Autoimmune polyendocrine syndrome pathophysiology: Difference between revisions
Jump to navigation
Jump to search
Iqra Qamar (talk | contribs) |
Iqra Qamar (talk | contribs) |
||
| Line 66: | Line 66: | ||
* '''APS type I:''' APS type 1 is [[inherited]] in an [[autosomal recessive]] fashion and 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> | * '''APS type I:''' APS type 1 is [[inherited]] in an [[autosomal recessive]] fashion and 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|genetic locus]] is on short arm (p) of [[chromosome 21]] at 21p22.3. | ** The [[Genetic|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 [[body]]. | ||
** The [[mutated]] [[ | ** 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 gland|thymus]]. | ||
** APS-1 has been associated with more than 60 different [[mutations]] of [[ | ** APS-1 has been associated with more than 60 different [[mutations]] of [[Autoimmune Regulator|AIRE]] gene, the majority of which results in truncated and nonfunctional [[Autoimmune Regulator|AIRE]]. | ||
** The two common [[mutations]] of [[AIRE]] gene include R257X and 1094-1106del. | ** The two common [[mutations]] of [[Autoimmune Regulator|AIRE]] gene include R257X and 1094-1106del. | ||
** According to a Finnish study the [[mutation]] R257X is responsible for 82% of cases in Finland. | ** According to a Finnish study the [[mutation]] R257X is responsible for 82% of cases in Finland. | ||
** It is also observed that patients with APS type 1 have an increased frequency of [[HLA-A28]] and [[HLA-A3]]. | ** It is also observed that patients with APS type 1 have an increased frequency of [[HLA-A28]] and [[HLA-A3]]. | ||
Revision as of 16:59, 23 October 2017
|
Autoimmune polyendocrine syndrome Microchapters |
|
Differentiating Autoimmune polyendocrine syndrome from other Diseases |
|---|
|
Diagnosis |
|
Treatment |
|
Case Studies |
|
Autoimmune polyendocrine syndrome pathophysiology On the Web |
|
American Roentgen Ray Society Images of Autoimmune polyendocrine syndrome pathophysiology |
|
Autoimmune polyendocrine syndrome pathophysiology in the news |
|
Directions to Hospitals Treating Autoimmune polyendocrine syndrome |
|
Risk calculators and risk factors for Autoimmune polyendocrine syndrome pathophysiology |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Akshun Kalia M.B.B.S.[2]
Overview
Autoimmune polyendocrine syndrome (APS) is a group of autoimmune disorders against multiple (poly) endocrine organs, although non-endocrine organs may be affected. Autoimmune polyendocrine syndrome is also known as polyglandular autoimmune syndrome and polyendocrine autoimmune syndrome. In autoimmune polyendocrine syndrome there is loss of self tolerance or defective T cell regulation and the immune system attacks various endocrine and nonendocrine organs throughout the body. APS is seen in genetically susceptible individuals who when exposed to certain environmental triggers (such as infection) leads to autoimmunity. The involvement of endocrine glands can be simultaneous or sequential. The autoimmune reaction can either be humoral or cell mediated which may lead to partial or complete destruction of the tissue involved. The common endocrine glands involved are parathyroids, adrenals, thyroid, and pancreas. However any other non endocrine gland/tissue of the body may be involved.
Pathophysiology
The pathogenesis in autoimmune polyendocrine syndrome (APS) includes:[1][2][3][4][5]
- APS can be defined as a group of rare autoimmune disorders against multiple (poly) endocrine glands, although non endocrine gland/tissues may be affected.
- In APS, there is either defective regulation of T cells or loss of self tolerance which causes the immune system to attack various endocrine and nonendocrine organs throughout the body.
- APS can be categorized into two major types namely:
- Type 1 (also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED)
- Type 2 (also known as Schmidt syndrome)
- Other rare types of APS include APS type 3 [IPEX (Immune Dysfunction Polyendocrinopathy X-linked syndrome) and APS type 4.
- In APS, the involvement of endocrine glands can be either simultaneous or sequential.
- The common endocrine glands involved are parathyroids, adrenals, thyroid, and pancreas. However any other endocrine/nonendocrine tissue of the body may be involved.
- The autoimmune reaction can either be humoral or cell mediated.
