Autoimmune polyendocrine syndrome pathophysiology
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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
- 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.[1][2][3][4][5][6][7]
- In patients of APS type 1, there is a 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.
- 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 DM 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 type 2 APS is more varied in its manifestations.
- 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.
Genetics
- 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 nine different mutations in the AIRE gene, of which the 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. [8]
- It is observed that patients with APS type 1 have an increased frequency of HLA-A28 and HLA-A3. [9]
- Type 2 : It is heterogenous, occurs more often and has not been linked to one gene. Rather, patients are at a higher risk when they carry a particular HLA genotype (DQ2, DQ8 and DRB1*0404).
- XPID: This is due to mutation of the FOXP3 gene on the X chromosome. Most patients develop diabetes and diarrhea as neonates and many die due to autoimmune activity against many organs. Boys are affected, while girls are carriers and might suffer mild disease.
Associated Conditions
- Diabetes mellitus Type 1
- Pure red cell aplasia
- Autoimmune thyroid disease
- Vitiligo
- Pernicious anemia
- Chronic atrophic gastritis
- Chronic active hepatitis
Gross Pathology
- On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
Microscopic Pathology
On microscopic histopathological analysis, the following features can be seen:
- Chronic inflammatory cell infiltration
- Lymphocytic/plasma cell infiltration
- Extensive fibrosis
References
- ↑ 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.
- ↑ 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.