May 2010). "Autoimmune polyglandular syndromes". Nature Reviews. Endocrinology. 6 (5): 270–7. doi:10.1038/nrendo.2010.40. PMID   20309000. S2CID   20395564.
  20. 1 2 Kitcharoensakkul, Maleewan; Cooper, Megan A. (2020-01-01), Rose, Noel R.; Mackay, Ian R. (eds.), "Chapter 28 - Autoimmunity in Primary Immunodeficiency Disorders", The Autoimmune Diseases (Sixth Edition), Academic Press, pp. 513–532, doi:10.1016/b978-0-12-812102-3.00028-2, ISBN   978-0-12-812102-3, S2CID   208377306 , retrieved 2021-01-29
  21. ↑ Powell, Berkley R.; Buist, Neil R.M.; Stenzel, Peter (1982). "An X-linked syndrome of diarrhea, polyendocrinopathy, and fatal infection in infancy". The Journal of Pediatrics. 100 (5): 731–737. doi:10.1016/s0022-3476(82)80573-8. ISSN   0022-3476. PMID   7040622.
  22. ↑ Yilmaz OK, Haeberle S, Zhang M, Fritzler MJ, Enk AH, Hadaschik EN (2019). "Scurfy Mice Develop Features of Connective Tissue Disease Overlap Syndrome and Mixed Connective Tissue Disease in the Absence of Regulatory T Cells". Frontiers in Immunology. 10: 881. doi: 10.3389/fimmu.2019.00881 . PMC   6491778 . PMID   31068947.

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