Animal Models

T cells play a vital role in the pathogenesis of experimental auto immune thyroiditis. Disease is easily transferable with T cells, whereas attempts to transfer disease using serum or antibodies produce only weak or inconsistent effects at best. Full- blown disease re quires the transfer of both CD4+ and CD8+ cells from an animal with experimental autoimmune thyroiditis to a naive recipient (disease being established in the donor by immunization with thyroglobulin in adjuvant). However, a subpopulation within the CD4+ cells also has an important regulatory function, being capable of preventing the action of thyroglobulin- specific, disease- inducing T cells. In essence, these findings are consistent with a model in which autoreactive T cells are largely, but not completely, deleted or rendered anergic in the thymus during development. These T cells are normally kept in check, either because they are controlled by a regulatory T- cell subset or through clonal ignorance in which the T cells fail to react to antigen in the absence of an appropriate costimulatory signal (Figure 1). Animal strains particularly prone to experimental autoimmune thyroiditis have genetic defects either in positive/ negative selection of T cells (which make it more likely that the adult animal has sufficient autoreactive T cells to develop dis ease), or in the regulatory T- cell subsets, and these defects interact with environmental factors to result in disease (Table 1).

Fig1. Alternative outcomes of major histocompatibility complex (MHC) class II molecule expression by thyroid cells, depending on the provision of costimulatory signals from antigen- presenting cells (APCs).

Table1. Interaction of experimental manipulations in animal models of autoimmune thyroiditis

An appropriate balance of Th1 and Th2 cells (Table 2) is needed for full expression of disease, and the reciprocal inhibition between these two subsets (Figure 2) may be one of the most important regulatory pathways controlling the activity of autoreactive T cells. For instance, blocking IL- 2 receptor activation or removing γ- interferon leads to a granulomatous rather than lymphocytic thyroiditis, and the production of high levels of thyroglobulin antibodies, due to preferential Th2 activation. Typical experimental autoimmune thyroiditis is most likely Th1- dependent.

Table2. Features of CD4+ T- cell helper (Th) cell subsets in the mouse; similar but not identical profiles are found in humans. Further subsets are also recognized, especially Th- 17 cells which secrete IL- 17, TNF, and IL- 6, and are highly pro- inflammatory

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.

Further support for this T- cell- dependent mode of pathogenesis comes from the induction of experimental autoimmune thyroiditis by modulation of the T- cell repertoire alone, without the need to immunize animals with thyroid antigen (Table 3). Certain strains of rat or mice develop experimental autoimmune thyroiditis after thymectomy, sometimes coupled with sublethal irradiation, when performed at a critical stage of postnatal development, and T- cell depletion/ reconstitution or cyclosporin A can have similar effects. More recently knockout mouse models have shown a crucial role both for Th1 cytokines and for the pro- inflammatory T h- 17 pathway in generating thyroiditis.

Table3. The main experimental models of autoimmune thyroiditis

Disease in these models is reversed by a subset of CD4+ T cells from untreated donors. One major regulatory CD4+ T- cell population can be identified because it expresses CD25 and Foxp3. Depletion of this T- cell subset causes severe thyroiditis in certain mouse strains and this subset also appears to be reduced when thymectomy is performed; knockout models have also confirmed the importance of T- regulatory cells in maintaining freedom from thyroiditis. From these studies it is clear that thyroid- reactive T cells are present early after birth and that depletion of a critical, regulatory subset of CD4+ T cells can induce organ- specific autoimmune disease. Transgenic mice have been used to confirm that tolerance, imposed in the thymus or periphery, is a major step in the production of thyroid reactivity: by contrast, B cells were not tolerized in animals overexpressing a membrane- bound antigen specifically on thyroid cells, presumably because the antigen is sequestered from B but not T cells. These B cells are harmless (or ‘ignorant’) unless specific T cells are available in a non- tolerized state, in which case help in the form of B- cell stimulation might be provided, leading to thyroid antibody formation. The frequency of thyroid antibodies (and focal thyroiditis) in the healthy population may be due to the existence of such untolerized B cells, which can be partially activated if T- cell tolerance is disrupted or bypassed, for example by the provision of B- cell- stimulatory cytokines by non- thyroid- specific T cells.

