A complex combination of genetic, environmental, and endogenous factors determines susceptibility (Figure 1). These factors operate differently in individuals, so that the factors leading to disease in one patient will differ from the next, which makes ana lysis of the importance of each factor difficult with present tools. Genetic effects are seen most clearly in children and adolescents, with environmental factors having an increasing chance to operate with age.

Fig1. Interaction of genetic, exogenous, and endogenous or ‘existential’ factors in the pathogenesis of autoimmune thyroid disease. Individual factors are frequent in the general population and by themselves do not cause disease; it is their concatenation which creates the necessary conditions, as in the Swiss cheese model of accident causation. Reproduced with permission from Weetman AP. The immunopathogenesis of chronic autoimmune thyroiditis one century after Hashimoto. European Thyroid Journal, 2013; 1(4): 243– 50. doi: 10.1159/ 000343834. Copyright © 2012 European Thyroid Association. Published by S. Karger AG, Basel.

Genetic Factors

 These are dealt with extensively in Chapter 3.2.1. However, a brief discussion is given here, in relation to genetic effects on the auto immune process. It is obvious clinically that thyroid diseases cluster in families more often than expected by chance, although the association of Graves’ disease and autoimmune hypothyroidism in such families, and their coassociation with autoimmune polyglandular syndrome type 2, indicates that at least some of the susceptibility is determined by genes that control a generalized tendency to organ- specific autoimmunity. One such determinant in Caucasians is the HLA- DR3 specificity, which is associated with all of the major auto immune endocrinopathies.

The reason why the highly polymorphic alleles of HLA class II genes (also called major histocompatibility complex or MHC class II genes) are associated with autoimmunity is that their products are expressed by antigen- presenting cells and are crucial in initiating any immune response (Figure 2). Autoimmune disease may arise because a certain class II allele is able to bind and present a crucial fragment of an autoantigen, called an epitope, to a CD4+ T cell. Alternatively, the effect of class II alleles in determining immune responsiveness may be exerted in the thymus during development, at which stage future autoreactive T cells may be deleted (negative selection) or allowed to develop (positive selection). Finally, some class II molecules may determine selection of regulatory T cells, and deficiencies in these cells have been postulated as a cause of auto immunity. It still remains unclear whether other genes in linkage disequilibium with HLA- D region genes confer additional susceptibility and it is possible that class I genes have a role independent of those in the class II region.

Fig2. Key steps in antigen presentation and T- cell activation. The dotted line represents an inhibitory pathway. Reproduced with permission from Weetman AP. Recent progress in autoimmune thyroid disease: an overview for the clinician. Thyroid Today, 1996; 19(2): 1Ð9.

The existence of non- HLA susceptibility genes is shown by the higher frequency of thyroid autoimmunity in monozygotic twins than in HLA- identical siblings, which in turn is higher than non- HLA- identical siblings. The critical role of CTLA- 4 in costimulation of T- cell responses is discussed next and this has made it an excel lent candidate to test as a susceptibility gene. It is now clear that polymorphisms in this gene have a significant role in autoimmune thyroid disease as well as several other autoimmune disorders that are associated with thyroid disease clinically. Polymorphisms in other T- cell regulatory genes, including PTPN22 and interleukin- 2 receptor/ CD25, can similarly increase susceptibility to autoimmune thyroid disease and related disorders. Overall it is now clear that many other genes, including those that encode autoantigens such as thyroglobulin and the TSH receptor, exert small effects which contribute to these diseases and their influence varies between individuals, which in turn may explain the diverse clinical presentations of thyroid autoimmunity.

Environmental Factors

The lack of complete concordance for thyroid autoimmunity in monozygotic twins, and the clinically obvious lack of a family history in many patients with autoimmune thyroid disease, point to a role for environmental factors in determining susceptibility. Furthermore, at least part of the family clustering of disease could be the result of shared exposure to environmental triggers. Some of the best evidence for the involvement of the environmental fac tors comes from epidemiological changes and from animal models of experimental autoimmune thyroiditis (Table 1) which resemble Hashimoto’s thyroiditis. Excess dietary iodide exacerbates the severity of the lymphocytic thyroiditis in rats with experimental autoimmune thyroiditis, and leads to enhanced pro duction of thyroglobulin antibodies, and similar observations have been made in the obese strain chicken and non- obese diabetic (NOD) mouse which develop spontaneous autoimmune hypothyroidism. Excess iodide may act directly on the immune system, the formation of an important part of a major T- cell epitope on the iodinated thyroid antigen thyroglobulin, or the generation of toxic metabolites within the thyroid which damage thyroid cells. There is epidemiological evidence to support a similar effect of excess iodide on human autoimmune thyroiditis. Selenium deficiency may predispose to thyroid autoimmunity although trials of selenium supplementation have little obvious effect on established thyroiditis.

