Autoimmune polyendocrine syndrome pathophysiology: Difference between revisions

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{{Autoimmune polyendocrine syndrome}}
{{Autoimmune polyendocrine syndrome}}


{{CMG}}; {{AE}}  
{{CMG}}; {{AE}}{{Akshun}}


==Overview==
==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.
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 non-[[endocrine]] [[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 gland]]s can be simultaneous or sequential. The [[autoimmune]] reaction can either be [[humoral]] or [[Cell mediated immunity|cell mediated]] which may lead to partial or complete destruction of the [[tissue]] involved. The common [[endocrine glands]] involved are [[parathyroids]], [[adrenal gland|adrenals]], [[thyroid]], and [[pancreas]]. However any other non endocrine [[gland]]/[[tissue]] of the body may be involved.


==Pathophysiology==
==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 syndrome) and APS type 4.
The [[pathogenesis]] in autoimmune polyendocrine syndrome (APS) includes:<ref name="pmid14280372">{{cite journal |vauthors=SOLOMAN N, CARPENTER CJ, BENNETT IL, HARVEY AM |title=SCHMIDT'S SYNDROME (THYROID AND ADRENAL INSUFFICIENCY) AND COEXISTENT DIABETES MELLITUS |journal=Diabetes |volume=14 |issue= |pages=300–4 |year=1965 |pmid=14280372 |doi= |url=}}</ref><ref name="LindmarkChen2013">{{cite journal|last1=Lindmark|first1=Evelina|last2=Chen|first2=Yunying|last3=Georgoudaki|first3=Anna-Maria|last4=Dudziak|first4=Diana|last5=Lindh|first5=Emma|last6=Adams|first6=William C.|last7=Loré|first7=Karin|last8=Winqvist|first8=Ola|last9=Chambers|first9=Benedict J.|last10=Karlsson|first10=Mikael C.I.|title=AIRE expressing marginal zone dendritic cells balances adaptive immunity and T-follicular helper cell recruitment|journal=Journal of Autoimmunity|volume=42|year=2013|pages=62–70|issn=08968411|doi=10.1016/j.jaut.2012.11.004}}</ref><ref name="LindhRosmaraki2010">{{cite journal|last1=Lindh|first1=Emma|last2=Rosmaraki|first2=Eleftheria|last3=Berg|first3=Louise|last4=Brauner|first4=Hanna|last5=Karlsson|first5=Mikael C.I.|last6=Peltonen|first6=Leena|last7=Höglund|first7=Petter|last8=Winqvist|first8=Ola|title=AIRE deficiency leads to impaired iNKT cell development|journal=Journal of Autoimmunity|volume=34|issue=1|year=2010|pages=66–72|issn=08968411|doi=10.1016/j.jaut.2009.07.002}}</ref><ref name="pmid15790357">{{cite journal |vauthors=Villaseñor J, Benoist C, Mathis D |title=AIRE and APECED: molecular insights into an autoimmune disease |journal=Immunol. Rev. |volume=204 |issue= |pages=156–64 |year=2005 |pmid=15790357 |doi=10.1111/j.0105-2896.2005.00246.x |url=}}</ref><ref name="BruserudOftedal2016">{{cite journal|last1=Bruserud|first1=Øyvind|last2=Oftedal|first2=Bergithe E.|last3=Landegren|first3=Nils|last4=Erichsen|first4=Martina M.|last5=Bratland|first5=Eirik|last6=Lima|first6=Kari|last7=Jørgensen|first7=Anders P.|last8=Myhre|first8=Anne G.|last9=Svartberg|first9=Johan|last10=Fougner|first10=Kristian J.|last11=Bakke|first11=Åsne|last12=Nedrebø|first12=Bjørn G.|last13=Mella|first13=Bjarne|last14=Breivik|first14=Lars|last15=Viken|first15=Marte K.|last16=Knappskog|first16=Per M.|last17=Marthinussen|first17=Mihaela C.|last18=Løvås|first18=Kristian|last19=Kämpe|first19=Olle|last20=Wolff|first20=Anette B.|last21=Husebye|first21=Eystein S.|title=A Longitudinal Follow-up of Autoimmune Polyendocrine Syndrome Type 1|journal=The Journal of Clinical Endocrinology & Metabolism|volume=101|issue=8|year=2016|pages=2975–2983|issn=0021-972X|doi=10.1210/jc.2016-1821}}</ref>
*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.
*APS can be defined as a group of rare [[autoimmune disorders]] against multiple (poly) [[endocrine glands]], although non-[[endocrine]] [[gland]]/[[tissues]] may be affected.  
**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 APS, there is either defective regulation of [[T cells]] or loss of self tolerance which causes the [[immune system]] to attack various [[endocrine]] and non-[[endocrine]] [[organs]] throughout the body.
**In addition there may be antibodies against tryptophan hydroxylase, tyrosine hydroxylase, mitochondria in liver and steroid hormone producing cells.
*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]], [[Adrenal gland|adrenals]], [[thyroid]], and [[pancreas]]. However any other [[endocrine]]/non-[[endocrine]] [[Tissue (biology)|tissue]] of the body may be involved.
**The [[autoimmune reaction]] can either be [[Humoral immunity|humoral]] or [[Cell-mediated immunity|cell mediated.]]
**Depending upon the [[inflammation]] and the [[lymphocytic]] infiltration of the [[endocrine]] and non-[[endocrine]] [[Tissue (biology)|tissue]], there may be partial or complete destruction of the [[tissue]] involved.


