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Autoantibodies against Aromatic L-Amino Acid Decarboxylase in Autoimmune Polyendocrine Syndrome Type I¹

Departments of Internal Medicine (E.S.H., G.G.-M., F.R., O.K.) and Pediatrics (J.G.), University Hospital, Uppsala University, S-751 85 Uppsala, Sweden; the Wallenberg Laboratory (T.T.) and Department of Endocrinology, University of Lund, S-205 02 Malmö General Hospital, Malmö, Sweden; the Children’s Hospital (J.P.), University of Helsinki, SF-00290 Helsinki, Finland; and the Department of Medicine (M.L.-O.), University Hospital, University of Lund, S-221 85 Lund, Sweden

Address all correspondence and requests for reprints to: Eystein S. Husebye, M.D., Ph.D., Department of Medicine, University Hospital, S-751 85 Uppsala, Sweden. E-mail: Eystein.Husebye{at}medicin.uu.se

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Patients with autoimmune polyendocrine syndrome type I (APS I) have autoantibodies against the enzyme aromatic L-amino acid decarboxylase (AADC) of pancreatic ß-cells. The aim of the present study was to investigate the presence of anti-AADC antibodies in a large cohort of patients with APS I, and in patients with isolated insulin-dependent diabetes mellitus (IDDM). We found autoantibodies against AADC in 35 of 69 patients (51%) with APS I but in none of 138 patients with isolated IDDM or 91 healthy controls. Among the patients with APS I, anti-AADC antibodies were more often found in those with hepatitis (11/12, 92%), than in those without hepatitis (24/57, 42%) (P = 0.003). Similarly, of 15 patients with vitiligo, 12 (80%) had anti-AADC antibodies, compared with 23/54 (43%) without vitiligo (P = 0.021). Of the 9 APS I patients with IDDM, 5 had antibodies against both AADC and glutamate decarboxylase, 2 against AADC only, and 2 against glutamate decarboxylase only. Interestingly, AADC is present in relatively large amounts in the liver, where its function is unknown. Thus, an autoimmune reactivity against AADC may be involved in the pathogenesis of autoimmune chronic active hepatitis and vitiligo in APS I patients, whereas the role of AADC in the development of IDDM in these patients remains to be determined.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
AUTOIMMUNE polyendocrine syndrome type I (APS I), also called autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, is an autosomal recessive disease characterized by organ-specific autoimmunity and ectodermal manifestations (1, 2). Mucocutaneous candidiasis, hypoparathyroidism, adrenocortical insufficiency, and gonadal failure (2) are classical components of APS I. Both cellular and humoral autoimmunity probably are involved in the pathogenesis of this disorder, and the underlying genetic defect, although unknown, has been been mapped to chromosome 21 (3). In the adrenal cortex and gonads, the cytochrome P450 side-chain cleavage enzyme (SCC) has been identified as the major target of autoantibodies (4, 5), whereas in patients with isolated adrenocortical insufficiency, the cytochrome P450 21-hydroxylase enzyme seems to be a major autoantigen (6). This latter enzyme is expressed only in the adrenal cortex. Thus, it seems that the tissue distribution of the autoantigens correlates with the clinical picture, which suggests that these are involved in the autoimmune process (7).

Autoimmune diabetes mellitus may occur as a component of APS I (1, 2, 8). In isolated insulin-dependent diabetes mellitus (IDDM) one of the major autoantigens in the insulin-producing ß-cells has been identified as glutamic acid decarboxylase (GAD) (9), an enzyme catalyzing the production of the inhibitory nerve transmitter -aminobutyric acid. Patients with APS I display reactivity against GAD (8, 10, 11) and against a 51-kDa autoantigen (9) recently identified as aromatic L-amino acid decarboxylase (AADC) (12). This enzyme participates in the generation of serotonin and dopamine (13). The function in ß-cell metabolism of the neurotransmitters produced by AADC and GAD is unknown. Besides the insulin-producing ß-cells and other cells capable of amine precursor uptake and decarboxylation, AADC is present in monoaminergic neurons of the peripheral and central nervous systems, the liver, and the kidney (14).

The aim of the present study was to investigate a large series of APS I patients for the presence of autoantibodies against AADC and to correlate these results with the presence of IDDM and other components of APS I. To accomplish this, an immunoprecipitation assay based on the in vitro transcribed and translated enzyme was established.

	Subjects and Methods

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Subjects

Sera were obtained from 62 Finnish (8) and 7 Swedish APS I patients. Nine of these had IDDM. From the patients with IDDM, samples were available before, at, and after the diagnosis of IDDM. Sera were obtained from 118 patients with isolated IDDM with onset before the age of 35, identified from the Swedish registry on type 1 diabetes (15). Sera from 20 patients with IDDM with onset beyond the age of 35 were obtained from the Department of Medicine, University Hospital, Helsinki, Finland. Sera from 91 healthy Swedish blood donors were used as controls.

