Autoimmune polyendocrine syndrome pathophysiology: Difference between revisions
Jump to navigation
Jump to search
Akshun Kalia (talk | contribs) No edit summary |
Akshun Kalia (talk | contribs) |
||
| Line 57: | Line 57: | ||
* '''Type 2 :''' APS type 2 is not a single gene disorder and has a complex inheritance pattern. | * '''Type 2 :''' APS type 2 is not a single gene disorder and has a complex inheritance pattern. | ||
* APS type 2 patients commonly have Addison's disease, type I diabetes mellitus and thyroiditis which have multiple | ** APS type 2 patients commonly have Addison's disease, type I diabetes mellitus and thyroiditis which themselves have multiple genes involvement and is one of the cause 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 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) and DR4/DQ8 (DQ8:DQA1*0301, DQB1*0302) and with DRB1*0404 and this syndrome inherits in an [[autosomal dominant]] fashion. | ***The strongest association for APS type 2 is with HLA DR3/DQ2 (DQ2:DQA1*0501, DQB1*0201) and DR4/DQ8 (DQ8:DQA1*0301, DQB1*0302) and with 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. | ***It has been observed that patients of APS type 2 with DR3 is often introduced into the family by more than one relative. | ||
*Other HLA antigens include HLA-DR3 or HLA-DR4. | |||
**Other HLA antigens include HLA-DR3 or HLA-DR4. | |||
* '''XPID''': This is due to mutation of the ''[[FOXP3]]'' gene on the X chromosome. | * '''XPID''': This is due to mutation of the ''[[FOXP3]]'' gene on the X chromosome. | ||
Revision as of 16:55, 2 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:
Overview
Autoimmune polyendocrine syndrome are 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. Autoimmune polyendocrine syndrome can be categorized into three different types namely type 1, type 2 and IPEX syndrome.
Pathophysiology
The pathogenesis in autoimmune polyendocrine syndrome includes:[1][2][3][4][5][6][7][8]
- Autoimmune polyendocrine syndrome are a group of rare autoimmune disorders against multiple (poly) endocrine glands, although non endocrine gland/tissues 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 and the immune system attacks various endocrine and nonendocrine organs throughout the body. Autoimmune polyendocrine syndrome can be categorized into two major types namely type 1 (also called autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED)) and type 2. However, other types of autoimmune polyendocrine syndromes exists but are rare in occurrence. These include APS type 3 [IPEX or XPID (Immune Dysfunction Polyendocrinopathy X-linked) syndrome] and APS type 4.
- In autoimmune polyendocrine syndrome, 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 non endocrine gland/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 invloved.
- In addition there may be antibodies against tryptophan hydroxylase, tyrosine hydroxylase, mitochondria in liver and steroid hormone producing cells.
Autoimmune polyendocrine syndrome type 1 (APS type 1)
The autoimmune polyendocrine syndrome 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 be to confer immune tolerance for antigens from endocrine organs. The pathogenesis of APS type 1 is as follow:[9]
- 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 various 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 are against parathyroid specific protein, NALP5 which leads to hypoparathyroidism.
- Autoantibody against enzyme GAD (glutamic acid decarboxylase) of pancreas leads 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, IL17F and IL22.
- 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 is related to MHC class II, primarily DQ2 and DQ8. As compared to type 1, APS type 2 is more varied in its manifestations and is the most common type of APS.
- APS type 2 is seen in genetically susceptible individuals who when exposed to certain environmental factors develop autoimmunity. It is also postulated, that there is a loss of self tolerance in these individuals.
- The autoantibodies are directed against various endocrine and nonendocrine organs.
- The strongest association for APS type 2 is with HLA DR3/DQ2 (DQ2:DQA1*0501, DQB1*0201) and DR4/DQ8 (DQ8:DQA1*0301, DQB1*0302) and with DRB1*0404.
- It has been observed that patients of APS type 2 with DR3 is often introduced into the family by more than one relative.
- Other HLA antigens include HLA-DR3 or HLA-DR4.
- HLA-B8 and DR3 associated illnesses include selective IgA deficiency, juvenile dermatomyositis, and dermatitis herpetiformis, alopecia, scleroderma, autoimmune thrombocytopenia 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 when exposed to certain environmental factors (such as viral infections) develop autoimmunity.
- 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.It is postulated, that there is a loss of self tolerance in patients of APS type 3.
- 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 organsims.
- 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:[13][14]
- Type I: As opposed to type 2, this syndrome inherits in an autosomal recessive fashion and is due to a defect in AIRE ("autoimmune regulator"), a gene located on the 21st chromosome. Normal function of AIRE, a transcription factor, appears to be to confer immune tolerance for antigens from endocrine organs. Type 1 autoimmune polyglandular syndrome (APS-1), has a unique pathogenic mechanism owing to mutations in the autoimmune regulator (AIRE) gene, which results in the loss of central tolerance-a process by which developing T cells with potential reactivity for self-antigens are eliminated during early differentiation in the thymus.
- The genetic locus is on short arm (p) of chromosome 21 at 21p22.3.
- APS-1 has been associated with more than 60 different mutations in the AIRE gene, the majority of which are translated into truncated and non-functional AIRE. The two common mutations are R257X and 1094-1106del. According to a Finnish study the mutation R257X is responsible for 82% of cases in Finland. [15]
- It is observed that patients with APS type 1 have an increased frequency of HLA-A28 and HLA-A3. [16]
- Type 2 : APS type 2 is not a single gene disorder and has a complex inheritance pattern.
- APS type 2 patients commonly have Addison's disease, type I diabetes mellitus and thyroiditis which themselves have multiple genes involvement and is one of the cause 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) and DR4/DQ8 (DQ8:DQA1*0301, DQB1*0302) and with 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.
- Other HLA antigens include HLA-DR3 or HLA-DR4.
- XPID: This is due to mutation of the FOXP3 gene on the X chromosome.
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:[17][18]
- 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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".