Anti-CD38 autoimmunity in patients with chronic autoimmune thyroiditis or Graves' disease.

Autoantibodies directed against human CD38 (an enzyme catalysing the interconversion of NAD(+) and cyclic ADP-ribose) have been demonstrated recently in patients with type 2 diabetes. We tested 220 consecutive Caucasian patients with autoimmune chronic thyroiditis, 104 patients with Graves' disease, 220 subjects from the general population (control I) and 78 healthy control subjects not affected by thyroid autoimmune disorders (control II) for the presence of anti-CD38 autoimmunity. Using Western blot analysis and optical densitometry, a specific band corresponding to human recombinant CD38 was identified in the serum of several subjects. By defining anti-CD38 positivity as a standardized optical reading > 3 s.d. higher than the mean value of control I, 10.4% of patients with thyroiditis and 7.7% of Graves' patients were anti-CD38 positive (P = 0.0009 versus 1.8% of control I). Similarly, 13.1% of patients with thyroiditis and 10.5% of Graves' patients had a standardized optical reading > 3 s.d. higher than the mean value of the subjects not affected by thyroid autoimmune disorders (P = 0.002 versus 1.2% of control II). Anti-CD38 autoimmunity did not differ between euthyroid, hyperthyroid or hypothyroid patients or between patients with or without thyroid hypoechogenicity. Anti-CD38 autoantibodies were associated with higher levels of circulating antithyroid-peroxidase antibodies (P = 0.03) and they were more frequent in Graves' patients with ophthalmopathy (P < 0.05). Anti-CD38 autoantibodies are a new autoimmune marker in chronic autoimmune thyroiditis and Graves' disease. The specific role of CD38 and its autoantibodies in the modulation of thyroid cell function or growth remains to be investigated.     

Immunology of the thyrotropin receptor.

Antibodies to the thyrotropin receptor appear to be responsible for hyperthyroidism in Graves' disease. The antibodies, described as thyroid-stimulating antibodies (TSAb) mimic the effects of thyrotropin (TSH) by binding to the TSH receptor and activating adenylate cyclase. TSAb consist of an electrophoretically heterogeneous population of IgG and the thyroid-stimulating site is formed by combination of heavy and light chains in the Fab part of the molecule. Binding studies indicate that the TSAb molecule interacts monovalently with membrane bound TSH receptors and that TSAb consists of an antibody population which shows a restricted heterogeneity with regard to TSH receptor affinity. Studies in patients with Graves' disease and hyperthyroidism indicate that the levels of TSAb correlate well with thyroidal iodine uptake and the absence of pituitary control of thyroid function. However in some patients with ophthalmic Graves' disease or autoimmune thyroiditis there is evidence of serum antibodies which interact with the TSH receptor but are unable to stimulate thyroid function.     

Studies on thyroid cell surface antigens using cultured human thyroid cells.

Human thyroid cells in primary culture were used for studies of thyroid cell surface antibodies in patients with thyroid autoimmune disorders. Radioiodinated IgG preparations containing thyroid microsomal antibody (TMAb), thyroid stimulating antibody (TSAb) and/or thyroglobulin antibody (TgAb) were tested for binding to thyroid cells. Binding was observed with radioiodinated IgG from patients with Graves' disease, Hashimoto's thyroiditis and idiopathic myxoedema containing TMAb, irrespective of the presence of TSAb and TgAb, while negative results were obtained with normal IgG. A dose-dependent inhibition of binding to thyroid cells was produced by the addition of the corresponding unlabelled IgG preparations. Evidence for tissue specificity was provided by the absence of binding to human skin fibroblasts used as controls. Preabsorption with human thyroid microsomes completely abolished the binding to thyroid cells of a radioiodinated TMAb positive IgG preparation, while only incomplete removal of the reactivity to thyroid microsomes was produced by preabsorption with thyroid cells. These data suggest that some but not all microsomal antigenic determinants are expressed on the thyroid cell surface. Binding to thyroid cells was also observed with purified TgAb, indicating that thyroglobulin antigenic determinants are present on the surface of thyroid cells. No evidence of binding was obtained with a TSAb positive Graves' IgG preparation with undetectable TMAb and TgAb. Unlabelled IgG preparations containing TMAb from patients with either Hashimoto's thyroiditis or idiopathic myxoedema were shown to inhibit the binding to thyroid cells of radioiodinated TMAb positive Graves' IgG and vice versa. These data indicate that antibodies present in these thyroid autoimmune disorders share common thyroid cell surface antigens. However, the binding of radioiodinated IgG from a patient with idiopathic myxoedema was only partially inhibited by Graves' or Hashimoto's IgG, suggesting that some of the thyroid cell surface antibodies of idiopathic myxoedema may not be detectable in other thyroid autoimmune disorders.     