Table1. The main experimental models of autoimmune thyroiditis

Infections could precipitate an autoimmune response by target cell damage, leading to release of autoantigens, by altering target cell expression of autoantigen or immunoregulatory molecules, such as HLA, or by molecular mimicry, in which an immune response against micro- organism antigens that resemble host autoantigens triggers an autoimmune response. Despite the appeal of the notion, and the success of animal models, there is surprisingly little evidence linking infection to human autoimmune disease. Autoimmune hypothyroidism occurs with increased frequency after congenital rubella infection, and some, but not all, epidemiological as well as serological studies have suggested a role for Yersinia infection in Graves’ disease. On the other hand, studies showing a lower frequency of thyroid and other types of autoimmunity in areas with a poor standard of hygiene suggest that in some settings infections may enhance immune responses in a way that avoids the emergence of autoimmunity, perhaps through skewing of the cytokine secretion of T helper cells, discussed next. Despite many attempts, no convincing role for retroviruses in autoimmune thyroid disease has been proven. Taking the opposite view, subacute thyroiditis is caused by a wide variety of viruses, and gives rise to thyroid destruction, yet rarely (if ever) triggers autoimmune thyroid disease. Only low and infrequent levels of thyroid antibodies occur in the course of infection and then disappear, although subacute thyroiditis may lead to permanent hypothyroidism in individuals who have coincidental subclinical autoimmune thyroiditis.

Stress appears to be an important precipitant of Graves’ disease, possibly mediated via its neuroendocrine effects. The obese strain chicken, which develops spontaneous autoimmune thyroiditis, has an abnormal corticosteroid secretion profile that may be one of the genetic determinants of this disease.

As the therapeutic armamentarium expands, an increasing number of iatrogenic factors have been found to precipitate auto immune thyroid disease. Mantle irradiation for lymphoma and other conditions is associated with an increased frequency of Graves’ disease and autoimmune thyroiditis, and rare cases of Graves’ disease have been reported following radioiodine treatment of nodular thyroid disease. While these examples could be the result of thyroid injury, leading to autoantigen release, the lack of a parallel response in the wake of virally induced thyroid damage suggests additional mechanisms, such as a differentially suppressive effect of radiation on critical immunoregulatory T cells. An increased prevalence of thyroid autoantibodies has also been reported in children exposed to fallout from the Chernobyl nuclear reactor explosion. Lithium treatment is also associated with an increased prevalence of thyroid autoantibodies, hypothyroidism, and probably Graves’ disease.

Therapeutic doses of cytokines precipitate autoimmune hypothyroidism, but rarely Graves’ disease. The major culprit is α- interferon, probably because it is the most extensively used, but granulocyte– macrophage colony stimulating factor, interleukin- 2 (IL- 2), and IL- 4 have also been implicated. How these effects relate to the role of the same cytokines, at far lower endogenous concentrations, in untreated patients is unknown. However, an association exists between attacks of allergic rhinitis and the time of relapse of Graves’ disease, which may well depend on the non- specific enhancing effects of cytokines released during the allergic response. A variety of new cancer therapies, in particular kinase inhibitors (like sunitinib) and those that modulate CTLA- 4 and the programmed death receptor protein PD1, are associated with destructive thyroiditis, sometimes with autoimmune features.

Environmental pollutants and toxins are theoretically important factors but remain underinvestigated. Administration of anthracene derivatives to genetically predisposed rats can precipitate experimental autoimmune thyroiditis. The potential of pollutants to operate in this way in man is illustrated by the association between cigarette smoking and thyroid- associated ophthalmopathy as well as, to a lesser extent, Graves’ disease, whereas smoking appears to decrease the risk of Hashimoto’s thyroiditis. Alcohol has a modest protective effect against the development of thyroid autoimmunity.

endogenous Factors

The most impressive of these is pregnancy, which can lead to postpartum thyroiditis in around 5% of ostensibly healthy women. However, the frequency of Graves’ disease is also increased in the 2 years postpartum and permanent hypothyroidism is frequently encountered after an episode of transient autoimmune hypothyroidism, indicating that pregnancy can produce a longer- lasting bias of the autoimmune response. Hyperprolactinaemia has only been inconsistently associated with an increased frequency of autoimmune thyroiditis, but clear evidence for a role of sex hormones has come from work on experimental autoimmune thyroiditis. Female animals given testosterone have a reduced frequency of thyroiditis, while castrated males, or those given oestrogen, have an increased frequency, which approaches that of females. These effects explain in large part the much higher rates of autoimmune thyroid disease in women, although it remains to be seen whether any other effects are encoded on the sex chromosomes to explain this dichotomy. Alterations in T- cell regulation during pregnancy, fetal microchimerism or skewed inactivation of the X chromosome are alternative possibilities. Ageing is associated with an increase in thyroid autoimmunity, although healthy centenarians may be relatively protected.

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مواضيع ذات صلة

Pathological Features of Autoimmune Thyroid Disease

The Spectrum of Thyroid Autoimmunity

Autoimmune lymphoproliferative syndrome

Severe Congenital Neutropenia

Autoimmune type 1 diabetes and immune checkpoint inhibitors

Autoimmune diabetes in adults

Genetic aetiology to initiate islet autoimmunity

Islet autoantibodies as biomarkers

Natural history and staging type 1 diabetes

Treatment of Rheumatoid Arthritis

Juvenile Idiopathic Arthritis

Diagnostic Evaluation of Rheumatoid Arthritis