凋亡相关因子参与自身免疫性甲状腺疾病发病的研究

目的:了解细胞凋亡相关蛋白Fas,FasL和Bcl-2表达在自身免疫性甲状腺疾病发病机制及病理变化中的作用及意义。方法:采用免疫组织化学方法,检测20例桥本甲状腺炎,20例Graves病以及20例甲状腺腺瘤(作为对照组)患者甲状腺标本中Fas、FasL和Bcl-2表达及分布。结果:Fas在所有的标本中表达,主要分布于甲状腺滤泡细胞表面和细胞质上。除3例甲状腺瘤标本外,其余均表达FasL。Bcl-2表达于15例桥本甲状腺炎、19例Graves病以及17例甲状腺瘤滤泡细胞上。在甲状腺瘤滤泡细胞上表达中等强度Fas,很少或是没有表达FasL。在桥本甲状腺炎中Fas和FasL免疫染色强阳性甲状腺滤泡细胞多分布于浸润淋巴滤泡附近,浸润淋巴细胞中Fas、FasL免疫染色相对较弱。在Graves病中,Fas表达强度与桥本甲状腺炎类似,但FasL表达却更弱。在Graves病和甲状腺瘤组织中,Bcl-2表达两者类似。但在桥本甲状腺炎组织中,分布于浸润淋巴细胞附近的甲状腺滤泡细胞以及生发中心的淋巴细胞上,Bcl-2表达很弱。结论:Fas、FasL和Bcl-2表达在桥本甲状腺炎和Graves病中相似。FasL高表达和Bcl-2低表达可能引起桥本甲状腺炎滤泡细胞凋亡。进一步证明3种凋亡相关因子在自身免疫性甲状腺疾病发病机制中的作用。在桥本甲状腺炎中,滤泡细胞凋亡并非由浸润淋巴细胞其FasL发挥作用直接杀伤,但是它们能分泌细胞因子促进滤泡细胞自身Fas、FasL表达,从而导致滤泡细胞凋亡。     

Identification of apoptotic proteins in thyroid gland from patients with Graves' disease and Hashimoto's thyroiditis

Apoptosis, i.e. natural programmed cell death, is a physiological phenomenon indispensable for normal functioning of the organism. The signal to apoptosis can be started practically in any cell. Disturbances in the apoptosis regulation determine the essential link of the pathogenesis of many diseases, including autoimmune thyroid disorders. The aim of the study was to assess the expression of Fas/FasL and caspase eight in the tissues of the thyroid gland in patients with Graves' disease (GD), non-toxic nodular goiter (NTNG) and Hashimoto's thyroiditis (HT). The analysis of Fas/FasL expression was performed by western blot and immunohistochemical investigation with DAB-visualization and Mayer's hematoxylin staining. Caspase-8 expression in thyroid follicular cells was assayed by western blot method. Identification of the proapoptotic proteins FasL and Fas exhibited their pronounced expression in the thyroid tissue in GD patients (++; ++) and HT (+++; +++) as compared to the NTNG group (0/+; 0/+). Among the study groups, the expression of caspase-8 was revealed in band 55 kDa from patients with autoimmune thyroid diseases. In GD patients, the percentage of thyrocytes with FasL expression correlated positively with TRAb (R = 0.58, p < 0.02). However, no such correlations were noted in HT or non-toxic multinodular goiter. There were no significant correlations between thyroid hormones and the percentage of thyrocytes with Fas and FasL expression. In conclusion, our findings suggest that the changes in the expression of apoptotic molecules on the surface of T lymphocytes and thyroid follicular cells in patients with autoimmune thyroid disorders reflect their substantial involvement in the pathogenesis of GD and HT. In addition, analysis of Fas/FasL and caspase-8 expression in thyroid tissue may indicate the disease activity and immunological phenotype.     

Identification of apoptotic proteins in thyroid gland from patients with Graves' disease and Hashimoto's thyroiditis

Apoptosis, i.e. natural programmed cell death, is a physiological phenomenon indispensable for normal functioning of the organism. The signal to apoptosis can be started practically in any cell. Disturbances in the apoptosis regulation determine the essential link of the pathogenesis of many diseases, including autoimmune thyroid disorders.