Antibodies to Yersinia enterocolitica in immunogenic thyroid diseases

In 1976 Shenkman et al. revealed that in patients with thyroid disorders antibodies against Yersinia enterocolitica could be demonstrated in increased frequency. In 1983 Ingbar et al. first established that the gram-negative bacterium Yersinia enterocolitica shows on its surface saturable binding sites for thyrotropin (TSH). If such binding sites resemble immunologically human TSH receptors this would indicate that TSH receptor antibodies could be produced in selected individuals having been infected with bacteria showing TSH receptors. The aim of our study was to compare the incidence of antibodies against Yersinia enterocolitica in two groups of thyroid disorders which are either immunogenic (Graves' disease and Hashimoto thyroiditis) or non-immunogenic (toxic adenomas, endemic goitre). In our series of 111 patients antibodies against Yersinia enterocolitica were demonstrated in a significantly higher percentage (36.3%) in patients suffering from immunogenic than in patients with non-immunogenic thyroid disorders (19.6%). The antibody titres were mainly directed towards Yersinia subtypes 8 and 3. It may, therefore, be assumed that the gram-negative bacterium Yersinia enterocolitica may have an active part in triggering immunogenic thyroid diseases such as Graves' disease or Hashimoto thyroiditis.     

Immunological of the Thyrotropin Receptor

Antibodies to the thyrotropin receptor appear to he responsible for hyperthyroidism in Graves disease. The antibodies, described as thyroid-stimulating antibodies (TSAb) mimic the effects of thyrotropin (TSH) by binding to the TSH receptor and activating adenylate cyclase. TSAb consist of an electrophoretically heterogeneous population of IgG and the thyroid-stimulating site is formed by combination of heavy and light chains in the Fab part of the molecule. Binding studies indicate that the TSAb molecule interacts monovalently with membrane bound TSH receptors and that TSAb consists of an antibody population which shows a restricted heterogeneity with regard to TSH receptor affinity. Studies in patients with Graves disease and hyperthyroidism indicate that the levels of TSAb correlate well with thyroidal iodine uptake and the absence of pituitary control of thyroid function. However in some patients with ophthalmic Graves' disease or autoimmune thyroiditis there is evidence of serum antibodies which interact with the TSH receptor but are unable to stimulate thyroid function.     

Assays of TSH-receptor antibodies in 576 patients with various thyroid disorders: their incidence, significance and clinical usefulness

The incidence and the significance of TSH-receptor antibodies in Graves' disease and in various thyroid disorders have been evaluated. TSH-binding inhibiting antibodies (TBIAb) and thyroid stimulating antibodies (TSAb) were detected in a large proportion of Graves' disease patients (TBIAb in 68.8% and TSAb in 77.8%), in a small number of patients with idiopathic myxoedema or Hashimoto's thyroiditis, and were not detected in patients with endemic euthyroid goitre, differentiated thyroid carcinoma and toxic adenoma. Furthermore, TSH-receptor antibodies were present in some patients with toxic multinodular goitre (TBIAb in 12.7% and TSAb in 15.9%). When TSH-receptor and other thyroid autoantibodies were compared, it was found that 13 of the 15 Graves' patients with negative tests for thyroglobulin and thyroid microsomal antibodies were positive for TSH-receptor antibodies. On the other hand, 9 of the 11 patients with toxic multinodular goitre who had positive TSH-receptor antibody tests, also had serum thyroglobulin and/or thyroid microsomal antibodies. No significant differences in the prevalence of TSH-receptor antibodies were found in Graves' patients irrespective of the presence of ophthalmopathy or pretibial myxoedema. Elevated TBIAb activity at the end of anti-thyroid drug treatment was found in 52.9% of Graves' patients who subsequently relapsed, while in Graves' patients in remission TBIAb was always negative. TSH-receptor antibody results were not predictive of the outcome of radioiodine treatment in Graves' disease. Finally no correlation could be found between TBIAb and TSAb in Graves' disease and Hashimoto's thyroiditis. In conclusion: the high incidence of TSH-receptor antibodies in Graves' disease confirms their pathogenetic role in the development of hyperthyroidism; TSH-receptor antibodies in Graves' disease are not significantly associated with the presence of ophthalmopathy or pretibial myxoedema; TSH-receptor antibody assays may be useful for the diagnosis of Graves' disease in the absence of other signs of autoimmunity. TBIAb seems to be a good predictor of relapse in Graves' patients treated with anti-thyroid drugs; a fraction of toxic multinodular goitre could be a nodular variant of Graves' disease.     

