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Identification of an Immunodominant Region Recognized by Human Autoantibodies in a Three-Dimensional Model of Thyroid Peroxidase¹

The Randall Centre and Guy’s, King’s and St. Thomas’ School of Medicine (A.M.M., J.P.B.), King’s College London, London, United Kingdom SE1 1UL; and Medical Centre of Postgraduate Education (A.G.) and Department of Medical Informatics, Warsaw University Medical School (R.R.), 99 01-813 Warsaw, Poland

Address all correspondence and requests for reprints to: Dr. B. J. Sutton, The Randall Centre, King’s College London, New Hunt’s House, Guy’s Campus, London Bridge, London, United Kingdom SE1 1UL. E-mail: brian.sutton{at}kcl.ac.uk

Autoimmune thyroid diseases (AITD) are characterized by the presence of autoantibodies to thyroid peroxidase (TPO). This response is dominated by autoantibodies to two conformational determinants, termed A and B, that have been defined by monoclonal antibodies but whose structures and location within TPO are unknown. We have modeled the three-dimensional structure of the extracellular region of TPO, raised antisera to prominent surface structures, and identified an epitope that we show to be a critical part of the B determinant. Antibodies to this epitope inhibit the binding to TPO of human autoantibodies in virtually all serum samples from 65 patients with AITD that were tested. This first description of a model of the three-dimensional structure and location of a major autoantigenic determinant within the TPO molecule may provide structural clues for identifying causative agents or developing novel therapeutic strategies.

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