Polyglandular autoimmune syndromes

in European Journal of Endocrinology
(Correspondence should be addressed to G J Kahaly; Email: kahaly@ukmainz.de)

The polyglandular autoimmune syndromes (PAS) comprise a wide spectrum of autoimmune disorders and are divided into a very rare juvenile (PAS type I) and a relatively common adult type with (PAS II) or without adrenal failure (PAS III). First clinical manifestation of PAS I usually occurs in childhood, whereas PAS II mostly occurs during the third and fourth decades. PAS I is caused by mutations in the autoimmune regulatory (AIRE) gene on chromosome 21 and is inherited in an autosomal recessive manner. Mutations in the AIRE gene result in defect proteins which cause autoimmune destruction of target organs by disturbing the immunological tolerance of the patients. Genetic testing may identify patients with PAS I, but not those with PAS II/III. For PAS II/III, susceptibility genes are known which increase the risk for developing autoimmune disorders, but must not be causative. These are certain HLA genes, the cytotoxic T lymphocyte antigen gene, and the protein tyrosine phosphatase non-receptor type 22 gene on chromosomes 6, 2 and 1 respectively. Actual diagnosis of PAS involves serological measurement of organ-specific autoantibodies and subsequent functional testing. Management of patients with PAS including their family relatives is best performed in centres with special expertise in autoimmune endocrine disorders.

Abstract

The polyglandular autoimmune syndromes (PAS) comprise a wide spectrum of autoimmune disorders and are divided into a very rare juvenile (PAS type I) and a relatively common adult type with (PAS II) or without adrenal failure (PAS III). First clinical manifestation of PAS I usually occurs in childhood, whereas PAS II mostly occurs during the third and fourth decades. PAS I is caused by mutations in the autoimmune regulatory (AIRE) gene on chromosome 21 and is inherited in an autosomal recessive manner. Mutations in the AIRE gene result in defect proteins which cause autoimmune destruction of target organs by disturbing the immunological tolerance of the patients. Genetic testing may identify patients with PAS I, but not those with PAS II/III. For PAS II/III, susceptibility genes are known which increase the risk for developing autoimmune disorders, but must not be causative. These are certain HLA genes, the cytotoxic T lymphocyte antigen gene, and the protein tyrosine phosphatase non-receptor type 22 gene on chromosomes 6, 2 and 1 respectively. Actual diagnosis of PAS involves serological measurement of organ-specific autoantibodies and subsequent functional testing. Management of patients with PAS including their family relatives is best performed in centres with special expertise in autoimmune endocrine disorders.

Definition and epidemiology

The polyglandular autoimmune syndromes (PAS) form different clusters of autoimmune disorders and are rare endocrinopathies characterized by the coexistence of at least two glandular autoimmune mediated diseases (1). Two major subtypes of PAS, types I and II are distinguished according to age of presentation, characteristic patterns of disease combinations, and different modes of inheritance (2, 3). The coexistence of adrenal failure with either autoimmune thyroid disease (AITD) and/or type 1 diabetes (T1D) is defined as Schmidt's or Carpenter's syndrome. A third subtype has been described in adults that, contrary to types I and II, does not involve the adrenal cortex. Since apart from absence of adrenal failure no clinical differences between types II and III have been described, PAS may be divided into a very rare, foremost juvenile type I and a more common adult type II.

PAS I, also known as autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy or multiple endocrine deficiency autoimmune candidiasis syndrome, usually manifests in infancy or childhood at age 3–5 or in early adolescence and, therefore, is also called juvenile autoimmune polyendocrinopathy (4, 5). It is defined by a persistent fungal infection (chronic mucocutaneous candidiasis), the presence of acquired hypoparathyroidism, and Addison's disease. In most patients, mucocutaneous candidiasis precedes the other immune disorders, usually followed by hypoparathyroidism (Table 1 and Fig. 1). The female-to-male ratio varies from 0.8:1 to 2.4:1. The highest prevalences of PAS I have been found in populations characterized by a high degree of consanguinity or descendant of small founder populations, particularly in Iranian Jews (1:600–9000) and Finns (1:25 000). In the general population, PAS I is a very uncommon disease in contrast to what is observed in selected populations; however, genetic screening of first-degree relatives of affected subjects may unravel a higher prevalence than expected due to the detection of clinically milder or atypical cases.

Table 1

Characteristics of the polyglandular autoimmune syndromes (PAS).

PAS type IPAS type II
PrevalenceVery rareRelatively common
Incidence<1:100 000/year1–2:10 000/year
M/F ratio3:41:3
OnsetChildhoodChildhood through adulthood
InheritanceMonogenic (AIRE gene)Polygenic
Autoimmune endocrine diseasesHypoparathyroidism (80–85%)Thyroid disease (70–75%)
Addison's disease (60–70%)Type 1 diabetes (50–60%)
Type 1 diabetes (<20%)Addison's disease (40%)
Hypogonadism (12%)Hypoparathyroidism (3%)
Thyroid disease (10%)Hypopituitarism (0–2%)
Concomitant diseaseMucocutaneous candidiasis (70–80%)No candidiasis
Non-endocrine diseasesImmune gastritis, pernicious anemia, celiac disease, immune hepatitis, vitiligo, alopecia areata, Sjögren's syndrome, systemic lupus erythematodus, rheumatoid arthritis, myasthenia gravis
Figure 1
Figure 1

Prevalence of most frequent autoimmune endocrine component diseases in PAS type I (white bars) and PAS type II (grey bars). Abbreviations: parathyr., hypoparathyroidism; adrenal, Addison's disease; gonads, hypogonadism; pancreas, type 1 diabetes mellitus or T1D; thyroid, autoimmune thyroid disease or AITD.

Citation: European Journal of Endocrinology 161, 1; 10.1530/EJE-09-0044

By contrast, prevalence of PAS II is 1:20 000 (6). It is more frequently encountered in women, and the male-to-female ratio is 1:3 (7). This syndrome has a peak incidence at ages 20–60 years, mostly in the third or fourth decade, and it is common for multiple generations to be affected by one or more component diseases. There is familial clustering and family members of patients are often affected (2). While there is some correlation between the ages of onset of one PAS illness with another, many years may separate the onset of different diseases (7). All the disorders resulting in tissue destruction appear to have a prolonged phase of cellular loss preceding overt autoimmune glandular disease.

Pathogenesis

Cell-mediated immune processes play an important role in the immunopathogenesis of PAS. Naive CD4+T-cells, upon encountering their cognate antigens presented on professional antigen-presenting cells, differentiate into effector cells (TH1, TH2, TH17, regulatory or iTreg) that are characterized by their cytokine production profiles and immune regulatory functions. TH1 cells produce interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) and regulate antigen presentation and immunity against intracellular pathogens, whereas TH2 cells, which produce interleukin (IL)-4, IL-5, and IL-13, mediate humoral responses and immunity against parasites, and are important mediators of allergic diseases. TH17 cells express IL-17, IL-17F, IL-21, and IL-22 (and IL-26 in humans) and participate in inflammation and autoimmunity processes. iTregs express forkhead box P3 (Foxp3) transcription factor and mediate immune suppression by secretion of transforming growth factor-β (TGF-β) and IL-10 and by contact-dependent mechanisms (8, 9). TH17 cells develop via an independent lineage from TH1 or TH2 cells. Differentiation of TH cells is steered by the innate immune system, which provides T-cell receptor (TCR), and co-stimulatory signals as well as an appropriate cytokine microenvironment that ultimately leads to the preferential induction of one specific cell lineage over the other. IFN-γ, IL-12 or IL-4, which are important for TH1 and TH2 differentiation, have been shown to be dispensable for TH17 cell differentiation in vitro and in vivo, providing one of the first clues that TH17 cells are indeed an independent lineage from TH1 or TH2 cells. Finally, IL-6 and TGF-β potently initiate TH17 differentiation (9).

Lymphocyte infiltrations of the various glands are associated with functional loss of epithelial cells with scarring. The cellular defect in PAS may be associated with abnormal balances in cytokine production by T-cells. A polarized Th2 response is associated with Graves' disease (GD) and Th1 with T1D. By contrast, PAS I results from biased Th2 immune responses to self-antigens and defective protective Th1 responses against invasion of yeast Candida albicans (10, 11). A dominance of T-helper cells and a deficiency of T suppressor cells have been demonstrated for endocrine autoimmunity (12). Also, a hypothesis for the pathogenesis of PAS has been recently presented (13). Accordingly, a genetically predisposed person might develop an autoimmune process after initiation by an infectious agent. This might initiate via cross-reactivity in the area of antigen presenting major histocompatibility complex (MHC) molecules, a TH2-dependent immune process which is primarily of humoral origin and partly local. This immune process probably chronifies due to deficient T-suppressor cell activity.

In PAS, several organ-specific autoimmune diseases are clustered. Although PAS I is caused by loss of central tolerance (1), the precise aetiology of PAS II is unknown. Further evidence refers to the Tregs which are implicated in self-tolerance and autoimmunity. As previously stated, the adaptive immune system does not only consist of immune-stimulatory CD4+ helper or effector T-cells and cytotoxic CD8+T-cells but is also regulated by immunosuppressive T-cells. Three classes of immunosuppressive CD4+T-cells are known to date: induced Th3, Tr1 cells, and the naturally present CD4+CD25+FoxP3+Tregs (14). Tregs are generated in the thymus and are present in all healthy animals and humans. Because the FOXP3-encoded scurfin protein interferes with IL-2 gene activation, Tregs do not secrete IL-2 and do not proliferate upon TCR-stimulation. Tregs suppress the activation of CD4+ and CD8+ cells in vitro and in vivo. They thereby prevent autoimmune disease, although the exact mechanism of suppression is unknown, and cell contact is crucial, at least in vitro. Depletion of Treg leads to autoimmunity in mice (15) and dysfunction of Tregs has been linked to autoimmune diseases (16). Defects in survival of suppressive function of Tregs may contribute to uncontrolled expansion of autoaggressive lymphocytes. Reduced numbers of Tregs are observed in myasthenia gravis (17) and a reduction of suppressive Treg function was reported in multiple sclerosis (18).

