Identification of a novel autoantigen UACA in patients with panuveitis

To identify the target autoantigens in Vogt-Koyanagi-Harada disease, we made use of an immunoscreening of a bovine uveal cDNA expression library with serum samples obtained from patients with Vogt-Koyanagi-Harada disease. We identified a novel bovine antigen and homologous human autoantigen and designated it as UACA (uveal autoantigen with coiled coil domains and ankyrin repeats). mRNA of human UACA is expressed most abundantly in skeletal muscles and in various human tissues, including choroid, retina, and epidermal melanocytes. IgG autoantibodies were quantitated in an ELISA, using recombinant C-terminal 18.0% fragment of human UACA. The prevalence of IgG anti-UACA autoantibodies in patients with panuveitis (Vogt-Koyanagi-Harada disease, Beh?et's disease, sarcoidosis) was significantly higher than that in healthy controls (19.6-28.1% vs 0%, P < 0.05) indicating that autoimmunity directed against UACA is a common phenomenon in these diseases.     

Decreased nerve growth factor levels in hyperthyroid Graves' ophthalmopathy highlighting the role of neuroprotective factor in autoimmune thyroid diseases

Nerve growth factor (NGF), which is a neurotrophic factor, is involved in autoimmune and inflammatory processes. Serum NGF levels were investigated in 131 patients with autoimmune (95 with Graves' disease, of whom 57 had ophthalmopathy, 19 with Hashimoto's thyroiditis) and nonimmune thyroid diseases (17 with toxic nodular goitre), and 20 controls. NGF levels were measured via enzyme-linked immunosorbent assay. Twenty-nine positive cases for NGF were detected: 21 cases in Graves' disease, 7 cases in Hashimoto's thyroiditis, no case in toxic nodular goitre and one case in controls. NGF levels were higher in patients with Graves' disease and particularly with Hashimoto's thyroiditis compared with controls (1786.47+/-34.79 pg/ml and 1996.27+/-77.71pg/ml vs 1579.16+/-57.45pg/ml, P<0.049 and P<0.0001, respectively). Increased NGF levels associated with Graves' hyperthyroidism and correlated with FT(3) (P<0.01). Patients with the presence of antibodies against TSH receptor showed higher NGF levels than those with no antibodies (1938.61+/-56.44pg/ml vs 1712.12+/-54.22pg/ml, P<0.009). Decreased NGF levels were demonstrated in hyperthyroid Graves' ophthalmopathy compared with those without eye symptoms (1746.65+/-51.98pg/ml vs 1910.47+/-55.62pg/ml, P<0.036). NGF may be involved in the pathomechanism of autoimmune thyroid diseases. Decreased NGF levels in hyperthyroid Graves' ophthalmopathy highlight the importance of NGF in the neuroprotection of orbital tissues.     

Analysis of Fas, FasL and Caspase-8 expression in thyroid gland in young patients with immune and non-immune thyroid diseases

INTRODUCTION: Apoptosis, programmed cell death is a regulating mechanism enabling the removal of superabundantly produced and unnecessary at the certain moment cells. Disturbances of the apoptosis regulation contribute to the pathogenesis of many diseases, including autoimmune thyroid disorders. The aim of this study was to estimate expression of proapoptotic Fas/FasL and caspase-8 in thyroid tissues in patients with Graves' disease (GD), non-toxic nodular goiter (NTNG) and Hashimoto's thyroiditis (HT). MATERIAL AND METHODS: Inclusion criteria of Graves' patients were: large goiter, ophthalmopathy, TRAb > 5 U/L, positive titre of anti-TPO and anti-TG antibodies and concentration of TSH < 0.45 microIU/mL for more the 2-3 months from an onset of the disease. Isolated thyrocytes were identified by indirect method: in the first stage mouse monoclonal antibodies (mAbs) anti-TPO were bound to rabbit anti-mouse antibodies IgG (Fab')2 labeled FITC. To obtained cellular suspension mAbs directed against apoptotic Fas/FasL molecules labeled with PE (Phycoerythrin) was added. All investigations were performed on Coulter EPICS XL flow cytometer. Detection of apoptotic proteins was confirmed by Western Blot and immunohistochemistry methods using mAbs in DAB chromogene visuality and marked by Mayer's haematoxylin. Evaluation of caspase-8 expression in thyroid follicular cells was performed by Western Blot test. RESULTS: The analysis of Fas and FasL expression on surface of thyroid follicular cells was higher in patients with Hashimoto's thyroiditis (38%, 26%) in comparison with patients with Graves' disease (18%, 14%). In case of patients with Hashimoto's thyroiditis significantly lower percentage of thyroid tissue infiltrating immune Fas+ (13%) and FasL+ (22%) T cells in comparison with Graves' patients (33%, 43% respectively) was observed . Identification of proapoptotic Fas and FasL molecules in the thyroid follicular cells revealed higher expression of both proteins in patients with GD (++,++) and HT (+++; +++, respectively) in comparison with NTNG patients (+/0; +/0). Caspase-8 expression was detected in band 55 kDa using Western Blot test in patients with thyroid autoimmune diseases. CONCLUSIONS: We conclude that alteration in the expression of proapoptotic proteins in thyroid follicular cells may play a role in pathogenesis of thyroid autoimmune disorders. In addition, suppression of apoptosis in Graves' disease led to increased proliferation of thyroid follicular cells which is responsible for goiter formation.     

