Interactions among thyroid hormone (FT4), chemokine (MCP-1) and neurotrophin (NGF-ß) levels studied in Hungarian postmenopausal and obese women.

Thyroid dysfunction is more frequent in postmenopause and metabolic syndrome characterized by increased proinflammatory cytokines (IL-1, IL-6, TNFα), insulin resistance and overweight. Serum levels of monocyte chemoattractant protein-1 (MCP-1) chemokine and nerve growth factor-ß (NGF-ß) and their effects were studied on thyroid hormone levels in 133 Hungarian women (postmenopausal 66, obese 32, control 35). MCP-1 and NGF-ß levels were measured with enzyme-linked, and thyroid hormones with chemiluminescence immunoassays. Subclinical hypothyroidism in postmenopause (7/66 vs 1/32 cases) and the presence of low FT4 levels in obese women were more frequent (6/32 vs 2/66 cases, p < 0.0447). Obese women showed reduced serum FT4 and higher MCP-1 or NGF-ß levels compared to those in postmenopausal women [geometric mean (95%CI): 13.6 (10.9-21.69) vs 15.37 (9.06-20.42) pmol/l, p < 0.003 for FT4, and 19.36 (14.27-26.26) vs 17.29 (12.65-23.63) ng/ml, p < 0.0013 for MCP-1 or 18.64 (6.8-51.11) vs 14.01 (8.59-22.83) ng/ml, p < 0.0003 for NGF-ß]. Serum FT4 levels inversely associated with MCP-1 (p < 0.0023, r = -0.1971) or estradiol levels (p < 0.0286, r = -0.1913), and positively associated with age (p < 0.0175, r = 0.2058). As opposed to estradiol and NGF-ß levels, BMI had no effects on serum FT4 levels in postmenopausal and obese women forming 3 subgroups displaying only MCP-1, both MCP-1 and NGF-ß positivities or no positivities at all. In summary, not only proinflammatory cytokines, but also MCP-1 chemokine and NGF-ß levels can play a role in reduced serum FT4 levels in postmenopausal and obese women. Particularly, the decreased FT4 levels were connected to both increased MCP-1 and NGF-ß levels in obese women.

Effect of antithyroid drugs on the occurrence of antibodies against type 2 deiodinase (DIO2), which are involved in hyperthyroid Graves' disease influencing the therapeutic efficacy.

Graves' disease is an organ-specific autoimmune disease with hyperthyroidism, diffuse goiter and autoantibodies against TSH receptor, thyroid peroxidase (TPO) and/or thyroglobulin (Tg). Graves' hyperthyroidism is characterized by T3 dominance due to the conversion of T4 into T3 through type 1 and 2 deiodinase enzymes (DIO1, DIO2). Methimazole (MMI) and propylthiouracil (PTU) therapies inhibit thyroid hormone synthesis blocking the activity of deiodinase and TPO enzymes. The study investigated the occurrence of autoantibodies against DIO2 peptides (cys- and hom-peptides) with the effect of antithyroid drugs on their frequencies in 78 patients with Graves' disease and 30 controls. In hyperthyroidism, the presence of DIO2 peptide antibodies was as follows: 20 and 11 cases out of 51 for cys- and hom-peptide antibodies, respectively, of whom 8 cases possessed antibodies against both peptides. Antithyroid drugs differently influenced their frequencies, which were greater in PTU than in MMI (3/6 vs 13/45 cases, P < 0.016 for cys- and 0/6 vs 2/45 cases for hom-peptide antibodies). Antibodies against both peptides demonstrated more reduced levels of anti-TPO (P < 0.003) and anti-Tg antibodies (P < 0.002) compared with those without peptide antibodies. PTU compared with MMI increased the levels of TSH receptor antibodies (32.5 UI/l vs 2.68 IU/l, P < 0.009). MMI treatment led to more reduced FT3 levels and FT3/FT4 ratios in hyperthyroid Graves' ophthalmopathy (P < 0.028 for FT3, P < 0.007 for FT3/FT4 ratio). In conclusion, the presence of DIO2 peptide antibodies is connected to Graves' hyperthyroidism influencing the levels of antibodies against TPO, Tg and TSH receptor, as well as the therapeutic efficacy of antithyroid drugs.

Hyperthyroidism in Patients with Graves' Ophthalmopathy, and Thyroidal, Skeletal and Eye Muscle Specific Type 2 Deiodinase Enzyme Activities.

Graves' ophthalmopathy is characterized by hyperthyroidism, which is associated with higher serum T3 levels than T4 due to deiodinase enzymes.The effect of Graves' patient's sera (n=52) with elevated thyroid hormone and TSH receptor or thyroid peroxidase antibody (anti-TPO) levels was investigated on thyroidal, skeletal and eye muscle type 2 deiodinase enzyme (DII) activities. DII activities were measured with 125I-T4 substrate, while thyroid hormone and antibody levels with immunoassays.In Graves' ophthalmopathy, sera with elevated FT4 or FT3 levels reduced DII activites remarkably in all tissue fractions. Thyroidal DII activities were lower than those using eye muscle fraction (0.6±0.22 vs 1.14±0.43 pmol/mg/min, P<0.006). Effect of sera with increased FT3 levels demonstrated also reduced DII activities in patients with Graves' ophthalmopathy after methimazole therapy compared to those who had no ophthalmopathy (2.88±2 vs 20.42±11.82 pmol/mg/min, P<0.006 for thyroidal fraction, 4.07±2.72 vs 29.22±15.46 pmol/mg/min, P<0.004 for skeletal muscle, 5.3±3.47 vs 37.87±18.82 pmol/mg/min, P<0.003 for eye muscle). Hyperthyroid sera with TSH receptor antibodies resulted in increased DII activities, while sera with anti-TPO antibodies were connected to lower DII activities in Graves' ophthalmopathy.In summary, the actions of hyperthyroid sera derived from patients with Graves' disease were tested on tissue-specific DII activities. Elevated FT4 level-induced DII inactivation is present in Graves' ophthalmopathy, which seems to be also present at the beginning of methimazole therapy. Stimulating TSH receptor antibiodies increased DII activities via their nongenomic effects using sera of hyperthyroid Graves' ophthalmopathy, but anti-TPO antibodies could influence DII activities via altering FT4 levels.

