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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 7 2983-2992
Copyright © 2003 by The Endocrine Society

EXTENSIVE PERSONAL EXPERIENCE

Polyglandular Autoimmune Syndromes: Immunogenetics and Long-Term Follow-Up

Manuela Dittmar and George J. Kahaly

Departments of Medicine I (M.D., G.J.K.) and Biology (M.D.), Gutenberg University, Mainz, Germany 55101

Address all correspondence and requests for reprints to: Prof. George J. Kahaly, Department of Medicine I, Gutenberg University Hospital, Mainz 55101, Germany. E-mail: gkahaly{at}mail.uni-mainz.de.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Polyglandular autoimmune syndromes (PAS) are rare polyendocrinopathies characterized by the failure of several endocrine glands as well as nonendocrine organs, caused by an immune-mediated destruction of endocrine tissues. This article summarizes extensive clinical, epidemiological, serological, and genetic data of a large collective of patients with PAS (n = 360). Since 1988, more than 15,000 adult patients with endocrine diseases have been screened at the endocrine center of the Mainz University, and 151 of 360 patients with PAS have regularly been followed. Type 1 diabetes, Graves’ disease, Hashimoto thyroiditis, Addison’s disease, vitiligo, alopecia, hypogonadism, and pernicious anemia were observed in 61%, 33%, 33%, 19%, 20%, 6%, 5%, and 5%, respectively. The most common disease combination was type 1 diabetes and autoimmune thyroid disease. In most patients, type 1 diabetes was the first manifestation of PAS (48%). The longest time intervals between manifestations of the first and second immune endocrinopathies occurred between type 1 diabetes and thyroid disease (13.3 ± 11.8 yr) and between vitiligo and thyroid disease (16.3 ± 13.3 yr), but a shorter time interval was observed between Addison’s and thyroid diseases. Of the 471 patients with type 1 diabetes screened, 83 (17.6%) were positive for PAS. Subsequently, sera of 126 patients with PAS, 287 with type 1 diabetes, and 303 matched controls were compared for human leukocyte antigens. Patients with PAS had significantly higher frequencies of the human leukocyte antigens A24, A31, B8, B51, B62, DR3, and DR4 (relative risk, 2.35, 2.74, 2.47, 7.17, 2.22, 1.94, and 2.46) vs. controls, and for A31, B15, B52, B55, DR2, DR11, and DR13 (relative risk, 2.51, 7.96, 3.99, 5.36, 4.46, 2.89, and 3.26) vs. type 1 diabetes patients without PAS. In conclusion, patients with autoimmune endocrine disease should be followed on a regular basis. In subjects at risk for PAS, functional screening every 3 yr is warranted. If clinical disease is present, serological measurement of organ-specific antibodies should follow.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
POLYGLANDULAR AUTOIMMUNE SYNDROMES (PAS, PGA, or PGAS; synonyms are autoimmune polyglandular syndromes, polyglandular failure syndromes, and polyglandular autoimmune diseases) are rare immune endocrinopathies characterized by the coexistence of at least two endocrine gland insufficiencies that are based on autoimmune mechanisms. Associations with nonendocrine immune diseases may occur. 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 (1, 2). A third subtype, PAS III, has subsequently been described in adults, and, contrary to types I and II, it does not involve the adrenal cortex (3). Apart from the absence of adrenal failure, no clinical differences between types II and III have been described. Therefore, we will call the adult form, with or without adrenal failure, PAS II and the juvenile form PAS I (Table 1Go).


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  		TABLE 1. Characteristics of the PAS

 
PAS I, also known as APECED (autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy) or MEDAC (multiple endocrine deficiency autoimmune candidiasis syndrome), usually appears in childhood at age 3–5 yr or in early adolescence and, therefore, is also called juvenile autoimmune polyendocrinopathy (4). It is defined by a persistent fungal infection (chronic mucocutaneous candidiasis), the presence of acquired hypoparathyroidism, and adrenal failure (Addison’s disease, Refs. 5 and 6). In most patients, chronic mucocutaneous candidiasis precedes the other immune disorders, usually followed by hypoparathyroidism. Although the first clinical manifestation occurs in childhood, the main component diseases develop in the first 20 yr of life, and further associated diseases may not evolve until the fifth decade or later (7, 8). The female-to-male ratio varies from 0.8:1 to 2.4:1 (5). The highest prevalence of the rare PAS I syndrome has been found in populations who are characterized by a high degree of consanguinity or who are descendants of small founder populations, particularly in Iranian Jews (1:600 to 1:9,000; Ref. 9) and Finns (1:25,000; Ref. 7). Genetic studies have shown an autosomal recessive inheritance in a single gene.