Pathogenesis of thyroid eye disease - does autoimmunity against the TSH receptor explain all cases?

Thyroid associated ophthalmopathy, or thyroid eye disease (TED), is a complex inflammatory disorder of the eye that, as its name implies, is usually associated with thyroid disease. Clinical observation supports the existence of three main TED subtypes, namely ocular myopathy, congestive myopathy, and mixed congestive and myopathic ophthalmopathy. Although the precise pathophysiology of TED remains unclear, it is likely to reflect an autoimmune reaction involving sensitised T lymphocytes and autoantibodies directed against a specific orbital or thyroid-and-orbital shared antigen(s). One well-studied candidate in this immune reaction is the thyroid-stimulating hormone receptor (TSHR), which is also expressed in the orbital fibroblast and preadipocyte. Most patients with ophthalmopathy have associated Graves' disease, 10% have Hashimoto's thyroiditis in which the eye changes are often mild and expressed mainly as upper eyelid retraction (UER), and 10% have no apparent associated thyroid disease - so-called "euthyroid Graves' disease". Ophthalmopathy can also occur in some patients with transient thyroiditis, thyroid cancer, and Graves' disease many years after treatment of the hyperthyroidism - situations where TSHR antibodies are not expected to be present, suggesting that the relationship between TSHR antibodies and the eye disorder has not been established for all cases. In our studies of TED we have investigated the nature and significance of antibodies targeting other eye muscle and orbital connective tissue (OCT) antigens, in particular the calcium binding protein calsequestrin (CASQ1) and the orbital fibroblast membrane antigen collagen XIII. Our working hypotheses for the pathogenesis of TED are: i) the initial reaction in the orbit is antibody and T lymphocyte targeting of the TSHR in the OCT compartment, and ii) the associated extra ocular and upper eyelid muscle inflammation reflects either autoimmunity against primary skeletal muscle antigens such as CASQ1 or a secondary, non specific effect of the OCT reactions as proposed by the main proponents of the "TSHR hypothesis". Here, we review the evidence that autoimmunity against the TSHR expressed in the orbit can be implicated in the development of all cases of TED. Although there is a close general correlation between ophthalmopathy and TSHR antibodies there are many exceptions, suggesting that the continued study of the possible role of autoimmunity against calsequestrin and collagen XIII is justified.     

Etiopathogenesis of Graves' disease

Graves' disease is an autoimmune disorder, caused by thyroid-stimulating antibodies, which bind to and activate the thyrotropin receptor on thyroid cells, inducing the synthesis and release of thyroid hormones. It is a polygenic and multifactorial disease that develops as a result of complex interaction between genetic susceptibility and environmental and/or endogenous factors. Graves' disease differs from other autoimmune diseases of the thyroid by specific clinical features, including hyperthyroidism, vascular goitre, ophthalmopathy and--less commonly--infiltrative dermopathy. This article discusses current theories, regarding the etiology and pathogenesis of Graves' disease, including possible predisposing factors, autoimmune aspects of Graves' disease, ophthalmopathy, and dermopathy.     

