Identification of endothelin-converting enzyme-2 as an autoantigen in autoimmune polyendocrine syndrome type 1

Abstract

Autoimmune polyendocrine syndrome type 1 (APS1) is a rare monogenic autoimmune disorder caused by mutations in the autoimmune regulator (AIRE) gene. High titer autoantibodies are a characteristic feature of APS1 and are often associated with particular disease manifestations. Pituitary deficits are reported in up to 7% of all APS1 patients, with immunoreactivity to pituitary tissue frequently reported. We aimed to isolate and identify specific pituitary autoantigens in patients with APS1. Immunoscreening of a pituitary cDNA expression library identified endothelin-converting enzyme (ECE)-2 as a potential candidate autoantigen. Immunoreactivity against ECE-2 was detected in 46% APS1 patient sera, with no immunoreactivity detectable in patients with other autoimmune disorders or healthy controls. Quantitative-PCR showed ECE-2 mRNA to be most abundantly expressed in the pancreas with high levels also in the pituitary and brain. In the pancreas ECE-2 was co-expressed with insulin or somatostatin, but not glucagon and was widely expressed in GH producing cells in the guinea pig pituitary. The correlation between immunoreactivity against ECE-2 and the major recognized clinical phenotypes of APS1 including hypopituitarism was not apparent. Our results identify ECE-2 as a specific autoantigen in APS1 with a restricted neuroendocrine distribution.

Keywords:

• APS1
• endothelin-converting enzyme-2
• ECE-2
• pituitary autoantibodies
• pancreas

Acknowledgements

We are grateful to Professors Olle Korsgren and Göran Åkerström for the provision and cell preparations of human pancreatic fractions. Professor Mats Ulfvendahl, Center for Hearing and Communication Research and Department of Clinical Neuroscience, Karolinska Institutet, for support. We thank Åsa Hallgren and Blanca Silva-Lopez for excellent technical advice. We are grateful to Professor Björn Meister for the donation of antibodies raised against insulin and glucagon. We also thank the APS1 patients and their families for their participation and ongoing support.

Disclosure statement

The authors report no conflicts of interest.

Additional information

Funding

 This work was supported by grants from National Health and Medical Research Council (NHMRC) [Grant 100952] and PhD scholarship to CJAS. The regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet, Lisa and Johan Grönberg Foundation, Tore Nilsson Foundation for Medical Research, the Swedish Society for Medical Research and Karolinska Institutet to SB. Agnes and Mac Rudbergs Foundation and Lennanders Fund supported MA. The Hunter Children’s Research Foundation, The John Hunter Charitable Trust and HMRI (Hunter Medical Research Institute) supported PAC. EU FP6 Program on rare diseases, project entitled EurAPS, EU FP7 [Grant number 201167], Euradrenal and the Swedish Research Council to OK and the Swedish Research Council supported TH.