PAS II is more common and occurs in adulthood, mainly in the third or fourth decade. It is characterized by primary adrenal failure (Addison’s disease) with autoimmune thyroid disease (Schmidt’s syndrome) and/or type 1 diabetes (Carpenter’s syndrome). Adrenal failure may precede other endocrinopathies (10). Vitiligo and gonadal failure are more rarely associated with PAS II than with type I. Instead, other disorders like immunogastritis (11), pernicious anemia, and alopecia areata may occur in type II. Immunogastritis, eventually leading to pernicious anemia, is an organ-specific autoimmune disease characterized by pathological lesions, affecting the fundus and body of the stomach, that are typified by gastric mucosal atrophy, selective loss of parietal cells from the gastric mucosa, submucosal lymphocytic infiltration, as well as circulating gastric parietal cell autoantibodies. Subsequently, pernicious anemia, which is considered to be the most common cause of vitamin B12 deficiency, may develop. In this case, additional autoantibodies to the intrinsic factor, itself a secretory product of gastric chief cells, are found in the circulation and in gastric secretions. The prevalence of PAS II is estimated to be 1:20,000 (Ref. 10), and females are affected three times more frequently than males. In contrast to type I, family members of PAS II patients are often affected (1). PAS II is believed to be polygenic, characterized by autosomal dominant inheritance. This paper summarizes extensive long-term follow-up results regarding the management of one of the largest groups of patients with PAS II to be described.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Since 1988, more than 15,000 patients with endocrine diseases have been screened for PAS at our institution. PAS was defined by the presence of at least two clinical endocrine autoimmune diseases. Of these patients, 360 were positive for PAS II. Hypogonadism was diagnosed by enhanced FSH and low serum testosterone in men and by FSH measurement by the presence of secondary amenorrhea with low estradiol levels in women. Adrenal insufficiency was suspected in the case of low blood pressure, skin pigmentation, low serum sodium and cortisol levels, as well as elevated serum ACTH and potassium concentrations. For pernicious macrocytic anemia, autoantibodies to the intrinsic factor, low vitamin B12 concentration, as well as glossitis and neuropathy were required. Histological examination of biopsies of the gastric mucosa proved immune atrophic gastritis. In the first screening cohort, 471 patients with type 1 diabetes (mean age, 39 ± 16 yr; duration of diabetes, 15 ± 10 yr) were screened for the presence of a further autoimmune disorder, and 83 were diagnosed with PAS II. These patients were tested for autoantibodies against various PAS endocrine and nonendocrine component diseases. In a subsequent human leukocyte antigen (HLA)-typing study, the sera of an additional 126 patients with PAS II (mean age, 47 yr; male-to-female ratio, 1:2.4), 287 patients with type 1 diabetes without PAS (mean age, 37 yr; male-to-female ratio, 1.3:1), and 303 matched controls were tested for a large panel of HLA class I (A, B, and C) and HLA class II (DR) antigens. The age- and sex-matched unrelated controls were selected by random sampling from potential bone marrow donors at the university transfusion center. Furthermore, 151 patients with PAS II have been followed on a regular basis analyzing clinical, epidemiological, serological, and biochemical data of the various component diseases.