In a murine model, depletion of thymically derived CD4 (+) CD25 (+) Tregs, which exert suppression in a contact-dependent manner, resulted in a syndrome which is similar to human PAS with multiple endocrinopathies (19). Hence, loss of active suppression in the periphery could be a hallmark of PAS. Tregs from peripheral blood of both patients with PAS, as well as control patients with single autoimmune endocrinopathies, and normal healthy donors showed no differences in quantity, except for patients with isolated autoimmune diseases, in functionally important surface markers, or in apoptosis induced by growth factor withdrawal (16). Strikingly, PAS Tregs were defective in their suppressive capacity. The defect was persistent and not due to responder cell resistance, whereas overt quantitative or phenotypic abnormalities in Tregs from these patients were not observed. Also samples of FOXP3 messenger RNA from PAS Tregs were semi-quantified and showed similar levels of FOXP3 transcripts compared with normal donor Tregs despite defective suppressor function, indicating that true Tregs were dysfunctional. Defective Treg function in humans with PAS has wide implications for autoimmunity in general. The results indicate that once molecular mechanisms of suppressor function are better delineated, manipulations of human Tregs may allow improvement of immunomodulatory strategies in diseases with impaired suppressor function. Another category of immunosuppressive cells are the Tregs Tr1/Th3, and knowledge of development and functions of such immunoregulatory cells may elucidate the aetiology for developing autoimmunity (20).

Innate immunity and the enzyme deoxyribonuclease 1

Another important aspect is related to the activity of the enzyme deoxyribonuclease 1 (DNase 1). This glycoprotein is ubiquitously expressed in human tissues and plays a role in the regulation of apoptosis. It catalyzes DNA hydrolysis by cleaving double-stranded DNA. The activity of this enzyme was lowered in patients with PAS compared to healthy subjects (21, 22). Such a deficiency in DNase 1 may result in reduced or delayed removal of DNA from nuclear antigens and, thereby, may promote disease susceptibility to autoimmune disorders. Antigen complexes containing DNA can initiate the manifestation of endocrine autoimmunity by stimulation of an innate immune signalling pathway via toll-like receptors (TLRs). The innate immune response is activated by the recognition of a set of highly conserved molecular structures found in most micro-organisms. These pathogen associated molecular patterns are detected by a set of ten TLRs that are mainly expressed on macrophages, B cells and dendritic cells (23, 24). TLR9 is a receptor for unmethylated CpG motifs that are common in bacterial DNA and are also present in mammalian DNA. The activation of TLR9 promotes the production of IL-12 and a shift towards a Th1 immune response, activities that are accompanied by the breakdown of tolerance. Antigen complexes containing DNA can initiate the production of autoantibodies (Abs) by their ability to activate B-cells without a second signal from T-helper cells. This ‘single handed’ B-cell activation is mediated by antigen recognition with cell-surface antigen receptors and the additional co-stimulatory activation of TLR9 by antigen-associated self DNA (25). Decreased serum DNase activity with elevated levels of circulating DNA and resulting activation of the TLR9 immunostimulating pathway can also trigger organ-specific autoimmune disease. Most of the natural insulin Abs are polyreactive and bind in addition to insulin one or more antigens including thyroglobulin (Tg), IgG and DNA (21). Complexes containing DNA between polyreactive natural Abs, i.e. insulin, anti-insulin and circulating DNA, may initiate an autoimmune process by TLR9 co-activation. Thus, susceptibility for immune co-activation by autoantigen receptor activation and TLR9 stimulation may be increased in individuals with reduced serum DNase activity.

Genetics

PAS type II

The inheritance of PAS II is complex, with genes on chromosome 6 playing a predominant role. In man, this chromosome contains the major histocompatibility loci. Within some families, autoimmune endocrine disease susceptibility appears to be inherited as an autosomal dominant form associated with a specific HLA haplotype. Nevertheless, family members may manifest different diseases, though the more common the disease in the general population, the higher its prevalence in affected families.

While genetic factors determine disease susceptibility, there is <100% concordance in monozygotic twins for the respective diseases. This suggests that environmental factors may be involved in disease pathogenesis and that together with genetic factors they may contribute to the loss of immune self tolerance. Based on a genetic predisposition, epigenetic external factors, like viral or bacterial infections (26), and psychosocial factors might induce an autoimmune cascade. Environmental factors may have an important influence on the development of autoimmune diseases, but the exposure to environmental pathogens does not always lead to disease. With respect to genetics, PAS II is supposed to be a polygenic disease with autosomal dominant inheritance and incomplete penetrance. Also, familial clustering provided evidence for a genetic predisposition.

Many of the PAS II component diseases are associated with HLA alleles B8 and DR3. The DR antigen has two glycoprotein chains coded for by the DR loci of chromosome 6. The alleles HLA-B8 and DR3, which are coded for by separate genes, are found together on the same chromosome more often than one would predict from their frequency in the general population. Such associations are common for alleles of different genes in the histocompatibility region (linkage disequilibrium). The allele DR3 is most closely associated with autoimmune endocrine disease. PAS II is associated with HLA DR3 and DR4 antigens, and interestingly frequencies for DQA1*0301 and *0501 were increased in patients with PAS II compared to controls (27). The genotype DR3/4, DQ2/DQ8 with DRB1*0404 has been found to be the highest HLA genotype risk for Addison's disease, either as a single disease or within PAS II (28). An association of PAS II with HLA-B8 has been observed in three generations of a family, whereas ten unaffected subjects did not show B8 (29). HLA associations have also been described for PAS II component diseases T1D (DR4-DQB1*0302) and GD (B8). T1D locus 1 contains the MHC region (6p21) and in whites revealed a positive association with HLA DRB1*04-DQA1*0301-DQB1*0302 (DR4-DQ8) or DRB1*03-DQA1*0501-DQB1*0201 (DR3-DQ2) and a negative association with DRB1*15-DQA1*0102-DQB1*0602 (30, 31). A significant association between Hashimoto's thyroiditis (HT) and HLA DR3 was identified (32), whereas an increase in HLA-DR5 in affected family members with HT was found (33). A whole genome linkage study on a data set of 56 multiplex, multigenerational AITD families, using 387 microsatellite markers was performed (34). Only one locus on chromosome 6 was linked with both GD and HT. This locus was close to, but distinct from, the HLA region.

Furthermore, there is evidence that MHC class III genes are associated with PAS II, most specifically the gene encoding TNF-α, a multifunctional proinflammatory cytokine, which mediates inflammatory and immune functions (35). Within the TNF-α gene, the −308*A allele of an A/G single nucleotide dimorphism occurred more frequently in patients with PAS II than in healthy controls. PAS patients with AITD and the TNF-α −308 AA genotype showed the highest prevalence of Abs against thyroid peroxidase (TPO) and Tg. Compared with patients carrying the wild GG genotype, those with the AA genotype showed a four- or twofold increase in Tg and TPO Abs, respectively. Since TNF-α inhibits the expression of thyroid specific genes such as TPO and Tg and thereby, thyroid function, these findings may partially explain the decrease in serum thyroid hormone concentrations in HT. Therefore, an inhibition of the TNF-α by TNF-α inhibitors might be useful in diagnosis and in therapy in both AITD and PAS.

In patients with PAS, presence of the TNF-α −308*A allele was significantly related to the presence of the HLA-DRB1*03 allele, suggesting that HLA-DRB1*03 and TNF-α -308*A alleles are associated. The TNF-α gene lies within the MHC class III region, telomeric to the class II region. Thus, PAS is associated with the TNF-α −308*A allele in adults. TNF-α −308*A allele might directly confer susceptibility to PAS by affecting TNF-α cytokine production, as outlined above. However, another closely linked gene, particularly the HLA-DRB1*03 allele, may primarily determine disease susceptibility to PAS. Hence, the observed association of TNF-α −308*A with PAS could be secondary due to linkage disequilibrium of TNF-α −308*A with HLA-DRB1*03. Linkage disequilibrium describes the non-random association of alleles at linked loci during meiosis as well as the resultant co-segregating allele combinations that are observed in the patients. TNF-α might be a silent polymorphic locus which is in linkage disequilibrium with the causative HLA-DRB1*03 allele, and could be used as a surrogative genetic marker. Also, an interaction between the protein products of the TNF-α and HLA alleles may follow since TNF-α both mobilizes immune cells as well as induces the aberrant expression of MHC class II antigens. As a consequence, an increased expression of TNF-α protein, being observed for the TNF-α −308 AA genotype, might cause inflammation leading to tissue damage. Finally, heterozygosis for TNF-α increased the risk for T1D in DQA1*0501-DQB1*0201/DQA1*0301-DQB1*0302 positive individuals, most probably due to a linkage disequilibrium with HLA class II genes (36).

