Acta endocrinologica. Supplementum最新文献

An association exists between certain MHC polymorphisms and autoimmune thyroid disease in animals and humans. The observation of MHC class II antigen expression by the thyroid suggests that such associations may have mechanistic explanations at the level of the thyroid cell. Such class II antigen expression, rather than being a constitutive property of thyroid epithelium, appears to be primarily mediated by lymphokine secretion from intrathyroidal T lymphocytes and a variety of agents, for example TSh and TSH receptor antibodies, may amplify such lymphokine action. Thyroid cell class II antigens participate in activation and amplification of T cells and are involved in presentation of thyroid antigen to the immune system. The relationship between these local immune interactions and the initial events leading to the development of autoimmune thyroid disease requires a more fundamental understanding of the workings of the immune system at the site of antigenic stimulation.

An autoantibody to orbital antigens is found in patients with Graves' ophthalmopathy. This autoantibody also binds to skeletal muscle antigen. Occasional positive responses have been seen in patients with Hashimoto's disease and with non-organ-specific autoimmune disease. Eye muscle has a higher innervation ratio than skeletal muscle and may be of different embryological origin, but it is nevertheless closely related to skeletal muscle and it is perhaps not surprising that the antibody should interact with both these types of muscle. What remains quite unexplained, is why the disease process apparently affects eye muscle only. The antigen appears to be distinct from thyroidal antigens, but further work with a larger patient population is necessary before one can be certain of this. To date it has been possible to exclude the cytoskeletal proteins, myosin and actin, and also the TSH receptor as possible candidates for the responsible antigens. Further studies are in progress to elucidate the nature of this muscle antigen.

Purification of the thyrotropin (TSH) binding sites from cloned human thyroid cells (GEJ) was performed after biosynthetic labelling of the cells, affinity chromatography on a human TSH-sepharose column and polyacrylamide gel electrophoresis in sodium dodecyl sulphate (PAGE-SDS). The relative molecular mass (Mr) of the GEJ cell TSH receptor (TSH-R) was approximately 48,000. This was confirmed by cross-linking [125I]TSH to GEJ binding sites with two homobifunctional agents: dimethyl suberimidate and disuccinimidyl suberate. Moreover, the absence of a dithiothreitol effect demonstrated that the TSH binding site on GEJ cells is formed by a single chain lacking disulphide bonds.

In patients with Graves' hyperthyroidism, the relapse rate after antithyroid drug treatment is in the range of about 30-70%. Different attempts have been made to obtain criteria for the prediction of the clinical outcome after drug therapy, especially HLA-DR typing and measurement of TSH receptor antibodies. So far, very conflicting results have been reported. This is not surprising in view of the many genetically controlled and environmental factors that play a role in the pathogenesis of this disease. Moreover, most reports are based on retrospective studies with a relatively small number of patients. Our own data, obtained in a prospective multicenter study, yield strong evidence against the relevance of HLA-DR3 typing (n = 187, sensitivity = 0.38, specificity = 0.67) or measurement of TSH receptor antibodies at the end of therapy (n = 269, sensitivity = 0.49, specificity = 0.72) for the prediction of the clinical course after drug treatment.

Evidence has been accumulated that human thyroid microsomal/microvillar autoantigen (M) is expressed both in the cytoplasm and on the surface of thyroid follicular cells. The availability of this autoantigen to the immune system, possibly associated with abnormally expressed HLA-DR antigens may be relevant both to the triggering and to maintenance of thyroid autoimmune reactions. Preliminary biochemical characterization of M suggested that it was a glycoprotein with a mol. wt. of about 100-110 kD. recent studies carried out in our laboratories taking advantage of monoclonal antibodies provided evidence that the structure presently referred as M-Ag is represented by thyroid peroxidase (TPO). The identity between TPO and M is further supported by four-layer immunofluorescence analysis showing a complete overlap of the two antigens both in the surface and in the cytoplasm of thyroid cells and by the observation that the expression of M and TPO is similarly modulated by TSH, possibly through a cAMP-dependent mechanism.