Long-term pathologic changes of alpha1-acid glycoprotein (orosomucoid) glycoforms in autoimmune thyroid disease

OBJECTIVE: We measured alpha1-acid-glycoprotein (AGP) in patients with autoimmune thyroid disease to study a possible relationship between microheterogeneity of the naturally occurring glycoforms of AGP and autoimmune thyroid disease. DESIGN, PATIENTS, MEASUREMENTS: In a group of 12 fasting thyrotoxic patients (11 females, mean age: 43 years) with newly diagnosed Graves' disease (subgroup 1), we measured serum concentrations of total AGP and its 3 glycoforms (micromol/l, crossed affinity immunoelectrophoresis with con A in the first dimension gel) as well as total thyroxine, total triiodothyronine, thyrotropine, thyroid peroxidase antibodies (anti-TPO), antibodies against the TSH receptor (TRAb, TRAK), at baseline and after 12 months of antithyroid drug therapy (ATD). For comparison, 4 subgroups of thyroid patients (patients with Graves' disease and thyroid associated ophthalmopathy (TAO) (subgroup 2, n = 10), radioiodine treated Graves' patients (subgroup 3, n = 7), Graves' patients without TAO (subgroup 4, n = 13), patients with Hashimoto's thyroiditis (subgroup 5, n = 8)) and 25 normal controls (17 females, mean age: 38 years) were studied. RESULTS: In subgroups of TRAb positive Graves patients' serum levels of glycoform 1, 2 or 3 increased significantly (p < 0.005) after 12 months of ATD as compared to both baseline of that person or normal controls. No significant changes were found in the TRAb negative Hashimoto subgroup. CONCLUSION: Patients with autoimmune Graves' disease changed their relationship to AGP, and thus a role of AGP and its 3 glycoforms is suggested in the pathogenesis of Graves' disease.     

Heterogeneity of thyroid autoantigens identified by immunoblotting

Autoimmune thyroid disease in man is commonly associated with autoantibodies against thyroglobulin, microsomes, and the TSH receptor, and the character and specificity of these antithyroid antibodies have been extensively utilized in investigating these conditions. In the present study we have asked whether other thyroid-related antigens exist, against which autoantibodies may be directed. A crude thyroid extract was separated by polyacrylamide gel electrophoresis followed by immunoblotting with serum obtained from patients with Graves' disease or Hashimoto's thyroiditis. Antibodies in sera from patients with Graves' disease and Hashimoto's thyroiditis reacted with many antigenic determinants in immunoblots of the thyroid membrane preparation (2000g supernatant). These determinants were disease specific in that sera from normals and patients with Addison's disease and rheumatoid arthritis did not react, but there was no difference between the patterns of reactivity with Graves' disease or Hashimoto's thyroiditis sera. Thyroglobulin produced two predominant bands of reactivity at 320 and 200 kDa, whereas purified microsomal antigen produced a triplet of bands around 105 kDa, when these preparations were reacted with appropriate autoimmune sera. Nonetheless, some sera produced additional bands with the microsomal antigen blots, indicating that some of the antigens which were detected using crude thyroid membrane remained in the microsome preparation to produce multiple antibody binding reactivities. We were unable to inhibit any of the antibody binding with TSH. Purification of individual thyroid antigens on the basis of their molecular weights should standardize current antibody assays and permit more detailed evaluation of the cellular immune responses in Graves' disease and Hashimoto's thyroiditis.     

Clinical value of a bispecific antibody binding to thyroglobulin and thyroperoxidase (TGPO-aAb) in various thyroid diseases.

