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__NOTOC__ | __NOTOC__ | ||
{{Autoimmune polyendocrine syndrome}} | {{Autoimmune polyendocrine syndrome}} | ||
{{CMG}}; {{AE}} | {{CMG}}; {{AE}}{{Akshun}} | ||
==Overview== | ==Overview== | ||
Common causes of autoimmune polyendocrine syndrome include mutation in AIRE gene, FOXP3 gene and certain HLA alleles such as DR3/DQ2, DR4/DQ8 and DRB1*0404. | Common causes of autoimmune polyendocrine syndrome include [[mutation]] in [[Autoimmune Regulator|AIRE]] gene, [[FOXP3]] gene and certain [[HLA]] [[alleles]] such as DR3/DQ2, DR4/DQ8 and DRB1*0404. | ||
==Causes== | ==Causes== | ||
===Genetic Causes=== | ===Genetic Causes=== | ||
Autoimmune polyendocrine syndrome is caused by a mutation in: | Autoimmune polyendocrine syndrome is caused by a [[mutation]] in: | ||
* '''APS type I:''' APS type 1 is due to a defect in ''[[Autoimmune regulator|AIRE]]'' (autoimmune regulator), a [[gene]] located on [[chromosome]] | * '''APS type I:''' APS type 1 is due to a defect in ''[[Autoimmune regulator|AIRE]]'' (autoimmune regulator), a [[gene]] located on [[chromosome 21]].<ref name="pmid9888391">{{cite journal |vauthors=Heino M, Scott HS, Chen Q, Peterson P, Mäebpää U, Papasavvas MP, Mittaz L, Barras C, Rossier C, Chrousos GP, Stratakis CA, Nagamine K, Kudoh J, Shimizu N, Maclaren N, Antonarakis SE, Krohn K |title=Mutation analyses of North American APS-1 patients |journal=Hum. Mutat. |volume=13 |issue=1 |pages=69–74 |year=1999 |pmid=9888391 |doi=10.1002/(SICI)1098-1004(1999)13:1<69::AID-HUMU8>3.0.CO;2-6 |url=}}</ref><ref name="pmid10677297">{{cite journal |vauthors=Björses P, Halonen M, Palvimo JJ, Kolmer M, Aaltonen J, Ellonen P, Perheentupa J, Ulmanen I, Peltonen L |title=Mutations in the AIRE gene: effects on subcellular location and transactivation function of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy protein |journal=Am. J. Hum. Genet. |volume=66 |issue=2 |pages=378–92 |year=2000 |pmid=10677297 |pmc=1288090 |doi=10.1086/302765 |url=}}</ref> | ||
** The genetic locus is on short arm (p) of chromosome 21 at 21p22.3. | ** The [[genetic]] [[locus]] is on [[short arm]] (p) of [[chromosome 21]] at 21p22.3. | ||
** The normal function of AIRE gene is to confer [[immune tolerance]] for antigens present in the body. | ** The normal function of [[Autoimmune regulator|AIRE]] gene is to confer [[immune tolerance]] for [[antigens]] present in the [[Human body|body]]. | ||
** The mutated AIRE gene results in the loss of self tolerance - a process by which developing T cells with potential reactivity for self-antigens are eliminated during early differentiation in the thymus. | ** The [[mutated]] [[Autoimmune Regulator|AIRE]] [[gene]] results in the loss of self tolerance - a process by which developing [[T cells]] with [[potential]] [[reactivity]] for self-[[antigens]] are eliminated during early differentiation in the [[thymus]]. | ||
** According to a Finnish study the mutation R257X is responsible for 82% of APS type 1 cases in Finland. | ** According to a Finnish study the [[mutation]] R257X (in [[Autoimmune Regulator|AIRE]] [[gene]]) is responsible for 82% of APS type 1 cases in Finland. | ||
*'''APS type 2:''' APS type 2 is not a single gene disorder and has a complex inheritance pattern.<ref name="pmid17116738">{{cite journal |vauthors=DeVoss J, Hou Y, Johannes K, Lu W, Liou GI, Rinn J, Chang H, Caspi RR, Caspi R, Fong L, Anderson MS |title=Spontaneous autoimmunity prevented by thymic expression of a single self-antigen |journal=J. Exp. Med. |volume=203 |issue=12 |pages=2727–35 |year=2006 |pmid=17116738 |pmc=2118158 |doi=10.1084/jem.20061864 |url=}}</ref><ref name="pmid9920103">{{cite journal |vauthors=Yu L, Brewer KW, Gates S, Wu A, Wang T, Babu SR, Gottlieb PA, Freed BM, Noble J, Erlich HA, Rewers MJ, Eisenbarth GS |title=DRB1*04 and DQ alleles: expression of 21-hydroxylase autoantibodies and risk of progression to Addison's disease |journal=J. Clin. Endocrinol. Metab. |volume=84 |issue=1 |pages=328–35 |year=1999 |pmid=9920103 |doi=10.1210/jcem.84.1.5414 |url=}}</ref><ref name="pmid19890026">{{cite journal |vauthors=Bratland E, Skinningsrud B, Undlien DE, Mozes E, Husebye ES |title=T cell responses to steroid cytochrome P450 21-hydroxylase in patients with autoimmune primary adrenal insufficiency |journal=J. Clin. Endocrinol. Metab. |volume=94 |issue=12 |pages=5117–24 |year=2009 |pmid=19890026 |doi=10.1210/jc.2009-1115 |url=}}</ref> | *'''APS type 2:''' APS type 2 is not a single [[gene]] [[disorder]] and has a complex [[inheritance]] pattern.