Mhc Class Ii Expression On Autoimmune And Malignant Thyroid Cells

3.1. Regulatory Effects of IFN-y and TNF-a

Many investigators have used the thyroid gland as a model for research of autoimmune processes. Autoimmune thyroid diseases are the archetype of organ specific autoimmune disorders, and shares with them T-cell dependency as a common characteristic. Inappropriate MHC class II expression has been first observed on thyroid cells derived from patients with Graves' autoimmune thyroid disease [40], and lead to the hypothesis that such expression would result in antigen presentation of thyroid autoantigens to T cells, thereby starting an autoimmune response [41]. Expression of MHC class II molecules was found to be common also on malignant thyroid cells [42], and has been recently suggested to represent local antitumor response, which prevents metastatic spread of the malignant cells [43]. We and others have shown that T and inflammatory cell products, such as IFN-Y alone or synergistically with TNF-a, induced class II expression on normal and malignant thyrocyte cell lines derived from patients with thyroid carcinomas in a variety of in vivo and in vitro systems [19, 44-46]. In contrast, reduction of MHC class II by IFN-y and TNF-a was found in one tumor thyroid cell line, which constitutively expressed these molecules [19]. Although IFN-y was demonstrated to induce HLA-DR in both nonmalignant and malignant thyroid cells, different signal transduction pathways were shown to be utilized, since protein kinase C pathway had stimulatory effects in malignant thyroid cells, but inhibitory effects in normal thyroid cells [47],

3.2. Relevance of Tumor Suppressor Proteins

In addition, recent findings indicate, that tumor suppressor molecules such as retinoblastoma (Rb) and P53 may have a role in regulation of MHC class II antigens in thyroid tumor cells. Induction of MHC class II molecules required the expression of intact tumor suppressor proteins [48, 49], but their absence or mutated forms have been suggested to diminish the expression of MHC class II antigens, and thereby reducing the activation of CD4+ cytotoxic T cells and their activity against tumor cells.

3.3. Immune and Nonimmune Mechanisms in MHC Class II Induction

Migration of cytokine-secreting immune cells into the thyroid as a result of viral infection may occur, but viral infections can also induce MHC class II expression on thyrocytes independent of immune ac tivation. Reovirus, SV40 and cytomegalovirus have been demonstrated to induce MHC class II expression on cultured thyrocytes in the absence of T cells [50— 52], A direct correlation between high expression of MHC class II and dense inflammatory infiltration has been observed in autoimmune thyroiditis, but not in most tumor specimen [53], This suggests that MHC class II expressions on tumor cells, whether virally induced or caused by the neoplastic transformation, may, in many cases, be independent of immunological processes [54], whereas MHC class II expression in autoimmunity is always associated with triggering of immune response.

Population studies have demonstrated that thyroid autoimmune diseases, mainly Graves and Hashimoto thyroiditis, are associated with specific MHC class II alleles [55-59]. Associations of MHC class II alleles with thyroid cancer were also observed [42, 48], In both cases the efficiency with which certain MHC class II allotypes present autoantigens (including tumor antigens) may affect either failure or success to mount productive immune response, and thereby determine the fate of the patient.

3.4. Polymorphism of MHC and Non-MHC Allele Expression in Autoimmune and Malignant Thyroid Diseases

We have found enhanced induction of MHC class II molecules by IFN-y and thyroid stimulating hormone (TSH) on thyroid cells derived from rats which were susceptible to autoimmune thyroiditis [44], compared to thyrocytes of nonsusceptible rats. The same phenomenon has been described in thyrocytes from Graves patients [60]. One possible molecular basis for higher inducibility has been provided, by the finding of allelic polymorphism in the promoter of HLA-DQ/9 and HLA-DR/? [61, 62], Such polymorphism may confer differences in expression, inducibility and even tissue specificity of MHC class II molecules. Whereas, hyperinducibility of MHC class II expression on thyroid cells have been suggested to be part of the overall susceptibility to autoimmune thyroid diseases, both high and low induced amounts of these molecules have been observed on malignant thyrocytes [63], but were not correlated to the type and severity of the tumor. Recent data point to non-MHC genes and proteins, that contribute to the susceptibility to thyroid autoimmunity in addition to MHC class II molecules

[64], Potential synergy in conferring susceptibility to Graves' disease between specific alleles of HLA-DR and polymorphism in TSH-receptor codon 52 has been suggested [65].