- Depending upon the inflammation and the lymphocytic infiltration of the endocrine and non-endocrine tissue, there may be partial or complete destruction of the tissue involved.
Autoimmune polyendocrine syndrome type 1 (APS type 1)
The pathogenesis of APS type 1 is as follow:[6][7][8][9]
- The APS type 1 is primarily related to mutation in the AIRE (Autoimmune Regulator gene) gene on chromosome 21.
- Normal function of AIRE, a transcription factor, appears to confer immune tolerance for antigens present in the body.
- In patients of APS type 1, mutated AIRE gene leads to loss of peripheral antigen expression in the thymus.
- The decreased exposure of self antigens in thymus causes decreased deletion or apoptosis of self reactive T lymphocytes which leads to autoimmunity.
- Patients with APS type 1 have autoantibodies against endocrine and nonendocrine organs throughout the body. These antibodies may be directed against surface receptor proteins, intracellular structures and secreted products.
- The most commonly associated autoantibody is anti-adrenal antibody (against enzyme; 21-hydroxylase) which leads to Addison's disease.
- The second most commonly associated autoantibody is against parathyroid specific protein, NALP5 which leads to hypoparathyroidism.
- Autoantibody against enzyme, glutamic acid decarboxylase (GAD)of pancreas may lead to insulin deficiency.
- Patients with typical type 1 diabetes also have anti-GAD antibodies but can be differentiated from anti-GAD antibodies seen in APS type 1 with the help of western blot.
- Patients with anti-GAD antibodies in APS type 1 react with GAD on western blot and leads to inhibition of GAD enzyme activity. This is not present in typical patients with diabetes mellitus type I.
- Other antibodies include anti-cytokine autoantibodies such as anti-IL17A, IL-17F and IL-22.
- The presence of anti-cytokine antibodies predispose to defective antifungal response, which may lead to mucocutaneous candidiasis. APS type 1 is also termed as APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy) from the symptom complex associated with this condition.
- Recent studies have indicated that almost all patients with APS type 1 have antibodies against interferon-omega (IFN-ω) and interferon alpha (IFN-α).
Autoimmune polyendocrine syndrome type 2 (APS type 2)
The pathogenesis of APS type 2 includes:
- The pathogenesis of APS type 2 is related to MHC class II, primarily DQ2 and DQ8.
- The strongest association for APS type 2 is with HLA DR3/DQ2, DR4/DQ8 and DRB1*0404.
- APS type 2 is seen in genetically susceptible individuals who develop autoimmunity when exposed to certain environmental factors (such as viral infection).
- As seen in type 1, APS type 2 also has a loss of self tolerance to intrinsic antigenic proteins in the body.
- The autoantibodies are directed against various endocrine and nonendocrine organs.
- The classic triad of APS type 2 includes Addison's disease, autoimmune thyroiditis and type 1A diabetes.
- As compared to type 1, APS type 2 is more varied in its manifestations and is the most common type of APS.
- Other HLA DR3 and HLA B8 associated APS type 2 conditions include selective IgA deficiency, juvenile dermatomyositis, dermatitis herpetiformis, alopecia, scleroderma, autoimmune thrombocytopenic purpura, hypophysitis, metaphyseal osteopenia, serositis and premature ovarian failure.
Autoimmune polyendocrine syndrome type 3 (APS type 3)
Studies demonstrate that environmental factors, genetic factors and autoimmunity play an important role in the parthenogenesis of APS type 3.[10][11][12]
- As seen in APS type 1 and type 2, APS type 3 is also seen in genetically susceptible individuals who develop autoimmunity when exposed to certain environmental factors (such as viral infections).
- Patients of APS type 3 have a defect in regulatory T cells.
- Normally, T-regulatory cells have a vital role in creating and maintaining self tolerance.
- Self tolerance is the mechanism by which immune system recognize body's own proteins/antigens as 'self' and prevent the immune system from mounting an attack against them.
- In patients of APS type 3, defective function of regulatory T cells leads to loss of self tolerance which leads to autoimmunity.
- Recent case reports also suggest that, patients of APS type 3 have defective IL-2 and gamma-interferon production which leads to increased susceptibility to infections from bacterial, viral, and fungal organisms.
- Compared with APS type 1 and 2, APS type 3 does not involve the adrenal cortex. Instead autoimmune thyroiditis is the most commonly involved endocrine organ in APS type 3.
