3QRF , 4WK8
40-472: 50943 20371 ENSG00000049768 ENSMUSG00000039521 Q9BZS1 Q99JB6 NM_001114377 NM_014009 NM_001199347 NM_001199348 NM_054039 NP_001107849 NP_054728 NP_001186276 NP_001186277 NP_473380 FOXP3 ( forkhead box P3), also known as scurfin , is a protein involved in immune system responses. A member of the FOX protein family, FOXP3 appears to function as
80-466: 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 . 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
120-417: 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. While
160-424: 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
200-477: A Foxp3 mutation (a frameshift mutation that result in protein lacking the forkhead domain) is responsible for 'Scurfy', an X-linked recessive mouse mutant that results in lethality in hemizygous males 16 to 25 days after birth. These mice have overproliferation of CD 4 T-lymphocytes, extensive multiorgan infiltration, and elevation of numerous cytokines . This phenotype is similar to those that lack expression of CTLA-4 , TGF-β , human disease IPEX, or deletion of
240-428: A common function is their involvement in early developmental decisions of cell fates during embryogenesis . Members of the class O of forkhead box transcription factors (FoxO) have important roles in metabolism, cellular proliferation, stress tolerance and probably lifespan. IPEX syndrome Immunodysregulation polyendocrinopathy enteropathy X-linked syndrome ( IPEX syndrome ) is a rare autoimmune disease . It
280-425: A number of transcription factors (including D. melanogaster FD1-5, mammalian HNF3 , human HTLF , Saccharomyces cerevisiae HCM1, etc.). This is referred to as the fork head domain but is also known as a " winged helix ". The fork head domain binds B-DNA as a monomer, but shows no similarity to previously identified DNA-binding motifs . Although the domain is found in several different transcription factors,
320-477: 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 . IPEX patients are usually born with normal weight and length at term. Nevertheless, the first symptoms may present in the first days of life, and some reported cases labeled newborns with intrauterine growth restriction and evidence of meconium in
360-520: 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 . Thyroid disorders are also common. 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 . The most common form of skin involvement
400-463: Is a recruiter of other anti-tumor enzymes such as CD39 and CD8 . The overexpression of CD39 is found in patients with multiple cancer types such as melanoma , leukemia , pancreatic cancer , colon cancer , and ovarian cancer . This overexpression may be protecting tumorous cells, allowing them to create their “escape phase”. A cancerous tumor's “escape phase” is where the tumor grows quickly and it becomes clinically invisible by becoming independent of
440-481: Is a type of protein domain that is often found in transcription factors and whose purpose is to bind DNA . The fork head protein of Drosophila melanogaster , a transcription factor that promotes terminal rather than segmental development, contains neither homeodomains nor zinc-fingers characteristic of other transcription factors. Instead, it contains a distinct type of DNA-binding region , containing around 100 amino acids, which has since been identified in
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#1732765535879480-635: Is generally considered the best treatment option. IPEX exclusively affects males and is inherited in an X-linked recessive manner; female carriers of pathogenic FOXP3 mutations do not have symptoms and no female cases are known. The classical triad describes the most common symptoms of IPEX: intractable diarrhea , type 1 diabetes , and eczema . Symptoms usually begin shortly after birth. Other symptoms include: thyroid disease , kidney dysfunction, blood disorders, frequent infections, autoimmune hemolytic anemia , and food allergies, among others. The most common endocrinopathy associated with IPEX
520-399: 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. 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
560-435: Is truncated, causing functional deficiency of Treg cells. Then, autoreactive CD4 T cells and inflammatory cells cause tissue damage. 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. From 2000 - 2001, multiple studies confirmed that IPEX is the human equivalent of scurfy mice and that
600-410: Is usually diagnosed based on the following criteria: 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. Drugs used include: Currently,
640-547: The amniotic fluid . IPEX syndrome is inherited in males in an X-linked recessive pattern through the FOXP3 gene. FOXP3' s cytogenetic location is Xp11.23. 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
680-501: The coding regions of the mouse and human genes. By genomic sequence analysis, the FOXP3 gene maps to the p arm of the X chromosome (specifically, X p 11.23). Foxp3 is a specific marker of natural T regulatory cells ( nTregs , a lineage of T cells ) and adaptive/induced T regulatory cells (a/iTregs), also identified by other less specific markers such as CD25 or CD4 5RB. In animal studies, Tregs that express Foxp3 are critical in