TGPO-aAb is a bispecific antibody which binds to thyroglobulin as well as thyroid peroxidase. It is supposed to be raised in some patients with autoimmune thyroid disease. We investigated 205 patients suffering from Graves' disease (n = 81), Hashimoto's thyroiditis (n = 36), toxic nodular goitre (n = 50), differentiated carcinoma of the thyroid (n = 10), and autoimmune thyropathy of unknown origin (n = 28). An immunoradiometric assay was used to measure serum TGPO-aAb. Eighty-nine of 205 patients had elevated titres of TGPO-aAb. If TGPO-aAb were raised then autoantibodies against thyroglobulin and thyroid peroxidase were always raised, too. This was, however, not true vice versa. We found TGPO-aAb in 61% of patients with Hashimoto's, 49% of patients with Graves', 64% of patients with autoimmune thyropathy, but only in 12% of patients with toxic nodular goitre. In patients with thyroid carcinoma TGPO-aAb was found only if there was evidence of paraneoplastic autoimmune thyroiditis. We re-examined 16 of 36 patients with Hashimoto's thyroiditis after 1 year: 8 patients had retained their raised TGPO-aAb, 4 patients showed no TGPO-aAb on both occasions, and 4 patients had 'lost' their previously raised TGPO-aAb on follow-up. We conclude that TGPO-aAb may provide additional information in Hashimoto's thyroiditis. Determination of TGPO-aAb does not allow to distinguish between various forms of autoimmune thyroid disease. Nevertheless, the presence of TGPO-aAb and its variation during the natural course of autoimmune thyroid disease remains to be understood which would give a better insight into its clinical significance.     

Superiority of thyroid peroxidase DNA over protein immunization in replicating human thyroid autoimmunity in HLA-DRB1*0301 (DR3) transgenic mice

Murine experimental autoimmune thyroiditis (EAT), characterized by thyroid destruction after immunization with thyroglobulin (Tg), has long been a useful model of organ-specific autoimmune disease. More recently, porcine thyroid peroxidase (pTPO) has also been shown to induce thyroiditis, but these results have not been confirmed. When (C57BL/6 x CBA)F(1) mice, recently shown to be susceptible to mouse TPO-induced EAT, were immunized with plasmid DNA to human TPO (hTPO) and cytokines IL-12 or GM-CSF, significant antibody (Ab) titres were generated, but minimal thyroiditis was detected in one mouse only from the TPO + GM-CSF immunized group. However, after TPO DNA immunization of HLA-DR3 transgenic class II-deficient NOD mice, thyroiditis was present in 23% of mice injected with TPO + IL-12 or GM-CSF. We also used another marker for assessing the closeness of the model to human thyroid autoimmunity by examining the epitope profile of the anti-TPO Abs to immunodominant determinants on TPO. Remarkably, the majority of the anti-TPO Abs was directed to immunodominant regions A and B, demonstrating the close replication of the model to human autoimmunity. TPO protein immunizations of HLA-DR3 transgenic mice with recombinant hTPO did not result in thyroiditis, nor did immunization of other mice expressing HLA class II transgenes HLA-DR4 or HLA-DQ8, with differential susceptibility to Tg-induced EAT. Moreover, our efforts to duplicate exactly the experimental procedures used with pTPO also failed to induce thyroiditis. The success of hTPO plasmid DNA immunization of DR3(+) mice, similar to our reports on Tg-induced thyroiditis and thyrotropin receptor DNA-induced Graves' hyperthyroidism, underscores the importance of DR3 genes for all three major thyroid antigens, and provides another humanized model to study autoimmune thyroid disease.     

Circulating antibodies to DNA-related antigens in patients with autoimmune thyroid disorders.

