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3ß Hydroxysteroid Dehydrogenase Autoantibodies in Patients with Idiopathic Premature Ovarian Failure Target N- and C-Terminal Epitopes

Department of Immunology (S.A., R.V.C., M.P.), Guy’s, King’s and St. Thomas’ School of Medicine, London, United Kingdom SE5 9NU; and the Division of Endocrinology (G.S.C.), Middlesex Hospital, London, United Kingdom W1N 8AA

Address all correspondence and requests for reprints to: Dr. Mark Peakman, Department Immunology, Guy’s, King’s & St. Thomas’ School of Medicine, Rayne Institute, 123 Coldharbour Lane, London, United Kingdom SE5 9NU. E-mail: mark.peakman{at}kcl.ac.uk

Abstract

The steroid cell enzyme 3ß hydroxysteroid dehydrogenase (3ß HSD) has been identified as a target of steroid cell autoantibodies, and autoantibodies to this enzyme are present in patients with premature ovarian failure and patients with autoimmune polyendocrine syndrome 1.

The aim of the present study was to develop a radioligand binding assay for 3ß HSD autoantibodies and to exploit this to examine regions of the molecule targeted by autoantibodies. We generated a construct of 3ß HSD coupled to a luciferase fusion partner in order to maximize the yield of ³⁵S-radiolabeled protein. Labeled 3ß HSD was then immunoprecipitated and the autoantibodies quantified by phosphoimaging. Autoantibodies to 3ß HSD were detected in 12 of 100 (12%) idiopathic premature ovarian failure patients and 0 of 103 (0%) healthy age-matched controls (P < 0.0001). Three overlapping fragments of 3ß HSD cDNA were cloned downstream of luciferase to examine autoantibody binding sites. Two of nine sera with 3ß HSD autoantibodies (22%) displayed reactivity to the N terminus of 3ß HSD, and seven (77%) showed reactivity to the C terminal; no sera reacted with the middle region. Our study demonstrates a markedly enhanced disease specificity of autoantibodies to 3ß HSD detected using this novel assay and shows that distinct regions of the molecule are targeted.

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