Methods

Quantitative enzyme immunoassay (IRMA method; Brahms, Berlin, Germany) was used to test for the presence of autoantibodies against TSH receptor. ELISA (Pharmacia/Upjohn GmbH, Freiburg, Germany) was applied for autoantibodies against thyroid peroxidase (TPO), thyroglobulin (Tg; positive, >100 IU/ml), and glutamic acid decarboxylase (GAD; positive, >1500 U/ml). Qualitative interference testing (Pharmacia/Upjohn GmbH) was performed to detect insulin autoantibodies. Indirect immunofluorescence was used for adrenal cortex, parietal cell, antinuclear, and islet cell autoantibodies (ICA). ICA were detected in cryostat sections of pancreas of primates with fluorescein isothiocyanate-antihuman-antibodies (Euroimmun GmbH, Groß Grönau, Germany; positive cutoff, serum dilution of 1:10). Cryostat sections of monkey adrenal cortex were labeled with fluorescein isothiocyanate-antihuman-antibodies (BIOS GmbH, Gräfeling, Germany; positive cut off, serum dilution 1:10). Parietal cell antibodies were detected on cryostat-combined sections of rat liver, kidney, and stomach with Quantafluor-antibody-fluorescence test (Sanofi Diagnostics Pasteur GmbH, Freiburg, Germany; positive cutoff, serum dilution of 1:20). HLA classes I (A, B, and Cw) and II (DR) antigens were tested with the lymphocytotoxicity method.

Statistical analysis

Group comparisons were performed by the use of Wilcoxon’s test for paired samples. Autoantibody prevalences were compared by means of Fisher’s exact test (two-tailed). Relative risks (RR) were calculated for HLA antigen frequencies. Statistical significance was set at P value less than 0.05.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Long-term follow-up of patients with PAS II

Since 1990 and for the next 13 yr, 151 (114 females and 37 males) of the 360 patients with PAS II have been followed regularly. This corresponds to a 3:1 female-to-male ratio. Analysis of clinical data showed that, taken together, both autoimmune thyroid diseases had the highest prevalence (n = 99; 65.6%), with equal numbers of Graves’ disease (n = 50; 33.1%) and autoimmune thyroiditis (n = 49; 32.5%). However, type 1 diabetes (n = 92; 60.9%) was the most frequent endocrine component disease of PAS, whereas Addison’s disease (n = 28; 18.5%) and gonadal failure (n = 8; 5.3%) occurred less frequently. With regard to nonendocrine autoimmune component diseases, vitiligo (n = 30; 19.9%) was most frequently observed, followed by alopecia areata (n = 9; 6%) and pernicious anemia (n = 8; 5.3%). Significant male and female preponderances were noted for manifest type 1 diabetes and immunothyroiditis, respectively. In contrast, this was not found for manifest Graves’ and Addison’s diseases. Epidemiological data indicated a clear variation in age at first manifestation for PAS component diseases in our patients (Fig. 1Go). Type 1 diabetes was manifested early (mean age, 27.5 yr), whereas other component diseases appeared later, ranging from an age of 36.5–40.5 yr. Type 1 diabetes was the first component disease of PAS in half of the patients (48.3%), whereas Graves’ disease (19.2%), Hashimoto’s thyroiditis (17.2%), Addison’s disease (14.6%), and vitiligo (12.6%) were less likely to be the first component disease (Fig. 2AGo). The most frequent coexistence of PAS component diseases was between type 1 diabetes and thyroid disease (Fig. 2BGo). Less commonly, coexistences occurred between thyroid and Addison’s diseases, type 1 diabetes and vitiligo, as well as thyroid disease and vitiligo. In Fig. 2BGo, only the most frequent disease combinations are shown. Patients with more than two diseases were also noted. The same holds true for both disease combinations for hypogonadism and either thyroid disease or diabetes. The time interval between manifestations of the first and second autoimmune endocrinopathies varied considerably (Fig. 3Go), with longest time intervals between type 1 diabetes and thyroid disease (13.3 ± 11.8 yr) and between vitiligo and thyroid disease (16.3 ± 13.3 yr), but a short time interval between Addison’s disease and thyroid disease. In general, when a thyroid disease waspresent as a first component disease, the time interval until the onset of a further immunopathy was relatively short. On the other hand, when thyroid disease was a second component disease of PAS, a longer period of time elapsed. In addition, when vitiligo was the first component disease, the time interval until the onset of the second component disease was long. Thus, time intervals between first and second disease manifestations were significantly different (P < 0.01), where thyroid disease and vitiligo, respectively, were the first disease components.



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  		FIG. 1. Age at manifestation of the three main component autoimmune endocrinopathies in 151 patients with PAS II followed at our institution.

 


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  		FIG. 2. First disease manifestation (A) and most frequent combinations of endocrine and nonendocrine component diseases (B) in 151 patients with PAS II followed at our institution. Only the most frequent disease combinations are shown. Patients with more than two diseases were also noted. The same holds true for both disease combinations hypogonadism and either thyroid disease or diabetes. Adrenal, Addison’s disease; Thyroid, autoimmune thyroid disease; Diabetes, type 1 diabetes; Gonads, gonadal failure; Pernic., pernicious anemia.

