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Autoantibodies against Aromatic L-Amino Acid Decarboxylase Identifies a Subgroup of Patients with Addison’s Disease¹

Department of Clinical Sciences (A.S., F.R., O.E., O.K.), University Hospital, SE-751 85 Uppsala, Sweden; Hospital for Children and Adolescence (M.H.), Helsinki University Hospital, FIN-00290 Helsinki, Finland; Department of Human Molecular Genetics (P.B.), Finland National Public Health Institute, FIN-00300, Helsinki, Finland; and Division of Endocrinology, Institute of Medicine (E.S.H.), Haukeland University Hospital, N-5021 Bergen, Norway

Address correspondence and requests for reprints to: Annika Söderbergh, M.D., Department of Medical Sciences, University Hospital, Uppsala University, SE-751 85 Uppsala, Sweden. E-mail: annika.soderbergh{at}medicin.uu.se

	Abstract

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Autoantibodies against aromatic L-amino acid decarboxylase (AADC) are present in about 50 percent of sera from patients with autoimmune polyendocrine syndrome type I (APS I) but absent in sera from patients with different organ-specific autoimmune diseases, such as insulin-dependent diabetes mellitus, Hashimoto’s thyroiditis, and Graves’ disease. AADC is expressed in the pancreatic ß-cells, the liver, and the nervous system; and the presence of AADC antibodies has been shown to correlate to hepatitis and vitiligo in APS I patients.

Among 101 investigated patients with autoimmune Addison’s disease, 15 had high titers of AADC antibodies. According to the clinical characteristics of these patients, only 3 had APS I. The remaining 12 had either isolated Addison’s disease or associated diabetes mellitus, hypothyroidism, vitiligo, alopecia, gonadal failure, and pernicious anemia. Autoantibodies against 21-hydroxylase were present in 9 of 12, whereas autoantibodies against side-chain cleavage enzyme and 17-hydroxylase were present in 3 of 12. Two patients had only autoantibodies against AADC. DNA was available from 3 of these 12 patients. One of the patients, a woman with Addison’s disease, autoimmune thyroiditis, and premature menopause was heterozygous for a point mutation (G1021A, Val301Met) in the first plant homeodomain zinc finger domain of the autoimmune regulator (AIRE) gene.

The presence of AADC autoantibodies identifies patients with APS I and a subgroup of Addison patients who may have a milder atypical form of APS I or represent a distinct entity. Measurement of autoantibodies against AADC should be included in the evaluation of Addison’s disease.

	Introduction

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IDIOPATHIC Addison’s disease is generally caused by autoimmune adrenalitis, which is associated with autoantibodies directed against the adrenal cortex, particularly 21-hydroxylase (21OH) (1, 2). A large fraction of these patients have other organ-specific autoimmune disorders, affecting particularly the thyroid, gonads, and insulin-producing ß-cells, as part of an autoimmune polyendocrine syndrome type II (APS II) (3, 4).

A clinical diagnosis of the rare hereditary disease APS I requires the presence of two of the three components of the classical triad of hypoparathyroidism, adrenalitis, and mucocutaneous candidiasis (5, 6). APS I usually develops during early childhood and also includes nonendocrine manifestations such as chronic active hepatitis, malabsorbtion, pernicious anemia, enamel hypoplasia, nail dystrophy, keratopathy, vitiligo, and alopecia. The gene causing APS I has recently been identified and named autoimmune regulator (AIRE) (7, 8). It is predominantly expressed in certain cells in the immune system and is thought to be involved in transcriptional regulation (9, 10, 11).

Patients with Addison’s disease and polyglandular syndromes have autoantibodies against several of the steroidogenic enzymes. Autoantibodies against 21OH seem to correlate to the presence of isolated Addison’s disease and APS II (2, 12, 13, 14, 15), whereas patients with APS I have autoantibodies against 21OH, 17-hydroxylase (17OH), and the side-chain cleavage enzyme (SCC) (14, 16, 17, 18, 19). APS I patients also have autoantibodies against several enzymes involved in the biosynthesis of neurotransmitters such as glutamic acid decarboxylase (20), tryptophan hydroxylase (21), and aromatic L-amino acid decarboxylase (AADC) (22). Autoantibodies against AADC in APS I patients are associated with the presence of autoimmune hepatitis and vitiligo (23). Reactivity against AADC could not be detected in sera from patients with isolated insulin-dependent diabetes mellitus, Graves’ disease, or Hashimoto’s thyroiditis, or from healthy blood donors (23). In the present study, we have identified a subgroup of patients with Addison’s disease with high titers of autoantibodies against AADC. The majority of these patients do not fulfill the clinical criteria for APS I, thus perhaps representing an entity distinct from both APS I and APS II.