'''Autoimmune polyendocrine syndrome type 1 (APS type 1)'''
'''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.
*In these patients, 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.
*The most commonly associated autoantibody is anti-adrenal antibody (against enzyme; 21-hydroxylase) which leads to Addison's disease.
*Other antibodies include autoantibody against enzyme GAD (glutamic acid decarboxylase) of pancreas which leads to insulin deficiency.
**Patients with typical type 1 diabetes also have anti-GAD antibodies but can be differentiated from anti-GAD antibodies in APS type 1 with western blot.
**Patients with APS type 1 and anti-GAD antibodies react with GAD on western blot and is able to inhibit GAD enzyme activity. This is not present in typical patients with DM type I.
* Recent studies have indicated that almost all patients with APS type 1 have antibodies against interferon-omega (IFN-ω) and interferon alpha (IFN-α).


The major mechanism behind the [[pathogenesis]] of APS type 1 is as follows:<ref name="pmid18322283">{{cite journal |vauthors=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 |title=Autoimmune polyendocrine syndrome type 1 and NALP5, a parathyroid autoantigen |journal=N. Engl. J. Med. |volume=358 |issue=10 |pages=1018–28 |year=2008 |pmid=18322283 |doi=10.1056/NEJMoa0706487 |url=}}</ref><ref name="pmid20123958">{{cite journal |vauthors=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 |title=Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I |journal=J. Exp. Med. |volume=207 |issue=2 |pages=291–7 |year=2010 |pmid=20123958 |pmc=2822614 |doi=10.1084/jem.20091983 |url=}}</ref><ref name="AlimohammadiBjörklund2008">{{cite journal|last1=Alimohammadi|first1=Mohammad|last2=Björklund|first2=Peyman|last3=Hallgren|first3=Åsa|last4=Pöntynen|first4=Nora|last5=Szinnai|first5=Gabor|last6=Shikama|first6=Noriko|last7=Keller|first7=Marcel P.|last8=Ekwall|first8=Olov|last9=Kinkel|first9=Sarah A.|last10=Husebye|first10=Eystein S.|last11=Gustafsson|first11=Jan|last12=Rorsman|first12=Fredrik|last13=Peltonen|first13=Leena|last14=Betterle|first14=Corrado|last15=Perheentupa|first15=Jaakko|last16=Åkerström|first16=Göran|last17=Westin|first17=Gunnar|last18=Scott|first18=Hamish S.|last19=Holländer|first19=Georg A.|last20=Kämpe|first20=Olle|title=Autoimmune Polyendocrine Syndrome Type 1 and NALP5, a Parathyroid Autoantigen|journal=New England Journal of Medicine|volume=358|issue=10|year=2008|pages=1018–1028|issn=0028-4793|doi=10.1056/NEJMoa0706487}}</ref><ref name="pmid21574164">{{cite journal |vauthors=Kisand K, Lilic D, Casanova JL, Peterson P, Meager A, Willcox N |title=Mucocutaneous candidiasis and autoimmunity against cytokines in APECED and thymoma patients: clinical and pathogenetic implications |journal=Eur. J. Immunol. |volume=41 |issue=6 |pages=1517–27 |year=2011 |pmid=21574164 |doi=10.1002/eji.201041253 |url=}}</ref>
