Pituitary autoantibodies in autoimmune polyendocrine syndrome type 1

doi:10.1073/pnas.0610070104

Pituitary autoantibodies in autoimmune polyendocrine syndrome type 1

*Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, 171 76 Stockholm, Sweden;
^‡Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden;
^¶Hospital for Children and Adolescents, Helsinki University Hospital, 00029, Helsinki, Finland;
^‖Department of Women's and Children's Health, Uppsala University, 751 85 Uppsala, Sweden;
**Institute of Medicine, University of Bergen, and Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway;
^††Department of Medical Sciences, Uppsala University, 751 85 Uppsala, Sweden; and
^‡‡Department of Paediatric Endocrinology, The John Hunter Children's Hospital, Newcastle, New South Wales 2310, Australia

Contributed by Tomas Hökfelt, November 14, 2006 (received for review October 5, 2005)

Abstract

Autoimmune polyendocrine syndrome type 1 (APS1) is a rare autosomal recessive disorder caused by mutations in the autoimmune regulator (AIRE) gene. High titer autoantibodies (Aabs) toward intracellular enzymes are a hallmark for APS1 and serve as diagnostic markers and predictors for disease manifestations. In this study, we aimed to identify pituitary autoantigens in patients with APS1. A pituitary cDNA expression library was screened with APS1 sera and a tudor domain containing protein 6 (TDRD6) cDNA clone was isolated. Positive immunoreactivity against in vitro translated TDRD6 fragments was shown in 42/86 (49%) APS1 patients but not in patients with other autoimmune diseases or in healthy controls. By using immunohistochemistry, sera from 3/6 APS1 patients with growth hormone (GH) deficiency showed immunostaining of a small number of guinea pig anterior pituitary cells, and 40–50% of these cells were GH-positive. No such immunostaining was seen with sera from healthy controls. The APS1 Aab-positive, GH-negative cells may represent a novel subpopulation of anterior pituitary cells. In addition, 4/6 patient sera showed staining of a fiber-plexus in the pituitary intermediate lobe recognizing enzymes of monoamine and GABA synthesis. Thus, we have identified TDRD6 as a major autoantigen in APS1 patients and shown that several sera from GH-deficient patients stain specific cell populations and nerves in the pituitary gland.

Footnotes

^†To whom correspondence may be addressed. E-mail: sophie.bensing{at}ki.se or tomas.hokfelt{at}ki.se
↵ ^§Present address: Groupe Appareil Digestif Environnement Nutrition (ADEN), Faculté de Médecine-Pharmacie, 22 Boulevard Gambetta, 761 83 Rouen Cedex 1, France.
Author contributions: S.B., S.O.F., T.H., A.-L.H., and O.K. designed research; S.B. and S.O.F. performed research; J.P., J.G., E.S.H., P.A.C., and O.K. contributed new reagents/analytic tools; S.B., S.O.F., J.M., M.O., O.E., T.H., and O.K. analyzed data; and S.B., S.O.F., T.H., and O.K. wrote the paper.
The authors declare no conflict of interest.
Data deposition: The TDRD6 mRNA reference sequence reported in this paper has been deposited in the GenBank database (accession no. EF 185284).
This article contains supporting information online at www.pnas.org/cgi/content/full/0610070104/DC1.
↵ §§ Zamboni L, De Martino C (1967) J Cell Biol 35:148A (abstr).
Abbreviations:

Aab,

autoantibody;

AADC,

aromatic-l-amino acid decarboxylase;

APS1,

autoimmune polyendocrine syndrome type 1;

GAD,

glutamic acid decarboxylase;

GH,

growth hormone;

ITT,

in vitro transcription and translation;

TDRD6,

tudor domain containing protein 6;

TH,

tyrosine hydroxylase;

TPH,

tryptophan hydroxylase.