Thyroid hormone modulates insulin-like growth factor-I(IGF-I) and IGF-binding protein-3, without mediation by growth hormone, in patients with autoimmune thyroid diseases.

The expression and synthesis of insulin-like growth factor-1 (IGF-I) and IGF-binding protein-3 (IGFBP-3) are regulated by various hormones and nutritional conditions. We evaluated the effects of thyroid hormones on serum levels of IGF-I and IGFBP-3 levels in patients with autoimmune thyroid diseases including 54 patients with Graves' disease and 17 patients with Hashimoto's thyroiditis, and in 32 healthy age-matched control subjects. Patients were subdivided into hyperthyroid, euthyroid and hypothyroid groups that were untreated, or were treated with methylmercaptoimidazole (MMI) or L-thyroxine (L-T4). Serum levels of growth hormone (GH), IGF-I and IGFBP-3 were determined by radioimmunoassay. Serum GH levels did not differ significantly between the hyperthyroid and the age-matched euthyroid patients with Graves' disease. The serum levels of IGF-I and IGFBP-3 showed a significant positive correlation in the patients (R=0.616, P<0.001). The levels of both IGF-I and IFGBP-3 were significantly higher in the hyperthyroid patients with Graves' disease or in those with Hashimoto's thyroiditis induced by excess L-T4 administration than in control subjects. Patients with hypothyroid Graves' disease induced by the excess administration of MMI showed significantly lower IGFBP-3 levels as compared to those in healthy controls (P<0.05). Levels of IGFBP-3, but not IGF-I levels, showed a significant positive correlation with the levels of free T4 and free T3. In Graves' disease, levels of TPOAb, but not of TRAb, showed a significant positive correlation with IGFBP-3. We conclude that in patients with autoimmune thyroid diseases, thyroid hormone modulates the synthesis and/or the secretion of IGF-I and IGFBP-3, and this function is not mediated by GH.     

IgA and IgG antigliadin,IgA anti-tissue transglutaminase and antiendomysial antibodies in patients with autoimmune thyroid diseases and their relationship to thyroidal replacement therapy

Celiac disease is a chronic illness of the small bowel caused by gliadin intolerance in genetically predisposed subjects. The aim of this study was to investigate serum levels of IgA and IgG antigliadin antibodies, IgA antiendomysial antibodies, and IgA anti-tissue transglutaminase antibodies in 169 patients with autoimmune thyroid diseases, i.e. chronic thyroiditis and Graves' disease. Antiendomysial antibodies were positive in 2 out of 169 persons (1.18%), IgA antigliadin antibodies in 15.98%, IgG antigliadin antibodies in 51.48%, and IgA anti-tissue transglutaminase in 14.79%. The prevalence of positivity was higher compared to the 1312 control blood donors described in our previous study (Vancíková et al. 2002) (p<0.05). Patients with chronic thyroiditis treated with a high replacement dosage of levothyroxin (125-200 microg daily) had higher serum levels of IgA antigliadin antibodies in comparison with patients treated with a lower dosage (50-100 microg daily) (medians: 13.00 vs. 19.69, p=0.033). We found a negative correlation of IgA anti-tissue transglutaminase antibodies and total calcium serum levels (r = -0.480, p=0.0236, n=22). We can conclude that in persons with autoimmune thyropathy there is a high prevalence of positive antigliadin, anti-tissue transglutaminase and antiendomysial antibodies. Latent celiac disease may lead to impaired resorption of therapeutically administered levothyroxine, calcium, or other substances.     