Human Studies

The methods used to examine thyroid- reactive T cells in humans are shown in Table4 and, despite their limitations, have provided important insights into the pathogenesis of autoimmune thyroid disease. A major problem has been the difficulty of access to critical thyroid- infiltrating T cells in untreated patients: blood- borne lymphocytes contain only a small proportion of thyroid- specific T cells which happen to be trafficking at the time of sampling, and although Graves’ thyroid tissue is often available for study, such patients have usually received treatment with antithyroid drugs which reduce the severity of the lymphocytic infiltrate, making the remaining T cells unrepresentative. Furthermore, it is obvious that any immune response, initially directed against a single epitope on a single antigen, rapidly diversifies to involve other epitopes and antigens, and this phenomenon of determinant spreading makes any analysis of T- cell reactivity in autoimmune diseases as chronic as those affecting the thyroid very difficult to interpret.

Table4. Methods used for examining T- cell responses to thyroid antigens

T- cell Phenotypes

Perhaps the simplest type of analysis, but giving easily misunderstood information, is the definition of T- cell phenotypes using monoclonal antibodies against an array of surface molecules. From such studies on peripheral blood, it is now fairly clear that CD8+ T- cell numbers are decreased in Graves’ disease, active Hashimoto’s thyroiditis, and postpartum thyroiditis, giving a rise in the ratio of CD4 to CD8 cells, and so- called activated T cells, expressing HLA- DR and other activation molecules, are also increased. However, the cause and meaning of these changes remain unclear, and their original interpretation as showing a defect in so- called T- suppressor cells is now regarded as naive. It should also be noted that similar changes are found in other autoimmune diseases.

Thyroid- infiltrating T cells are a mix of CD4+ and CD8+ cells, many expressing activation markers, and CD4+ cells often predominate in Hashimoto’s thyroiditis. Most of the T cells express the αβ T- cell receptor, but a minor population of uncertain significance expresses the γδ receptor. Analysis of clonality within the T- cell population expressing the αβ receptor families by the unfractionated thyroid- infiltrating T- cell population in Hashimoto’s thyroiditis and Graves’ disease shows no evidence of restriction, even in the activated T- cell population which might be predicted to contain the most disease- specific cells. Although it is likely that the autoimmune response begins with a clonally restricted response, this response rapidly di versifies, particularly when multiple thyroid autoantigens are known to be involved. Detailed analysis of the T- cell infiltrate in auto immune thyroiditis shows that there is an influx of recent thymic emigrants early on in the disease process, which in turn implies that there may be some disturbance of central tolerance, in addition to a problem with peripheral tolerance, in these patients.

Functional Responses

Thyroglobulin- , thyroid peroxidase- , and TSH- receptor- reactive T cells can be identified in the circulating and thyroid lymphocyte populations of patients with thyroid autoimmunity but such responses tend to be weak and epitope mapping studies have generally revealed a remarkably heterogeneous response.

Recent work has identified the importance of regulatory T cells, now known to have a central role in maintaining tolerance to autoantigens. Perhaps the clearest evidence for their importance comes from the rare, lethal disorder IPEX (immunodysregulation polyendocrinopathy enteropathy X- linked) syndrome in which there are mutations in the FOXP3 gene that result in a defect in immunoregulatory T cells which express CD25 and Foxp3. Babies with this syndrome have very early onset autoimmune disorders including thyroid disease. Further possible examples of thyroid autoimmunity appearing in the wake of a disturbance of T- cell- mediated immunoregulation occur during reconstitution of the immune system after monoclonal antibody treatment directed against lymphocytes, or after antiretroviral treatment for HIV.

