Endocrine Abstracts

Background: Autoimmune polyendocrine syndrome type 1 (APS1) is a disorder caused by mutations of the autoimmune regulator (AIRE) gene, that controls central tolerance. Tetrahydrobiopterin (BH₄)-dependent hydroxylases, consisting of tryptophan hydroxylase (TPH1 and TPH2), tyrosine hydroxylase (TH) and phenylalanine hydroxylase (PAH) are commonly targeted autoantigens. Nevertheless, detailed characterization of their epitopes and independent roles of TPH isoforms has not been systematically studied. We aimed to localize the epitopes of these enzymes and explore the independent of TPH2 in APS1.

Materials and methods: We obtained sera from 51 APS1 patients. The chimeras were composed of N-PAH fused with the catalytic domain of the respective antigen. Recombinant antigens for wild-type enzymes, truncated fragments and chimera were utilized in RIA. The ethical clearance was granted by Health West Region, Norway.

Results: The prevalence of antibodies against wild-type enzymes was 65% (33/51) and for individual antigens were 24/51 (47%), 24/51 (47%) and 21/51 (41%), respectively for TPH1, TPH2 and TH. One patient reacted exclusively against TPH2. N-PAH did not show any immunogenicity. The N-TPH1 exhibited low reactivity (n=8, median 14%, range 2–43%) while its chimera preserved reactivity in most sera (n=8, median 52%, range 35–62%). The N-TPH2 displayed significant reactivity in a-half of the sera while others showed complete loss (n=10, median 57%, range 0–83%). The chimeric TPH2 appeared less immunogenic (n=10, median 28%, range 0–82%). The N-TH seemed more immunogenic (n=9, median 48%, range 0–55%) while TH chimera retained low reactivity (n=9, median 14%, range 10–45%).

Conclusion: Autoantibodies targeting BH₄-dependent hydroxylases are frequent in APS1 and TPH2 is a novel autoantigen in APS1.