Autoimmune thyroid diseases in women with breast cancer and colorectal cancer

The aim of the study was to compare the prevalence of autoimmune thyroid diseases in three groups of women (66 with breast cancer (CaB), 68 with colorectal cancer (CaC) and 49 without oncological diseases as a control group). Serum levels of thyroid-stimulating hormone (TSH), free thyroxin (fT4), antibodies to thyroglobulin (TGB-ab) and thyroperoxidase (TPO-ab) and tumor markers CEA, CA 15-3 and CA 19-9 were investigated in all subjects by using the chemiluminiscence method. In contrast to Graves' disease (no observed case), autoimmune thyroiditis was diagnosed in 24.2 % women with CaB (4.5 % euthyroid and 19.7 % with subclinical or overt hypothyroidism), compared to 16.7 % in women with CaC (2.0 % euthyroid and 14.7 % with subclinical or overt hypothyroidism) and 16.2 % controls (4.0 % euthyroid and 12.2 % with subclinical or overt hypothyroidism). Serum levels of TGB-ab were higher in the group with breast cancer as compared to those with colorectal cancer and the control group (medians: 35.80 vs. 31.75 vs. 27.70, p<0.001). Similarly, the percentage of positive TGB-ab and TPO-ab serum levels was higher in women with breast cancer as compared to those with colorectal cancer and the control group. The results of the study support the controversial theory that there is an increased prevalence of autoimmune thyroiditis in women with breast cancer.     

Anterior pituitary cell antibodies detected in Hashimoto's thyroiditis and Graves' disease

An immunofluorescence study using unfixed cryostat sections of rat pituitary glands was carried out on sera from 34 patients with Hashimoto's thyroiditis, 28 patients with Graves' disease, 10 patients with thyroid adenoma and 50 healthy subjects. After absorption of sera with rat liver tissues, 19 of 34 patients retained reactivity to anterior pituitary cell antibodies (PCA, 55.8%). On the other hand, immunofluorescence in anterior pituitary cells was faint and detected in only 2 of 28 patients with Graves' disease (7.1%) after absorption of their sera with rat liver aceton powder. A similar result was also obtained when PCA were compared in the sera of Hashimoto's thyroiditis and Graves' disease with high titers of thyroid microsomal autoantibodies. PCA were detected neither in the sera of patients with thyroid adenoma nor in the healthy subjects. The present study suggests that PCA were considerably more prevalent in Hashimoto's thyroiditis than in Graves' disease.     

Serum IL-18 levels are not increased in patients with untreated Graves' ophthalmopathy.

OBJECTIVE: Cytokines play an important role in autoimmune thyroid diseases, and serum levels may reflect the activity of the immune process. This is particularly interesting in Graves' ophthalmopathy, where a reliable serum activity marker is warranted. Interleukin-18 (IL-18) is a potent Th1 cytokine, known to induce interferon (IFN)-gamma and the aim of this study was to evaluate serum IL-18 levels in Graves' ophthalmopathy. METHODS: Serum IL-18 was measured by ELISA in 52 patients with untreated Graves' ophthalmopathy (who all had been rendered euthyroid with antithyroid drugs), 52 healthy controls matched for sex, age, and smoking habits, and 15 euthyroid patients who had been treated for Graves' hyperthyroidism and ophthalmopathy in the past. RESULTS: Serum IL-18 (median values in pg/ml with range) levels did not differ between the untreated Graves' ophthalmopathy patients-226 (61-704) pg/ml, matched healthy controls-194 (17-802) pg/ml, and Graves' ophthalmopathy patients treated in the past-146 (0-608) pg/ml. No correlation was observed between serum IL-18 levels and thyroid function or antithyroid antibodies. There was no correlation between serum IL-18 levels and smoking habits. CONCLUSION: We conclude that Graves' ophthalmopathy does not affect serum IL-18.     

Immunoglobulin G subclasses of anti-thyroid peroxidase autoantibodies in human autoimmune thyroid diseases

A distribution of immunoglobulin G (IgG) subclass of anti-thyroid peroxidase (TPO) autoantibodies was studied to know whether anti-TPO autoantibodies are closely implicated in the pathogenesis of human autoimmune thyroid diseases. As a result of analyzing 14 patients' sera, 7 with Graves' disease and 7 with Hashimoto's thyroiditis, anti-TPO autoantibodies were found to consist of mainly IgG1 subclass. Percentages of both IgG1 and IgG2 subclasses in IgG class of autoantibodies corresponded to those in the normal serum composition, whereas IgG3 subclass was scarcely contained in anti-TPO autoantibodies and IgG4 subclass markedly increased. It was thought that anti-TPO autoantibodies had a capability to lyse thyroid follicular cells by the mechanism of antibody-dependent complement-mediated cytolysis, because IgG1 and IgG2 subclasses of antibodies can fix complement and TPO locates in apical membrane surface of thyroid follicular cells. Comparing Graves' disease with Hashimoto's thyroiditis, mean percentages of both IgG1 and IgG2 subclasses of 2 groups were statistically different. Namely, sera of patients with Graves' disease had higher and lower mean percentages of IgG1 and IgG2 subclasses of autoantibodies, respectively, than those with Hashimoto's thyroiditis, though no plausible explanation for these differences can be offered at the present time.     