 


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  		FIG. 3. Time interval between manifestation of first (abscissa) and second (non)endocrine component diseases (ordinate) in 151 patients with PAS II. Medians, first and third quartiles as well as ranges of time between manifestation of first and further diseases are shown. Adrenal, Addison’s disease; Thyroid, autoimmune thyroid disease; Diabetes, type 1 diabetes mellitus.

 
Regarding autoantibodies in patients with PAS II, antibodies reactive to the TSH receptor and/or TPO were detected in 81% of the patients (Fig. 4Go). Fifty-two percent of the PAS subjects had positive thyroid-associated antibodies without any manifestation of thyroid disease. Type 1 diabetes-associated antibodies directed against ICA, insulin, and/or GAD were found in only 37.4%. In comparison, in patients with clinical Addison’s disease and pernicious anemia, antibodies to adrenal cortex and parietal cells were observed in 26% and 54%, respectively.



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  		FIG. 4. Prevalence of organ-specific autoantibodies in patients with PAS II. AC, Adrenal cortex; PC, parietal cells; TSHR, TSH receptor.

 
Comparison of type 1 diabetes patients vs. patients with PAS II

A total of 471 patients with type 1 diabetes were examined for the presence of PAS II. Most of the patients were identified through screening of a type 1 diabetes clinic population. Type 1 diabetes was defined as the presence of islet antibodies, and/or undetectable insulin levels, and/or initial insulin use, and/or marked weight loss before first manifestation of the disease. Of these 471 patients, 83 (17.6%) were positive for PAS II (12). Other autoimmune diseases in the diabetes patients were Hashimoto’s’ thyroiditis (6.8%), adrenal failure (4.2%), Graves’ disease (3.4%), vitiligo (4.3%), and autoimmune gastritis (1.7%). The patients had different mean ages for the development of type 1 diabetes, depending on the type of second autoimmune disease. In patients with immunogastritis, Hashimoto’s’ thyroiditis, vitiligo, or Graves’ disease, the mean age for the development of diabetes was 24.6, 31.8, 33.4, and 45.4 yr, respectively (P < 0.05, Student’s t test for independent samples). Autoantibody screening in type 1 diabetes patients with at least one further autoimmune endocrine disorder detected antibodies against parietal cells (28%), Tg (22%), TPO (19%), nuclear antigen (15%), and adrenal cortex (4.2%). Compared with patients with type 1 diabetes only (n = 388; 211 males and 177 females; mean age 37.4 ± 15.3 yr), patients with PAS (n = 83; 30 males and 53 females; 48.2 ± 19.1 yr) showed increased prevalence of antibodies against parietal cells (10.1% vs. 27.7%; P = 0.003), Tg (0.7% vs. 21.9%; P < 0.001), and TPO (1.5% vs. 18.8%; P < 0.001), but did not differ in prevalence of antibodies against nuclear antigen (12.7% vs. 14.2%; P = 0.774) and adrenal cortex (3.2% vs. 4.2%; P = 0.696).

HLA typing in patients with PAS II, type 1 diabetes, and controls

In a subsequent serological study, HLA typing of 126 additional PAS patients, 287 type 1 diabetes patients without PAS, and 303 age- and sex-matched controls was performed. Diabetes patients with PAS had higher frequencies of the HLA antigens A31 and DR2, and lower frequencies of A24, DR1, DR3, and DR4 than patients with diabetes only (Table 2Go). Compared with controls, patients with PAS II had significantly increased prevalence of A24, B8, DR3, and DR4, but decreased prevalence of A2, Cw2, Cw6, DR6, DR7, and DR11 (Table 3Go). Cw blank, the phenotypic nonexpression of the Cw allele, was found in 43.2% of the PAS group vs. 32.5% in controls vs. 28.9% in diabetes patients without PAS (each, P < 0.05). Considering the absence of one or both Cw antigens for individual persons, the prevalence was 72% of cases in the total PAS group vs. 56% in controls vs. 53% in patients with diabetes without PAS (each, P < 0.05). When diabetes patients were excluded from the PAS group, Cw blank was present in heterozygous or homozygous form in 93% of cases. Further research is being conducted using molecular genetic and family studies of patients who have serologically undetectable allele Cw blank, to clarify whether Cw blank is a serological artifact or might be due to homozygosity of Cw (13, 14).


