Identification of an immunodominant region recognized by human autoantibodies in a three-dimensional model of thyroid peroxidase

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