Second-generation thyrotropin receptor antibodies assay and quantitative thyroid scintigraphy in autoimmune hyperthyroidism.

Graves' disease (GD) is characterized by circulating TSH receptor antibodies (TRAb), and so-called hyperthyroid autoimmune thyroiditis (H-AIT) generally shows negative TRAb results with first-generation assays. However, a positive titer was observed in up to 13% of patients with euthyroid or hypothyroid autoimmune thyroiditis (AIT) by second-generation TRAb assays, and a larger increase is expected in hyperfunctioning forms. A thyroid 99mTc-pertechnetate uptake (TcTUs) cutoff of 2% previously was shown to accurately discriminate between GD and H-AIT. Here we evaluated the relationship between second-generation TRAb assays and TcTUs in 139 patients with untreated autoimmune hyperthyroidism. An increase in TRAb levels was found in 114 of 139 patients (82%). All patients with TcTUs >2% and 66% of those with lower values had positive TRAb measurements. When the cutoff was increased to 5.9 U/l, positive TRAb occurred in 92.6% of those having higher TcTUs and in 1.4% of those with lower TcTUs. TRAb levels significantly increased in patients with TcTUs higher than 2% as compared with those having lower values, while no differences occurred in patients with TcTUs ranging from 0 to 1%, from 1.1 to 1.5%, or from 1.6 to 2%. A significant relationship between TRAb and TcTUs (as well as fT3, fT4, and thyroid volume) was found. TcTUs, fT4, fT3, and thyroid volume significantly increased in patients with positive TRAb (cutoff 1.5 U/l) compared with those testing negative. Our data indicate that a large proportion of patients with hyperthyroidism and hypoechoic thyroid, including those previously diagnosed as having H-AIT, actually have circulating TRAb. TRAb levels predicate the degree of iodine uptake (as measured by TcTUs) and thyroid hyperfunction. The role of baseline TRAb measurement by second-generation assays to predict patients' outcome needs to be further evaluated and compared with TcTUs in prospective studies.     

Incidences of antibodies to Yersinia enterocolitica: high incidence of serotype O5 in autoimmune thyroid diseases in Japan

Antibodies to Yersinia enterocolitica serotype O3, O5, O6 and O9 were measured by the micro-agglutination method in 445 healthy subjects and patients with Grave's disease (n = 70), Hashimoto's disease (n = 45) and thyroid tumor (n = 29). In contrast to previous reports, the incidence of antibodies to serotype O3 in each group of patients with thyroid diseases was not significantly different from that in healthy subjects. However, the incidence of antibodies to serotype O5 was significantly higher in patients with Graves' disease (81.4%, P less than 0.001) and Hashimoto's disease (91.1%, P less than 0.001) than in healthy subjects (258.9%). Significantly increased incidence of antibodies to serotypes O6 and O9 was observed only in patients with Hashimoto's disease (40.0% and 51.1% vs healthy subjects 24.7% and 29.9%, respectively). Patients with thyroid tumor showed no increase in any serotype of Yersinia enterocolitica. No correlations was found between the titers of anti-Yersinia antibodies and anti-thyroglobulin or anti-microsomal antibodies. These data indicate an association between thyroid autoimmunity and antibodies to Yersinia enterocolitica. These results are different from those in reports from other countries, suggesting that serotype specificity may be influenced by racial or genetic factors.     