The MHC class I related gene A (MICA), located on chromosome 6 within the HLA region, is an additional locus associated with PAS. The MICA exon 5 microsatellite is of special interest, because this trinucleotide (GCT) repeat lies in the transmembrane region encoding alanine residues. It is characterized by five common alleles (MIC-A4, -A5, -A5.1, A6 and A9); allele A5.1 shows an additional 1-bp insertion (GGCT). The MICA molecule is a membrane-bound glycoprotein. It binds to NKG2D which is an activating receptor of natural killer (NK) cells (37). The G-insertion in the MIC A5.1 allele results in a frameshift mutation accompanied by a premature stop codon. It codes for a protein with a shortened transmembrane segment lacking its cytoplasmic tail. Compared to healthy controls, frequency of the MICA 5.1 allele and the A5.1/A5.1 genotype was increased in patients with PAS II (38), indicating that the MICA microsatellite polymorphism may contribute to genetic susceptibility to PAS. Frequencies of the MIC-A5.1 allele were not significantly different in HLA-DRB1*03-carriers and non-carriers, suggesting that the risk conferred by MICA association might be independent of HLA-DRB1*03 risk. In another study, combination of MIC-A5 and HLA-DR3-DQ2 and/or HLA-DR4-DQ8 represented a strong genetic marker for T1D with PAS (39).

Further susceptible genes encompass the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) gene, a strong inhibitor of T-cells (40). CTLA-4 is a T-lymphocyte surface antigen that interacts with B7-1 (CD80) and B7-2 (CD86) of antigen presenting cells. It inhibits T-cell activation by reducing IL-2 production and IL-2 receptor expression and by arresting T cells at the G1 phase of the cell cycle (41, 42, 43). An A/G single nucleotide polymorphism (designated as CT60) downstream the CTLA-4 gene has been associated recently with GD, HT with odds ratios of 1.5 and 1.6 respectively (42, 43). It has been reported that the disease susceptible genotype G/G induces a reduced mRNA expression of the soluble form of CTLA-4 which might lead to a less efficient T-cell inhibition. This could explain why autoimmune processes can be induced more easily in CT60 G/G carriers. An association between patients with both AITD and T1D (PAS) and the CTLA-4 CT60 SNP was also detected and was even stronger than the association of CT60 with AITD alone. This is supported by the odds ratio of 2.0 that is larger than those reported for GD or HT alone. Therefore, the CTLA-4 CT60 SNP seems to play a role in the joint susceptibility for both diseases.

Of further interest is the recent finding that the protein tyrosine phosphatase non-receptor 22 (PTPN22) gene might contribute to susceptibility to PAS II (44). This gene encodes an intracellular phosphatase with negative regulatory effects on T-cell activation. A functional single nucleotide polymorphism (C1858T) in the PTPN22 gene is associated with several autoimmune diseases (45, 46, 47, 48). Due to the higher prevalence, previous studies investigated associations of PTPN22 C1858T with AITD and T1D as single diseases. With respect to T1D and AITD as separate entities, for each a less than twofold increased risk (OR) for PTPN22 T allele carriers was reported (49). When examining patients with both diseases, we noted a fourfold increased risk for T allele carriers to develop PAS, indicating that PTPN22 plays a more important role in the overall genetic risk for PAS than it does for AITD or T1D alone and that PTPN22 C1858T plays a role in this obvious cumulative and concurrent presence of both diseases (50, 51). Also, these findings do not suggest the existence of a separate set of susceptibility genes for the disease combination, but rather indicate the presence of combined susceptibility genes. The underlying pathophysiology is a key factor for understanding autoimmune processes. LYP encoded by PTPN22 is expressed in lymphocytes where it binds to the protein kinase, a suppressor of the lymphocyte-specific protein tyrosine kinase and the protein tyrosine kinase p59fyn, which are associated with the TCR signalling pathway (44, 49). The C→T exchange at position 1858 at codon 620 leads to the substitution of arginine (CGG) by tryptophan (TGG). Paradoxically, the disease predisposing T allele for tryptophan is a gain of function variant that leads to an even higher T-cell suppression (44, 51). It is speculated that autoreactive T-cells escape thymic deletion more easily due to a loss in TCR signalling and thus remain in the periphery. The key status of T-cells in AITD and T1D might explain why PTPN22 1858T is associated with the joint susceptibility for both diseases. In our recent study (50), patients with adult PAS who carried the PTPN22 1858 T allele, were significantly more frequent carriers of DRB1*03 than T non-carriers, showing that the combination of PTPN22 1858T and DRB1*03 provides patients with a higher risk than expected.

PAS type I

PAS I is a monogenic disease with autosomal recessive inheritance (52, 53, 54, 55, 56, 57, 58, 59, 60). Mutations of a single gene termed the autoimmune regulator (AIRE) gene play a crucial role. The AIRE gene is assigned to chromosome 21q22.3 and has been cloned by two independent research groups (52, 57). The AIRE gene is expressed in tissues which are involved in the maturation of the immune system such as thymus, lymph nodes, and peripheral blood cells (CD14-positive monocytes), but not in CD4-positive T-cells. It is mainly expressed in epithelial antigen-presenting cells in the thymus where it is possibly involved in the central induction of self-tolerance. Thus, the AIRE gene is an important mediator of central tolerance. AIRE may regulate negative selection of organ-specific T-cells. The AIRE gene encodes a 545-amino-acid protein of 57.5 kDa which comprises several domains that may be involved in nuclear transport, DNA binding, homomultimerization and transcriptional activity. It shows several motifs indicative of a transcription factor, includes two zinc fingers and upregulates the transcription of organ-specific self-antigens in medullar thymic epithelial cells. Also, it plays a role in the negative selection of organ-specific thymocytes. At least three splice variant mRNAs products have been described including one which results in a premature stop codon in the AIRE protein and a transcript predicted to be a candidate for nuclear-mediated decay (NMD). The mutated AIRE gene results in defect AIRE proteins which cause autoimmune destruction of target organs by disturbing the immunological tolerance of the patients (59). Many AIRE mutations alter the nucleus–cytoplasm distribution of AIRE, thereby disturbing its association with nuclear dots and cytoplasmic filaments. In the coding region of the AIRE gene, 45 different mutations have been reported. Mutations comprise nonsense and missense mutations, deletions, and small insertions (5, 61). The R257X mutation results in a stop codon instead of CGA (coding for arginine), and therefore, leading to a truncated regulator protein. Mutational analysis of AIRE helps identify patients with atypical phenotypes resembling PAS I, e.g. the AIRE mutation R257X was responsible for 82% of PAS I alleles in a Finn population. In contrast, the AIRE R257x and 13bpdel mutations were never observed in our investigated population with PAS II (35).

Associations with HLA class II alleles, e.g. DR3, were also reported in PAS I. In a study comprising patients with PAS I 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 out of 85 patients without this allele, had not developed Addison's disease (4). In these patients, the component disease alopecia was significantly associated with HLA-DRB1*04 (RR 4.8) and DQB1*0302 (RR 6.6). In contrast, the most common protective alleles for T1D (DRB1*15 and DQB1*0602) were similarly protective in PAS I patients, as indicated by significant negative correlations (1, 28).

Clinical spectrum

First clinical manifestation of the very rare PAS I usually occurs in childhood. Nevertheless, the main component diseases of type I develop in the first 20 years of life, and further associated diseases may not evolve until the fifth decade or later. In comparison, PAS II mostly occurs in adulthood during the third and fourth decades. PAS II presenting in childhood is extremely rare; a case with hypothyroidism, followed by diabetic ketoacidosis, and adrenal insufficiency has recently been reported (62). In adults, the presence of one autoimmune endocrine disease is associated with an increased risk of developing autoimmunity to other tissues. Each of these disorders is characterized by several stages beginning with active autoimmunity and followed by metabolic abnormalities with overt disease. T1D is a very frequent component disorder of PAS II and is often its first symptom. At our institution, screening of 471 patients with T1D showed in 127 cases (27%, 85/127 females) multiple glandular involvement. Additionally, 19 (4%) and 8 (2%) had vitiligo and immune gastritis respectively. Subsequent screening of 15 000 consecutive subjects with endocrine disorders revealed a PAS prevalence of 1% (n=151, 75% female). These 151 subjects have been followed since then (63). There is often a long time-interval between the manifestation of the first and second component disease of PAS II which often comprises years to decades. Most frequent disease combinations are T1D/AITD (41%), followed by AITD/Addison's disease (14.6%), T1D/vitiligo (9.9%), AITD/vitiligo (9.9%), T1D/AITD/pernicious anaemia (5.3%), hypogonadism/alopecia (5.3%), and T1D/Addison's disease (3.3%).

The simultaneous occurrence of immune hypothyroidism and T1D is often accompanied by hypoglycaemia due to decreased insulin need and increased insulin sensitivity. Hypothyroid children show growth disorders caused by chronic hypoglycaemia and decreased food intake. Nevertheless, growth disorders of hypothyroid children are essentially due to hypothyroidism itself; if properly treated, growth is normal as well as the metabolic status, including insulin requirements. Substitution therapy with levothyroxine leads to increased insulin dosage. Similarly, concomitant presence of Addison's disease and T1D also leads to frequent hypoglycaemia due to decreased gluconeogenesis and increased insulin sensitivity. In contrast, hyperthyroidism is accompanied in 50% of the cases by glucose intolerance and in 3% of the cases by overt diabetes. Impaired glucose tolerance is due to decreased insulin sensitivity and hepatic storage of glycogen, whereas both secretion of glucagon and intestinal glucose absorption are enhanced. In diabetic children with concomitant Graves' disease and its risk of fluctuating thyroid functional status, treatment of T1D is much more difficult, which might call for a decision of definitive treatment, especially when remission is not obtained after an antithyroid drug course of reasonable duration.