*The APS type 1 is primarily related to [[mutation]] in the AIRE (Autoimmune Regulator) 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 [[Antigen|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 non-[[endocrine]] 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|21-hydroxylase]]) which leads to [[Addison's disease|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 1|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 syndrome|APECED]] ([[Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome|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 [[Human leukocyte antigen|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 non-[[endocrine]] [[organs]].
*The classic triad of APS type 2 includes [[Addison's disease]], [[autoimmune thyroiditis]] and [[Type 1 diabetes mellitus|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]], [[Thrombocytopenic purpura, autoimmune|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|genetic factors]] and [[autoimmunity]] play an important role in the [[parthenogenesis]] of APS type 3.<ref name="pmid16741580">{{cite journal |vauthors=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 |title=Defective regulatory and effector T cell functions in patients with FOXP3 mutations |journal=J. Clin. Invest. |volume=116 |issue=6 |pages=1713–22 |year=2006 |pmid=16741580 |pmc=1472239 |doi=10.1172/JCI25112 |url=}}</ref><ref name="pmid7040622">{{cite journal |vauthors=Powell BR, Buist NR, Stenzel P |title=An X-linked syndrome of diarrhea, polyendocrinopathy, and fatal infection in infancy |journal=J. Pediatr. |volume=100 |issue=5 |pages=731–7 |year=1982 |pmid=7040622 |doi= |url=}}</ref><ref name="pmid18264745">{{cite journal |vauthors=Moraes-Vasconcelos D, Costa-Carvalho BT, Torgerson TR, Ochs HD |title=Primary immune deficiency disorders presenting as autoimmune diseases: IPEX and APECED |journal=J. Clin. Immunol. |volume=28 Suppl 1 |issue= |pages=S11–9 |year=2008 |pmid=18264745 |doi=10.1007/s10875-008-9176-5 |url=}}</ref>
*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, [[Regulatory T cell|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 cell|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-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===
===Genetics===
* '''Type I:''' As opposed to type 2, this syndrome inherits in an [[autosomal recessive]] fashion and is due to a defect in ''[[Autoimmune regulator|AIRE]]'' ("''a''uto''i''mmune ''re''gulator"), 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 [[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 ''[[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 normal function of [[Autoimmune Regulator|AIRE]] [[gene]] is to confer [[immune tolerance]] for [[antigens]] present in the [[body]].
** 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 [[Autoimmune Regulator|AIRE]] [[gene]], the majority of which results in truncated and non-functional [[Autoimmune Regulator|AIRE]].
** 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.
** It is also observed that patients with APS type 1 have an increased frequency of [[HLA-A28]] and [[HLA-A3]].  


* '''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).
* '<nowiki/>'''''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 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 exhibits an [[autosomal dominant]] inheritance.
***It has been observed that patients of APS type 2 with DR3 is often introduced into the family by more than one relative.