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  		TABLE 2. Comparison of serological HLA typing in patients with type 1 diabetes without vs. those with a further endocrine autoimmune disease (PAS type II)

 

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  		TABLE 3. Comparison of serological HLA typing in patients with PAS II vs. controls

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Long-term follow-up

This study reports clinical, epidemiological, and serological data of 360 patients with PAS II, collected in the last 15 yr at the endocrine center of the Gutenberg University. Extensive serological and immunogenetic screening of patients with endocrine diseases indicated significant differences in prevalence of organ-specific autoantibodies and disease-associated HLA antigens between patients with PAS II, patients with monoglandular autoimmunity (type 1 diabetes), and controls. Epidemiological data showed varying time intervals between manifestations of different component diseases of PAS II. The results suggest that early immunogenetic screening of patients with autoimmune endocrine diseases enhances the possibility of identifying patients at risk for PAS II. Compared with the early studies of Neufeld et al. (15, 16), the present long-term follow-up study in patients with PAS II found similar prevalence for thyroid diseases, but a lower prevalence of Addison’s disease and higher prevalences for type 1 diabetes, vitiligo, and alopecia. Also, similar prevalences were noted for gonadal failure in both Neufeld’s group and our group. Compared with recent findings in Italian subjects with PAS (17), a similar prevalence of gonadal insufficiency and alopecia areata, a lower prevalence of Addison’s disease and thyroid disease, as well as a higher prevalence of type 1 diabetes, vitiligo, and pernicious anemia was noted. We observed a female-to-male ratio of 3:1 that is similar to the 4:1 ratio found among Italian patients (17). This study also showed that the various endocrine component disorders of PAS II occurred more frequently in patients with PAS than in the general population. PAS is a serious disorder that may cause major disability. This has been recently demonstrated in a case report showing multiple component diseases of PAS type I (18). The patient developed autoimmune thyroiditis at age 9 yr, hypoparathyroidism and Addison’s disease at 10 yr, malabsorption at 34 yr, diabetes insipidus at 44 yr, and mucocutaneous candidiasis and gonadal failure at 45 yr. Many years often arise between the onset of two endocrine disorders in the same patient. Such a time period can take up to 22 yr (19). 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 (2, 13). In view of the tendency of autoimmune diseases to associate with other disorders, of the metachronous manifestations of the component diseases, and of the chronic and 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.

Table 4Go summarizes organ- and tissue-specific autoantibodies that occur in the various component diseases of PAS (20, 21, 22). At presentation of type 1 diabetes, ICA, antibodies to GAD, insulin, and protein tyrosine phosphatase (IA2) can be detected. The prevalence of autoantibodies is very high at clinical onset of endocrinopathy, whereas antibody titers often fall or become negative in the clinical course of the disorder (22). The risk for developing type 1 diabetes increases proportionally with the number of diabetes-related antibodies (23, 24). Already within the first years of life, offspring from parents with type 1 diabetes (BABYDIAB; Ref. 25) who subsequently developed type 1 diabetes had evidence of disease in the form of autoantibodies against the insulin-producing ß-cells. Moreover, early appearance of antibodies to several ß-cell autoantigens was associated with a 100% risk of developing type 1 diabetes during infancy. The first antibodies appeared against the insulin hormone itself. Spreading of the autoimmunity to GAD and IA2 was an important prerequisite for the development of clinical disease and, therefore, presumably an indicator of sustained ß-cell destruction. Early appearance of autoimmunity in these offspring who are genetically at risk was further influenced by the presence of type 1 diabetes-susceptible alleles; offspring with DR3/4 or DR4/4 genotypes developed islet autoantibodies 10 times more frequently than offspring without these genotypes. This indicates that the early years of life should be targeted in an attempt to identify environmental factors influencing autoimmune endocrine disease, and primary prevention should be initiated in the first years of life.


