It is now clear that TSH- receptor- stimulating antibodies cause Graves’ disease, but there is no clear correlation between the circulating level of these antibodies and the severity of hyperthyroidism. The most likely reason for this discrepancy is that humoral and cellular factors, identical to those operating in autoimmune hypothyroidism, are also active in Graves’ disease, and it is the balance between the level of stimulatory antibodies and these conflicting processes, including antibodies which block the TSH receptor, that determines the degree of hyperthyroidism. As already noted, the natural history of Graves’ disease tends to thyroid destruction over 20 years in a small proportion of patients.

The mechanisms mediating hypothyroidism are less clear, in particular with regard to the relative importance of each in the pathogenesis of thyroid cell dysfunction and destruction, and these processes are considered next.

Humoral Immunity

The role of thyroglobulin antibodies is uncertain, as they do not f ix complement, but these antibodies may be involved in mediating antibody- dependent cell- mediated cytotoxicity. In this, the effector cell is a natural killer cell which binds to the antibody via Fc receptors on the natural killer cell surface. This allows the natural killer cell to destroy a specific target cell, in this case a thyroid cell, as otherwise natural killer cell- mediated destruction is not restricted by recognition of specific antigen. Antibody- dependent cell- mediated cytotoxicity is demonstrable in vitro with both thyroglobulin and thyroid peroxidase antibodies, small numbers of natural killer cells appear in the thyroid infiltrate, and monocytes may also be involved in this destructive pathway. However, transplacental transfer of thyroglobulin antibodies is not accompanied by thyroid dysfunction, and similar considerations apply to the frequent presence of thyroglobulin antibodies in euthyroid individuals. Thyroid peroxidase antibodies can fix complement but, for similar reasons, would seem to be of minor importance as primary mediators of thyroid cell destruction. Thyroid peroxidase may well be sequestered from access by autoantibodies until late in the disease process, when cell- mediated injury will permit access and antibody binding.

A second reason for the failure of complement- fixing thyroid peroxidase antibodies to destroy thyroid cells is that, in common with all nucleated cells, thyroid cells express complement regulatory proteins which prevent lethal injury by interfering with C3 convertase activity or by impairing terminal complement component formation. The most important of these regulatory proteins functionally is CD59, and its expression is upregulated by IL- 1, γ- interferon, and tumour necrosis factor, all of which are produced by the lymphocytic infiltrate, thus enhancing the ability of thyroid cells to defend themselves from complement attack. There is good evidence that complement is activated in thyroid autoimmunity, with elevated serum levels of terminal complement complexes, and local deposition of such complexes around the thyroid follicles in both Graves’ disease and Hashimoto’s thyroiditis. Unless formed in overwhelming amounts, complement membrane attack complexes do not overcome the thyroid cell’s defences, but none the less, sub lethal effects of complement attack are demonstrable in vitro, and include impaired responses to TSH stimulation and the release of cytokines, reactive oxygen metabolites, and prostaglandins, which will contribute to the local inflammatory response. Antithyroid drugs block this pro- inflammatory response to complement attack, which may explain the selective immunomodulatory effects of these drugs.

A final mechanism by which antibodies can cause hypothyroidism is through their direct effects on cell function, most clearly illustrated by TSH- receptor antibodies. Although all patients with Graves’ disease must, by definition, have TSH- receptor stimulating antibodies, these may be absent in the serum of occasional patients. As well as assay insensitivity as an explanation, it is possible in these cases that there is exclusively intrathyroidal production of autoantibody which is sufficient to sustain disease.

Cell- Mediated Immunity

Cytokines released locally by the infiltrating lymphocytes and macrophages may have a number of effects that exacerbate thyroid injury. Some of these effects are related to the metabolic activity of the thyroid cells, such as decreased synthesis of thyroglobulin or thyroid peroxidase, which will ultimately impair thyroid hormone production (Table 1), while others evoke responses by thyroid cells which have direct immunological relevance. One of these has already been discussed, namely the expression of MHC class II molecules induced by γ- interferon, but many other effects are being uncovered. Adhesion molecules allow cytotoxic T cells and natural killer cells to bind initially to their targets, and the upregulation of thyroid cell adhesion molecule expression by cytokines will enhance the susceptibility of thyroid cells to such attack. Nitric oxide and reactive oxygen species may play a key role in thy roid injury and their production by thyroid cells is initiated by the intrathyroidal pro- inflammatory environment which exists in auto immune thyroiditis. Finally, IL- 1, IL- 6, IL- 8, IL- 12, IL- 13, IL- 14, IL- 15, and IL- 16 are all produced by thyroid cells themselves in response to inflammatory cytokines, especially IL- 1, and this may set up a mutually reinforcing pathway of cytokine interactions which results in escalation and perpetuation of the autoimmune process (Figure 1).

