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 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.
- 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).
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.
- 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
Gross Pathology
- On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
Microscopic Pathology
- On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].