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  		TABLE 4. Autoantigens in patients with PAS

 
Production of high titers of autoantibodies against TPO and Tg often preceded the development of clinical thyroid disease. The time interval between the detection of autoantibodies and presentation of disease was longer for thyroid diseases than for other immunopathies. In adrenal autoimmunity, autoantibodies are directed against antigens identified as P450 cytochromes, i.e. enzymes involved in the synthesis of steroid hormones. These are 21-hydroxylase (21-OH), 17-{alpha}-hydroxylase, and the side chain cleavage enzyme (20, 21, 22). The 21-OH has been identified as a major target antigen in Addison’s disease and has been detected in 85% of patients with PAS II and adrenal failure (21, 22). Thus, actual diagnosis of PAS involves functional screening with serological measurement of autoantibodies. Functional screening confirms diagnosis and comprises determination of blood count, electrolytes, and baseline hormone values (Table 5Go). Detecting organ-specific autoantibodies verifies etiology of the disease and identifies patients who may develop autoimmune polyendocrinopathies. According to the literature, genetic screening is useful for PAS I, less for type II, because one would likely identify the alleles associated with a disease that is already identified, e.g. DR3 and DR4 in patients with type 1 diabetes.


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  		TABLE 5. Diagnostic screening of patients for presence of PAS

 
Immunogenetics

Significant associations of PAS II with various HLA class I antigens were observed in the present immunogenetic studies. In part, this may be explained by the observation that PAS 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 (26). PAS II is polygenically inherited, characterized by dominant inheritance. Several component diseases of PAS have a common immunogenetic background (27, 28), but the major genetic factor remains to be detected in the HLA region. One factor in the pathogenesis of PAS may be an immunological dysfunction that results from one or more genes on chromosome 6, in linkage disequilibrium with the HLA-B8 allele (29). This is in line with our results that showed a RR of 2.47 for association of PAS II with HLA B8. PAS II is also associated with the HLA antigens DR3 and/or DR4, and DRw3 (30, 31, 32), whereas HLA DR3 is associated with almost all immune endocrinopathies of PAS II. In our patients with PAS, prevalence of the antigens DR3 and DR4 was significantly increased. The RR for association of PAS II with the HLA DR3 antigen was 1.94 compared with 2.3 observed in Italian patients (33). Further detailed analyses of the HLA DR3 alleles showed that the HLA DR3-DQB1*0201 haplotype may be associated with multiple component diseases of PAS, whereas the HLA DR4-DQB1*0302 haplotype is implicated in ß-cell autoimmunity only (28). Patients with polyglandular failure may be highly selected for HLA-B8/DRw3 positivity (30). 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 (34). Recent studies have proposed a major gene [cytotoxic T lymphocyte-associated (CTLA-4) gene] that contributes to the genetic susceptibility of thyroid antibody production, located on chromosome 2q33 (35, 36). Susceptibility to PAS II diseases has further been associated with the major HLA class I chain-related MIC-A genes (37). Moreover, quantitative defects in the density of conformationally correct HLA class I complexes on the surface of lymphocytes were found in patients with diverse HLA-linked autoimmune diseases (30).

In contrast to earlier studies, associations with HLA class II alleles also have recently been reported in PAS type I. An increased frequency of the HLA-DR3 allele was observed in 17 patients with PAS I (5). In a study comprising 104 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 (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 (38). Moreover, in these patients with PAS I, 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 PAS I patients, as indicated by significant negative correlations (38). However, in the immunogenetics of PAS I, 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 (39, 40, 41, 42, 43) and has been cloned by two independent research groups (43, 44). In the coding region of the AIRE gene, 45 different mutations have been reported so far (45, 46, 47). Mutations comprise nonsense and missense mutations, deletions, and small insertions (48, 49). A few mutations are responsible for the expression of a truncated regulator protein. AIRE encodes a 545-amino acid protein of 57.5 kDa (43) that contains structural domains characteristic for transcription regulators (50). AIRE is also an important DNA binding molecule that is involved in immune regulation (51). The AIRE gene is expressed in immunologically relevant tissues, particularly in the thymic medulla, as well as in lymph nodes and peripheral blood cells (i.e. CD14-positive monocytes), but not in CD4-positive T cells (52, 53). Mutational analysis of AIRE helps identify patients with atypical phenotypes resembling PAS I (54, 55). In this context, the AIRE mutation R257X was responsible for 82% of PAS I alleles in a Finn population (43).

