There are three major autoantigens in autoimmune thyroid dis ease, detailed next, but there are also a number of specific and non- specific autoantigens whose involvement is suggested by molecular cloning of candidates or by the demonstration of antibodies to cytoskeletal or nuclear components. Thyroid hormones are occasion ally the target of autoantibody formation. These antibodies have no physiological consequences but can interfere in some assays for thyroid hormones, although this is now less of a problem with improved methods. The significance of autoantibodies against pendrin and the sodium iodide symporter, found in up to 10% of patients, is not yet known.

Thyroglobulin

Thyroglobulin is a homodimeric 660 kDa glycosylated iodoprotein which is secreted by thyroid follicular cells and stored in the luminal colloid: thyroglobulin also circulates. There are around 100 tyrosine molecules in each molecule and around 25 are normally iodinated, but this varies greatly depending on iodine uptake and thyroid activity. The iodination reaction depends on thyroid peroxidase and occurs at the apical border of the thyroid cells. Four thyroglobulin domains, termed A to D, have been identified from analysis of internal homology, and contain between them four to eight hormonogenic sites, two of which, at residues 5 and 2746, correspond to sites of preferential T4 and T3 synthesis, respectively. When stimulated by TSH or thyroid- stimulating antibodies, thyroglobulin is endocytosed and hydrolysed in lysosomes to release T3 and T4.

Although iodination of thyroglobulin plays a major role in the antigenicity of the molecule in animal models of autoimmune thyroiditis, the place of iodination in human autoimmune thy roid disease is less clear, with continuing uncertainty over whether the hormonogenic sites are part of T- or B- cell epitopes. As the immune response diversifies with time, an increasing number of epitopes are recognized, especially by sera with high levels of thyroglobulin antibodies, but patients with autoimmune thyroid disease show greater restriction of epitope recognition by autoantibodies than those who have autoantibodies but remain clinically euthyroid. These epitopes are largely conformational, although certain Hashimoto sera recognize linear determinants; all thyroglobulin antibodies cloned from patients so far recognize native but not denatured thyroglobulin. The immunopathogenic non- dominant nature of thyroid autoantibody epitopes suggests that the disease may arise from unmasking of cryptic epitopes which leads to a loss of tolerance.

The antibody response to thyroglobulin is relatively restricted, with a predominance of IgG1 and IgG4 subclasses and over- representation of certain immunoglobulin variable (V) genes. However, thyroglobulin antibodies, even of the IgG1 subclass, do not fix complement due to the wide spacing of epitopes, which prevents cross- linking. The potential role of these antibodies in pathogenesis is considered next. Less is known about T- cell epitopes on thyroglobulin, information about which could lead to important insights regarding molecular mimicry with other self- determinants or microbial antigens.

Thyroid Peroxidase

 Thyroid peroxidase is a glycosylated haemoprotein which exists in two alternatively spliced forms of 100 to 105 kDa. The predominant form, TPO- 1, is responsible for tyrosine iodination and coupling to form thyroid hormones and is predominantly located at the apical border of the thyroid cell, anchored by a transmembrane segment near the carboxyl terminus, with the catalytic domain facing the follicular lumen. TPO- 2 has no enzymatic activity and is restricted to the endoplasmic reticulum: its role in autoimmunity is unknown.

Initial studies of B- cell epitopes on thyroid peroxidase found two sequences, C2 (amino acids 590– 622) and C21 (710– 722), which are linear epitopes recognized by the majority of Hashimoto sera and a smaller proportion of Graves’ sera. It is likely that these and other linear determinants identified subsequently are only the target of antibodies late in disease when degradation of thyroid peroxidase allows spreading of the immune response. In the initial stages, however, conformational epitopes are probably involved in antibody binding, and these have been identified by human and mouse monoclonal antibodies. There are two large overlap ping domains, A and B, which are the target of more than 80% of thyroid peroxidase antibodies in Graves’ disease and Hashimoto’s thyroiditis and, in the absence of thyroid peroxidase crystals, modelling has allowed prediction of the structure of these. Furthermore the immunoglobulin V gene usage of thyroid peroxidase antibodies is remarkably restricted, with domain B- binding antibodies using a particular light- chain sequence (Vκ 012), irrespective of heavy chain, although heavy chain V gene usage is also relatively restricted. Relative binding of thyroid peroxidase antibodies to the individual domains varies little over time, indicating a genetic com ponent to the control of thyroid peroxidase antibody formation.

Thyroid peroxidase antibodies in general show the same type of IgG subclass restriction as those against thyroglobulin but are able to fix complement.

T- cell epitopes are multiple and individual patients respond to different combinations of epitopes without any apparent correlation with disease type or chronicity . As the T- cell response is likely to have had many months to diversify or ‘spread’ by the time of diagnosis, this observation is not surprising, but it does emphasize how difficult identification of any dominant epitope (which might cross- react with a microbial epitope) will be.

TSH Receptor

The TSH receptor is a typical G- protein- coupled receptor, with an extracellular domain of 398 amino acids, a transmembrane region of 266 amino acids organized in seven loops, and an intracellular domain of 93 amino acids. There are two subunits, A (55 kDa) and B (40 kDa), which correspond to the extracellular and transmembrane domains and are joined by disulphide bonds. The A- subunit, uniquely for this type of receptor, can be shed from the cell surface, which may well have immunological consequences by allowing greater access of the autoantigen to the immune system.

Although clearly highly expressed in the thyroid, where the receptor is fundamental for cell activation, there is now considerable evidence that the TSH receptor is expressed in fat, particularly pre- adipocytes, where it may make a contribution to thyroid- associated ophthalmopathy. The main physiological regulator of the TSH receptor is obviously TSH, which causes a rise in intracellular cyclic adenosine monophosphate (AMP) and these actions are mimicked by thyroid- stimulating antibodies in Graves’ disease. The interaction of TSH- receptor antibodies with the receptor is even more complex, with additional antibodies blocking the effect of TSH, contributing to hypothyroidism in around 10% of patients, and others (neutral antibodies) do not stimulate function but may induce apoptosis, at least in vitro. The terminology of these antibodies has been obscure, and Table1 gives an overview.

Table1. Nomenclature and assay of the major types of TSH- receptor antibodies

As would be predicted from the heterogeneous nature of TSH- receptor antibodies, multiple B- cell epitopes have been identified. In summary, the majority are conformational and comprise discontinuous sequences. Both stimulating and blocking antibodies bind to sites on the receptor which overlap with, but are distinct from, the TSH biding site. The greatest separation between the binding of these three entities occurs at the N- terminal region of the receptor. Much is still to be determined, including whether receptor desensitization might explain the poor correlation between circulating TSH- receptor- stimulating antibody levels and the degree of abnormal thyroid function in patients. TSH- receptor- stimulating antibodies show restriction immunoglobulin of heavy and light chain usage, implying oligoclonality of the B- cell repertoire.

TSH- receptor T- cell epitopes have been identified and, as with thyroid peroxidase, there is considerable heterogeneity both within and between patients in the regions recognized, with no clear dominant epitope. Certain TSH- receptor sequences are recognized by 10– 20% of healthy individuals, but it is not known whether these represent potentially pathogenic T cells kept in check by regulatory mechanisms or low- affinity, non- specific interactions of unlikely relevance to the initiation of Graves’ disease.

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مواضيع ذات صلة

B- cell Function in Autoimmune Thyroid Disease

T- cell Function in Autoimmune Thyroid Disease

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

Natural history and staging type 1 diabetes