The aim of the study was to assess the expression of Fas/FasL and caspase eight in the tissues of the thyroid gland in patients with Graves' disease (GD), non-toxic nodular goiter (NTNG) and Hashimoto's thyroiditis (HT). The analysis of Fas/FasL expression was performed by western blot and immunohistochemical investigation with DAB-visualization and Mayer's hematoxylin staining. Caspase-8 expression in thyroid follicular cells was assayed by western blot method.

Identification of the proapoptotic proteins FasL and Fas exhibited their pronounced expression in the thyroid tissue in GD patients (++; ++) and HT (+++; +++) as compared to the NTNG group (0/+; 0/+). Among the study groups, the expression of caspase-8 was revealed in band 55 kDa from patients with autoimmune thyroid diseases.

In GD patients, the percentage of thyrocytes with FasL expression correlated positively with TRAb (R = 0.58, p < 0.02). However, no such correlations were noted in HT or non-toxic multinodular goiter. There were no significant correlations between thyroid hormones and the percentage of thyrocytes with Fas and FasL expression.

In conclusion, our findings suggest that the changes in the expression of apoptotic molecules on the surface of T lymphocytes and thyroid follicular cells in patients with autoimmune thyroid disorders reflect their substantial involvement in the pathogenesis of GD and HT. In addition, analysis of Fas/FasL and caspase-8 expression in thyroid tissue may indicate the disease activity and immunological phenotype.     

Graves病和桥本病甲状腺细胞凋亡与Fas表达的研究

为了研究正常、Graves病 (GD )和桥本甲状腺炎 (HT )甲状腺细胞凋亡和凋亡相关蛋白Fas的变化特征及其临床意义 ,采用细胞培养方法和流式细胞术检测正常、GD和HT甲状腺细胞凋亡率和Fas表达量。结果发现 :(1)GD和HT甲状腺细胞凋亡率明显高于正常甲状腺细胞 (P <0 0 1)。其中 ,尤以HT甲状腺细胞凋亡增加最为显著 ;(2 )HT甲状腺细胞Fas表达阳性率明显高于正常和GD甲状腺细胞 (P <0 0 1) ,而GD与正常对照相比无统计学差异。以上结果表明 ,自身免疫性甲状腺疾病 (AITD )患者甲状腺细胞存在细胞凋亡和Fas表达的异常变化 ,尤以HT为显著 ,提示Fas介导的细胞凋亡参与AITD的发病过程 ,可能与HT甲状腺细胞破坏有关。     

Expression of CD40 and apoptosis related molecules in autoimmune thyroid diseases.

Apoptosis is responsible for the loss of thyrocytes in autoimmune thyroiditis. Recent investigations into the pathogenesis of apoptosis have revealed that the important roles of suicide molecules expression on both thyrocytes and cytotoxic T-lymphocytes. To study the mechanism of thyrocyte loss in various forms of thyroiditis, we evaluated in situ expression patterns of CD40, Fas, and Fas-L on thyrocytes and infiltrating inflammatory cells by immunohistochemical staining of thyroid samples obtained from 49 patients (Graves' disease, n=10: Hashimoto's thyroiditis, n=14; nonspecific lymphocytic thyroiditis, n=11; subacute granulomatous thyroiditis, n=11; normal, n=3). The role of cytotoxic T-lymphocytes was also evaluated by analyzing the expression of granzyme B along with their phenotypic characteristics. CD40 was not expressed on thyrocytes of normal controls while they showed a diffuse expression of Fas and a scattered focal expression of Fas-L. The plump thyrocytes proximal to the inflammatory infiltrates showed more intense expressions of these three molecules in various forms of thyroiditis and a close correlation was found between CD40 and Fas-L expression on thyrocytes. Unlike Fas, which was expressed on infiltrating lymphocytes in all groups, Fas-L was not expressed on infiltrating lymphocytes, except those in subacute granulomatous thyroiditis. Granzyme B expressing activated cytotoxic T-lymphocytes occupied a negligible proportion of CD8+ T-lymphocytes in various forms of thyroiditis, and no difference was found in terms of their proportions according to the type of thyroiditis. These results show the acquisition of CD40, Fas and Fas-L molecules on thyrocytes proximal to inflammatory cell aggregates and the negligible expression of granzyme B and Fas-L on the infiltrating lymphocytes, and suggest that Fas and Fas-L mediated apoptosis of thyrocytes (fratricide) may be more important than T cell-mediated cytotoxicity in various forms of thyroiditis.     

