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Mapping of Human Autoantibody Epitopes on Aromatic L-Amino Acid Decarboxylase

Department of Internal Medicine (P.C., S.L., F.S., A.F.), Section of Internal Medicine and Endocrine and Metabolic Sciences, University of Perugia, 06126 Perugia, Italy; Department of Morphological and Biochemical Sciences (C.B.V., M.B.), University of Verona, 37134 Verona, Italy; Pediatrics Unit (R.P.), Regional Hospital "Vito Fazzi", 73100 Lecce, Italy; Department of Medical and Surgical Sciences (C.B.), University of Padova, 35131 Padova, Italy; Department of Clinical Pathophysiology (M.M.), Section of Endocrinology, University of Florence, 50139 Florence, Italy; Division of Endocrinology and Metabolism (R.G.), Department of Internal Medicine, University of Turin, 10126 Turin, Italy; Department of Clinical and Experimental Medicine and Surgery "F. Magrassi, A. Lanzara" (A.D.B.), Second University of Naples, 80131 Naples, Italy; and Department of Clinical Sciences (C.T.), University of Rome "La Sapienza", 00161 Rome, Italy

Address all correspondence and requests for reprints to: Alberto Falorni, M.D., Ph.D., Department of Internal Medicine, Section of Internal Medicine and Endocrine and Metabolic Sciences, Via E. Dal Pozzo, 06126 Perugia, Italy. E-mail: falorni{at}dimisem.med.unipg.it.

Context: Aromatic L-amino acid decarboxylase (AADC) is target of autoantibodies in autoimmune polyendocrine syndrome I (APS I), especially in patients with autoimmune hepatitis. Little information is currently available on AADC autoantibody epitopes and on the interrelation between autoantibody-mediated inhibition of enzymatic activity and epitope specificity.

Design: We tested the immunoreactivity of full-length porcine AADC and of eight fragments of the enzyme with human serum from 18 patients with APS I, 199 with non-APS I autoimmune Addison’s disease, 124 with type 1 diabetes mellitus, 36 with Graves’ disease, and 141 healthy control subjects, and we evaluated the autoantibody-mediated enzymatic inhibition.

Results: AADC antibodies (Ab) were detected in 12 of 18 (67%) APS I patients and in six of 199 (3%) autoimmune Addison’s disease patients. Four patients with autoimmune hepatitis were all positive for AADCAb. None of the 141 healthy control subjects, 82 patients with nonautoimmune adrenal insufficiency, 124 with type 1 diabetes mellitus, and 36 with Graves’ disease were found positive. Two epitope regions, corresponding to amino acids 274–299 (E1) and 380–471 (E2) were identified. Localization of E1 was confirmed by displacement studies with synthetic peptides corresponding to peptides of porcine AADC. All 12 AADCAb-positive APS I sera reacted with E1, and seven of 12 (58%) reacted also with E2. E2-specific, but not E1-specific, autoantibodies were associated with a significant inhibition of in vitro AADC enzymatic activity.

Conclusions: We mapped the human AADCAb epitopes to the middle and COOH-terminal regions of the enzyme. Autoantibodies to the COOH-terminal region induce a significant inhibition of enzymatic activity.