title: 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.
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.
authors.affiliation: Section for Endocrinology, Department of Medicine, Haukeland University Hospital, N-5021 Bergen, Norway. eirik.bratland@med.uib.no
authors.forename: Eirik
authors.initials: E
authors.lastname: Bratland
authors.forename: Ng'weina Francis
authors.initials: NF
authors.lastname: Magitta
authors.forename: Anette Susanne
authors.initials: AS
authors.lastname: Bøe Wolff
authors.forename: Trude
authors.initials: T
authors.lastname: Ekern
authors.forename: Per Morten
authors.initials: PM
authors.lastname: Knappskog
authors.forename: Olle
authors.initials: O
authors.lastname: Kämpe
authors.forename: Jan
authors.initials: J
authors.lastname: Haavik
authors.forename: Eystein Sverre
authors.initials: ES
authors.lastname: Husebye
mesh_terms: D000595:Amino Acid Sequence; D000918:Antibody Specificity / Q000276:immunology; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D001665:Binding Sites / Q000235:genetics / Q000276:immunology; D055162:Biocatalysis; D015331:Cohort Studies; D003718:Denmark; D000939:Epitopes / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D005387:Finland; D006801:Humans; D015151:Immunoblotting; D007527:Isoenzymes / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009664:Norway; D016884:Polyendocrinopathies, Autoimmune / Q000097:blood / Q000201:enzymology / Q000276:immunology*; D017434:Protein Structure, Tertiary; D013548:Sweden; D014365:Tryptophan Hydroxylase / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D000939:Epitopes; D007527:Isoenzymes; D014446:Tyrosine 3-Monooxygenase; C497467:TPH1 protein, human; C494784:TPH2 protein, human; D014365:Tryptophan Hydroxylase