A high prevalence of antibodies to double-stranded DNA (AbDNAds) has been recently reported in serum of patients with autoimmune thyroid disorders, but the specificity of this finding has been questioned. For this reason, the prevalence of several antibodies to DNA-related nuclear antigens (AbDRENA) has been evaluated in sera of patients with autoimmune and non-autoimmune thyroid disease. The study group included: 46 Graves' disease patients, 28 Hashimoto's thyroiditis patients, 25 patients with toxic nodular goitre and 11 with non-toxic nodular goitre. Twenty-eight Graves' patients were retested during methimazole (MMI) therapy, and 5 after radioiodine administration. Twenty-two patients with systemic lupus erythematosus and 28 normal subjects served as positive and negative controls, respectively. AbDRENA included: AbDNAds by RIA or immunofluorescence (IF); antibodies to single-stranded DNA (AbDNAss) and antibodies to histone (AbHist) by ELISA methods; antibodies to nuclear antigens (ANA) by immunofluorescence. RIA values were considered to be abnormal when 2 SD above the mean of normal controls. In our study 13% of Graves' patients were positive for AbDNAds by RIA: all of them had negative tests by IF; 11% were positive for AbDNAss, 2% for AbHist and 7% for ANA. A comparable prevalence of positive results for AbDNAds by RIA, with negative IF tests, was found in Hashimoto's thyroiditis patients. No significant changes of antibody levels were observed in Graves' patients during MMI treatment or after radioiodine administration. A positivity for AbDNAds or AbDNAss was found in 8% of patients with toxic nodular goitre, but in none of those with non-toxic goitre.(ABSTRACT TRUNCATED AT 250 WORDS)     

In vitro production of interferon-gamma by peripheral blood from patients with Graves'' disease, Hashimoto''s thyroiditis and rheumatoid arthritis.

The production of interferon-gamma (IFN-gamma) by peripheral blood mononuclear cells (PBMC), CD4 cells, or CD8 cells in response to interleukin-2 (IL-2) stimulation has been studied; the samples were obtained from 12 healthy control subjects, 19 patients with Graves' disease (10 hyperthyroid and nine euthyroid), 13 patients with Hashimoto's thyroiditis (four hypothyroid and nine euthyroid), and 15 patients with rheumatoid arthritis (11 active and four inactive). A dose of IL-2 (25 U/ml) was utilized to induce IFN-gamma by PBMC from all four groups. The incremental increase in IFN-gamma values (with IL-2 stimulation minus without stimulation) was significantly less in PBMC from patients with Graves' disease, Hashimoto's thyroiditis, and rheumatoid arthritis than that in PBMC from control subjects. The values from PBMC in patients with Graves' disease in a euthyroid state were below normal but greater than those from patients with Graves' disease in a hyperthyroid state. The incremental increase in IFN-gamma values from Graves' disease PBMC correlated with the serum TSH values (r = 0.622, P less than 0.01), but not with thyroid autoantibodies (anti-thyroid microsomal antibodies, anti-thyroid microsomal antibodies, nor TSH-binding inhibitory immunoglobulin activities). The incremental increase in IFN-gamma from PBMC from both control subjects and Graves' disease was correlated with that from CD4 cells (r = 0.711, P less than 0.01), but not with that from CD8 cells. The production of IFN-gamma in response to IL-2 from PBMC in Graves' disease correlated inversely with thyroid function, appearing to reflect the very effect of hyperthyroidism in this process. The precise explanation of these phenomena remains unclear. The decreased response of IFN-gamma to IL-2 stimulation by PBMC from patients with Graves' disease, Hashimoto's thyroiditis, and rheumatoid arthritis seems to be a non-specific phenomenon occurring in both organ specific autoimmune disease and systemic autoimmune disease. It may be due to a down-regulation in autoimmune disease of CD4 cells in response to IL-2, a decreased level of IL-2 cellular receptors or a decreased receptor affinity, associated increased soluble IL-2 receptors, or a defect of the intra-CD4 cellular IL-2 signal to produce or release IFN-gamma in the conditions studied.     

Ultrastructural localization of endogenous peroxidase activity in Hashimoto's thyroiditis

Ultrastructural localization and intensity of endogenous thyroid peroxidase (TPO) in Hashimoto's thyroiditis were examined in relation to the serum thyroid hormone level, thyroid-stimulating hormone (TSH) concentration and anti-thyroid autoantibody titer. In Hashimoto's thyroiditis, TPO activity on the microvilli of follicular cells was more intense than that of normal thyroid tissue, but the intensity of the intracytoplasmic peroxidase reaction was generally weaker than that of Graves' or normal thyroid tissue. Microvillar TPO reaction products were positive in all thyroid follicular cells in patients with increased TSH levels, but no TPO activity was observed on the microvilli of patients with normal or low TSH levels, irrespective of their histological type or serum anti-microsomal antibody titer. It is suggested that TPO activity on the surface of microvilli of thyroid follicular cells in Hashimoto's thyroid gland is modulated by thyrotropin but is not affected by anti-thyroid autoantibodies.     