Antibodies to Yersinia enterocolitica serotype 3 in autoimmune thyroid diseases

The prevalence of increased titres of antibodies to Yersinia enterocolitica (serotype 3) has been studied in sera from patients with various thyroid diseases. In contrast to the low prevalences of the antibodies in healty subject (24.3%), titres (greater than 10) of anti-Yersinia enterocolitica (anti-Yersinia) were found more frequently in patients with thyroidal disorders, especially in Graves' disease (70.0%). Furthermore, high titres of the antibodies (greater than or equal to 160) were found only in patients with Graves' disease. There was no significant correlation between the titers of anti-Yersinia antibodies and those of anti-TSH receptor antibodies in sera from patients with Graves' disease. In seven individual samples of sera, the anti-Yersinia antibody titer was high before treatment, but the decrease in the anti-TSH receptor antibody titer following treatment was associated with a simultaneous decline in anti-Yersinia antibodies in all of them. A highly positive and significant correlation between the titers of anti-TSH receptor antibodies and anti-Yersinia antibodies was obtained in each of them. These findings could be merely a reflection of the measurement of the cross-reaction of anti-Yersinia antibodies with anti-TSH receptor antibodies but the possibility of an association between Yersinia infection and the production of anti-TSH receptor antibodies in at least some patients with Graves' disease cannot be ruled out.     

Enhanced prednisolone elimination: a possible cause for failure of glucocorticoid therapy in Graves' ophthalmopathy

This study was undertaken to determine the pharmacokinetics of intravenous prednisolone in patients with Graves' eye disease. 6 women with Graves' ophthalmopathy treated with prednisolone for severe endocrine exophthalmos were compared with 6 healthy female volunteers. All subjects with Graves' disease had been taking carbimazole and I-thyroxine as concurrent drugs for at least 4 months prior to study day. All subjects were euthyroid. Each subject received .54 mg/kg prednisolone as an i.v. bolus. Plasma concentrations for total and unbound prednisolone were determined by HPLC and equilibrium dialysis. Significant increase (p less than .01) in clearance values and significant decreases in half-life times (p less than .01) were found for both total and unbound prednisolone in women with Graves' disease compared with the control subjects. Volumes of distribution at steady-state were unchanged in both groups. The data suggest that patients with Graves' ophthalmopathy show an enhanced elimination for prednisolone and that is why they may need higher doses of corticoid although the function of the thyroid gland is euthyroid.     

Mechanisms of immune damage in Graves' ophthalmopathy

We have studied the role of immunologically mediated cytotoxicity in the orbital tissue damage of Graves' ophthalmopathy. Antibody-dependent cell-mediated cytotoxicity (ADCC) against eye muscle (EM) cells and orbital fibroblasts (OF) was demonstrated in a small proportion of patients, all of whom had severe, recent disease. Antibody-mediated (complement-dependent) cytotoxicity against OF was found in only a few patients. No patients showed lysis above background with EM targets. ADCC activity against OF was absorbed by preincubation of serum with thyroid cells, eye muscle cells, and orbital fibroblasts, as well as thyroid, eye muscle and orbital connective tissue membranes. Both EM and OF were able to express class II MHC HLA-DR antigens when stimulated by gamma interferon, phytohemagglutinin or activated T lymphocytes. DR-positive target cells were much more susceptible to lysis, in both ADCC and lymphocyte-mediated cytotoxicity, than DR negative cells. When DR-positive OF and EM were used as targets in ADCC assays, the degree of lysis determined as 51Cr release given by serum from patients with Graves' ophthalmopathy was enhanced, but only in those patients showing positive tests with DR-negative targets. Intrathyroidal T lymphocytes obtained from a patient with Graves' ophthalmopathy were more cytotoxic against DR-positive OF and EM than equal numbers of her peripheral blood T lymphocytes. Antibody-dependent cell-mediated cytotoxicity and lymphocyte-mediated cytotoxicity against orbital fibroblasts and eye muscle cells are thus associated with target cell HLA-DR antigen expression and are likely to be mechanisms for in vivo tissue damage in Graves' ophthalmopathy. The identity of the mononuclear cell subpopulation effecting cell-mediated cytotoxicity against orbital target cells, and the possible significance of reaction of cytotoxic antibodies against orbital, thyroid-shared antigens are unclear.     

