Clinical presentation
Autoimmune polyglandular syndromes (APS) are rare endocrinopathies characterized by the coexistence of at least two gland diseases that are based on autoimmune mechanisms. Associations with non-endocrine immune diseases may occur. Two major subtypes of APS, types 1 and 2, are distinguished according to age of presentation, characteristic patterns of disease combinations, and different modes of inheritance. APS 1, also known as autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy or multiple endocrine deficiency autoimmune candidiasis syndrome, usually appears in childhood at age three to five years or in early adolescence and, therefore, is also called juvenile autoimmune polyendocrinopathy. It is defined by a persistent fungal infection (mucocutaneous candidiasis), the presence of acquired hypoparathyroidism, and Addison's disease. In most patients, candidiasis precedes the other immune disorders, usually followed by hypoparathyroidism. While first clinical manifestation occurs in childhood, the main component diseases develop in the first 20 years of life, and further associated diseases may not evolve until the fifth decade or later. The female-to-male ratio varies from 0.8:1 to 2.4:1. The highest prevalences of the rare APS 1 have been found in populations who are characterized by high degree of consanguinity or who are descendant of small founder populations, particularly in Iranian Jews and Finns. Genetic studies have shown an autosomal recessive inheritance in a single gene. APS 2 is more common and occurs in adulthood, mainly in the third or fourth decade. It is characterized by autoimmune thyroid disease and/or type 1 diabetes with or without Addison's disease. Disorders like autoimmune gastritis, pernicious anemia, vitiligo and alopecia may occur in type 2. The prevalence of APS 2 is estimated to be 1: 20,000, and females are affected three times more frequently than males. In contrast to type 1, family members of APS 2 patients are often affected. APS type 2 is believed to be polygenic, characterized by autosomal dominant inheritance (1-6).

Immunopathogenesis
Autoaggression in polyglandular autoimmunity is considered multifactorial. The principal antigen-specific immune response is initiated by antigen presenting cells (7). Ubiquitous dendritic cells are the most important APC’s. Immature dendritic cells pick up antigen molecules in non-lymphoid organs, fragment the antigens, and migrate to the secondary lymphoid organs presenting their HLA class I or II associated antigen fragments. This activates antigen-specific T helper cells that stimulate by use of different cytokines the cellular immune response via cytotoxic T lymphocytes (Th1) and/or the humoral immune response via B lymphocytes (Th2). During the Th1 response, activation of mononuclear phagocytes also occurs, because Th1 cytokines comprise proinflammatory mediators. T suppressor cells regulate the immune responses; when immune tolerance is lost, autoaggression occurs. Recently, a T cell population (CD4⁺CD25⁺) with potent regulatory properties that inhibit the activation of CD4⁺CD25^- T effector cells has been described (8-9). These T cells regulate autoaggressive T and B cells and may have profound influence on the control of human autoimmune diseases.
Animal models of the pathogenesis of APS are consistent with a viral infection theory as well as a suppressor effect theory. The viral infection-theory couples autoimmune disease with viral infection. The so-called “molecular mimicry” is characterized by an immune response to an environmental agent that cross-reacts with a host antigen, resulting in disease. In an animal model, mice infected with reovirus type 1 developed APS (10-11). Some of the resultant autoantibodies showed cross-species reactivity, recognizing similar antigenic determinants in mouse and human organs. With respect to the suppressor effect theory, administration of the immunosuppressive drug cyclosporine to newborn BALB/c mice caused a selective defect of the regulatory T suppressor cells (12). Thymectomy conserved the T-cell defect and produced autoimmune diseases in a wide spectrum of organs (thyroiditis, insulitis, adrenalitis, oophoritis/orchitis, and gastritis) with pathology similar to that of human organ-specific immune diseases. These pathological processes lead to the pre-clinical phase of APS, with production of organ-specific antibodies and progressive immune-mediated destruction of endocrine tissues. In the clinical phase, major organ destruction occurs due to the autoimmune activity that is primarily characterized by chronic inflammatory infiltration of lymphocytes. Destruction of endocrine glands causes their secretory insufficiency.
The role of apoptosis in immunodestruction has been associated with deregulation of apoptotic signaling pathways. Dysfunction of the Fas apoptotic pathway or production of soluble factors including soluble Fas and soluble Fas ligand may be involved in the pathogenesis of endocrine diseases. In the case of type 1 diabetes it has been postulated that increased susceptibility of islet cells to the induction of apoptosis by cytotoxic T cells – presumably through the cell surface receptor Fas pathway – may be responsible for facilitated death of islet ß cells (3, 13).