The pathogenetic connection between Graves' disease and chronic lymphocytic thyroiditis. (The role and incidence of thyroid stimulating antibodies)

Antibody-positivity to thyroid specific antigens (Htg, microsomal) and/or lymphocytic infiltration of the gland's parenchyma were observed in 207 (55%) of 377 patients with Graves's disease. Only in 48 (12.7%) of the cases were the findings in agreement with the criteria of chronic lymphocytic thyroiditis. Human thyroid stimulating antibody (HTSab) was detected in 135 (65%) of these 207 patients. In cases of Graves' disease associated with chronic lymphocytic thyroiditis, this proportion was found to be as high as 89.6% and attained even 100% in cases of Hashitoxicosis (39 patients). The presence of HTSab thus seems to form one of the features of patients with Hashitoxicosis. Infiltrative ophthalmopathy also showed a remarkably high incidence (59%) in this porcess. The typical prevalence of Graves' disease in females in the present material attained a 15:1 female-to-male ratio when the disease was associated with chronic lymphocytic thyroiditis. The results of the present study suggest that chronic lymphocytic thyroiditis associated with Graves' disease promotes the formation of thyroid stimulating antibodies.     

Comparison of radioassay and haemagglutination methods for anti-thyroid microsomal antibodies.

Parallel measurements of circulating anti-thyroid microsomal (anti-M) antibodies by radioassay and haemagglutination were performed on subjects with or without thyroid disorders. Three-quarters (75.4%) of control subjects had undetectable antibody levels (less than 10 u/ml) by radioassay and only 3.1% had concentrations of greater than or equal to 75 u/ml. Abnormally elevated levels (greater than or equal to 75 u/ml) were found in most of the patients with Hashimoto's thyroiditis (94.1%) or idiopathic myxoedema (86.7%), in the majority (75.0%) of those with Graves' disease and only in a minority of those with other thyroid disorders. The percentage of positive sera by haemagglutination was very similar in all groups to that of abnormal values observed in the radioassay. Direct comparison of parallel tests on a total of 631 sera revealed a highly significant correlation (r = 0.91, P less than 0.001) between the two methods, but elevated antibody titres by haemagglutination were found in some sera with negative radioassays. All these sera were from a single patient with thyroid carcinoma associated with Hashimoto's thyroiditis and had elevated levels of anti-thyroglobulin (anti-Tg) antibodies. Evidence that such discrepancies were due to anti-Tg antibodies reacting with microsomal-bound Tg was provided by the demonstration that the haemagglutination produced by these sera could be completely inhibited by the addition of Tg. A similar inhibition was observed with two rabbit antisera to human Tg, but not with sera from patients with thyroid autoimmune disorders containing high levels of anti-microsomal anti-bodies.     

运用ROC曲线方法评价TRAb、TPO-Ab和TGA在Graves'病和HT鉴别诊断中的意义

目的:应用临床诊断性能(ROC)曲线方法评价TSH受体抗体(TRAb)、甲状腺过氧化物酶抗体(TPO-Ab)和甲状腺球蛋白抗体(TGA)在Graves'病(格雷夫斯病)和桥本甲状腺炎鉴别诊断中的意义.方法:以甲状腺细针穿刺细胞学检查结果作为诊断金标准,以采用化学发光法测定63例自身免疫性甲状腺病患者血清的TRAb、TP...     

The expression and role in T cell adhesion of LFA-3 and ICAM-2 on human thyroid cells.

Thyroid follicular cells from patients with Graves' disease and Hashimoto's thyroiditis express intercellular adhesion molecule-1 (ICAM-1) and this is in part responsible for T cell adherence in vitro. To assess the potential role of other adhesion molecules in autoimmune thyroiditis, we investigated the expression and function of lymphocyte function-associated antigen-3 (LFA-3) and ICAM-2 on thyroid cells. Under basal culture conditions, a mean of 22.7% of Graves' thyroid cells (n = 8) expressed LFA-3 and this was enhanced by a mixture of T cell-derived cytokines and by IL-1, but not by TSH. LFA-3 was also demonstrated on Graves' (n = 4) and Hashimoto (n = 2) thyroid cells by immunohistochemical staining ex vivo. A small number of thyroid cells (mean 5.5%, n = 5) expressed ICAM-2 by flow cytometry but this was not altered by cytokines, and ICAM-2 could only be demonstrated on endothelial cells by immunohistochemical staining. It seems likely that contamination of primary thyroid cultures by such cells accounted for the small number of ICAM-2+ cells found using flow cytometry. Almost all of the cultured cells expressing LFA-3 or ICAM-2 also expressed ICAM-1, as assessed by dual staining. Blocking LFA-1, LFA-3, and ICAM-1 with monoclonal antibodies inhibited the adherence of T cells to thyroid follicular cells in assays of cell clustering; antibodies against ICAM-2 had no effect. These results show that two important adhesion receptor ligands, ICAM-1 and LFA-3, are expressed by thyroid cells in autoimmune thyroiditis and that these are likely to have functional importance in allowing T cells to bind to thyroid cell targets. This may play an important role in the initiation and maintenance of Graves' disease and Hashimoto's thyroiditis.     