Other disorders like immune gastritis, pernicious anemia, and alopecia areata may occur in PAS. Immune gastritis, eventually leading to pernicious anemia, is an organ-specific autoimmune disease characterized by pathological lesions, affecting the fundus and body of stomach, which are typified by gastric mucosal atrophy, selective loss of parietal cells from the gastric mucosa, submucosal lymphocyte infiltration, as well as circulating gastric parietal cell Abs. Subsequently, pernicious anemia, which is considered to be the most common cause of vitamin B12 deficiency, may develop. In this case, Abs to the intrinsic factor, itself a secretory product of gastric chief cells, are found in the circulation and in gastric secretions.

Diagnosis, screening, and treatment

Actual diagnosis of PAS involves serological measurement of organ-specific Abs and subsequent functional testing (63, 64, 65, 66, 67, 68). These special diagnostic approaches and the management of patients with PAS including their family relatives are best performed in centres with special expertise in autoimmune endocrine diseases. Although the clinical recommendations are not evidence based and a cost–benefit analysis that has shown the following is useful is lacking, the following suggestions rely on an ∼20 year, long term and extensive personal experience with more than 350 patients with PAS and their corresponding families, kindred's, siblings, first and second degree relatives. Therefore, they may be viewed as expert recommendations reflecting the author's own individual practice.

Detecting organ-specific Abs verifies etiology of the disease and identifies patients who may develop autoimmune polyendocrinopathies. Circulating organ-specific Abs are present in each of the component diseases of PAS (Table 2). Occasionally, as in antigonadal and antiadrenal Abs, a given group of Abs will cross-react with more than one gland (steroid-producing cells). Abs may bind to a cell surface without functional effects, or may be blocking or stimulatory. Examples of blocking Abs include those directed at the acetylcholine receptor in myasthenia gravis. Prevalence of organ-specific Abs is high in healthy relatives of PAS patients and is associated with the number of involved glands. These ‘silent’ Abs (e.g. anti-islet Abs) may precede clinical disease by years and are predictive for the development of future autoimmune endocrine disorders.

Table 2

Localization of the different autoantigen(s) and the corresponding diseases.

DiseaseAutoantigenTissue/cells
Type 1 diabetesGAD65, IA-2, islet cells, insulinβ-cells
Graves' diseaseTSH receptorThyrocytes
Hashimoto's thyroiditisTPO/TgEnzyme/protein
HypoparathyroidismCa2+ sensitive receptorParathyroid
Addison's disease21-OH, 17-OH, P450sccEnzyme
Hypogonadism17-OH, CYP450sccLeydig/theca cells
Immune gastritisH+, K+-ATPaseGastric parietal cells
Pernicious anaemiaIntrinsic factorChief cells (stomach)
Celiac diseaseTransglutaminase, gliadinSmall intestine
Immune hepatitisP450D6, 2C9, P4501A2Liver
Alopecia areataTyrosinhydroxylaseHair follicles
VitiligoTyrosinaseMelanocytes

GAD, glutamic acid decarboxylase; IA2, protein tyrosine phosphatase; 17-OH and 21-OH, 17- and 21-alpha-hydroxylase (steroidogenic P450 enzymes); SCC, side chain cleavage enzyme (steroidogenic P450 enzyme); Tg, thyroglobulin; TPO, thyroid peroxidase.

In adrenal autoimmunity, Abs are directed against antigens identified as P450 cytochromes, i.e. enzymes involved in the synthesis of steroid hormones. These are 21-hydroxylase (OH), 17-alpha-OH, and the side chain cleavage enzyme. The 21-OH has been identified as major target antigen in Addison's disease and has been detected in 85% of patients with PAS and adrenal failure (65). Abs against steroidal enzymes (21-OH) are of high prognostic value and will help identify patients at risk for developing Addison's disease. This might prevent delayed diagnosis of adrenal failure. In contrast, thyroid Abs without clinical disease manifestation are noted in nearly 50% of the PAS patients, and the time interval between the detection of Abs and presentation of disease is longer for AITD than for other immunopathies. Thus, high titers of Abs against TPO and Tg do not automatically precede the development of clinical AITD.

With respect to T1D, it has been demonstrated that antiidiotope reagents were able to distinguish between childhood-onset T1D and adult-onset T1D with polyendocrine susceptibility (69). Childhood-onset T1D-islet cell Abs differed from adult-onset T1D-islet cell Abs in their specificity for human insulin and from their antiidiotope amino acid sequence. Based on improved immunogenetic understanding and Ab screening assays, T1D is now predictable (1, 28). Finally, genetic investigation is especially useful for PAS I, less for type II, because one would likely identify the alleles associated with disease that is already identified, e.g. DR3/DR4 in patients with T1D (70).

Screening

Approximately one in seven first degree relatives of patients with PAS have an unrecognized endocrine disorder, usually the relatively common immune thyroiditis. Most specifically, in subjects with either monoglandular T1D or the relatively rare immune adrenal failure, organ-specific Ab screening and functional testing will help identify both patients at risk for developing PAS as well as an already present subclinical polyglandular syndrome. In the presence of a patient with clinical and biochemical signs of primary adrenal failure, the determination of 21-OH Abs enables the unequivocal demonstration of the autoimmune origin of the disease. In subjects with Addison's disease, screening for other endocrine disorders is recommended, given the frequent association of autoimmune adrenal insufficiency with AITD, T1D or other immune-mediated diseases. Thus, in any patient with Addison's disease, determination of TPO, Tg, glutamic acid decarboxylase 65 (GAD 65), and islet cell Abs is recommended and if negative, repeated every 2–3 years. Since most PAS II patients are adults, determination of insulin or IA2 Abs is not strictly necessary, given the low diagnostic sensitivity of these markers for adult-onset T1D (71, 72). In the case of positivity for GAD65 and islet cell Abs, an oral glucose tolerance is needed to demonstrate a glucose intolerance not revealed by fasting blood glucose. Although T1D develops frequently before Addison's disease, GAD65 Abs are detected in 5–7% Addison patients without T1D and a proper follow-up should also be performed in those islet cell Ab positive patients. The determination of 17OH and P450scc Abs will enable the identification of subjects at high risk for autoimmune primary hypogonadism, with a high positive predictive value in women. Furthermore, determination of transglutaminase Abs could be included in the screening of PAS children with T1D. Also, determination of 21-OH Abs may be performed in patients with T1D and AITD, as the identification of subjects positive for adrenal Abs is highly predictive for future adrenal insufficiency. In subjects with 21OH Abs and normal cortisol levels, an ACTH stimulation test, will enable the identification of subjects with pre-clinical adrenal dysfunction. Subjects with normal cortisol response could simply be followed-up, with re-evaluation of adrenal Ab levels, basal and ACTH-stimulated cortisol on a yearly basis (Table 3).

Table 3

Diagnostic investigation for polyglandular autoimmune syndromes.

Autoantibodies to
 • Islet cells, GAD, (optional IA2)
 • TPO, TSH receptor
 • Cytochrome P450 enzymes (especially 21-hydroxylase)
 • H+-K+-ATPase of the parietal cells, intrinsic factor
 • Transglutaminase, (optional gliadin)
Functional testing
 • TSH, FSH, LH, fT4, testosterone, estradiol, glucose, fasting morning cortisol
 • ACTH stimulation test (when adrenal autoantibodies are present)
 • Serum Na+, K+, Ca+, blood cell count
Molecular analysis of AIRE gene for PAS type I, only
HLA-typing and subtyping (optional and for scientific purpose)

AIRE gene, autoimmune regulator gene; GAD, glutamic acid decarboxylase; IA2, protein tyrosine phosphatase; TPO, thyroid peroxidase.

Treatment

Many of the endocrine disorders of PAS are adequately treated with hormonal replacement therapy if the disease is recognized early. Subjects with pathological ACTH test and increased levels of basal plasma ACTH require close clinical follow-up with repetition of the test every six months. A replacement therapy with hydrocortisone or cortisone acetate should be considered in the case of undercurrent stressful events. Hypoglycaemic episodes and a decreasing insulin requirement in a type 1 diabetic can be one of the earliest signs of the development of adrenal failure. Replacement of levothyroxin without simultaneous adrenal steroid replacement in a hypothyroid patient with Addison's disease can precipitate an adrenal crisis (73). Replacement of levothyroxin increases the cortisol turnover rate in the liver, and this may tax a failing adrenal gland.

Concluding remarks

In PAS II, genetic associations with HLA haplotypes and polymorphisms of genes encoding immunologically relevant gene products have been reported. The associations of autoimmune endocrinopathies with polymorphisms of these particular genes support the hypotheses that they may function to influence general predisposition, increase susceptibility, or influence the clinical presentation of autoimmune diseases. Other factors such as environmental triggers and yet unidentified genetic loci may modulate disease or target tissue phenotype. Therefore, future research is required to identify the other players in the process of regulating immune tolerance and the process of defining the tissue targets of autoimmune diseases. Since actual data are scarce, further studies are necessary to elucidate the specific and general immunologic mechanisms which underlie the development of PAS. Nowadays, genetic screening is useful for the monogenic PAS I, but not for the polygenic type II. Continuing research is warranted to further clarify the genetic background of PAS II, to identify susceptibility genes, and to understand their interactions. Potential susceptibility genes to PAS II are – besides the HLA genes – the CTLA-4 and cytokine-related genes TNF-α and/or PTPN22 (74). Additional knowledge regarding these genes will allow genetic screening of patients at risk. Advances in genetics and in pathogenesis of PAS II may be valuable in the prevention of morbidity and mortality of the subjects involved. Future research should also focus on family studies with a large number of samples from different population groups. This might offer further knowledge on the inheritance of PAS II as well as on the familial risk to develop this syndrome.