Immunogenetics
Significant associations of APS type 2 with HLA class I antigens were observed in various studies (14). In part, this may be explained by the observation that APS patients with HLA linkage showed a decreased HLA class I expression on the surface of their lymphocytes and a defective transcription of HLA class-I processing genes. APS type 2 is polygenically inherited, characterized by dominant inheritance. Several component diseases of APS have a common immunogenetic background, but the major genetic factor remains to be detected in the HLA region. One factor in the pathogenesis of APS may be an immunologic dysfunction that results from one or more genes on chromosome 6, in linkage disequilibrium with the HLA-B8 allele. APS type 2 is also associated with the HLA antigens DR3 and/or DR4, and DRw3, whereas HLA DR3 is associated with almost all immune endocrinopathies of APS type 2. Further detailed analyses of the HLA DR3 alleles showed that the HLA DR3-DQB1*0201 haplotype may be associated with multiple component diseases of APS, while the HLA DR4-DQB1*0302 haplotype is implicated in beta-cell autoimmunity only. Patients with APS may be highly selected for HLA-B8/DRw3 positivity. In comparison, for autoimmune thyroid diseases, a high percentage of family members of patients showed significant titers of thyroid autoantibodies and segregation analyses favored a dominant mode of inheritance. Genetic transmission of autoimmune thyroid diseases seems to be complex and the familial pattern indicates a multigenic disease in which multiple genes may contribute to the clinical phenotype. Recent studies have proposed the cytotoxic T lymphocyte-associated gene that contributes to the genetic susceptibility to thyroid antibody production, located on chromosome 2q33. Susceptibility to APS type 2 diseases has further been associated with the major HLA class I chain-related MIC-A genes. Moreover, quantitative defects in the density of conformational correct HLA class I complexes on the surface of lymphocytes were found in patients with diverse HLA-linked autoimmune diseases (13-15).
Associations with HLA class II alleles also have recently been reported in APS type 1. An increased frequency of the HLA-DR3 allele was observed in these patients. In a study comprising patients with APS type 1 from 12 different countries, Addison’s disease was found to be significantly and positively associated with the HLA-DRB1*03 allele (relative risk RR 8.8). Here, only one of 19 patients with HLA-DRB1*03, in contrast to 28 of 85 patients without this allele, had not developed Addison’s disease (4). Moreover, in these patients with APS 1, the component disease alopecia was significantly and positively associated with HLA-DRB1*04 (RR 4.8) and DQB1*0302 (RR 6.6). In contrast, the most common protective alleles for type 1 diabetes (DRB1*15 and DQB1*0602) were similarly protective in APS 1 patients, as indicated by significant negative correlations (3, 15). However, in the immunogenetics of APS type 1, mutations of a single gene that is termed the autoimmune regulator (AIRE) gene, play an important role. The AIRE gene is assigned to chromosome 21q22.3 and has been cloned by two independent research groups. In the coding region of the AIRE gene, 45 different mutations have been reported. Mutations comprise nonsense and missense mutations, deletions, and small insertions (6, 25). A few mutations are responsible for the expression of a truncated regulator protein. AIRE encodes a 545-amino-acid protein of 57.5 kDa that contains structural domains characteristic for transcription regulators. AIRE is also an important DNA binding molecule that is involved in immune regulation. The AIRE gene is expressed in immunologically relevant tissues, particularly in the thymic medulla, as well as in lymph nodes and peripheral blood cells (CD14-positive monocytes), but not in CD4-positive T cells. Mutational analysis of AIRE helps identify patients with atypical phenotypes resembling to APS type 1, e.g. the AIRE mutation R257X was responsible for 82 % of APS 1 alleles in a Finn population (17-26).

Diagnostic recommendations
The clinical presentation of APS is often preceded by an asymptomatic latent period characterized by the presence of circulating disease-associated antibodies which are useful markers for the prediction of the development of APS (27-28). Absence of these antibodies does not exclude the disease, because not all patients show positive antibodies. In view of the possible long time interval between the manifestation of the first and further autoimmune endocrinopathies, regular and long-term observation of patients with autoimmune endocrine disorders is warranted. Moreover, if a patient has one endocrinopathy and a family member has another, it is likely that they also may have antibodies against other endocrine tissues. In view of the tendency of autoimmune diseases to associate with other disorders, of the metachronous manifestations of the component diseases, and of the subclinical course, it is necessary to suspect in all patients with one immune endocrinopathy the existence of a further autoimmune disorder, particularly in patients with positive family histories.
For patients with monoglandular autoimmune endocrinopathy, functional screening for autoimmune polyglandular syndromes is therefore recommended. If pathological findings, e.g. occurrence of a second autoimmune endocrine disease, are noted, measurement of organ-specific autoantibodies should be added. Furthermore, functional screening for autoimmune endocrine diseases of the first-degree relatives of these patients with newly diagnosed APS may be also done. Especially in the offspring of patients with type 1 diabetes, serological testing for the presence of diabetes associated antibodies should be considered. Genetic screening is especially useful in APS type 1. Thus, in subjects at risk, regular functional screening is warranted. If clinical disease is present, serological measurement of organ-specific antibodies should follow (29-30).