<ref name="pmid17116738">{{cite journal |vauthors=DeVoss J, Hou Y, Johannes K, Lu W, Liou GI, Rinn J, Chang H, Caspi RR, Caspi R, Fong L, Anderson MS |title=Spontaneous autoimmunity prevented by thymic expression of a single self-antigen |journal=J. Exp. Med. |volume=203 |issue=12 |pages=2727–35 |year=2006 |pmid=17116738 |pmc=2118158 |doi=10.1084/jem.20061864 |url=}}</ref><ref name="pmid9920103">{{cite journal |vauthors=Yu L, Brewer KW, Gates S, Wu A, Wang T, Babu SR, Gottlieb PA, Freed BM, Noble J, Erlich HA, Rewers MJ, Eisenbarth GS |title=DRB1*04 and DQ alleles: expression of 21-hydroxylase autoantibodies and risk of progression to Addison's disease |journal=J. Clin. Endocrinol. Metab. |volume=84 |issue=1 |pages=328–35 |year=1999 |pmid=9920103 |doi=10.1210/jcem.84.1.5414 |url=}}</ref><ref name="pmid19890026">{{cite journal |vauthors=Bratland E, Skinningsrud B, Undlien DE, Mozes E, Husebye ES |title=T cell responses to steroid cytochrome P450 21-hydroxylase in patients with autoimmune primary adrenal insufficiency |journal=J. Clin. Endocrinol. Metab. |volume=94 |issue=12 |pages=5117–24 |year=2009 |pmid=19890026 |doi=10.1210/jc.2009-1115 |url=}}</ref> | ||
** The highest genetic risk for APS type 2 maps to the HLA locus. Other low risk genes include CLTA4 and PTPN22. | ** The highest [[genetic]] risk for APS type 2 maps to the [[HLA|HLA locus]]. Other low risk [[genes]] include CLTA4 and [[PTPN22]]. | ||
***The strongest association for APS type 2 is with HLA DR3/DQ2 (DQ2:DQA1*0501, DQB1*0201), DR4/DQ8 (DQ8:DQA1*0301, DQB1*0302), DRB1*0404 and this syndrome inherits in an [[autosomal dominant]] fashion. | ***The strongest [[Association (statistics)|association]] for APS type 2 is with HLA DR3/DQ2 (DQ2:DQA1*0501, DQB1*0201), DR4/DQ8 (DQ8:DQA1*0301, DQB1*0302), DRB1*0404 and this syndrome inherits in an [[autosomal dominant]] fashion. | ||
* '''APS type 3 or''' '''XPID''': This is due to a mutation in the [[FOXP3|FOXP''3'']] gene on the X chromosome.<ref name="pmid12612578">{{cite journal |vauthors=Fontenot JD, Gavin MA, Rudensky AY |title=Foxp3 programs the development and function of CD4+CD25+ regulatory T cells |journal=Nat. Immunol. |volume=4 |issue=4 |pages=330–6 |year=2003 |pmid=12612578 |doi=10.1038/ni904 |url=}}</ref><ref name="pmid16227984">{{cite journal |vauthors=Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY |title=A function for interleukin 2 in Foxp3-expressing regulatory T cells |journal=Nat. Immunol. |volume=6 |issue=11 |pages=1142–51 |year=2005 |pmid=16227984 |doi=10.1038/ni1263 |url=}}</ref> | * '''APS type 3 or''' '''XPID''': This is due to a [[mutation]] in the [[FOXP3|FOXP''3'']] gene on the [[X chromosome]].<ref name="pmid12612578">{{cite journal |vauthors=Fontenot JD, Gavin MA, Rudensky AY |title=Foxp3 programs the development and function of CD4+CD25+ regulatory T cells |journal=Nat. Immunol. |volume=4 |issue=4 |pages=330–6 |year=2003 |pmid=12612578 |doi=10.1038/ni904 |url=}}</ref><ref name="pmid16227984">{{cite journal |vauthors=Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY |title=A function for interleukin 2 in Foxp3-expressing regulatory T cells |journal=Nat. Immunol. |volume=6 |issue=11 |pages=1142–51 |year=2005 |pmid=16227984 |doi=10.1038/ni1263 |url=}}</ref> | ||
** The | ** The [[FOXP3]] [[gene]] is located on [[chromosome]] Xp11.3-q13.3 | ||
** | ** [[FOXP3]] plays a critical role in the function of [[CD4+]] [[CD25]]+ T regulatory [[Cells (biology)|cells]]. | ||
==References== | ==References== | ||
Latest revision as of 17:04, 27 October 2017
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Akshun Kalia M.B.B.S.[2]
Overview
Common causes of autoimmune polyendocrine syndrome include mutation in AIRE gene, FOXP3 gene and certain HLA alleles such as DR3/DQ2, DR4/DQ8 and DRB1*0404.