Genetics
The genes involved in the pathogenesis of APS include:
- APS type I: APS type 1 is inherited in an autosomal recessive fashion and is due to a defect in AIRE (autoimmune regulator), a gene located on chromosome 21.[13][14]
- 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.
- APS-1 has been associated with more than 60 different mutations of AIRE gene, the majority of which results in truncated and nonfunctional AIRE.
- The two common mutations of AIRE gene include R257X and 1094-1106del.
- According to a Finnish study the mutation R257X is responsible for 82% of cases in Finland.
- It is also observed that patients with APS type 1 have an increased frequency of HLA-A28 and HLA-A3.
- 'APS type' 2 : APS type 2 is not a single gene disorder and has a complex inheritance pattern.[15][16][17]
- APS type 2 patients commonly have Addison's disease, autoimmune thyroiditis and type I diabetes mellitus. Each one of these conditions involve multiple genes which is responsible for the complex inheritance pattern seen in APS type 2.
- 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.
- It has been observed that patients of APS type 2 with DR3 is often introduced into the family by more than one relative.
- APS type 3 or XPID: This is due to a mutation in the FOXP3 gene on the X chromosome.[18][19]
- 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.
- Since XPID is an 'X' linked condition, males are commonly affected. Females are carriers and may have mild disease.
Associated Conditions
- Diabetes mellitus type 1
- Common variable immunodeficiency (CVID)
- Pure red cell aplasia
- Autoimmune thyroiditis
- Hypogonadism (usually autoimmune oophoritis)
- Hypopituitarism
- Vitiligo
- Pernicious anemia
- Parkinson disease
- Chronic atrophic gastritis
- Chronic active hepatitis
- Idiopathic thrombocytopenic purpura
- Myasthenia gravis
Gross Pathology
On gross pathology the characteristic findings include:[20][21]
- The endocrine gland is usually diffusely enlarged and firm.
- Chronically inflamed glands can be irregularly shrunken.
Microscopic Pathology
Autoimmune polyendocrine syndrome can involve a variety of endocrine and nonendocrine organs. On microscopic histopathological analysis, the following features can be seen:
- Chronic inflammatory cell infiltration
- Lymphocytic/plasma cell infiltration (cell mediated autoimmunity)
- Extensive fibrosis and atrophy
- Sparing of adjacent non-target tissue
References
- ↑ SOLOMAN N, CARPENTER CJ, BENNETT IL, HARVEY AM (1965). "SCHMIDT'S SYNDROME (THYROID AND ADRENAL INSUFFICIENCY) AND COEXISTENT DIABETES MELLITUS". Diabetes. 14: 300–4. PMID 14280372.
- ↑ Lindmark, Evelina; Chen, Yunying; Georgoudaki, Anna-Maria; Dudziak, Diana; Lindh, Emma; Adams, William C.; Loré, Karin; Winqvist, Ola; Chambers, Benedict J.; Karlsson, Mikael C.I. (2013). "AIRE expressing marginal zone dendritic cells balances adaptive immunity and T-follicular helper cell recruitment". Journal of Autoimmunity. 42: 62–70. doi:10.1016/j.jaut.2012.11.004. ISSN 0896-8411.
- ↑ Lindh, Emma; Rosmaraki, Eleftheria; Berg, Louise; Brauner, Hanna; Karlsson, Mikael C.I.; Peltonen, Leena; Höglund, Petter; Winqvist, Ola (2010). "AIRE deficiency leads to impaired iNKT cell development". Journal of Autoimmunity. 34 (1): 66–72. doi:10.1016/j.jaut.2009.07.002. ISSN 0896-8411.
- ↑ Villaseñor J, Benoist C, Mathis D (2005). "AIRE and APECED: molecular insights into an autoimmune disease". Immunol. Rev. 204: 156–64. doi:10.1111/j.0105-2896.2005.00246.x. PMID 15790357.