Assay of antibodies against AADC

The full-length rat complementary DNA (cDNA) clone for AADC was isolated by immunoscreening of a ZAP cDNA library from the rat insulinoma cell line RIN m5F (12). After in vitro excision of Bluescript containing the AADC cDNA clone (12), in vitro transcription and translation were performed using the TNT T3 coupled reticulocyte lysate system (Promega, Madison, WI). [³⁵S]-radiolabeled AADC was used for immunoprecipitation of patient sera as described below.

Microtiter plates (96 wells) with filter bottoms (MABV N12, Millipore, Bedford, MA) were used for immunoprecipitation experiments. Each well was preincubated with 200 µL of a buffer containing 150 mmol/L NaCl, 20 mmol/L Tris-HCl, and 0.02% NaN₃, pH 8.0 (buffer A), for 1 h. Buffer A was discarded then, and the wells were coated with 1% (wt/vol) BSA (Sigma, St. Louis, MO) in buffer A for 2 h and subsequently washed twice with 0.05% (vol/vol) Tween-20 in buffer A. Finally, the wells were washed once with 0.1% (wt/vol) BSA and 0.15% (vol/vol) Tween-20 in buffer A (buffer B).

AADC (5 x 10⁵ to 1 x 10⁶ cpm per well) and patient serum (1:10 dilution) were mixed in buffer B in a total vol of 50 µL, followed by incubation overnight at 4 C. The next day, the mixtures of sera and AADC were transferred to the wells, and 50 µL of a 50% (vol/vol) slurry of protein A-Sepharose (Pharmacia, Stockholm, Sweden) in buffer B was added to each sample. Then the plate was shaken on a rotating platform for 45 min at 4 C. Subsequently, the wells were washed three times using a vacuum manifold. After drying, each filter was transferred to a scintillation vial using plastic punch tips, and scintillation fluid was added. The vials were counted, and the results were expressed as an AADC index ( cpm sample - cpm_{negative control}/cpm_{positive control} - cpm_{negative control}) x 1000). Samples were analyzed in duplicate, whereas the positive control (an APS I patient) and the negative control (buffer B alone) were run in triplicate. An AADC index of 200 was chosen as the upper normal limit because this value divided the cohort of APS I patients into those with clearly elevated indices and those with normal and slightly elevated indices relative to the healthy controls (32 ± 49, mean ± 2 SD) (see Fig. 2). The intraassay and interassay coefficients of variation were 4% and 13%, respectively.

View larger version (17K): [in this window] [in a new window]   Figure 2. Autoantibodies against L-amino acid decarboxylase in patients with APS I, isolated IDDM, and in control subjects. Immunoprecipitations and calculations of indices were performed as described in Subjects and Methods. The horizontal line indicates the upper normal limit, AADC index 200.

Immunoprecipitation of lysates from COS cells transfected with AADC and from isolated rat islets of Langerhans, and separation of immunoprecipitates by SDS-PAGE, were performed as described previously (12, 16).

Statistics

The two-sided Fisher’s exact test was used to assess differences in proportions between groups.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In vitro transcription and translation of AADC

In a typical experiment, about 5% of the [³⁵S]-methionine became incorporated into the AADC protein. When the product was analyzed by SDS-PAGE, a major band (with an apparent molecular mass of 51 kDa) and two additional bands (with slightly higher molecular mass values) were observed (Fig. 1). The major band, comigrated with the band generated by AADC, transfected into COS cells (not shown). All three bands were immunoprecipitated by the specific rabbit anti-AADC antibody and by sera from APS I patients known to contain antibodies against AADC (Fig. 1).

View larger version (67K): [in this window] [in a new window]   Figure 1. SDS-PAGE analysis of AADC synthesized by in vitro ITT followed by immunoprecipitations with a specific rabbit anti-AADC antibody and patient sera. Lane a, the ITT product before immunoprecipitation; lane b, immunoprecipitations with rabbit polyclonal antiserum against AADC (Biogenesis, Poole, Dorset, UK); lanes c and d, patients with APS I; lanes e and f, healthy blood donors. Molecular mass markers are shown on the right.

Of the 69 patients with APS I, 35 (51%) had anti-AADC antibodies with an AADC index above 200 (Table 1, Fig. 2). Most of these patients had high indices in a range similar to that of the positive control serum, which was also obtained from an APS I patient. There was no significant difference between females (21/36, 58%) and males (14/33, 42%). Twelve (17%) of the APS I patients had elevated levels of serum alanine aminotransferase (ALAT), and in 8 of these, a diagnosis of chronic active hepatitis was verified by biopsy (Table 1). Of the 12 patients with elevated ALAT levels, 11 (92%) had anti-AADC antibodies, in contrast to 24/57 (42%) with normal ALAT values (P = 0.003). None of the 8 patients with autoimmune chronic active hepatitis (AI-CAH), 7 (88%) had anti-AADC antibodies. The one without anti-AADC antibodies had had normal serum ALAT levels during the 3.3 yr immediately preceding this study.

