Autoimmune Polyendocrine Syndrome type II (APS2) describes the onset of multiple disorders involving the dysfunction of hormone-producing organs due to autoimmunity.  All APS2 cases exhibit Addison’s disease (AD), caused by autoimmune destruction of the adrenal glands.  Forms of APS2 constitute additional autoimmune diseases of the thyroidand pancreatic glands.  Autoimmune thyroid disordersincludeHashimoto’s Thyroiditis (hypothyroidism) and Grave’s Disease (hyperthyroidism). Pancreatic autoimmunity leads to insulin dependent diabetes mellitus (IDDM).The association of AD withhypothyroidism is most common among APS2 cases, while the association of all three glandular disorders, representing the complete form of APS2, is least common, with an estimated prevalence of 1.4-4.5 cases per 100,000 individuals.APS2 is the most common immunoendocrinopathy syndrome; approximately 75% of affected cases are female, and the age of onset occurs typically after the third decade of life.  APS2 cases can further develop relativelyminor autoimmune diseases including vitiligo, atrophic gastritis, pernicious anemia,hypergonodotropic hypogonadism, and celiac disease.

Lymphoplasmacytic infiltration of adrenal, thyroid, and pancreatic glands is the primary pathological process in APS2.Circulating autoantibodies target specific self-antigens, blocking organ activity (AD, hypothyroidism, IDDM), or stimulating organ activity (hyperthyroidism).  Diagnosis involves organ imaging and autoantibody screening following the onset of symptoms pertaining to the autoimmune disorders. Management of APS2 involves hormone replacement therapy with the exception of hyperthyroidism and celiac disease treatment.   Due to the variable latency in the onset between specific disordersin APS2, cases with monoglandular autoimmune diseasemust undergo repeated screening of organ-specific autoantibodies.

Humoral and cellular autoimmunity is triggered in genetically susceptible individuals following environmental or intrinsic stimuli.  APS2 is a polygenic disorderinherited in an autosomal dominant fashion withvariable expressivity.Certain genotypeswithin thehuman leukocyte antigen (HLA) gene locus, located on chromosome 6, are associated with susceptibility to developing multiple autoimmune diseases.

HLA-DR3 and HLA-DR4 haplotypes are significantly associated with APS2; specifically,the DRB1*03; DQA1*0501; DQB1*0201 (HLA-DR3/DQ2) and DRB1*04; DQA1*0301, DQB1*0302 (HLA-DR4/DQ3) haplotypes confer an increased risk of developingAddison’s disease (AD), insulin dependent diabetes mellitus(IDDM), and celiac disease.  A microsatellite polymorphism on exon 5 of the Major Histocompatibility Complex Class 1 polypeptide related sequence A (MICA5.1)and the HLA-DR3/DQ2 haplotype together associate with significant risk of developing AD.  The HLA-DR4/DQ3 haplotype is associated with cases exhibiting both pancreatic autoimmunity and AD.Cases with IDDM expressing 21-hydroxylase antibodies (autoantibodies disrupting adrenal function), and exhibiting the DRB1*0404 allele, are at a 100 fold higher risk of developing AD. In contrast, the HLA-DR1 haplotype (DRB1*01; DQA1*01; DQB1*0501) is negatively associated with AD.HLA typing and autoantibody screening of relatives of affected cases can identify potential risks and lead to early management.