	Subjects and Methods

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Subjects

Patients were recruited from the Norwegian Addison Society and were asked to fill in a questionnaire concerning their medical history, medication, and hereditary disorders (15). One hundred and seventeen members answered and provided sera for the studies. Sixteen patients were excluded either because of pituitary insufficiency secondary to tumor growth or because they had undergone adrenalectomy. Of the remaining 101 patients, 78 were women, and 23 were men. The patients’ ages ranged from 16–77 yr (mean, 35.5 yr), and the duration of Addison’s disease ranged from 0.5–42 yr (mean, 15.6 yr). Forty-one patients had isolated Addison’s disease, 4 patients had APS I, and the remaining 56 patients had a polyendocrine syndrome other than APS I. In addition to the questionnaire used by Söderbergh and co-workers (15), a new questionnaire, with specific questions about symptoms and signs of the different components of APS I, was distributed to the patients. Eighty-six patients answered this latter questionnaire. The study was performed in accordance with the Helsinki declaration.

Assay of antibodies against AADC, 21OH, 17OH, and SCC

Antibodies against these enzymes were assayed by a method based on the in vitro transcribed and translated protein, as described by Ekwall et al. (21).

Mutational analysis of the AIRE gene

All Addison patients with antibodies against AADC that did not have APS I (n = 12, Table 1) were invited to send samples for DNA analysis. Three patients responded. DNA was extracted from 10 mL of patient EDTA blood samples, according to standard protocols (24). All 14 exons of the AIRE gene (EMBL accession no. AJ009610) were amplified by PCR from the patient DNA, using primers and conditions described in Table 2. The products were purified for ABI377 automated sequencing using 2.5 U exonuclease I and 0.5 U shrimp alkaline phosphatase to 4.6 µL of PCR product (25). The nucleotide sequences of both strands were determined using PCR oligonucleotides according to ABI PRISM BigDye Terminator Cycle Sequencing protocols (Perkin-Elmer Corp., Norwalk, CT), but both the reaction volume and the volume of BigDye RR-mix were halved.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

Antibodies against AADC in patients with Addison’s disease

Antibodies against AADC were found in 15 (15%) of the 101 patients. Of these, 3 patients fulfilled the clinical criteria for APS I. The remaining 12 patients had either isolated Addison’s disease (n = 4) or presented with individual components of APS I or APS II (Table 1). The mean age at which Addison’s disease first appeared in these 12 patients was higher (29 yr ± 9.8, mean ± SD) than in the 4 that fulfilled the clinical criteria of APS I (16 yr ± 5.6, mean ± SD). In Finnish APS I patients, adrenal insufficiency is reported to occur during the first 2 decades of life (5). The 12 AADC-positive Addison patients without APS I were further characterized by autoantibody measurements and mutational analysis of AIRE.

Presence of antibodies against 21OH, 17OH, and SCC in Addison patients with AADC

The frequency of 21OH antibodies in AADC-positive Addison patients (9 of 12, 75%) did not differ from those without both anti-AADC and APS I (60 of 85, 71%). Three of the 12 AADC-positive Addison patients (25%) had either 17OH or SCC antibodies (Table 3), compared with 2 of 4 APS I patients and 16 of the remaining 85 Addison patients (19%). Two of the 12 AADC-positive Addison patients (no. 5 and 7) lacked autoantibodies against 21OH, 17OH, and SCC (Table 3).

View this table: [in this window] [in a new window]   Table 3. Presence of autoantibodies in the patients displayed in Table 1.

Samples where available from patients no. 1, 2, and 10 and their relatives (Table 1). Patient no. 2, a woman with Addison’s disease, autoimmune thyroiditis, and premature menopause, was found to be heterozygous for a point mutation in the region coding for first plant homeodomain (PHD) zinc finger domain (G1021A). This mutation changes a valine residue at position 301 into a methionine. This mutation was not found in any of 50 European control samples, of which 15 were Norwegian. No mutations were found in the coding region of AIRE in any of the 2 other patients.

	Discussion

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We have previously cloned AADC from the insulin-producing ß-cells of the pancreas and have shown that it is an autoantigen in APS I (22). About 50% (35 of 69) of APS I patients have autoantibodies against AADC (23); whereas, in patients with other organ-specific autoimmune diseases (such as isolated type 1 diabetes mellitus, Hashimoto’s thyroiditis, and Graves’ disease), these autoantibodies are absent (23).