Declaration of interest

The author declares that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This paper did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Acknowledgements

I am most grateful to N Matheis and M Dittmar, biologists, to G Dultz and S Barkia, scientific collaborators, and to M Kanitz, Lab technician, all thyroid research laboratory, Gutenberg University Medical Centre, for both constructive and helpful discussion as well as for collecting the presented data. The experimental work in the thyroid lab is partly funded by the research program of the Gutenberg University (‘Maifor’).

References

  • 1

    EisenbarthGSGottliebPA. Autoimmune polyendocrine syndromes. New England Journal of Medicine200435020682079.

  • 2

    NeufeldMMacLarenNBlizzardR. Autoimmune polyglandular syndromes. Pediatric Annals19809154162.

  • 3

    JenkinsRCWeetmanAP. Disease associations with autoimmune thyroid disease. Thyroid200212977988.

  • 4

    BetterleCGreggioNAVolpatoM. Clinical review 93: autoimmune polyglandular syndrome type 1. Journal of Clinical Endocrinology and Metabolism19988310491055.

    • Search Google Scholar
    • Export Citation
  • 5

    Obermayer-StraubPStrassburgCPMannsMP. Autoimmune polyglandular syndrome type 1. Clinical Reviews in Allergy and Immunology200018167183.

    • Search Google Scholar
    • Export Citation
  • 6

    TenSNewMMacLarenN. Clinical review 130: Addison's disease 2001. Journal of Clinical Endocrinology and Metabolism20008629092922.

  • 7

    FörsterGKrummenauerFKühnIBeyerJKahalyG. Polyglandular autoimmune syndrome type II: epidemiology and forms of manifestation. Deutsche Medizinische Wochenschrift199912414761481.

    • Search Google Scholar
    • Export Citation
  • 8

    ZhuJPaulWE. CD4 T cells: fates, functions, and faults. Blood200811215571569.

  • 9

    MartinezGJNurievaRIYangXODongC. Regulation and function orf proinflammatory TH17 cells. Annals of the New York Academy of Sciences20081143188211.

    • Search Google Scholar
    • Export Citation
  • 10

    AndersonMS. Autoimmune endocrine diseases. Current Opinion in Immunology200214760764.

  • 11

    DevendraDEisenbarthGS. Immunologic endocrine disorders. Journal of Allergy and Clinical Immunology2003111S624S636.

  • 12

    ToplissDHowJLewisMRowVVolpeR. Evidence for cell-mediated immunity and specific suppressor T lymphocyte dysfunction in Graves' disease and diabetes mellitus. Journal of Clinical Endocrinology and Metabolism198357700705.

    • Search Google Scholar
    • Export Citation
  • 13

    CanbayAGieselerREllaRFinkHSallerBMannK. Manifestation of adrenal insufficiency after administration of levothyroxine in a patient with polyglandular autoimmune syndrome type II (Schmidt-syndrome). Internist200041588591.

    • Search Google Scholar
    • Export Citation
  • 14

    SakaguchiS. Naturally arising CD4+regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annual Review of Immunology200422531562.

    • Search Google Scholar
    • Export Citation
  • 15

    ShevachEM. Regulatory T cells in autoimmmunity. Annual Review of Immunology200018423449.

  • 16

    KriegelMALohmannTGablerCBlankNKaldenJRLorenzHM. Defective suppressor function of human CD4+CD25+regulatory T cells in autoimmune polyglandular syndrome type II. Journal of Experimental Medicine200419912851291.

    • Search Google Scholar
    • Export Citation
  • 17

    LutherCPoeschelSVargaMMelmsATolosaE. Decreased frequency of intrathymic regulatory T cells in patients with myasthenia – associated thymoma. Journal of Neuroimmunology2005164124128.

    • Search Google Scholar
    • Export Citation
  • 18

    VigliettaVBaecher-AllanCWeinerHLHaflerDA. Loss of functional suppression by CD4+CD25+regulatory T cells in patients with multiple sclerosis. Journal of Experimental Medicine2004199971979.

    • Search Google Scholar
    • Export Citation
  • 19

    SakaguchiSSakaguchiNAsanoMItohMTodaM. Immunologic self-tolerance maintained by activated T cells expression IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. Journal of Immunology199515511511164.

    • Search Google Scholar
    • Export Citation
  • 20

    LanRYAnsariAALianZXGershwinME. Regulatory T cells: development, function and role in autoimmunity. Autoimmunity Reviews20054351363.

  • 21

    DittmarMPoppeRBischofsCFredenhagenGKanitzMKahalyGJ. Impaired deoxyribonuclease activity in monoglandular and polyglandular autoimmunity. Experimental and Clinical Endocrinology and Diabetes2007115387391.

    • Search Google Scholar
    • Export Citation
  • 22

    DittmarMBischofsCMatheisNPoppeRKahalyGJ. A novel mutation in the DNAse I gene is related with protein instability and decreased enzyme activity in thyroid autoimmunity. Journal of Autoimmunity200932713.

    • Search Google Scholar
    • Export Citation
  • 23

    RockFLHardimanGTimansJCKasteleinRABazanJF. A family of human receptors structurally related to Drosophila Toll. PNAS199895588593.

  • 24

    ChuangTUlevitchRJ. Identification of hTLR10: a novel human Toll-like receptor preferentially expressed in immune cells. Biochimica et Biophysica Acta20011518157161.

    • Search Google Scholar
    • Export Citation
  • 25

    LeadbetterEARifkinIRHohlbaumAMBeaudetteBCSchlomchikMJMarshak-RothsteinA. Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature2002416603607.

    • Search Google Scholar
    • Export Citation
  • 26

    GiananiRSarvetnickN. Viruses, cytokines, antigens, and autoimmunity. PNAS19969322572259.

  • 27

    WallaschofskiHMeyerATuschyULohmannT. HLA-DQA1*0301-associated susceptibility for autoimmune polyglandular syndrome type II and III. Hormone and Metabolic Research200335120124.

    • Search Google Scholar
    • Export Citation
  • 28

    RoblesDTFainPRGottliebPAEisenbarthGS. The genetics of autoimmune polyendocrine syndrome type II. Endocrinology and Metabolism Clinics of North America200231353368.

    • Search Google Scholar
    • Export Citation
  • 29

    EisenbarthGSWilsonPWardFLebovitaH. HLA type and occurrence of disease in familial polyglandular failure. New England Journal of Medicine19782989294.

    • Search Google Scholar
    • Export Citation
  • 30

    TischRMcDevittH. Insulin-dependent diabetes mellitus. Cell199685291297.

  • 31

    SanjeeviCBLybrandTPDeWeeseCLandin-OlssonMKockumIDahlquistGSundkvistGStengerDLernmarkA. Polymorphic amino acid variations in HLA-DQ are associated with systematic physical property changes and occurrence of IDDM. Members of the Swedish Childhood Diabetes Study. Diabetes199544125131.

    • Search Google Scholar
    • Export Citation
  • 32

    TandonNZhangLWeetmanAP. HLA associations with Hashimoto's thyroiditis. Clinical Endocrinology199134383386.

  • 33

    RomanSHGreenbergDRubinsteinPWallensteinSDaviesTF. Genetics of autoimmune thyroid disease: lack of evidence for linkage to HLA within families. Journal of Clinical Endocrinology and Metabolism199274496503.

    • Search Google Scholar
    • Export Citation
  • 34

    TomerYBarbesinoGGreenbergDAConcepcionEDaviesTF. Mapping the major susceptibility loci for familial Graves' and Hashimoto's diseases: evidence for genetic heterogeneity and gene interactions. Journal of Clinical Endocrinology and Metabolism19998446564664.

    • Search Google Scholar
    • Export Citation
  • 35

    DittmarMKaczmarzykABischofsCKahalyGJ. The pro-inflammatory cytokine TNFalpha 308 genotype is associated with polyglandular autoimmunity. Immunological Investigations200938113.

    • Search Google Scholar
    • Export Citation
  • 36

    MoghaddamPHZwindermanAHde KnijffPRoepBOSchipperRFVan der AuweraBNaipalAGorusFSchuitFGiphartMJ. TNFa microsatellite polymorphism modulates the risk of IDDM in Caucasians with the high-risk genotype HLA DQA1*0501-DQB1*0201/DQA1*0301-DQB1*0302. Belgian Diabetes Registry. Diabetes19974615141515.

    • Search Google Scholar
    • Export Citation
  • 37

    BauerSGrohVWuJSteinleAPhillipsJHLanierLLSpiesT. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science1999285727729.

    • Search Google Scholar
    • Export Citation
  • 38

    DittmarMIdeMWurmMKahalyGJ. Early onset of polyglandular failure is associated with HLA-DRB103. European Journal of Endocrinology20081595560.

    • Search Google Scholar
    • Export Citation
  • 39

    GambelungheGGhaderiMCosentinoAFalorniABrunettiPFalorniASanjeeviCB. Association of MHC Class I chain-related A (MIC-A) gene polymorphism with type I diabetes. Diabetologia200043507514.

    • Search Google Scholar
    • Export Citation
  • 40

    KotsaKWatsonPFWeetmanAP. A CTLA-4 gene polymorphism is associated with both Graves disease and autoimmune hypothyroidism. Clinical Endocrinology199746551554.

    • Search Google Scholar
    • Export Citation
  • 41

    OstrovDAShiWSchwartzJCAlmoSCNathensonSG. Structure of murine CTLA-4 and its role in modulating T cell responsiveness. Science2000290816819.