Fas-FasL in Hashimoto's Thyroiditis

Hashimoto's thyroiditis is a common chronic autoimmune disease characterized by the loss of thyroid follicular cells (thyrocytes) that are gradually replaced by lymphocytic infiltration and diffuse fibrosis. These morphological findings suggested that autoreactive T-cell clones were responsible for thyrocyte destruction and hypothyroidism through effector–target cytotoxic recognition. Later, autonomous interaction between thyrocyte Fas and FasL has been proposed as a major mechanism of thyrocyte depletion in Hashimoto's thyroiditis. Here, we analyze the possible role of Fas and FasL in the pathogenesis of Hashimoto's thyroiditis. We suggest that the Fas–FasL system dictates the outcome of the autoimmune response by acting on both immune and target cells.     

ANALYSIS OF APOPTOSIS IN RELATION TO TISSUE DESTRUCTION ASSOCIATED WITH HASHIMOTO'S AUTOIMMUNE THYROIDITIS

The level of apoptosis has been investigated in thyroid tissue from eight patients with Graves's disease, one with Hashitoxicosis, three with Hashimoto's thyroiditis, and five patients with multinodular goitre, using flow cytometry and an in situ immunofluorescence technique. Cryostat sections have also been studied for Bcl-2 and APO-1/Fas expression in the thyrocytes and infiltrating lymphocytes, to determine their susceptibility to apoptosis. An increased level of apoptosis was detected in Hashimoto's glands. This was associated with decreased Bcl-2 staining and a patchy APO-1/Fas reactivity on thyrocytes. In addition, APO-1/Fas expression was noted within the germinal centres of lymphoid follicles. It is suggested that the dysregulation of apoptosis-related genes could be an important factor in the progression of destructive thyroid autoimmune disease. © 1997 John Wiley & Sons, Ltd.     

Antigenic alterations in autoimmune thyroid diseases. Observations and hypotheses

In order to further define the pathobiologic changes that occur in Hashimoto's thyroiditis (HT) and Graves' disease (GD), 47 cases of these conditions and six of nodular thyroid hyperplasia were studied. Antibodies to cytokeratin, vimentin, LN-2 (a B-lymphocyte marker), UCHL-1 (a T-lymphocyte marker), and HLA-DR, and biotinylated Helix pomatia (Roman snail) lectin, were applied to paraffin sections using the avidin-biotin-peroxidase complex method. Cytokeratin was not expressed in resting epithelium or nodular hyperplasia, but was strongly displayed by injured (HT) or diffusely hyperplastic (GD) glandular tissue. Vimentin was present throughout the cytoplasm of proliferating thyrocytes but was limited to basal portions of resting cells and those of nodular hyperplasia. HLA-DR was observed in injured and hyperplastic thyroid tissue, as was N-acetyl-alpha-D-galactosamine, the target of H pomatia lectin. UCHL-1-labeled infiltrating lymphocytes were observed in both HT and GD, in areas with minimal epithelial changes, while LN-2 was observed only in association with well-formed lymphoid follicles. These findings suggest that T cells are implicated in the mechanism of both conditions, but that inflammation is not the initiating event for HT and GD; and that a "switch" in intermediate filament synthesis accompanies HLA-DR and N-acetyl-alpha-D-galactosamine expression by thyroid epithelium. Since current theories implicate intermediate filaments as intracellular mediators, we hypothesize that certain cytokeratins may be associated with gene activity governing the expression of class II histocompatibility antigens and other membrane glycoproteins in HT and GD.     

Graves病和桥本甲状腺炎患者外周血T细胞表面及血清中Fas/FasL的表达特点

目的探讨Graves病(GD)和桥本甲状腺炎(HT)患者外周血中Fas+、FasL+细胞占总T淋巴细胞的比例(Fas%、FasL%)以及血清中sFas、sFasL、TGAb、TPOAb等指标的变化及意义。方法选择GD患者36例、HT患者32例、对照组20例。用流式细胞术检测外周血T细胞表面Fa(sCD95)、FasL(CD178)的表达特点,用双抗体夹心法(ELISA)测定血清中可溶性Fas及FasL的含量,用化学发光法测定相关抗体TGAb、TPOAb的含量。结果 GD及HT患者外周血Fas%均高于对照组(P<0.05),且以HT组更为显著,而各组均未检测到FasL的表达;GD及HT患者血清中sFas含量均高于对照组,尤以GD组显著;各组间均可检测到sFasL,但差异无统计学意义(P>0.05)。结论 Fas及其配体介导的凋亡在GD和HT的自身免疫反应过程中起着重要的作用。流式细胞术的应用,可为探讨AITD的发病机制提供新的方法。     