* '''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.
* '''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 ''[[FOXP3]]'' gene is located on [[chromosome]] Xp11.3-q13.3
** ''[[FOXP3]]'' plays a critical role in the function of [[CD4+|CD4]]+ [[CD25]]+ [[Regulatory T cells|T regulatory  cells]].
** Since XPID is an [[X linked|'X' linked]] condition, males are commonly affected. Females are carriers and may have mild disease.


==Associated Conditions==
==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==
==Gross Pathology==
*On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
On gross pathology the characteristic findings include:<ref name="pmid24434360">{{cite journal |vauthors=Caturegli P, De Remigis A, Rose NR |title=Hashimoto thyroiditis: clinical and diagnostic criteria |journal=Autoimmun Rev |volume=13 |issue=4-5 |pages=391–7 |year=2014 |pmid=24434360 |doi=10.1016/j.autrev.2014.01.007 |url=}}</ref><ref name="urlThyroiditis — NEJM">{{cite web |url=http://www.nejm.org/doi/full/10.1056/NEJMra021194 |title=Thyroiditis — NEJM |format= |work= |accessdate=}}</ref>
*The [[endocrine gland]] is usually diffusely enlarged and firm.
*Chronically [[inflamed]] [[glands]] can be irregularly shrunken.


==Microscopic Pathology==
==Microscopic Pathology==
*On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
Autoimmune polyendocrine syndrome can involve a variety of [[endocrine]] and non-[[endocrine]] organs. On [[microscopic]] [[histopathological]] analysis, the following features can be seen:<ref name="pmid20309000">{{cite journal |vauthors=Michels AW, Gottlieb PA |title=Autoimmune polyglandular syndromes |journal=Nat Rev Endocrinol |volume=6 |issue=5 |pages=270–7 |year=2010 |pmid=20309000 |doi=10.1038/nrendo.2010.40 |url=}}</ref>
*[[Chronic]] [[inflammatory]] cell [[Infiltration (medical)|infiltration]]
*[[Lymphocytic]]/[[plasma cell]] infiltration ([[Cell mediated immunity|cell mediated autoimmunity]])
*Extensive [[fibrosis]] and [[atrophy]]
*Sparing of adjacent non-target [[Tissue (biology)|tissue]]
*Renal involvement may exhibit the following histopathological findings:<ref name="urlKidney involvement in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy in a Finnish cohort | Nephrology Dialysis Transplantation | Oxford Academic">{{cite web |url=https://doi.org/10.1093/ndt/gfu064 |title=Kidney involvement in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy in a Finnish cohort &#124; Nephrology Dialysis Transplantation &#124; Oxford Academic |format= |work= |accessdate=}}</ref>
**Moderate [[inflammation]]
**Tubular [[atrophy]]
**Dilated tubuli with [[Protein|proteinaceous]] [[Periodic acid-Schiff stain|periodic acid-Schiff]]-positive material
**Fibrosis 


==References==
==References==

Latest revision as of 18:03, 3 November 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

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 non-endocrine 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]

Autoimmune polyendocrine syndrome type 1 (APS type 1)

The major mechanism behind the pathogenesis of APS type 1 is as follows:[6][7][8][9]


Autoimmune polyendocrine syndrome type 2 (APS type 2)

The pathogenesis of APS type 2 includes:

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]

Genetics

The genes involved in the pathogenesis of APS include:

Associated Conditions

Gross Pathology

On gross pathology the characteristic findings include:[20][21]

Microscopic Pathology

Autoimmune polyendocrine syndrome can involve a variety of endocrine and non-endocrine organs. On microscopic histopathological analysis, the following features can be seen:[22]

References

  1. ↑ 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.
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ "Thyroiditis — NEJM".
  22. ↑ Michels AW, Gottlieb PA (2010). "Autoimmune polyglandular syndromes". Nat Rev Endocrinol. 6 (5): 270–7. doi:10.1038/nrendo.2010.40. PMID 20309000.
  23. ↑ "Kidney involvement in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy in a Finnish cohort | Nephrology Dialysis Transplantation | Oxford Academic".

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