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Autoantibodies Against Aromatic Amino Acid Hydroxylases in Patients with Autoimmune Polyendocrine Syndrome Type 1 Target Multiple Antigenic Determinants and Reveal Regulatory Regions Crucial for Enzymatic Activity.

Bratland, E., Magitta, N.'w. F., Bøe Wolff, A. S., Ekern, T., Knappskog, P. M., Kämpe, O., Haavik, J. and Husebye, E. S. (2013) Autoantibodies Against Aromatic Amino Acid Hydroxylases in Patients with Autoimmune Polyendocrine Syndrome Type 1 Target Multiple Antigenic Determinants and Reveal Regulatory Regions Crucial for Enzymatic Activity. Immunobiology, 218. pp. 899-909. ISSN 1878-3279

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Abstract

Patients with autoimmune polyendocrine syndrome type 1 (APS-1) frequently have autoantibodies directed against the aromatic amino acid hydroxylases tryptophan hydroxylase (TPH) and tyrosine hydroxylase (TH). We aimed to characterize these autoantibodies with regard to their antigenic determinants, their influence on enzymatic activity and their clinical associations. In particular, we wanted to compare autoantibodies against the two different isoforms of TPH, which display different tissue distribution. Using sera from 48 Scandinavian APS-1 patients we identified 36 patients (75%) with antibodies against one or more of these three enzymes. Antibodies against TPH1, but not TPH2, were associated with malabsorption in the whole Scandinavian cohort, while TH antibodies were associated with dental enamel hypoplasia in Norwegian patients. Subsequent experiments with selected patient sera indicated that while the C-terminal domain was the immunodominant part of TPH1, the epitopes of TPH2 and TH were mainly located in the N-terminal regulatory domains. We also identified a TPH1 specific epitope involved in antibody mediated inhibition of enzyme activity, a finding that provides new insight into the enzymatic mechanisms of the aromatic amino acid hydroxylases and knowledge about structural determinants of enzyme autoantigens. In conclusion, TPH1, TPH2 and TH all have unique antigenic properties in spite of their structural similarity.

Item Type: Article
Keywords: Aire, Autoimmune polyendocrine syndrome type 1, Aromatic amino acid hydroxylases, Tryptophan hydroxylase, Tyrosine hydroxylase
Subjects: Biomedical Science > Immunology
Biomedical Science > Molecular biology
Divisions: Muhimbili University of Health and Allied Sciences (MUHAS)
Depositing User: Mr Joseph Madata
Date Deposited: 23 Apr 2013 07:05
Last Modified: 23 Apr 2013 07:05
URI: http://ihi.eprints.org/id/eprint/1326

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