    • Search Google Scholar
    • Export Citation
  • 42

    UedaHHowsonJMEspositoLHewardJSnookHChamberlainGRainbowDBHunterKMSmithANDi GenovaGHerrMHDahlmanIPayneFSmythDLoweCTwellsRCHowlettSHealyBNutlandSRanceHEEverettVSminkLJLamACCordellHJWalkerNMBordinCHulmeJMotzoCCuccaFHessJFMetzkerMLRogersJGregorySAllahabadiaANithiyananthanRTuomilehto-WolfETuomilehtoJBingleyPGillespieKMUndlienDERønningenKSGujaCIonescu-TîrgovişteCSavageDAMaxwellAPCarsonDJPattersonCCFranklynJAClaytonDGPetersonLBWickerLSToddJAGoughSC. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature2003423506511.

    • Search Google Scholar
    • Export Citation
  • 43

    KavvouraFKAkamizuTAwataTBanYChistiakovDAFrydeckaIGhaderiAGoughSCHiromatsuYPloskiRWangPWBanYBednarczukTChistiakovaEIChojmMHewardJMHirataniHJuoSHKarabonLKatayamaSKuriharaSLiuRTMiyakeIOmraniGHPawlakETaniyamaMTozakiTIoannidisJP. Cytotoxic T-lymphocyte associated antigen 4 gene polymorphisms and autoimmune thyroid disease: a meta-analysis. Journal of Clinical Endocrinology and Metabolism20079231623170.

    • Search Google Scholar
    • Export Citation
  • 44

    SiminovitchKA. PTPN22 and autoimmune disease. Nature Genetics20043612481249.

  • 45

    BottiniNMusumeciLAlonsoARahmouniSNikaKRostamkhaniMMacMurrayJMeloniGFLucarelliPPellecchiaMEisenbarthGSComingsDMustelinT. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nature Genetics200436337338.

    • Search Google Scholar
    • Export Citation
  • 46

    BegovichABCarltonVEHonigbergLASchrodiSJChokkalingamAPAlexanderHCArdlieKGHuangQSmithAMSpoerkeJMConnMTChangMChangSYSaikiRKCataneseJJLeongDUGarciaVEMc McAllisterLBJefferyDALeeATBatliwallaFRemmersECriswellLASeldinMFKastnerDLAmosCISninskyJJGregersenPK. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. American Journal of Human Genetics200475330337.

    • Search Google Scholar
    • Export Citation
  • 47

    KyogokuCLangefeldCDOrtmannWALeeASelbySCarltonVEChangMRamosPBaechlerECBatliwallaFMNovitzkeJWilliamsAHGillettCRodinePGrahamRRArdlieKGGaffneyPMMoserKLPetriMBegovichABGregersenPKBehrensTW. Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE. American Journal of Human Genetics200475504507.

    • Search Google Scholar
    • Export Citation
  • 48

    GomezLMAnayaJMGonzalezCIPineda-TamayoROteroWArangoAMartinJ. PTPN22 C1858T polymorphism in Colombian patients with autoimmune diseases. Genes and Immunotherapy20056628631.

    • Search Google Scholar
    • Export Citation
  • 49

    HuberAMenconiFCorathersSJacobsonEMTomerY. Joint genetic susceptibility to type 1 diabetes and autoimmune thyroiditis: from epidemiology to mechanisms. Endocrine Reviews200829697725.

    • Search Google Scholar
    • Export Citation
  • 50

    DultzGMatheisNDittmarMRöhrigBBenderKKahalyGJ. The protein tyrosine phosphatase non-receptor type 22 C1858T polymorphism is a joint susceptibility locus for immunthyroiditis and autoimmune diabetes. Thyroid200919143148.

    • Search Google Scholar
    • Export Citation
  • 51

    DultzGDittmarMKahalyGJ. Genetics of thyroid autoimmunity – update and clinical relevance. Medizinische Klinik2009104210219.

  • 52

    AaltonenJBjorsesPSandkuijlLPerheentupaJPeltonenL. An autosomal locus causing autoimmune disease: autoimmune polyglandular disease type I assigned to chromosome 21. Nature Genetics199488387.

    • Search Google Scholar
    • Export Citation
  • 53

    BjorsesPAaltonenJVikmanAPerheentupaJBen-ZionGChiumelloGDahlNHeidemanPHoorweg-NijmanJJMathivonLMullisPEPohlMRitzenMRomeoGShapiroMSSmithCSSolyomJZlotogoraJPeltonenL. Genetic homogeneity of autoimmune polyglandular disease type I. American Journal of Human Genetics199659879886.

    • Search Google Scholar
    • Export Citation
  • 54

    NagamineKPetersonPScottHSKudohJMinoshimaSHeinoMKrohnKJLaliotiMDMullisPEAntonarakisSEKawasakiKAsakawaSItoFShimizuN. Positional cloning of the APECED gene. Nature Genetics199717393398.

    • Search Google Scholar
    • Export Citation
  • 55

    PearceSHCheethamTImrieHVaidyaBBarnesNDBilousRWCarrDMeeranKShawNJSmithCSToftADWilliamsGKendall-TaylorP. A common and recurrent 13-bp deletion in the autoimmune regulator gene in British kindreds with autoimmune polyendocrinopathy type 1. American Journal of Human Genetics19986316751684.

    • Search Google Scholar
    • Export Citation
  • 56

    WangCYDavoodi-SemiromiAHuangWConnorEShiJDSheJX. Characterization of mutations in patients with autoimmune polyglandular syndrome type 1 (APS1). Human Genetics1998103681685.

    • Search Google Scholar
    • Export Citation
  • 57

    ChenQYLanMSSheJXMacLarenNK. The gene responsible for autoimmune polyglandular syndrome type 1 maps to chromosome 21q22.3 in US patients. Journal of Autoimmunity199811177183.

    • Search Google Scholar
    • Export Citation
  • 58

    HeinoMPetersonPKudohJShimizuNAntonarakisSEScottHSKrohnK. APECED mutations in the autoimmue regulator (AIRE) gene. Human Mutation200118205211.

    • Search Google Scholar
    • Export Citation
  • 59

    HalonenMEskelinPMyhreAGPerheentupaJHusebyeESKampeORorsmanFPeltonenLUlmanenIPartanenJ. AIRE mutations and human leukocyte antigen genotypes as determinants of the autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy phenotype. Journal of Clinical Endocrinology and Metabolism20028725682574.

    • Search Google Scholar
    • Export Citation
  • 60

    DittmarMKahalyGJ. Genetics of autoimmune hypoparathyroidism. Clinical Cases in Mineral and Bone Metabolism20041113116.

  • 61

    VogelAStrassburgCPObermayer-StraubPBrabantGMannsMP. The genetic background of autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy and its autoimmune disease components. Journal of Molecular Medicine200280201211.

    • Search Google Scholar
    • Export Citation
  • 62

    KumarRReddyDVUnikrishnanAGBhadadaSKAgrawalNKSinghSK. Polyglandular autoimmune endocrinopathy in type 2 diabetes. Journal of the Association of Physicians of India2004529991000.

    • Search Google Scholar
    • Export Citation
  • 63

    DittmarMKahalyGJ. Polyglandular autoimmune syndromes: Immunogenetics and long-term follow-up. Journal of Clinical Endocrinology and Metabolism20038829832992.

    • Search Google Scholar
    • Export Citation
  • 64

    BetterleC. Autoimmune adrenal insufficiency and autoimmune polyendocrine syndromes: autoantibodies, autoantigens, and their applicability in diagnosis and disease prediction. Endocrine Reviews200223327354.

    • Search Google Scholar
    • Export Citation
  • 65

    ChenSSawickaJBetterleCPowellMPrenticeLVolpatoMSmithBRFurmaniakJ. Autoantibodies to steroidogenic enzymes in autoimmune polyglandular syndrome. Addison's disease, and premature ovarian failure. Journal of Clinical Endocrinology and Metabolism19968118711876.

    • Search Google Scholar
    • Export Citation
  • 66

    BednarekJ. Steroid 21-hydroxylase is a major autoantigen involved in adult onset autoimmune Addison's disease. FEBS Letters199230951.

  • 67

    KrohnK. Identification by molecular cloning of an autoantigen associated with Addison' disease as steroid 17 α-hydroxylase. Lancet1992339770.

    • Search Google Scholar
    • Export Citation
  • 68

    DieterichW. Identification of tissue transglutaminase as the autoantigen of celiac disease. Nature Medicine19973797.

  • 69

    DevendraDFrankeBGallowayTSHortonSJKnipMWilkinTJ. Distinct idiotypes of insulin autoantibody in autoimmune polyendocrine syndrome type 2 and childhood onset type 1 diabetes. Journal of Clinical Endocrinology and Metabolism20048952665270.

    • Search Google Scholar
    • Export Citation
  • 70

    HrdáPSterzlIMatuchaPKoriothFKrommingaA. HLA antigen expression in autoimmune endocrinopathies. Physiological Research200453191197.

  • 71

    KahalyGJFörsterGOttoEHansenCSchulzG. Type 1 diabetes as part of the polyglandular autoimmune syndrome. In German. Diabetes Stoffwechsel199761927.

    • Search Google Scholar
    • Export Citation
  • 72

    Kahaly GJ & Dittmar M. Polyglandular failure syndromes. Harrison's Online Updates. New York: The McGraw-Hill Companies 2004.

  • 73

    BetterleCLazzarottoFPresottoF. Autoimmune polyglandular syndrome type 2: the tip of an iceberg?Clinical and Experimental Immunology2004137225233.

    • Search Google Scholar
    • Export Citation
  • 74

    DittmarMKahalyGJ. Immunoregulatory and susceptibility genes in thyroid and polyglandular autoimmunity. Thyroid200515239250.

If the inline PDF is not rendering correctly, you can download the PDF file here.