The expression and distribution of S-100 protein and CD 83 in thyroid tissues of autoimmune thyroid diseases

To investigate the expression and distribution of S-100 protein and CD83 in the thyroid tissues of autoimmunethyroid diseases(ATDs),and to study the role of the dendritic cells in the pathogenesis of ATDs,immunohistochemical staining was used on pathological tissues of 20 patients with Hashimoto's thyroiditis(HT)and 20 patients with Graves' disease(GD) to check the expression and distribution of S-100 protein and CD83.Compared with control group(20 cases of thyroid follicular adenoma,TFA),the higher expressions of S-100 inHT(139.38±5.92 vs 59.47±11.69) and GD(119.42±14.48 vs 59.47±11.69) were observed respectively(p<0.001).The increased positive expressions of CD83 which is known as a marker of mature and activated DCs inHT(22.58±13.96 vs 5.19±8.08) and GD(29.92±14.43 vs 5.19±8.08) were also found respectively(p<0.001).Serum TPO antibody(TPO-Ab,67.3±11.6%) and Tg antibody(Tg-Ab,59.8±10.1%) in HT were higher thanthose in GD(28.4±5.7%,23.1±4.9%) and TFA(6.1±3.4%,7.2±4.6%)(p<0.01).Serum TR-Ab in GD(16.3±5.6 U/L) was higher than those in HT(4.8±2.3 U/L) and TFA(2.5±1.2 U/L)(p<0.01).Our findings suggestthat the high expression of DCs' markers may be related to the pathogenesis of HT and GD.The upregulationof both the number and the matured functions of DCs,may lead to present more antigens and to produce moreauto-antibodies(such as Tg-Ab and TPO-Ab in HT,TR-Ab in GD),which may be involved in pathogenesis ofthe autoimmune thyroid diseases.Cellular & Molecular Immunology.2004;1(5):378-382.     

Control of target cell survival in thyroid autoimmunity by T helper cytokines via regulation of apoptotic proteins

After autoimmune inflammation, interactions between CD95 and its ligand (CD95L) mediate thyrocyte destruction in Hashimoto's thyroiditis (HT). Conversely, thyroid autoimmune processes that lead to Graves' disease (GD) result in autoantibody-mediated thyrotropin receptor stimulation without thyrocyte depletion. We found that GD thyrocytes expressed CD95 and CD95L in a similar manner to HT thyrocytes, but did not undergo CD95-induced apoptosis either in vivo or in vitro. This pattern was due to the differential production of TH1 and TH2 cytokines. Interferon gamma promoted caspase up-regulation and CD95-induced apoptosis in HT thyrocytes, whereas interleukin 4 and interleukin 10 protected GD thyrocytes by potent up-regulation of cFLIP and Bcl-xL, which prevented CD95-induced apoptosis in sensitized thyrocytes. Thus, modulation of apoptosis-related proteins by TH1 and TH2 cytokines controls thyrocyte survival in thyroid autoimmunity.     

Intrathyroidal HLA-DR expression and T lymphocyte phenotypes in Graves'' thyrotoxicosis, Hashimoto''s thyroiditis and nodular colloid goitre.

Thyroid surgical biopsies from 21 individuals were examined by a double immunoenzymatic technique with respect to HLA-DR expression and lymphocytic infiltration. HLA-DR positive thyrocytes were observed in two examined Hashimoto goitres and in nine of 11 specimens from patients with Graves' disease. HLA-DR positive thyrocytes were localized to areas harbouring infiltrating lymphocytes, whereas regions with no lymphocytes only rarely expressed HLA-DR antigens. In two specimens of nodular goitre HLA-DR positive thyrocytes were observed in the vicinity of lymphocytic infiltration. Tissues from another three nodular goitres, from one follicular adenoma and from two normal individuals contained no HLA-DR positive thyrocytes and no or only a few lymphocytes. The lymphocytic infiltrates were dominated by cells with the Leu 3a helper/inducer phenotype irrespective of underlying disease, although most pronounced in Hashimoto's thyroiditis. The results indicate that HLA-DR antigens is expressed on thyrocytes in thyroid disorder. The extent of expression correlated with lymphocytic infiltration, which suggests that the two findings are related and of importance for the development of thyroid autoimmunity.     

The role of Fas-mediated apoptosis in thyroid autoimmune disease.