As AADC initially was identified as an autoantigen in the pancreatic ß-cells, it was of particular interest to see whether there was any correlation between anti-AADC and IDDM. Of the 9 APS I patients with IDDM, 5 displayed both anti-GAD and anti-AADC antibodies, whereas 2 were positive only for anti-GAD and 2 were positive only for anti-AADC. No consistent pattern of AADC indices was found whether samples were collected before, at, or after the start of IDDM. Furthermore, none of the 138 patients with isolated IDDM had anti-AADC antibodies (Fig. 2).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Since our initial observation of anti-AADC antibodies in six patients with APS I (12), we have now investigated a large cohort of patients with this syndrome using an immunoprecipitation technique based on in vitro transcribed and translated (ITT) protein. This technique offers a fast and specific means of analyzing autoantibodies in sera of a large number of individuals. Similar techniques recently have been established for other autoantigens, e.g. GAD (17) and 21-hydroxylase (18). The ITT product contained a major band with an apparent molecular mass of 51 kDa and two minor bands with slightly higher molecular mass (Fig. 1). All three were precipitated by sera known to contain anti-AADC antibodies, indicating that they contain AADC. Phosphorylation of a small proportion of the AADC by protein kinases in the reticulocyte lysate may explain the altered electrophoretic mobility of the two minor bands (19).

We found autoantibodies against AADC in 35 (51%) of 69 patients with APS I but in none of the patients with isolated IDDM or in healthy controls. Together with antibodies against SCC (4, 5), anti-AADC antibodies seem to be major serological markers for this condition. The presence of anti-AADC antibodies was found more often in the APS I patients with AI-CAH and vitiligo. This may indicate that an autoimmune reaction against AADC is involved in the pathogenesis of AI-CAH and vitiligo in these patients. Even if a high proportion of the patients had autoantibodies against AADC without signs of AI-CAH and vitiligo, a subclinical autoimmune reactivity against the liver and skin may still occur. This presumption is supported by the finding that APS I patients without IDDM, but with autoantibodies against GAD, show reduced C peptide levels and insulin responses, indicating a subclinical autoimmune reactivity against ß-cells (8).

The liver is one of the organs outside the central nervous system with the highest levels of AADC (13, 14). Enzyme activity is found in the cytosol, the subcellular fraction that is usually used to purify the enzyme (13, 20). Even though the function of AADC as a biosynthetic enzyme in the synthesis of catecholamines and indolamines is well established, its function in liver metabolism remains elusive. AADC has not been reported to be present in the skin, but tyrosinase, the rate-limiting enzyme in the biosynthesis of melanin, catalyzes a reaction similar to that catalyzed by AADC, i.e. the conversion of dopa to dopaquinone. Furthermore, evidence has been presented indicating that tyrosinase is the major autoantigen in vitiligo (21). Whether there is a cross-reactivity between autoantibodies against AADC and tyrosinase remains to be seen.

The presence of anti-AADC antibodies did not correlate significantly with the presence of IDDM in the APS I patients. However, the possibility of a pathogenetic role of AADC cannot be totally ruled out on the basis of this study because only 9 of 69 patients with APS I had IDDM. It will be of interest to see whether a higher frequency of anti-AADC positive patients than of patients without these antibodies develop IDDM. In isolated IDDM, however, anti-AADC antibodies do not seem to be involved as a pathogenetic factor.

	Acknowledgments

 
We are grateful to Professor Stein Emil Vollset for help with the statistical analyses.

	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, and the Ernfors Family Fund.

Received June 4, 1996.

Revised August 7, 1996.