Thyroid peroxidase

Thyroid Peroxidase (TPO) is a key enzyme in the synthesis of thyroid hormone and is a major thyroid microsomal antigen corresponding to anti-microsomal autoantibodies in thyroid autoimmune diseases. We studied the autoantigenicity, thyroiditogenicity and gene structure of TPO. In micro-ELISA using human TPO as a target, all sera from patients with anti-microsomal antibodies contained IgG class of antibodies to TPO and some sera had IgM class of antibodies. The competitive inhibition test revealed that TPO is the major thyroid microsomal antigen. Experimental murine thyroiditis was successfully induced by the immunization of porcine TPO. Susceptibility of thyroiditis in each strain was very different from that of thyroiditis induced by thyroglobulin. T-cell line specific for porcine TPO could mediate thyroid lesions. Two kinds of full length cDNAs to human TPO were isolated from cDNA library which was constructed from mRNA purified from thyroid with Graves' disease. The longer one consisted of 3,048 nucleotides and its open-reading-frame was likely to encode 933 amino acids. The shorter one lacked 171 nucleotides at the middle portion of the longer one. The structure-gene for human TPO was located on 2q and consisted of 17 exons. One hundred and seventy-one nucleotides deleted in the shorter cDNA exactly corresponded to the 10th exon.     

Evidence for autoimmune mechanisms in the evolution of invasive fibrous thyroiditis (Riedel's struma)

The etiology of Riedel's invasive fibrous thyroiditis, a rare disorder confused in the past with the more common fibrous variant of Hashimoto's disease, has remained obscure. However, the presence of mononuclear cells in the fibrosclerotic process and the detection of autoantibodies directed against thyroid-specific antigens in a large proportion of patients with invasive fibrous thyroiditis favor an autoimmune pathogenesis of invasive fibrous thyroiditis. Further, an association between invasive fibrous thyroiditis and Hashimoto's thyroiditis has been suggested. Here we report the first two patients in whom invasive fibrous thyroiditis evolved from antecedent Graves' disease, documented by the presence of thyroid dysfunction, bilateral ophthalmopathy, and thyrotropin receptor stimulating autoantibodies. The diagnosis of invasive fibrous thyroiditis was established in both instances on the basis of the established histopathological criteria. The presence of extensive mononuclear cell infiltration within the invasive fibrosclerotic process in these two patients, the close relationship between thyroid-specific autoantibodies, inflammatory parameters, and disease activity, and the response to glucocorticoid therapy all suggest the existence of a link between Graves' disease and invasive fibrous thyroditis. These findings support the notion of autoimmune mechanisms playing a role in the pathogenesis of Riedel's invasive fibrous thyroiditis.Abbreviation IFT invasive fibrous thyroiditis Correspondence to: A.E. Heufelder     

Autoimmune thyroid disease and pregnancy: relevance for the child

As a group, the autoimmune thyroid diseases, including Graves' disease, Hashimoto's thyroiditis, and primary myxedema, are among the most common endocrine disorders encountered during pregnancy. Therefore, a substantial number of offspring will grow and develop in utero under conditions of maternal autoimmune thyroid disease and may be exposed to abnormal maternal thyroid function, maternal thyroid antibodies, and/or numerous therapeutic agents used to manage maternal thyroid dysfunction. This article reviews the effects that these various aspects of maternal autoimmune thyroid disorders can have on pregnancy outcome, as well as on the physical growth, neuropsychological development, and thyroid status of the developing fetus and neonate.