Analysis of cytokine production in thyroid autoimmunity, either in situ or by cultured T cells, has shown a complex picture, with both T h1 and Th2 cytokines being present. There is also an increase in pro- inflammatory Th17 production by intrathyroidal lymphocytes. It is likely that a Th1 (and Th17) pattern predominates in autoimmune hypothyroidism, but the expected Th2 predominance in Graves’ disease, shown by IL- 4 production, is not apparent, either because the disease has been studied too late or because other cytokines known to be produced in the thyroid, such as IL- 6, IL- 10, and IL- 13, are able to sustain antibody production. Besides CD4+ T cells, CD8+ T cells, macrophages, and the thyroid follicular cells themselves all contribute to the intrathyroidal cytokine profile, and the pathogenic implications of such cytokines are discussed next.

Antigen Presentation to T Cells

Antigen presentation is the fundamental first step in any immune response (Figure2) and in most cases is believed to be a function of specialized antigen- presenting cells, such as dendritic cells, macrophages, or B cells. These have the ability to take up antigen, process it into the form of epitopes, and present the epitope, bound to a MHC class II molecule, to a CD4+ T cell which recognizes this bimolecular complex through a specific T- cell receptor. In addition, a number of other molecules on the antigen- presenting cell interact with the T cell, either to stabilize this interaction or deliver additional or costimulatory signals. T cells vary in their requirement for costimulatory signalling to achieve activation; broadly speaking, naive T cells depend more on such signals than memory or activated T cells. Some antigen- presenting cell- derived signals may also mediate T- cell inhibition. For instance, the B7 surface proteins, CD80 and CD86, cause T- cell activation when they bind to CD28 on a T cell, but if they bind instead to CTLA- 4, T- cell anergy ensues. Moreover, T cells dependent on costimulatory signals are rendered anergic if antigen presentation occurs in the absence of the signal. This alternative outcome from antigen presentation is an important mechanism for determining peripheral tolerance, although much remains to be learned about what determines T- cell requirements for costimulatory signals.

Against this background, the identification of MHC class II molecule expression by thyroid cells in Hashimoto’s thyroiditis and Graves’ disease, but not under normal conditions, was initially taken as evidence that such expression could initiate or perpetuate the autoimmune response through the presentation of thyroid antigens by thyrocytes which, in effect, had been converted to antigen- presenting cells. Such class II expression is not an intrinsic property of thyroid cells in the disease state, but depends instead on the cytokine γ- interferon released by the infiltrating T cells, and therefore cannot be the initiating step in thyroid auto immunity: in experimental autoimmune thyroiditis, when class II molecules are expressed de novo on thyroid cells in transgenic mice, thyroiditis does not appear.

Thyroid- specific T cells can be stimulated to proliferate in response to antigen presented by class II- positive thyroid cells, but using cloned T cells it is apparent that this is not a universal property, as T cells requiring B7 costimulation cannot be stimulated by thyroid cells, which do not express B7 proteins. Moreover, the T cells that fail to respond are rendered anergic, as subsequent attempts at stimulation using conventional antigen- presenting cells fail, and this is achieved by at least two mechanisms, one partially reversible by addition of appropriate cytokines (especially IL- 2) and the other dependent on Fas- mediated signalling (see next). Therefore the peripheral tolerance induced by thy roid cells is complex and appears, teleologically, to be an appropriate mechanism for inducing peripheral tolerance in potentially autoreactive T cells, which could otherwise respond to released autoantigen, for instance, after viral thyroiditis (Figure 1). The local production of γ- interferon during the infection may ensure sufficient MHC class II expression by thyroid cells to ensure that autoimmune responses are not initiated, but this back fires in the setting of an already ongoing autoimmune response. In this case, conventional antigen- presenting cells provide initial costimulatory signals and the resulting T cells, no longer de pendent on costimulatory signals, will be further stimulated by class II- positive thyroid cells.

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مواضيع ذات صلة

B- 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

Natural history and staging type 1 diabetes