While many studies have shown a connection between stress and autoimmune disease, most of the evidence for stress contributing to the onset and course of autoimmune disease is circumstantial and the mechanisms by which stress affects autoimmune disease are not fully understood. The best circumstantial evidence for an effect of stress on autoimmune thyroid disease is the well-known relationship between the onset of Graves' hyperthyroidism and major stress but even this is debated. However, most of the recent case-control studies have supported stress as a factor that affects the onset and clinical course of Graves' disease. On the other hand, there have been few reports concerning the possible relationship between stress and Hashimoto's thyroiditis. Because the onset and course of Hashimoto's thyroiditis is generally insidious, the effect of stress on Hashimoto's thyroiditis might be overlooked. Numerous human and animal studies have demonstrated that psychological and physiologic stressors induce various immunologic changes. Stress affects the immune system either directly or indirectly through the nervous and endocrine systems. These immune modulations may contribute to the development of autoimmunity as well as the susceptibility to autoimmune disease in genetically predisposed individuals. Stress can be one of the environmental factors for thyroid autoimmunity.
Recovery of thyroid function in patients with both thyroid and renal dysfunction was studied. Among 245 patients with primary hypothyroidism (serum TSH >10 mU/l), 36 had mild to severe renal dysfunction (serum urea nitrogen >7.1 mmol/l and creatinine >106 μmol/l). Of these 36 patients, recovery of the thyroid function after iodine restriction was observed in 30(83%), in whom an elevated serum non-hormonal iodine level (median 236, range 67–15591 μg/l, N=19) and a high thyroidal radioactive iodine uptake (51.5±29.3%at24h, N = 26) were observed. The perchlorate discharge test was positive in 7 of 13 patients examined, suggesting an iodide organification defect rather than an atrophic or destructive change in the thyroid. Antithyroid antibodies were negative in 22 patients (73%) and an almost normal thyroid gland or colloid goitre was confirmed histologically in 8 of them. After a 13.2 mg potassium iodide loading test, 24 h urinary excretion of iodine was about 60% in normal controls, but only 10% in a different group of six euthyroid patients with renal dysfunction. These findings suggest that impaired renal handling of iodine rather than autoimmune mechanism may have a significant role in the pathogenesis of reversible hypothyroidism found in patients with renal dysfunction, probably through a prolonged Wolff-Chaikoff effect.
The extra ocular (eye) muscles are one of the principal tissues involved in the autoimmune-mediated inflammation of Graves' ophthalmopathy (GO). Several eye muscle proteins are targeted by autoantibodies or sensitized T lymphocytes, or both, and include: G2s, which is now identified as the terminal 141 amino acids of the winged-helix transcription factor FOXP1, the flavoprotein (Fp) subunit of the mitochondrial enzyme succinate dehydrogenase, the so-called "64kDa protein", a non-tissue specific membrane protein called 1D and the calcium binding protein calsequestrin. Of these, antibodies against G2s and Fp are the most sensitive markers of eye muscle damage in patients with thyroid autoimmunity even though neither antigen is specific to eye muscle and neither antibody is specific to GO. However, the recent finding that the calsequestrin gene is 4.7 times more expressed in eye muscles than other skeletal muscles suggests that we should reconsider the possible role of anti-calsequestrin autoantibodies in ophthalmopathy. GO may comprise two main subtypes with different pathogenetic mechanisms, namely ocular myopathy in which eye muscle inflammation predominates and congestive ophthalmopathy where inflammatory changes occur in the periorbital connective tissues in the absence of eye muscle dysfunction. Anti-G2s and anti-Fp antibodies are closely associated with the ocular myopathy subtype of GO while antibodies targeting type XIII collagen, the only member of the collagen family to have a transmembrane domain, are closely linked to congestive ophthalmopathy. Since both G2s and Fp are intracellular antigens it is unlikely that either antibody causes eye muscle fiber damage in GO, although a role in the later stages of the disease when the fiber has released its cellular contents has not been excluded. Eye muscle antibodies that are cytotoxic to eye muscle cells in antibody-dependent cell-mediated cytotoxicity (ADCC) are more likely to play a role in eye muscle fiber damage since they target a putative eye muscle cell membrane antigen, the identity of which is currently being investigated. While anti-G2s and anti-Fp antibodies are probably secondary to an underlying reaction, such as cytotoxic T lymphocyte targeting of an eye muscle membrane antigen that has yet to be identified, they are reliable markers of immunologically mediated eye muscle fiber damage in patients with Graves' hyperthyroidism. In conclusion, while a pathogenic role for eye muscle antibodies has not been excluded, they are most likely secondary to cytotoxic T cell reactions in GO and, as such, good markers of this autoimmune disease.
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