Accepted August 21, 1996.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Neufeld M, Maclaren N, Blizzard R. 1980 Autoimmune polyglandular syndromes. Pediatr Ann. 9:154–162.[Medline]
2. Ahonen P, Myllärniemi S, Sipilä I, Perheentupa J. 1990 Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients. N Engl J Med. 322:1829–1836.[Abstract]
3. Aaltonen J, Björses P, Sandkuijl L, Perheentupa J, Peltonen L. 1994 An autosomal locus causing autoimmune disease: autoimmune polyglandular disease type I assigned to chromosome 21. Nat Genet. 8:83–88.[CrossRef][Medline]
4. Winqvist O, Gustafsson J, Rorsman F, Karlsson FA, Kämpe O. 1993 Two different cytochrome P450 enzymes are the adrenal antigens in autoimmune polyendocrine syndrome type I and Addison’s disease. J Clin Invest. 92:2377–2385.
5. Uibo R, Aavik E, Peterson P, et al. 1994 Autoantibodies to cytochrome P450 enzymes P450scc, P450c17, and P450c21 in autoimmune polyglandular disease types I and II and in isolated Addison’s disease. J Clin Endocrinol Metab. 78:323–328.[Abstract]
6. Winqvist O, Karlsson FA, Kämpe O. 1992 21-hydroxylase, a major autoantigen in idiopathic Addison’s disease. Lancet. 339:1559–1562.[CrossRef][Medline]
7. Banga JP, McGregor AM. 1991 Enzymes as targets for autoantibodies in human autoimmune disease: relevance to pathogenesis. Autoimmunity. 9:177–182.[Medline]
8. Tuomi T, Björses P, Falorni A, et al. 1996 Antibodies to glutamic acid decarboxylase and insulin-dependent diabetes mellitus in patients with autoimmune polyendocrine syndrome type I. J Clin Endocrinol Metab. 81:1488–1494.[Abstract]
9. Bækkeskov S, Aanstoot H-J, Christgau S, et al. 1990 Identification of the 64K autoantigen in IDDM as the GABA synthesizing enzyme glutamic acid decarboxylase. Nature. 347:151–156.[CrossRef][Medline]
10. Velloso LA, Winqvist O, Gustafsson J, Kämpe O, Karlsson, FA. 1994 Autoantibodies against a novel 51 kDa islet antigen and glutamate decarboxylase isoforms in autoimmune polyendocrine syndrome type I. Diabetologia. 37:61–69.[Medline]
11. Björk E, Velloso LA, Kämpe O, Karlsson FA. 1994 GAD autoantibodies in IDDM, stiff-man syndrome, and autoimmune polyendocrine syndrome type I recognize different epitopes. Diabetes. 43:161–165.[Abstract]
12. Rorsman F, Husebye ES, Winqvist O, Björk E, Karlsson FA, Kämpe O. 1995 Aromatic L-amino acid decarboxylase, a pyridoxalphosphate-dependent enzyme, is a ß-cell autoantigen. Proc Natl Acad Sci USA. 92:8626–8629.[Abstract/Free Full Text]
13. Christenson JG, Dairman W, Udenfriend S. 1972 On the identity of DOPA decarboxylase and 5-hydroxytryptophan decarboxylase. Proc Natl Acad Sci USA. 69:343–347.[Abstract/Free Full Text]
14. Rahman MK, Nagatsu T, Kato T. 1981 Aromatic l-amino acid decarboxylase activity in central and peripheral tissues and serum of rats with lDOPA and l5-hydroxytryptophan as substrates. Biochem Pharmacol. 30:645–649.[CrossRef][Medline]
15. Landin-Olsson M, Karlsson FA, Lernmark A, Sundkvist G. 1992 Islet cell and thyrogastric antibodies in 633 consecutive 15- to 34-yr-old patients in the diabetes incidence study in Sweden. Diabetes. 41:1022–1027.[Abstract]
16. Kämpe O, Andersson A, Björk E, Hallberg A, Karlsson FA. 1989 High-glucose stimulation of 64,000-M_r islet cell antigen expression. Diabetes. 38:1326–1328.[Abstract]
17. Grubin CE, Daniels T, Toivola B, et al. 1994 A novel radioligand binding assay to determine diagnostic accuracy of isoform-specific glutamic acid decarboxylase antibodies in childhood IDDM. Diabetologia. 37:344–350.[Medline]
18. Falorni A, Nikoshkov A, Laureti S, et al. 1995 High diagnostic accuracy for idiopathic Addison’s disease with a sensitive radiobinding assay for autoantibodies against recombinant human 21-hydroxylase. J Clin Endocrinol Metab. 80:2752–2755.[Abstract]
19. Døskeland AP, Martinez A, Knappskog PM, Flatmark T. 1996 Phosphorylation of recombinant human phenylalanine hydroxylase: effect on catalytic activity, substrate activation and protection against non-specific cleavage of the fusion protein by restriction protease. Biochem J. 313:409–414.
20. Dominici P, Tancini B, Barra D, Voltattori CB. 1989 Purification and characterization of rat liver 3,4-dihydroxyphenylalanine decarboxylase. Eur J Biochem. 169:209–213.[Medline]
21. Song Y-H, Conner E, Li Y, Zorovich B, Balducci P, Maclaren N. 1994 The role of tyrosinase in autoimmune vitiligo. Lancet. 344:1049–1052.[CrossRef][Medline]

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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 Husebye, E. S. Articles by Kämpe, O. Search for Related Content PubMed PubMed Citation Articles by Husebye, E. S. Articles by Kämpe, O.