Apoptosis is a carefully regulated mechanism of cell death that differs from necrosis and plays an important role in normal tissue development and homeostasis, as well as disease processes. Apoptosis also plays an important role in autoimmunity. Defective apoptosis can cause systemic autoimmunity by allowing the survival of autoreactive lymphocytes. It may also be involved in the pathogenesis of organ-specific autoimmune diseases, such as Hashimoto's thyroiditis, through altered target organ susceptibility. Apoptosis signaling pathways can be initiated through activation of death receptors. One of these pathways employs the death receptor Fas and its ligand (FasL). Fas expression and death pathway signaling have been demonstrated in the thyroid, but there is controversy surrounding the expression of FasL and its role in thyroid autoimmunity. A number of proteins, including FAP-1, Bcl-2 and I-FLICE may regulate the Fas pathway in the thyroid and provide potential mechanisms for modifying the pathogenesis of autoimmune thyroid disease.     

The role of Fas/FasL system in the regulation of tumor-immune system interactions in papillary thyroid carcinoma in children and adolescents

Fas(APO-1/CD95) is a transmembrane protein that induces apoptosis in susceptible normal and neoplastic cells upon cross-linking by its ligand (FasL). Changes in the Fas and FasL expression were suggested to be a potential mechanism of tumor immune evasion. Thyroid cancer in children and young adults of the Republic of Belarus is the consequence of the Chernobyl accident. Papillary thyroid cancer (PTC) is the most common variant of thyroid carcinoma. This study was performed on the formalin-fixed and paraffin-embedded tissues obtained after surgery from 43 patients with PTC. The presence of Fas and FasL in thyroid tissue specimens was examined immunohistochemically. Positive staining for FasL was observed on neoplastic thyrocytes, whereas staining of normal thyroid cells was weak or absent. The pattern of staining was membranous and cytoplasmic. Staining of lymphocytes both in tumor tissue and in lymph nodes for FasL was weak or absent. Fas expression was found on normal thyroid cells, cancer cells and lymphocytes both in tumor and in lymph nodes with metastases. In lymph node metastases, in lymphocytes adjacent to FasL cancer cells morphological signs of apoptosis were observed.     

Fas/FasL mediated apoptosis of thyrocytes in Graves' disease.

We examined in the present study the possible involvement of Fas and its ligand (FasL) in the process of Graves' disease. Immunohistochemical analysis showed that few normal thyrocytes expressed Fas but many thyrocytes in Graves' disease expressed this molecule. The percentage of FasL-positive thyrocytes in Graves' thyroids was, however, less than in normal thyroids. Several apoptotic thyrocytes and infiltrating mononuclear cells (MNCs) were detected scattered throughout Graves' thyroid tissues and abundant proliferating cell nuclear antigen (PCNA)-positive thyrocytes were present. Apoptotic cells, as well as PCNA-positive cells, were scarcely detectable in normal thyroid glands, however. In vitro treatment of thyrocytes by IL-1beta a cytokine found to be expressed in Graves' thyroid glands, increased Fas but reduced FasL expression. IL-1beta-stimulated thyrocytes became sensitive to apoptosis by anti-Fas IgM monoclonal antibody (mAb). Activated T cells, which strongly expressed FasL, showed cytotoxic activity toward IL-1beta-stimulated thyrocytes but not toward unstimulated thyrocytes. This cytotoxic activity involved the Fas/FasL pathway. Importantly, unstimulated thyrocytes could kill activated, but not resting, T cells. IL-1beta-stimulated thyrocytes, with down-regulated FasL expression, could not efficiently kill activated T cells. The cytotoxic activity of unstimulated thyrocytes toward activated T cells was inhibited by anti-FasL mAb. Interestingly, unstimulated thyrocytes induced apoptosis in IL-1beta-stimulated thyrocytes but not in unstimulated thyrocytes. These interactions were also blocked by anti-FasL mAb. Our results suggest that the apoptotic cell death of both thyrocytes and infiltrating MNCs found in Graves' thyroid glands is regulated by IL-1beta through Fas/FasL interactions.     