Antigenic relation between thyroid peroxidase and the microsomal antigen implicated in auto-immune diseases of the thyroid

Pools of sera from patients with Graves' disease or Hashimoto's thyroiditis highly inhibit the binding to human thyroid membranes of one of 19 monoclonal antibodies raised against preparations of human thyroid membranes. This monoclonal antibody reacts with human and bovine thyroid peroxidase and bovine lactoperoxidase but not with human hemoglobin, cytochrome c and other related molecules. These results indicate that the thyroid peroxidase and the microsomal antigen are antigenically related. These data taken together with those from other groups, highly suggest that thyroid peroxidase is the microsomal antigen involved in autoimmune thyroid diseases.     

Interferon-induced thyroiditis during treatment of chronic hepatitis C

Thyroid function disorders affect between 5% and 15% of patients treated with IFNα and RBV for chronic hepatitis C. Women and patients with thyroid peroxidase antibodies (TPOAb) found before the treatment are at risk of developing the disorders (46.1% vs. 5.4%). The spectrum of IFNα-induced thyroiditis (IIT) includes two groups. Disorders with an autoimmune background are: presence of thyroid autoantibodies without clinical disease, Hashimoto's disease and Graves' disease. The second group comprises diseases caused by the direct toxic effect of IFNα on the thyroid gland, i.e. destructive thyroiditis and non-autoimmune hypothyroidism. Thyroid diseases are not an absolute contraindication for IFNα and RBV therapy. In patients diagnosed with thyroid dysfunction, before the antiviral therapy it is necessary to achieve euthyreosis. Thyroid function disorders may occur at any moment of the therapy. The earliest have been observed in the 4th week of treatment, and the latest 12 months after its termination. During the therapy, in order to diagnose IIT early, it is recommended to determine TSH level every 2-3 months depending on the presence of TPOAb before the treatment. The diagnosis and treatment of thyroid function disorders should be conducted in co-operation with an endocrinologist.     

Increase in autorosette-forming lymphocytes in thyroid diseases

A subpopulation of lymphocytes forming rosettes with autologous erythrocytes was studied on peripheral blood and thyroid tissues obtained from the patients with various thyroid diseases. The mean (+/-S.D.) percentage of autorosette-forming cells (ARFC) was 10.1(+/-5.5)% in the peripheral blood from patients with hyperthyroid Graves' disease, which was higher than that in normal subjects (5.6 +/- 2.8%), while the levels of ARFC in the peripheral blood from euthyroid patients with Graves' disease under treatment and Hashimoto's thyroiditis did not significantly differ from the normal level. The mean percentages of ARFC in the thyroid tissues from patients with Graves' disease and Hashimoto's thyroiditis were 14.7(+/-8.5) and 13.3(+/-7.8)%, respectively, which were higher than those in the peripheral blood from the same patients. Most of these cases with abnormally high levels of ARFC were accompanied with the abnormally low T cell to B cell ratios. The microscopic examination of the cytological materials from these patients showed an increased number of large stimulated lymphoid cells or lymphoblasts as compared with those who had few ARFC. These results suggest an increase in an activated T cell subset in the circulation and/or in the thyroid tissue, which is probably caused by active immune response to some stimuli.     

Similarity and dissimilarity between clinical and laboratory findings, especially anti-thyrotropin receptor antibody in ophthalmic Graves' disease without persistent hyperthyroidism and hyperthyroid Graves' disease

The aim of this study was to investigate thyroid states, significance of anti-TSH receptor antibodies and the clinical courses of patients with euthyroid Graves' ophthalmopathy. The clinical and laboratory finding of 30 patients with euthyroid Graves' ophthalmopathy were briefly as follows: 1) normal sized thyroid or small goiter; 2) negative or weakly positive thyrotropin binding inhibitor immunoglobulin (TBII); 3) normal thyroid [99 m-Tc] pertechnetate uptake; and 4) frequent observations of low serum TSH values. Besides TBII, thyroid stimulating antibody (TSAb) was measured under low salt and isotonic conditions using FRTL-5 rat thyroid cells. Both TBII and TSAb titers were lower in euthyroid Graves' ophthalmopathy than in hyperthyroid Graves' disease. Serum TSH levels frequently became low in patients considered as euthyroid upon the first examination as well as in Graves' patients in remission, reflecting preceding or mild hyperthyroidism. In follow-up studies, these patients with mildly elevated thyroid hormone levels and low TSH levels seldom reached a state of persistent hyperthyroidism, when TBII was negative or only weakly positive.