720-549: The neonatal period or later in life. Other individuals express no FOXP3 protein. 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 T reg development and functioning. The absence or dysfunction of T regs causes autoimmune symptoms. FOXP3 can function as both
760-409: The regulatory T cell (T reg ) lineage. FOXP3 mutation can lead to the dysfunction of CD4 T regs . In healthy people, T regs maintain immune homeostasis . When there is a deleterious FOXP3 mutation, T regs do not function properly and cause autoimmunity . IPEX onset usually happens in infancy . If left untreated, it is often fatal by the age of 2 or 3. A bone marrow transplant
800-400: The 19 affected males in the family survived past 3 years old. These individuals lived to 10 and 30 years old. Powel's study is now widely considered the first documentation of IPEX. 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
840-525: The Foxp3 gene in mice ("scurfy mice"). The pathology observed in scurfy mice seems to result from an inability to properly regulate CD4 T-cell activity. In mice overexpressing the Foxp3 gene, fewer T cells are observed. The remaining T cells have poor proliferative and cytolytic responses and poor interleukin-2 production, although thymic development appears normal. Histologic analysis indicates that peripheral lymphoid organs , particularly lymph nodes , lack
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#1732765535879880-464: The Foxp3 regulatory pathway can lead to organ-specific autoimmune diseases such as autoimmune thyroiditis and type 1 diabetes mellitus . These mutations affect thymocytes developing within the thymus . Regulated by Foxp3, it's these thymocytes that during thymopoiesis , are transformed into mature Treg cells by the thymus. It was found that patients who have the autoimmune disease systemic lupus erythematosus (SLE) possess Foxp3 mutations that affect
920-530: 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
960-449: The expression of suppression-mediating molecules. For instance, Foxp3 is able to facilitate the translocation of extracellular adenosine into the cytoplasm. It does this by recruiting CD39 , a rate-limiting enzyme that's vital in tumor suppression to hydrolyze ATP to ADP in order to regulate immunosuppression on different cell populations. Fork head domain The fork head domain
1000-615: The extracellular matrix and creating its own immunosuppressive tumor microenvironment. The consequences of a cancer cell reaching the “escape phase” is that it allows it to completely evade the immune system, which reduces the immunogenicity and ability to become clinically detected, allowing it to progress and spread throughout the body. Some cancer patients have also been known to display higher numbers of mutated CD4 cells. These mutated cells will then produce large quantities of TGF-β and IL- 10 , (a Transforming Growth Factor β and an inhibitory cytokine respectively,) which will suppress signals to
1040-513: The formation of cancerous cells. Conversely, patients with an autoimmune disease such as systemic lupus erythematosus (SLE) have a relative dysfunction of Foxp3 positive cells. The Foxp3 gene is also mutated in IPEX syndrome ( I mmunodysregulation , P olyendocrinopathy , and E nteropathy , X -linked ). Many patients with IPEX have mutations in the DNA -binding forkhead domain of FOXP3. In mice,
1080-400: The gene targets of Foxp3 could be crucial to the comprehension of the suppressive abilities of T reg cells. In human disease, alterations in numbers of regulatory T cells – and in particular those that express Foxp3 – are found in a number of disease states. For example, patients with tumors have a local relative excess of Foxp3 positive T cells which inhibits the body's ability to suppress
1120-478: The immune system and allow for tumor escape. So, Foxp3 polymorphism (rs3761548) might contribute to cancer development like gastric cancer through influencing Treg cell activity and secretion of immunomodulatory cytokines such as IL-10 , IL-35 , and TGF-β . In one experiment a 15-mer synthetic peptide, P60, was able to inhibit Foxp3's ability to function. P60 did this by entering the cells and then binding to Foxp3, where it hinders Foxp3's ability to translocate to
1160-872: The influence of solely TGF-β, so the difference between a proinflammatory and a pro-regulatory scenario is the presence of a single interleukin. IL-6 or IL-21 is being debated by immunology laboratories as the definitive signaling molecule. Murine studies point to IL-6 whereas human studies have shown IL-21. Foxp3 is the major transcription factor controlling T-regulatory cells (T reg or CD4 cells). CD4 cells are leukocytes responsible for protecting animals from foreign invaders such as bacteria and viruses. Defects in this gene's ability to function can cause IPEX syndrome (IPEX), also known as X-linked autoimmunity-immunodeficiency syndrome as well as numerous cancers. While CD4 cells are heavily regulated and require multiple transcription factors such as STAT -5 and AhR in order to become active and function properly, Foxp3 has been identified as