Causes
Genetic Causes
Autoimmune polyendocrine syndrome is caused by a mutation in:
- APS type I: APS type 1 is due to a defect in AIRE (autoimmune regulator), a gene located on chromosome 21.[1][2]
- The genetic locus is on short arm (p) of chromosome 21 at 21p22.3.
- The normal function of AIRE gene is to confer immune tolerance for antigens present in the body.
- The mutated AIRE gene results in the loss of self tolerance - a process by which developing T cells with potential reactivity for self-antigens are eliminated during early differentiation in the thymus.
- According to a Finnish study the mutation R257X (in AIRE gene) is responsible for 82% of APS type 1 cases in Finland.
- APS type 2: APS type 2 is not a single gene disorder and has a complex inheritance pattern.[3][4][5]
- The highest genetic risk for APS type 2 maps to the HLA locus. Other low risk genes include CLTA4 and PTPN22.
- The strongest association for APS type 2 is with HLA DR3/DQ2 (DQ2:DQA1*0501, DQB1*0201), DR4/DQ8 (DQ8:DQA1*0301, DQB1*0302), DRB1*0404 and this syndrome inherits in an autosomal dominant fashion.
- The highest genetic risk for APS type 2 maps to the HLA locus. Other low risk genes include CLTA4 and PTPN22.
- APS type 3 or XPID: This is due to a mutation in the FOXP3 gene on the X chromosome.[6][7]
References
- ↑ Heino M, Scott HS, Chen Q, Peterson P, Mäebpää U, Papasavvas MP, Mittaz L, Barras C, Rossier C, Chrousos GP, Stratakis CA, Nagamine K, Kudoh J, Shimizu N, Maclaren N, Antonarakis SE, Krohn K (1999). "Mutation analyses of North American APS-1 patients". Hum. Mutat. 13 (1): 69–74. doi:10.1002/(SICI)1098-1004(1999)13:1<69::AID-HUMU8>3.0.CO;2-6. PMID 9888391.
- ↑ Björses P, Halonen M, Palvimo JJ, Kolmer M, Aaltonen J, Ellonen P, Perheentupa J, Ulmanen I, Peltonen L (2000). "Mutations in the AIRE gene: effects on subcellular location and transactivation function of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy protein". Am. J. Hum. Genet. 66 (2): 378–92. doi:10.1086/302765. PMC 1288090. PMID 10677297.
- ↑ DeVoss J, Hou Y, Johannes K, Lu W, Liou GI, Rinn J, Chang H, Caspi RR, Caspi R, Fong L, Anderson MS (2006). "Spontaneous autoimmunity prevented by thymic expression of a single self-antigen". J. Exp. Med. 203 (12): 2727–35. doi:10.1084/jem.20061864. PMC 2118158. PMID 17116738.
- ↑ Yu L, Brewer KW, Gates S, Wu A, Wang T, Babu SR, Gottlieb PA, Freed BM, Noble J, Erlich HA, Rewers MJ, Eisenbarth GS (1999). "DRB1*04 and DQ alleles: expression of 21-hydroxylase autoantibodies and risk of progression to Addison's disease". J. Clin. Endocrinol. Metab. 84 (1): 328–35. doi:10.1210/jcem.84.1.5414. PMID 9920103.
- ↑ Bratland E, Skinningsrud B, Undlien DE, Mozes E, Husebye ES (2009). "T cell responses to steroid cytochrome P450 21-hydroxylase in patients with autoimmune primary adrenal insufficiency". J. Clin. Endocrinol. Metab. 94 (12): 5117–24. doi:10.1210/jc.2009-1115. PMID 19890026.
- ↑ Fontenot JD, Gavin MA, Rudensky AY (2003). "Foxp3 programs the development and function of CD4+CD25+ regulatory T cells". Nat. Immunol. 4 (4): 330–6. doi:10.1038/ni904. PMID 12612578.
- ↑ Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY (2005). "A function for interleukin 2 in Foxp3-expressing regulatory T cells". Nat. Immunol. 6 (11): 1142–51. doi:10.1038/ni1263. PMID 16227984.