 

     European Society of Endocrinology

Related Articles

Article Information

Metrics

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 1816 1816 50
PDF Downloads 1821 1821 94

Altmetrics

Figures

  • View in gallery

    Prevalence of most frequent autoimmune endocrine component diseases in PAS type I (white bars) and PAS type II (grey bars). Abbreviations: parathyr., hypoparathyroidism; adrenal, Addison's disease; gonads, hypogonadism; pancreas, type 1 diabetes mellitus or T1D; thyroid, autoimmune thyroid disease or AITD.

References

  • 1

    EisenbarthGSGottliebPA. Autoimmune polyendocrine syndromes. New England Journal of Medicine200435020682079.

  • 2

    NeufeldMMacLarenNBlizzardR. Autoimmune polyglandular syndromes. Pediatric Annals19809154162.

  • 3

    JenkinsRCWeetmanAP. Disease associations with autoimmune thyroid disease. Thyroid200212977988.

  • 4

    BetterleCGreggioNAVolpatoM. Clinical review 93: autoimmune polyglandular syndrome type 1. Journal of Clinical Endocrinology and Metabolism19988310491055.

    • Search Google Scholar
    • Export Citation
  • 5

    Obermayer-StraubPStrassburgCPMannsMP. Autoimmune polyglandular syndrome type 1. Clinical Reviews in Allergy and Immunology200018167183.

    • Search Google Scholar
    • Export Citation
  • 6

    TenSNewMMacLarenN. Clinical review 130: Addison's disease 2001. Journal of Clinical Endocrinology and Metabolism20008629092922.

  • 7

    FörsterGKrummenauerFKühnIBeyerJKahalyG. Polyglandular autoimmune syndrome type II: epidemiology and forms of manifestation. Deutsche Medizinische Wochenschrift199912414761481.

    • Search Google Scholar
    • Export Citation
  • 8

    ZhuJPaulWE. CD4 T cells: fates, functions, and faults. Blood200811215571569.

  • 9

    MartinezGJNurievaRIYangXODongC. Regulation and function orf proinflammatory TH17 cells. Annals of the New York Academy of Sciences20081143188211.

    • Search Google Scholar
    • Export Citation
  • 10

    AndersonMS. Autoimmune endocrine diseases. Current Opinion in Immunology200214760764.

  • 11

    DevendraDEisenbarthGS. Immunologic endocrine disorders. Journal of Allergy and Clinical Immunology2003111S624S636.

  • 12

    ToplissDHowJLewisMRowVVolpeR. Evidence for cell-mediated immunity and specific suppressor T lymphocyte dysfunction in Graves' disease and diabetes mellitus. Journal of Clinical Endocrinology and Metabolism198357700705.

    • Search Google Scholar
    • Export Citation
  • 13

    CanbayAGieselerREllaRFinkHSallerBMannK. Manifestation of adrenal insufficiency after administration of levothyroxine in a patient with polyglandular autoimmune syndrome type II (Schmidt-syndrome). Internist200041588591.

    • Search Google Scholar
    • Export Citation
  • 14

    SakaguchiS. Naturally arising CD4+regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annual Review of Immunology200422531562.

    • Search Google Scholar
    • Export Citation
  • 15

    ShevachEM. Regulatory T cells in autoimmmunity. Annual Review of Immunology200018423449.

  • 16

    KriegelMALohmannTGablerCBlankNKaldenJRLorenzHM. Defective suppressor function of human CD4+CD25+regulatory T cells in autoimmune polyglandular syndrome type II. Journal of Experimental Medicine200419912851291.

    • Search Google Scholar
    • Export Citation
  • 17

    LutherCPoeschelSVargaMMelmsATolosaE. Decreased frequency of intrathymic regulatory T cells in patients with myasthenia – associated thymoma. Journal of Neuroimmunology2005164124128.

    • Search Google Scholar
    • Export Citation
  • 18

    VigliettaVBaecher-AllanCWeinerHLHaflerDA. Loss of functional suppression by CD4+CD25+regulatory T cells in patients with multiple sclerosis. Journal of Experimental Medicine2004199971979.

    • Search Google Scholar
    • Export Citation
  • 19

    SakaguchiSSakaguchiNAsanoMItohMTodaM. Immunologic self-tolerance maintained by activated T cells expression IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. Journal of Immunology199515511511164.

    • Search Google Scholar
    • Export Citation
  • 20

    LanRYAnsariAALianZXGershwinME. Regulatory T cells: development, function and role in autoimmunity. Autoimmunity Reviews20054351363.

  • 21

    DittmarMPoppeRBischofsCFredenhagenGKanitzMKahalyGJ. Impaired deoxyribonuclease activity in monoglandular and polyglandular autoimmunity. Experimental and Clinical Endocrinology and Diabetes2007115387391.

    • Search Google Scholar
    • Export Citation
  • 22

    DittmarMBischofsCMatheisNPoppeRKahalyGJ. A novel mutation in the DNAse I gene is related with protein instability and decreased enzyme activity in thyroid autoimmunity. Journal of Autoimmunity200932713.

    • Search Google Scholar
    • Export Citation
  • 23

    RockFLHardimanGTimansJCKasteleinRABazanJF. A family of human receptors structurally related to Drosophila Toll. PNAS199895588593.

  • 24

    ChuangTUlevitchRJ. Identification of hTLR10: a novel human Toll-like receptor preferentially expressed in immune cells. Biochimica et Biophysica Acta20011518157161.

    • Search Google Scholar
    • Export Citation
  • 25

    LeadbetterEARifkinIRHohlbaumAMBeaudetteBCSchlomchikMJMarshak-RothsteinA. Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature2002416603607.

    • Search Google Scholar
    • Export Citation
  • 26

    GiananiRSarvetnickN. Viruses, cytokines, antigens, and autoimmunity. PNAS19969322572259.

  • 27

    WallaschofskiHMeyerATuschyULohmannT. HLA-DQA1*0301-associated susceptibility for autoimmune polyglandular syndrome type II and III. Hormone and Metabolic Research200335120124.

    • Search Google Scholar
    • Export Citation
  • 28

    RoblesDTFainPRGottliebPAEisenbarthGS. The genetics of autoimmune polyendocrine syndrome type II. Endocrinology and Metabolism Clinics of North America200231353368.

    • Search Google Scholar
    • Export Citation
  • 29

    EisenbarthGSWilsonPWardFLebovitaH. HLA type and occurrence of disease in familial polyglandular failure. New England Journal of Medicine19782989294.

    • Search Google Scholar
    • Export Citation
  • 30

    TischRMcDevittH. Insulin-dependent diabetes mellitus. Cell199685291297.

  • 31

    SanjeeviCBLybrandTPDeWeeseCLandin-OlssonMKockumIDahlquistGSundkvistGStengerDLernmarkA. Polymorphic amino acid variations in HLA-DQ are associated with systematic physical property changes and occurrence of IDDM. Members of the Swedish Childhood Diabetes Study. Diabetes199544125131.

    • Search Google Scholar
    • Export Citation
  • 32

    TandonNZhangLWeetmanAP. HLA associations with Hashimoto's thyroiditis. Clinical Endocrinology199134383386.

  • 33

    RomanSHGreenbergDRubinsteinPWallensteinSDaviesTF. Genetics of autoimmune thyroid disease: lack of evidence for linkage to HLA within families. Journal of Clinical Endocrinology and Metabolism199274496503.

    • Search Google Scholar
    • Export Citation
  • 34

    TomerYBarbesinoGGreenbergDAConcepcionEDaviesTF. Mapping the major susceptibility loci for familial Graves' and Hashimoto's diseases: evidence for genetic heterogeneity and gene interactions. Journal of Clinical Endocrinology and Metabolism19998446564664.

    • Search Google Scholar
    • Export Citation
  • 35

    DittmarMKaczmarzykABischofsCKahalyGJ. The pro-inflammatory cytokine TNFalpha 308 genotype is associated with polyglandular autoimmunity. Immunological Investigations200938113.

    • Search Google Scholar
    • Export Citation
  • 36

    MoghaddamPHZwindermanAHde KnijffPRoepBOSchipperRFVan der AuweraBNaipalAGorusFSchuitFGiphartMJ. TNFa microsatellite polymorphism modulates the risk of IDDM in Caucasians with the high-risk genotype HLA DQA1*0501-DQB1*0201/DQA1*0301-DQB1*0302. Belgian Diabetes Registry. Diabetes19974615141515.

    • Search Google Scholar
    • Export Citation
  • 37

    BauerSGrohVWuJSteinleAPhillipsJHLanierLLSpiesT. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science1999285727729.

    • Search Google Scholar
    • Export Citation
  • 38

    DittmarMIdeMWurmMKahalyGJ. Early onset of polyglandular failure is associated with HLA-DRB103. European Journal of Endocrinology20081595560.

    • Search Google Scholar
    • Export Citation
  • 39

    GambelungheGGhaderiMCosentinoAFalorniABrunettiPFalorniASanjeeviCB. Association of MHC Class I chain-related A (MIC-A) gene polymorphism with type I diabetes. Diabetologia200043507514.

    • Search Google Scholar
    • Export Citation
  • 40

    KotsaKWatsonPFWeetmanAP. A CTLA-4 gene polymorphism is associated with both Graves disease and autoimmune hypothyroidism. Clinical Endocrinology199746551554.

    • Search Google Scholar
    • Export Citation
  • 41

    OstrovDAShiWSchwartzJCAlmoSCNathensonSG. Structure of murine CTLA-4 and its role in modulating T cell responsiveness. Science2000290816819.