1200-458: The master regulator for T reg lineage. Foxp3 can either act as a transcriptional activator or suppressor depending on what regulators such as deacetylases and histone acetylases are acting on it. The Foxp3 gene is also known to convert naïve T-cells to T reg cells, which are capable of an in vivo and in vitro suppressive capabilities suggesting that Foxp3 is capable of regulating the expression of suppression-mediating molecules. Clarifying
1240-421: The nucleus. Due to this, Foxp3 could no longer properly suppress the transcription factors NF -kB and NFAT ; both of which are protein complexes that regulate transcription of DNA, cytokine production and cell survival. This would inhibit a cell's ability to perform apoptosis and stop its own cell cycle, which could potentially allow an affected cancerous cell to survive and reproduce. Mutations or disruptions of
FOXP3 - Misplaced Pages Continue
1280-429: The past decade. In 2010 there were only 20 mutations of FOXP3 known in the literature. Some mutations cause FOXP3 expression to malfunction, which leads to a defect in T reg production. Those individuals do not have circulating CD4+/CD25+/FOXP3+ T reg cells. Reduced expression of FOXP3 has been described, and these individuals may express normal levels of dysfunctional protein, which leads to mild symptoms during
1320-572: The precise control mechanism has not yet been established, FOX proteins belong to the forkhead/ winged-helix family of transcriptional regulators and are presumed to exert control via similar DNA binding interactions during transcription . In regulatory T cell model systems, the FOXP3 transcription factor occupies the promoters for genes involved in regulatory T-cell function, and may inhibit transcription of key genes following stimulation of T cell receptors. The human FOXP3 genes contain 11 coding exons . Exon- intron boundaries are identical across
1360-409: The proper number of cells. In addition to Foxp3's role in regulatory T cell differentiation, multiple lines of evidence have indicated that Foxp3 play important roles in cancer development. Down-regulation of Foxp3 expression has been reported in tumour specimens derived from breast, prostate, and ovarian cancer patients, indicating that Foxp3 is a potential tumour suppressor gene. Expression of Foxp3
1400-426: The standard treatment for IPEX is a bone marrow transplant. If donor-recipient chimerism is achieved, individuals with IPEX can achieve complete remission. 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
1440-403: The thymopoiesis process, preventing the proper development of T reg cells within the thymus. These malfunctioning T reg cells aren’t efficiently being regulated by its transcription factors, which cause them to attack cells that are healthy, leading to these organ-specific autoimmune diseases. Another way that Foxp3 helps keep the autoimmune system at homeostasis is through its regulation of
1480-407: 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. Early detection of the disease is crucial because IPEX has a high mortality level if left untreated. IPEX
1520-528: The transfer of immune tolerance , especially self-tolerance. The induction or administration of Foxp3 positive T cells has, in animal studies, led to marked reductions in (autoimmune) disease severity in models of diabetes , multiple sclerosis , asthma , inflammatory bowel disease , thyroiditis and renal disease . Human trials using regulatory T cells to treat graft-versus-host disease have shown efficacy. Further work has shown that T cells are more plastic in nature than originally thought. This means that
1560-405: The use of regulatory T cells in therapy may be risky, as the T regulatory cell transferred to the patient may change into T helper 17 (Th17) cells, which are pro-inflammatory rather than regulatory cells. Th17 cells are proinflammatory and are produced under similar environments as a/iTregs. Th17 cells are produced under the influence of TGF-β and IL-6 (or IL-21), whereas a/iTregs are produced under
1600-889: Was also detected in tumour specimens derived from additional cancer types, including pancreatic, melanoma, liver, bladder, thyroid, cervical cancers. However, in these reports, no corresponding normal tissues was analyzed, therefore it remained unclear whether Foxp3 is a pro- or anti-tumourigeneic molecule in these tumours. Two lines of functional evidence strongly supported that Foxp3 serves as tumour suppressive transcription factor in cancer development. First, Foxp3 represses expression of HER2, Skp2, SATB1 and MYC oncogenes and induces expression of tumour suppressor genes P21 and LATS2 in breast and prostate cancer cells. Second, over-expression of Foxp3 in melanoma, glioma, breast, prostate and ovarian cancer cell lines induces profound growth inhibitory effects in vitro and in vivo. However, this hypothesis need to be further investigated in future studies. Foxp3
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