Frequency and Distribution of DNA fragmentation in Hashimoto’s thyroiditis and development of papillary thyroid carcinoma

Downregulation of apoptosis and high expression of bcl-2 play an important role in the development of follicular lymphoma. However, little is known about apoptosis in thyroid disease, particularly with respect to the development of papillary carcinoma from Hashimoto’s thyroiditis. To study the early stages of cell death in various types of thyroid disease, surgical specimens from 31 patients including Hashimoto’s thyroiditis (HT,n=7), papillary carcinoma (PC,n=12), Hashimoto’s thyroiditis with papillary carcinoma (HTPC,n=5), and Graves’ disease (GD,n=7) were examined by anin situ nucleotidyl transferase assay (ISNTA), which detects DNA fragmentation. Control normal thyroid tissue (NT,n=7) was obtained from surgically resected papillary thyroid carcinomas sampled away from the primary tumor. An immunohistochemical (IHC) method was used to detect bcl-2 expression. Positive ISNTA nuclei in thyroid follicular cells or tumor cells per section were counted in all parenchymal areas, excluding areas of lymphocyte aggregates. The intensity of bcl-2 staining was graded on a scale of 1+ to 3+. The number of ISNTA-positive thyroid follicular cells was a significantly higher in HT compared to GD. In addition, there was significantly lower number of ISNTA positive non-neoplastic thyroid follicular cells in HTPC compared to HT alone. Strong expression of bcl-2 was found in all cases of GD and NT, but much less bcl-2 staining was seen in HT. There was moderate expression of bcl-2 in HTPC and PC. These findings suggest that (1) DNA fragmentation of the thyroid follicular cells plays an important role in the thyroid injury in HT but not in GD, (2) expression of bcl-2 may overcome the apoptosis in GD but not in HT, and (3) downregulation of DNA fragmentation of the follicular cells in Hashimoto’s thyroiditis associated with papillary carcinoma may suggest an important mechanism for tumor pathogenesis.     

Tumour necrosis factor synergises with gamma interferon on the induction of mRNA for DR alpha chain on thyrocytes from Graves' disease and non toxic goitre

In both thyroid autoimmune diseases Graves' and Hashimoto's thyroiditis, the epithelial thyroid follicular cells (TFC) have been shown to express HLA class II molecules, and can restimulate autoreactive T cells cloned from the diseased tissue. This aberrant class II expression is important in the mechanism of perpetuation of the disease process, therefore we have compared the effect of interferon gamma (IFN gamma) and tumour necrosis factor (TNF alpha) on the HLA-DR alpha mRNA expression of thyroid follicular cells derived from Graves' disease (GD) and a non autoimmune disease, non toxic goitre (NTG). Our results indicate that TNF alpha synergises with IFN gamma in the induction of HLA class II mRNA. There was no consistent difference in DR alpha mRNA expression between the GD and NTG thyroid follicular cell preparations in response to induction by a combination of these lymphokines at various concentrations. Our data suggest that the differences in the level of expression of class II molecules observed in vivo in Graves' disease and non toxic goitre, which is much higher in the former, is probably due to local release of lymphokines by infiltrating T lymphocytes, although other factors may be involved.     

Costimulatory molecules and autoimmune thyroid diseases

At least two signals for proliferation and cytokine secretion by T-cells are required. The first signal is delivered through the interaction of the T-cell receptor with major histocompatibility complex (MHC) molecules expressed on the surface of antigen-presenting cells (APC). The second or costimulatory signal is delivered by cell surface molecules expressed by APC. The interaction of B7.1/B7.2 with CD28 provide the most potent costimulatory signal for T-cell activation. CD40 antigen and its ligand (CD40L) have been shown to play a major role in regulating both humoral and cellular immune responses. In autoimmune thyroid diseases autoantigen presentation could be provided by "professional" APC, such as dendritic cells, as well as "nonprofessional" APC, such as thyroid follicular cells (TFC). In fact, these cells aberrantly express MHC class II molecules in Graves' disease (GD) and Hashimoto's thyroiditis (HT), together with large amounts of MHC class I antigens: moreover, the expression of CD40 on TFC, has been demonstrated. On the other hand B7.1 has been demonstrated in HT, but not in GD TFC. This could provide in HT a local costimulatory signal for T-cell differentiation towards a type 1 cytokine secretion pattern and also result in rescue from apoptosis of infiltrating lymphocytes. The presence of ICAM-1 on the surface of HT TFC may further strengthen contact and facilitate cross-signaling between T-cells and TFC. In contrast, the absence of B7 and ICAM-1 antigens in most GD TFC may more easily be associated with anergy and apoptosis of infiltrating T-cells, preventing the perpetuation and expansion of a "destructive" autoimmune reaction.