3.5. Regulatory Effects of Specific Thyroid Associated Molecules

The receptor for thyroid stimulating hormone (TSHR), as well as thyroglobulin and thyroid peroxidase (TPO), have been recognized as potential autoantigens that may bind to MHC class II molecules, leading to autoimmunity. The relationship between MHC class II (HLA-DR being the most studied molecule) to these and other specific thyroid molecules, antibodies directed to them and therapeutic agents used in the treatment of thyroid autoimmunity are complex. Auto-antibodies to hormone receptors were found in autoimmune disease such as Graves' and Myasta-nia Gravis, and a structural similarity between the hormone receptor and MHC class II genes was documented [66], suggesting co-regulation. Indeed it has been found, that anti-TSHR monoclonal antibodies induced expression of MHC class II and Ii proteins in the thyroid with intensity comparable to that of IFN-y, thus suggesting a new role for these autoantibodies in thyroid autoimmunity [66],phenothiazines [67], TSH, triiodothyronine (T3) and thyroxine (T4) [68], as well as methymazole (MMI) and iodide [69], have been found to be involved in the regulation of expression of MHC class II molecules. The therapeutic effectiveness of MMI and iodide has been correlated with their ability to reduce MHC class II [69], although TSH was shown to have both stimulatory [68,44] and inhibitory [47] influences on IFN-y-induced MHC class II expression. The simultaneous expression of TPO and HLA-DR on thyroid cells may be part of the autoimmune triggering. IFN-y has been found to reduce TPO content and to inhibit TSH-induced TPO in thyroid cells, in addition to its MHC class II enhancing effects [70], From this point of view, this cytokine has both anti- and pro-autoimmune functions. In thyroid cancer the same differentiation antigens (thyroglobulin, TPO and TSHR), may also be presented to T cells in the context of MHC class II molecules, and thus direct the immune response against thyrocytes, to the benefit of the patient. Although in poorly differentiated thyroid carcinomas these antigens may be lost or altered [71, 72], other tumor antigens associated with the neoplas tic transformation [73-75] may also serve as antigens. If correctly presented in the context of MHC class II, all these molecules may serve as potential targets for immunotherapy in thyroid cancers.

3.6. The Debated Significance of Thyrocytes as Antigen Presenting Cells

It has been hypothesized that intrathyroidal professional APCs acquire soluble thyroid antigens, which were shedded from live thyrocytes or spilled by dead cells. These antigens are processed inside the APCs, complexed with MHC class II molecules and presented to neighboring bypassing T cells [23, 24]. These cells following recognition of MHC/antigen complexes, secrete IFN-y which induce MHC class II on thyrocytes and cause presentation of autoantigens. As T-cell infiltration occurs before expression of thyrocyte MHC class II molecules, such expression is a secondary event or a consequence rather than a cause of the autoimmune response. Support for conventional presentation of thyroid antigens comes from experimental autoimmune thyroiditis, that can be evoked with exogenously administered thyroglobulin [39, 76,77] or TPO [78, 79], Another line of evidence supports this premise: the distribution of MHC class II molecules on autoimmune thyrocytes correlates with the presence of IFN-y secreting lymphocytes, implying a direct relationship between the two [80]. Principally, the same immunological mechanisms are at work in thyroid tumors, which contain mononuclear cell infiltrates, in this case, to the benefit of the host.

Thyroid cells can be easily induced to express MHC class II molecules, but they may lack other characteristics of professional APCs, such as the expression of co-stimulatory molecules. Failure to deliver co-stimulatory signals seems to be the main obstacle for the ability of thyroid cells to present antigens. Early interest focused on IL-1, however, conflicting evidence for its synthesis by thyrocytes [81, 82] rendered it an improbable candidate for a co-stimulatory molecule. Expression of CD80 or CD86 co-stimulatory molecules could not be demonstrated on either nonmalignant [83], or on malignant thyrocytes [84], However, inflammatory infiltrating cells could provide the co-stimulatory signals necessary for productive immune response directed against the antigen presenting thyrocytes [85]. In contrast, it has been postulated that limited stimulation of CD4+ T cells by thyroid cell expressing MHC class II molecules without co-stimulatory molecules have an active protective role in prevention of thyroid autoimmunity [86]. The inhibitory effect of IFN-y on the synthesis of thyroid differentiation antigens, mentioned earlier, is in line with this premise. However, in thyroid tumors that do not contain immune-cell infiltrate, the expression of MHC class II alone on the thyroid cell only, is not sufficient to trigger CD4+ T cells, and may lead to detrimental anergy [87].

Expression of other auxiliary molecules, such as Ii or HLA-DM, may also play a role in the final consequence of MHC class II expression. In Hashimoto thyroiditis strong MHC class II and weak Ii expression have been observed [88], This aberration of the antigen loading pathway of the MHC class II would imply that MHC class II molecules could be loaded with endogenous peptides, and support a role for the expression of Ii in thyroid autoimmunity. Lack of Ii or its alternate regulation could equally apply to presentation of antigens through MHC class II on professional APCs or thyroid cells.

Conflicting data are available as to the actual ability of thyroid cells to present antigens. Presentation of processed viral antigens by human thyroid cells to T cells in a system using influenza peptides have been described [89]. We have found that MHC class II molecules on human cultured thyrocytes were essential for T-cell cytotoxicity directed towards autologous thyrocytes, but inhibited antithyroid natural killing [90]. We have also shown that MHC class II molecules on nonautoimmune thyrocytes stimulated the proliferation of autologous T cells in the high suppressor activity [91]. On the other hand, primary cultures of mouse thyrocytes triggered by IFN-yto express MHC class II, failed to present antigens to self T cells [92, 93]. These variable results could be explained by possible contamination of primary thyroid cultures with professional APCs. We and others, however, confirmed the ability of cloned thyrocytes to trigger syngeneic CD4+ T cells or cloned T cells [94-96], in the absence of any other APCs. The ability of malignant thyroid cells to activate CD4+ T cells has not yet been studied.

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