In our study of 101 Norwegian Addison patients, 12 had AADC autoantibodies at similar titers to those of APS I patients. They had either isolated Addison’s disease or polyglandular failure other than APS I (Table 1). The finding of high titers of AADC autoantibodies in patients with Addison’s disease, but not in any other autoimmune disorder examined, was unexpected; and it was unclear whether these patients represented cases of undiagnosed APS I. It thus became important to establish whether they carried mutations in the AIRE gene. DNA from 3 of the 12 patients was available for analysis. One of these had a heterozygous missense (Val 301Met) mutation in the first PHD zinc finger domain. The PHD zinc finger is thought to be an important functional domain in the AIRE gene product, and a substitution of Val for Met in this region could well interfere with the normal function of the protein. This finding does not confirm the diagnosis of APS I, because we were not able to detect any mutation in the other allele of this patient. On the other hand, the diagnosis cannot be excluded, because only the coding region of the gene was analyzed, and a second mutation may be present in the promoter region or in the introns. In fact, lack of mutations in the AIRE coding region has been reported in up to 10% of APS I kindreds (Petra Björses et al., manuscript in preparation). The two remaining patients had no mutations in the coding region of the AIRE gene.

The 12 AADC-positive Addison patients differed from patients with APS I in additional respects. The mean age at onset of the adrenal insufficiency was 29 yr, in contrast to the APS I patients, who developed Addison’s disease at a mean age of 16, results similar to those reported in Finnish APS I patients (5). Serologically, the majority had autoantibodies against 21OH (75%), whereas only 3 of the 12 patients (25%) had autoantibodies against either SCC or 17OH (Table 3). In typical APS I patients, these latter antibodies are found in frequencies ranging from 50–100% (see Results and Refs. 14, 17, 18, 19). Thus, the 12 AADC-positive Addison patients have an autoantibody profile more similar to patients with Addison’s disease/APS II, i.e. a high frequency of 21OH antibodies and low frequencies of autoantibodies against SCC and 17OH (14, 22, 23). Furthermore, 2 Addison patients were 21OH-negative and only displayed reactivity against AADC, suggesting that the measurement of autoantibodies against AADC may be included in the evaluation of patients with Addison’s disease. The presence of AADC autoantibodies may explain those cases in which an autoimmune cause is suspected in adrenal insufficiency, but no 21OH autoantibodies are detected.

The cellular function of AIRE is still unknown. It contains two PHD zinc finger domains (7, 8), four LXXLL nuclear receptor binding domains (26), and a putative DNA-binding domain called SAND (27). Recently, the protein has been shown to be located in distinct nuclear structures (9, 10). The localization and the structural features indicate that the AIRE gene product is involved in gene expression of importance to the immune system.

AADC, which is an autoantigen in APS I, catalyzes the decarboxylation of 3,4-dihydroxyphenylalanine (DOPA) and 5-hydroxytryptophan to dopamine and serotonin. This enzyme has a much wider tissue distribution than other autoantigens identified in this syndrome. It is located in the central and peripheral nervous systems, the liver, the kidney, and in APUD cells of the endocrine pancreas and small intestine (28). Interestingly, the presence of AADC antibodies in APS I is correlated to the presence of chronic autoimmune hepatitis (23, 29) and vitiligo (23). AADC is present in several of the organs affected in APS I [in hair follicles (alopecia) (30), in C cells of the thyroid gland (autoimmune thyroid disease) (31), in the testis (gonadal insufficiency) (32), and indeed also, to some extent, in the adrenal cortex (Addison’s disease) (33)]. Whether AADC is expressed in the parathyroid glands is not known. Thus, autoantibodies against AADC, which has a relatively wide tissue distribution, can be expected to be involved in an autoimmune process affecting many organs, such as in APS I.

In conclusion, the finding of high titers of autoantibodies against AADC in a subgroup of patients with Addison’s disease, without any previously described mutations in the AIRE gene typical of APS I, emphasizes the importance of AADC as an autoantigen in Addison’s disease, in addition to 21OH. The presence of AADC autoantibodies identifies patients with APS I and a subgroup of Addison patients, which may have a milder atypical form of APS I or perhaps represent a distinct entity.

	Acknowledgments

 
We are greatly indebted to the members of the Norwegian Addison Society for participating in this study.

	Footnotes

 
¹ This study was supported by grants from the Swedish Medical Research Council, the Torsten and Ragnar Söderberg Fund, the Lars Johan Hierta Fund, the Bergwall Fund, the Åke Wiberg Foundation, the Ernfors Family Fund, the Norwegian Diabetes Association, Novartis, the Aagot Giertsen Fund, and the Tore Nilson Fund.

Received July 9, 1999.

Revised August 23, 1999.

Accepted September 20, 1999.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Söderbergh, A. Articles by Husebye, E. S. Search for Related Content PubMed PubMed Citation Articles by Söderbergh, A. Articles by Husebye, E. S.