Each year, the American Thyroid Association (ATA) recognizes the outstanding research contributions of one of its members to a greater understanding of thyroid physiology or the pathophysiology of thyroid disease, with its presentation of the John B. Stanbury Pathophysiology Medal at its Annual Meeting. During the Annual Banquet, held tonight as part of its 81st Annual Meeting, the ATA will bestow the 2011 John B. Stanbury Pathophysiology Medal to Basil Rapoport, MB, ChB, Professor and Director of the Autoimmune Disease Unit at Cedars-Sinai Medical Center, in Los Angeles, California, and Professor of Medicine in residence at University of California - Los Angeles. The award recognizes the impact that Dr. Rapoport's research has had on research and clinical practice related to thyroid disease.
Dr. Rapoport has devoted more than 40 years to the study of thyroid pathophysiology, and his laboratory has carried out molecular cloning of thyroid peroxidase and thyroid stimulating hormone receptor (TSHR), the main autoantigens involved in autoimmune thyroid disease. He has cloned, expressed, and characterized the immunoglobulin genes that code for the repertoire of human thyroid peroxidase autoantibodies, and these have proven to be invaluable tools for the discovery that epitopic recognition of thyroid peroxidase autoantibodies within an innumodominant region of the enzyme is inherited. Dr. Rapoport's work on TSHR has provided novel insights into the protein's structure and function and has demonstrated that the receptor undergoes intramolecular cleavage and contains two cleavage site regions. He also helped overcome a hurdle in the ability to generate conformationally intact recombinant TSHR protein that is secreted by transfected cells. This led to the ability to produce sufficient amounts of protein for crystallization studies of the TSHR leucine-rich repeat domain, which forms the major component of the A-subunit.
The availability of large quantities of recombinant A-subunits contributed to several discoveries in the field, including that the free A-subunit is the primary autoantigen in Graves' disease, and that genetic immunization with adenovirus vectors expressing the A-subunit greatly improves the induced mouse model of Graves' hyperthyroidism, a modification that is now widely used. The development of this highly effective animal model of Graves' disease contributed to a number of novel observations, including the role of regulatory T-cells in disease development, the ability of pretreatment with A-subunit to attenuate the development of induced hyperthyroidism, and the localization of genes that influence susceptibility or resistance to induced Graves' disease.
Dr. Rapoport's laboratory generated the first TSHR monoclonal antibody with inverse agonist activity. The discovery of an antibody inverse agonist offers the potential to silence TSHR constitutive activity in metastases of well-differentiated thyroid carcinomas, which cannot be achieved with the suppression of thyroid stimulating hormone or the use of thyroid stimulating hormone blocking antibodies.
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