The pathogenesis Graves' disease, an autoimmune disorder, is not fully understood. Immune disturbances, genetic predisposition and environmental factors, affecting thyroid gland, appear to play the main role in contribution and development of the disease. Autoreactive T lymphocyte infiltrates in the thyroid gland and/or in the retroorbital tissues and autoantibodies to TSH receptor detected in almost all of the patients, have been considered to be responsible for hyperthyroidism, ophtalmopathy, pretibial dermopathy and goiter. In this review, we describe some recent reports on the pathophysiological and immunological aspects of the thyroidal and extrathyroidal manifestations of the Graves' disease.
Graves' disease (GD) is an autoimmune disease believed to be caused by a combination of environmental and genetic factors. The gene encoding cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is one of the candidate genes for conferring susceptibility to thyroid autoimmunity. The aim of the study was to investigate the association between the exon 1 CTLA-4 gene polymorphism A(49)G and susceptibility to GD and Graves' ophthalmopathy (GO) as well as its severity in a Polish population of the Lower Silesia region. We analyzed the A(49)G exon 1 CTLA-4 gene polymorphism in 99 unrelated Polish patients with GD, of whom 50 had clinically evident GO (NOSPECS class III and higher), and 154 matched healthy subjects from the Lower Silesia region. Genomic DNA was isolated from whole frozen blood using the NucleoSpinR Blood kit. A/G transition was genotyped by polymerase chain reaction followed by labeling with the SnaPshot kit of PE Applied Biosystems and detected using an ABI PRISM 310 capillary genetic analyzer. The distribution of CTLA-4 exon 1 A(49)G genotype, allele, and phenotypic frequencies did not differ between patients with GD and healthy subjects. There was a significantly lower frequency of the AA genotype in the group of patients with clinically evident GO than in patients without severe GO (22% vs. 43%; p=0.02, OR=2.6). Our results showed that the AA genotype in patients with GD is associated with a lower risk of GO severity.
There is an increasing evidence that CD3+ cells, bearing gamma delta T cell receptors representing a minor subpopulation of T cells in the peripheral blood of humans are involved in the development of autoimmunity. The aim of the present study was determination of the gamma delta T cell subpopulation levels in the peripheral blood of subjects with Graves' disease and newly diagnosed type 1 diabetes in comparison to age-matched healthy controls. The percentages of CD3+, CD8+, gamma delta TCR+CD8+, gamma delta TCR+CD8? lymphocyte subsets were measured by flow cytometry. In the peripheral blood of newly diagnosed Graves' disease patients we showed a significant decrease of gamma delta TCR+ cells and gamma delta TCR+CD8? subset content in comparison to the percentages observed in subjects after methimazole treatment and in healthy controls. We also found a significant increase of TCR+CD8+ cells in the peripheral blood of subjects with insulin-dependent diabetes, treated with insulin for 3?6 months. The present findings confirm our previous hypothesis that gamma deltaTCR+CD8+ lymphocyte subset could play a role in the pathogenesis of diabetes type 1, probably as regulatory T cells and could be induced by delivery of exogenous insulin. Our results suggest that gamma deltaT cells (gamma delta TCR+CD8? subset) could also play an important role in the development of Graves' disease and that their levels are modulated by thyreostatic treatment.
Increased metabolism due to hyperthyroidism leads to the dysfunction of the mitochondria respiratory chain, resulting in elevated formation of the reactive oxygen species in the course of Graves-Basedov disease. It has also been reported that excessive thyroid hormone level may induce oxidative tissue injury. Furthermore, Graves-Basedow disease is frequently associated with changes of the antioxidant defence system activity. The disturbed balance between oxidative and antioxidative processes may be of significant importance in the pathogenesis of Graves-Basedow disease.
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