Table1. Functional effects of cytokines on human thyroid cells

Fig1. Cytokine interactions between the immune system and thyroid cells in autoimmune thyroid disease. Reproduced with permission from Weetman AP, Ajjan RA, Watson PF. Cytokines and Grave’s disease. Bailliere’s Clinical Endocrinology and Metabolism, 1997; 11(3): 481– 97. https:// doi.org/ 10.1016/ S0950- 351X(97)80708- 2. Copyright © 1997 Published by Elsevier Ltd.

As well as thyroid cells, vascular endothelial cells in the thyroid are exposed to cytokines which upregulate expression of selectins and other molecules essential to the egress of inflammatory cells from the blood. Thyroid cells can also produce an array of chemokines, molecules which are able to enhance the recruitment of lymphocytes to the gland in disease. Chemokine synthesis may also be critical in the formation of lymphoid germinal centres in chronically affected thyroid tissue [39]. The process of adhesion molecule ex pression and chemokine synthesis must be essential to the recruitment of lymphocytes to the infiltrate, although it is unknown what proportion of these are blood- derived and what proportion result from local expansion.

Specific cytotoxic T cells have long been thought to be key mediators of thyroid cell destruction in autoimmune thyroiditis, but evidence for their existence is surprisingly sparse and best docu mented in experimental autoimmune thyroiditis [9] . As well as releasing cytokines, cytotoxic T cells kill either by insertion of per forin into the target cell membrane, or by interaction of Fas ligand on the T- cell surface with the widely expressed Fas molecule on the target cell. Perforin- expressing T cells are present in the thy roid infiltrate in both Hashimoto’s thyroiditis and Graves’ disease, with slightly differing phenotypes in the two conditions. This certainly indicates the potential for perforin- mediated cell destruction, although attention has also focused on Fas- mediated apoptosis as a major mechanism for thyroid cell death. This interest has been sparked by the demonstration of Fas ligand ex pression by thyroid cells in Hashimoto’s thyroiditis, but not other conditions. Fas ligand expression was enhanced in vitro by IL- 1β but not by other cytokines, suggesting that, in addition to the classical pathway of apoptosis mediated by T cells, Fas and Fas ligand on thyroid cells could interact and lead to cell suicide. Normally Fas ligand expression is limited to sites of immunological privilege, such as the trophoblast and Sertoli cells, where it is clear that suicide is not an outcome: instead, Fas ligand expression at these sites ensures tolerance by deleting any autoaggressive Fas- expressing lymphocytes specific for these tissues. Thus, a major effect of thy roid cell Fas ligand expression in vivo may be the evasion of thyroid cell recognition by T cells.

In summary, thyroid cell dysfunction and destruction result from a wide array of insults (Figure 2) and, in the initial stage at least, seem dependent on cell- mediated autoimmune processes. It is likely that within the same clinically identified disease there are interindividual differences in the relative contributions from each type of injury. This variation would account for the diversity of pathological processes previously described, and because of this complexity, it is highly improbable that only two types of mechanism predominate, one resulting in atrophic thyroiditis and the other in goitrous thyroiditis.

Fig2. Main mechanisms involved in thyroid cell dysfunction in autoimmune hypothyroidism.

اخر الاخبار

اخبار العتبة العباسية المقدسة

قسم الشعائر يشارك في حملة إغاثة الشعبين الإيراني واللبناني عبر منافذ العتبة العباسية المقدسة

ضمن برنامج بيوت النعيم.. قسم الشؤون الفكرية ينظّم مجلسًا عزائيًّا في بابل

المجمَع العلمي يقيم الحفل الختامي لدورتي (زينة القرآن والإتقان القرآني) في المثنى

شعبة التوجيه الديني النسوي تنظم برنامج مفتاح البصيرة الأسبوعي

المزيد

الآخبار الصحية

الشاشات ليست مجرد ترفيه.. تأثيرات طويلة المدى على دماغ طفلك

الأسباب الرئيسية لنقص الطاقة في الجسم

الكاكاو وتأثيره على العين.. نتائج واعدة من تجارب مخبرية

طبيب يحذر: أطعمة شائعة الاستهلاك أخطر على صحتنا من التدخين

المزيد

الآخبار التكنلوجية

باحثون في "نيويورك أبوظبي" يطورون تقنيات لرصد وعلاج الأورام

جيتكس إفريقيا.. المغرب يجمع "رواد التكنولوجيا" من 103 دول

طاقم أرتميس 2 يحطم رقما قياسيا ويستعرض الجانب البعيد للقمر

"أرتيميس 2" تنطلق حول القمر وتحطم الرقم القياسي

المزيد

مواضيع ذات صلة

B- cell Function in Autoimmune Thyroid Disease

T- cell Function in Autoimmune Thyroid Disease

Autoimmune Thyroid Disease: Autoantigens

Factors Determining Susceptibility of Autoimmune Thyroid Disease

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