- ↑ Bruserud, Øyvind; Oftedal, Bergithe E.; Landegren, Nils; Erichsen, Martina M.; Bratland, Eirik; Lima, Kari; Jørgensen, Anders P.; Myhre, Anne G.; Svartberg, Johan; Fougner, Kristian J.; Bakke, Åsne; Nedrebø, Bjørn G.; Mella, Bjarne; Breivik, Lars; Viken, Marte K.; Knappskog, Per M.; Marthinussen, Mihaela C.; Løvås, Kristian; Kämpe, Olle; Wolff, Anette B.; Husebye, Eystein S. (2016). "A Longitudinal Follow-up of Autoimmune Polyendocrine Syndrome Type 1". The Journal of Clinical Endocrinology & Metabolism. 101 (8): 2975–2983. doi:10.1210/jc.2016-1821. ISSN 0021-972X.
- ↑ Alimohammadi M, Björklund P, Hallgren A, Pöntynen N, Szinnai G, Shikama N, Keller MP, Ekwall O, Kinkel SA, Husebye ES, Gustafsson J, Rorsman F, Peltonen L, Betterle C, Perheentupa J, Akerström G, Westin G, Scott HS, Holländer GA, Kämpe O (2008). "Autoimmune polyendocrine syndrome type 1 and NALP5, a parathyroid autoantigen". N. Engl. J. Med. 358 (10): 1018–28. doi:10.1056/NEJMoa0706487. PMID 18322283.
- ↑ Puel A, Döffinger R, Natividad A, Chrabieh M, Barcenas-Morales G, Picard C, Cobat A, Ouachée-Chardin M, Toulon A, Bustamante J, Al-Muhsen S, Al-Owain M, Arkwright PD, Costigan C, McConnell V, Cant AJ, Abinun M, Polak M, Bougnères PF, Kumararatne D, Marodi L, Nahum A, Roifman C, Blanche S, Fischer A, Bodemer C, Abel L, Lilic D, Casanova JL (2010). "Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I". J. Exp. Med. 207 (2): 291–7. doi:10.1084/jem.20091983. PMC 2822614. PMID 20123958.
- ↑ Alimohammadi, Mohammad; Björklund, Peyman; Hallgren, Åsa; Pöntynen, Nora; Szinnai, Gabor; Shikama, Noriko; Keller, Marcel P.; Ekwall, Olov; Kinkel, Sarah A.; Husebye, Eystein S.; Gustafsson, Jan; Rorsman, Fredrik; Peltonen, Leena; Betterle, Corrado; Perheentupa, Jaakko; Åkerström, Göran; Westin, Gunnar; Scott, Hamish S.; Holländer, Georg A.; Kämpe, Olle (2008). "Autoimmune Polyendocrine Syndrome Type 1 and NALP5, a Parathyroid Autoantigen". New England Journal of Medicine. 358 (10): 1018–1028. doi:10.1056/NEJMoa0706487. ISSN 0028-4793.
- ↑ Kisand K, Lilic D, Casanova JL, Peterson P, Meager A, Willcox N (2011). "Mucocutaneous candidiasis and autoimmunity against cytokines in APECED and thymoma patients: clinical and pathogenetic implications". Eur. J. Immunol. 41 (6): 1517–27. doi:10.1002/eji.201041253. PMID 21574164.
- ↑ Bacchetta R, Passerini L, Gambineri E, Dai M, Allan SE, Perroni L, Dagna-Bricarelli F, Sartirana C, Matthes-Martin S, Lawitschka A, Azzari C, Ziegler SF, Levings MK, Roncarolo MG (2006). "Defective regulatory and effector T cell functions in patients with FOXP3 mutations". J. Clin. Invest. 116 (6): 1713–22. doi:10.1172/JCI25112. PMC 1472239. PMID 16741580.
- ↑ Powell BR, Buist NR, Stenzel P (1982). "An X-linked syndrome of diarrhea, polyendocrinopathy, and fatal infection in infancy". J. Pediatr. 100 (5): 731–7. PMID 7040622.
- ↑ Moraes-Vasconcelos D, Costa-Carvalho BT, Torgerson TR, Ochs HD (2008). "Primary immune deficiency disorders presenting as autoimmune diseases: IPEX and APECED". J. Clin. Immunol. 28 Suppl 1: S11–9. doi:10.1007/s10875-008-9176-5. PMID 18264745.
- ↑ 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.
- ↑ Caturegli P, De Remigis A, Rose NR (2014). "Hashimoto thyroiditis: clinical and diagnostic criteria". Autoimmun Rev. 13 (4–5): 391–7. doi:10.1016/j.autrev.2014.01.007. PMID 24434360.
- ↑ "Thyroiditis — NEJM".