    • Search Google Scholar
    • Export Citation
  • 42

    UedaHHowsonJMEspositoLHewardJSnookHChamberlainGRainbowDBHunterKMSmithANDi GenovaGHerrMHDahlmanIPayneFSmythDLoweCTwellsRCHowlettSHealyBNutlandSRanceHEEverettVSminkLJLamACCordellHJWalkerNMBordinCHulmeJMotzoCCuccaFHessJFMetzkerMLRogersJGregorySAllahabadiaANithiyananthanRTuomilehto-WolfETuomilehtoJBingleyPGillespieKMUndlienDERønningenKSGujaCIonescu-TîrgovişteCSavageDAMaxwellAPCarsonDJPattersonCCFranklynJAClaytonDGPetersonLBWickerLSToddJAGoughSC. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature2003423506511.

    • Search Google Scholar
    • Export Citation
  • 43

    KavvouraFKAkamizuTAwataTBanYChistiakovDAFrydeckaIGhaderiAGoughSCHiromatsuYPloskiRWangPWBanYBednarczukTChistiakovaEIChojmMHewardJMHirataniHJuoSHKarabonLKatayamaSKuriharaSLiuRTMiyakeIOmraniGHPawlakETaniyamaMTozakiTIoannidisJP. Cytotoxic T-lymphocyte associated antigen 4 gene polymorphisms and autoimmune thyroid disease: a meta-analysis. Journal of Clinical Endocrinology and Metabolism20079231623170.

    • Search Google Scholar
    • Export Citation
  • 44

    SiminovitchKA. PTPN22 and autoimmune disease. Nature Genetics20043612481249.

  • 45

    BottiniNMusumeciLAlonsoARahmouniSNikaKRostamkhaniMMacMurrayJMeloniGFLucarelliPPellecchiaMEisenbarthGSComingsDMustelinT. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nature Genetics200436337338.

    • Search Google Scholar
    • Export Citation
  • 46

    BegovichABCarltonVEHonigbergLASchrodiSJChokkalingamAPAlexanderHCArdlieKGHuangQSmithAMSpoerkeJMConnMTChangMChangSYSaikiRKCataneseJJLeongDUGarciaVEMc McAllisterLBJefferyDALeeATBatliwallaFRemmersECriswellLASeldinMFKastnerDLAmosCISninskyJJGregersenPK. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. American Journal of Human Genetics200475330337.

    • Search Google Scholar
    • Export Citation
  • 47

    KyogokuCLangefeldCDOrtmannWALeeASelbySCarltonVEChangMRamosPBaechlerECBatliwallaFMNovitzkeJWilliamsAHGillettCRodinePGrahamRRArdlieKGGaffneyPMMoserKLPetriMBegovichABGregersenPKBehrensTW. Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE. American Journal of Human Genetics200475504507.

    • Search Google Scholar
    • Export Citation
  • 48

    GomezLMAnayaJMGonzalezCIPineda-TamayoROteroWArangoAMartinJ. PTPN22 C1858T polymorphism in Colombian patients with autoimmune diseases. Genes and Immunotherapy20056628631.

    • Search Google Scholar
    • Export Citation
  • 49

    HuberAMenconiFCorathersSJacobsonEMTomerY. Joint genetic susceptibility to type 1 diabetes and autoimmune thyroiditis: from epidemiology to mechanisms. Endocrine Reviews200829697725.

    • Search Google Scholar
    • Export Citation
  • 50

    DultzGMatheisNDittmarMRöhrigBBenderKKahalyGJ. The protein tyrosine phosphatase non-receptor type 22 C1858T polymorphism is a joint susceptibility locus for immunthyroiditis and autoimmune diabetes. Thyroid200919143148.

    • Search Google Scholar
    • Export Citation
  • 51

    DultzGDittmarMKahalyGJ. Genetics of thyroid autoimmunity – update and clinical relevance. Medizinische Klinik2009104210219.

  • 52

    AaltonenJBjorsesPSandkuijlLPerheentupaJPeltonenL. An autosomal locus causing autoimmune disease: autoimmune polyglandular disease type I assigned to chromosome 21. Nature Genetics199488387.

    • Search Google Scholar
    • Export Citation
  • 53

    BjorsesPAaltonenJVikmanAPerheentupaJBen-ZionGChiumelloGDahlNHeidemanPHoorweg-NijmanJJMathivonLMullisPEPohlMRitzenMRomeoGShapiroMSSmithCSSolyomJZlotogoraJPeltonenL. Genetic homogeneity of autoimmune polyglandular disease type I. American Journal of Human Genetics199659879886.

    • Search Google Scholar
    • Export Citation
  • 54

    NagamineKPetersonPScottHSKudohJMinoshimaSHeinoMKrohnKJLaliotiMDMullisPEAntonarakisSEKawasakiKAsakawaSItoFShimizuN. Positional cloning of the APECED gene. Nature Genetics199717393398.

    • Search Google Scholar
    • Export Citation
  • 55

    PearceSHCheethamTImrieHVaidyaBBarnesNDBilousRWCarrDMeeranKShawNJSmithCSToftADWilliamsGKendall-TaylorP. A common and recurrent 13-bp deletion in the autoimmune regulator gene in British kindreds with autoimmune polyendocrinopathy type 1. American Journal of Human Genetics19986316751684.

    • Search Google Scholar
    • Export Citation
  • 56

    WangCYDavoodi-SemiromiAHuangWConnorEShiJDSheJX. Characterization of mutations in patients with autoimmune polyglandular syndrome type 1 (APS1). Human Genetics1998103681685.

    • Search Google Scholar
    • Export Citation
  • 57

    ChenQYLanMSSheJXMacLarenNK. The gene responsible for autoimmune polyglandular syndrome type 1 maps to chromosome 21q22.3 in US patients. Journal of Autoimmunity199811177183.

    • Search Google Scholar
    • Export Citation
  • 58

    HeinoMPetersonPKudohJShimizuNAntonarakisSEScottHSKrohnK. APECED mutations in the autoimmue regulator (AIRE) gene. Human Mutation200118205211.

    • Search Google Scholar
    • Export Citation
  • 59

    HalonenMEskelinPMyhreAGPerheentupaJHusebyeESKampeORorsmanFPeltonenLUlmanenIPartanenJ. AIRE mutations and human leukocyte antigen genotypes as determinants of the autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy phenotype. Journal of Clinical Endocrinology and Metabolism20028725682574.

    • Search Google Scholar
    • Export Citation
  • 60

    DittmarMKahalyGJ. Genetics of autoimmune hypoparathyroidism. Clinical Cases in Mineral and Bone Metabolism20041113116.

  • 61

    VogelAStrassburgCPObermayer-StraubPBrabantGMannsMP. The genetic background of autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy and its autoimmune disease components. Journal of Molecular Medicine200280201211.

    • Search Google Scholar
    • Export Citation
  • 62

    KumarRReddyDVUnikrishnanAGBhadadaSKAgrawalNKSinghSK. Polyglandular autoimmune endocrinopathy in type 2 diabetes. Journal of the Association of Physicians of India2004529991000.

    • Search Google Scholar
    • Export Citation
  • 63

    DittmarMKahalyGJ. Polyglandular autoimmune syndromes: Immunogenetics and long-term follow-up. Journal of Clinical Endocrinology and Metabolism20038829832992.

    • Search Google Scholar
    • Export Citation
  • 64

    BetterleC. Autoimmune adrenal insufficiency and autoimmune polyendocrine syndromes: autoantibodies, autoantigens, and their applicability in diagnosis and disease prediction. Endocrine Reviews200223327354.

    • Search Google Scholar
    • Export Citation
  • 65

    ChenSSawickaJBetterleCPowellMPrenticeLVolpatoMSmithBRFurmaniakJ. Autoantibodies to steroidogenic enzymes in autoimmune polyglandular syndrome. Addison's disease, and premature ovarian failure. Journal of Clinical Endocrinology and Metabolism19968118711876.

    • Search Google Scholar
    • Export Citation
  • 66

    BednarekJ. Steroid 21-hydroxylase is a major autoantigen involved in adult onset autoimmune Addison's disease. FEBS Letters199230951.

  • 67

    KrohnK. Identification by molecular cloning of an autoantigen associated with Addison' disease as steroid 17 α-hydroxylase. Lancet1992339770.

    • Search Google Scholar
    • Export Citation
  • 68

    DieterichW. Identification of tissue transglutaminase as the autoantigen of celiac disease. Nature Medicine19973797.

  • 69

    DevendraDFrankeBGallowayTSHortonSJKnipMWilkinTJ. Distinct idiotypes of insulin autoantibody in autoimmune polyendocrine syndrome type 2 and childhood onset type 1 diabetes. Journal of Clinical Endocrinology and Metabolism20048952665270.

    • Search Google Scholar
    • Export Citation
  • 70

    HrdáPSterzlIMatuchaPKoriothFKrommingaA. HLA antigen expression in autoimmune endocrinopathies. Physiological Research200453191197.

  • 71

    KahalyGJFörsterGOttoEHansenCSchulzG. Type 1 diabetes as part of the polyglandular autoimmune syndrome. In German. Diabetes Stoffwechsel199761927.

    • Search Google Scholar
    • Export Citation
  • 72

    Kahaly GJ & Dittmar M. Polyglandular failure syndromes. Harrison's Online Updates. New York: The McGraw-Hill Companies 2004.

  • 73

    BetterleCLazzarottoFPresottoF. Autoimmune polyglandular syndrome type 2: the tip of an iceberg?Clinical and Experimental Immunology2004137225233.

    • Search Google Scholar
    • Export Citation
  • 74

    DittmarMKahalyGJ. Immunoregulatory and susceptibility genes in thyroid and polyglandular autoimmunity. Thyroid200515239250.

Cited By

PubMed

Google Scholar