Immunopathogenesis

Pathogenesis of autoaggression in endocrine autoimmunity is considered multifactorial. A hypothesis for the pathophysiological mechanism of PAS is shown in Fig. 5Go (Ref. 56). The principal antigen-specific autoimmune response is initiated by antigen-presenting cells (57, 58). Ubiquitous dendritic cells are the most important antigen-presenting cells. Immature dendritic cells pick up antigen molecules in nonlymphoid 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 [T helper (Th)1] and/or the humoral immune response via B lymphocytes (Th2; Refs. 59, 60, 61). 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. These T cells regulate autoaggressive T and B cells and may have profound influence on the control of human autoimmune diseases (62).



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  		FIG. 5. Hypothesis for the pathophysiological mechanism of PAS II. CD, Cluster of differentiation; ELAM, endothelial leukocyte adhesion molecule; ICAM, intercellular adhesion molecule; IFN, interferon; LFA, leukocyte function-associated antigen; VCAM, vascular cell adhesion molecule. Modified according to Ref. 67 .

 
Animal models of the immunopathogenesis of PAS 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 an autoimmune polyendocrinopathy (63). Some of the resultant autoantibodies showed cross-species reactivity, recognizing similar antigenic determinants in mouse and human organs (64). With respect to the suppressor effect theory, administration of the immunosuppressive drug cyclosporin A to newborn BALB/c mice caused a selective defect of the regulatory T suppressor cells. Thymectomy conserved the T cell defect and produced autoimmune diseases in a wide spectrum of organs (i.e. thyroiditis, gastritis, insulitis, adrenalitis, oophoritis/orchitis) with pathology similar to that of human organ-specific immune diseases (65). These pathological processes lead to the preclinical phase of PAS, 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 (66). Destruction of endocrine glands causes their secretory insufficiency.

The role of apoptosis in immunodestruction has been associated with dysregulation 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 (58).

Conclusions

The clinical presentation of PAS component diseases is often preceded by an asymptomatic latent period of months or years characterized by the presence of circulating disease-associated antibodies. Autoantibodies are useful markers for the prediction of the development of PAS. The absence of these antibodies does not exclude the disease, because not all patients show positive antibodies. The present long-term follow-up data emphasize that the detection of these antibodies facilitates early diagnosis of autoimmune endocrine disorders. In view of the possibly long time interval between the manifestation of the first and further autoimmune endocrinopathies, regular and long-term observation of patients with endocrine autoimmune disorders seems necessary. For patients with monoglandular autoimmune endocrinopathy, functional screening for PAS is recommended every 3 yr until the age of 75 yr. If pathological findings, e.g. occurrence of a second autoimmune endocrine disease, are noted, measurement of organ-specific autoantibodies should be added (Fig. 6Go). Furthermore, functional screening for autoimmune endocrine diseases of the first-degree relatives of these patients with newly diagnosed PAS may also be done. Especially in the offspring of patients with type 1 diabetes, serological testing for the presence of diabetes-associated antibodies should be considered. According to the literature, genetic screening may be useful in PAS I, only (43). In summary, functional screening rather than a combination of functional, serological, and genetic screening makes actual diagnosis.



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  		FIG. 6. Recommendations for screening of PAS type II.

 


   Acknowledgments
 
We thank David S. Cooper, M.D. (Baltimore, MD), for his most constructive criticism. We also thank Anja Victor (Department of Medical Statistics, Gutenberg University) for statistical analysis of the large Mainz data file, and Cecilia Antunes (Endocrine Research Laboratory, Gutenberg University Hospital) for data collection.


   Footnotes
 
This study contains parts of the doctoral theses of S. Drewitz, C. Kautzmann, U. Klein, A. Leischker, and J. Svitek (Endocrine Research Laboratory).

Abbreviations: AIRE, Autoimmune regulator; DR, HLA class locus; GAD, glutamic acid decarboxylase; HLA, human leukocyte antigen; IA2, protein tyrosine phosphatase; ICA, islet cell autoantibodies; 21-OH, 21-hydroxylase; PAS, polyglandular autoimmune syndrome(s); RR, relative risk; Tg, thyroglobulin; Th, T helper cell; TPO, thyroid peroxidase.

Received November 22, 2002.

Accepted March 6, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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