High prevalence of increased interleukin-17A serum levels in postmenopausal estrogen deficiency.

OBJECTIVE: Postmenopausal estrogen deficiency is associated with chronic inflammatory events that cause cardiovascular and osteoporosis diseases. The aim of this study was to investigate the relationship between interleukin (IL)-17 and serum estradiol levels, age, and postmenopausal duration, as well as bone loss. METHODS: The relationship between serum IL-17A and estradiol levels was studied in 72 postmenopausal women and 22 premenopausal women. Enzyme-linked immunosorbent assay and chemiluminescence were used to detect IL-17A and estradiol, respectively. RESULTS: Estradiol levels were significantly higher and IL-17A levels were significantly lower in premenopausal women compared with postmenopausal women (estradiol: 239.44 [226.17] vs 74.21 [4.44] pmol/L, P < 0.0001; IL-17A: 2.88 [0.08] vs 3.5 [0.56] ng/mL, P < 0.0001). Seventy-eight of 94 women had lower estradiol levels (<83 pmol/L) with elevated IL-17A levels, in comparison with 16 women who had normal estrogen levels (3.43 [0.56] vs 3.01 [0.38] ng/mL, P < 0.0001). IL-17A levels inversely correlated with the total lumbar T-scores calculated in all women (P < 0.0001). IL-17A levels showed age-related dependency and a remarkable association with the postmenopausal period (P < 0.03). CONCLUSIONS: The results demonstrate a high prevalence of increased serum IL-17A levels in postmenopausal estrogen deficiency, which can play an inducing role in chronic inflammatory events such as bone loss.

Autoantibodies to novel membrane and cytosolic antigens of the lachrymal gland in primary Sjögren's syndrome.

Sjögren's syndrome (SS) is a prototypical systemic autoimmune disease, where autoimmune processes lead to the dysfunction of the exocrine glands. The key feature of the disease is autoimmune exocrinopathy, causing reduced tear secretion and subsequent keratoconjunctivitis sicca (KCS). The aim of this study was to investigate the connection between the presence of autoantibodies to lachrymal gland antigens and the reduced tear production in patients with primary SS. Ninety-nine patients, 90 women and 9 men, were investigated in the study. Twenty healthy young women served as controls. Enzyme-linked immunosorbent assay (ELISA) and Western blotting were applied to detect autoantibodies to antigen fractions prepared from the human lachrymal gland membrane and cytosolic fractions. Autoantibodies of the IgG, IgA and IgM isotypes to the lachrymal membrane and cytosolic fractions were detected in about one third (27%) of the patients with primary SS. IgA antobodies to the membrane and cytosolic fractions occurred most frequently in SS patients. A significant difference was found in the presence of IgA antibodies to the membrane lachrymal fraction between patients and controls given in ELISA indices (1.23 +/- 0.3 vs 1 +/- 0.19, p < 0.001). IgG, IgA, and IgM isotypes of autoantibodies directed to the membrane lachrymal fraction of 200-180, 120-116, 80-70, 58, 50, 48.5, 40 and 28.8 kDa were also identified in patients. Membrane IgG antibody levels showed a positive correlation (R = 0.998; p = 0.045) with the clinical loss of secretory function (Schirmer's test values). Positive correlation was found between membrane IgM and anti-SS-A levels (R = 0.962; p = 0.038) and also between cytosolic IgM antibodies and anti-SS-A levels (R = 0.982; p = 0.018). IgG, IgA and IgM types of autoantibodies may play a role in the development of the impaired lachrymal secretion and therefore may be involved in the pathogenesis of KCS.

[What is the role of allergic sensitization in Graves' disease?]. / Milyen szerepe lehet Graves-kórban az allergiás sensitisatiónak?

INTRODUCTION: Recent data supported the presence of T helper 2 dominance in the immune processes of Graves' disease and allergic diseases. A common role of regulatory T cells in the antigen- (or allergen-) specific immune responses was also demonstrated. AIMS: To study whether allergic events may play a role in the initiation or progression of autoimmune Graves' disease. The occurrence of seasonal allergy may explain the fluctuation in the onset of Graves' disease. METHODS: The presence of specific IgE levels against inhalative allergens was investigated in 327 patients with thyroid disease (Graves' disease, Hashimoto's thyroiditis, euthyroid goitre). Western blot method was used for the measurement of allergen-specific IgE levels with densitometric evaluation. RESULTS: Allergic sensitization was found in 88 cases (58%) for Graves' disease, 51 cases (46%) for Hashimoto's thyroiditis and 31 cases (55%) for euthyroid goitre. According to allergens, significant difference was demonstrated by Penicillium notatum, Dermatophagoides farinae, alder - rye (pollens) between Graves' disease (depending ophthalmopathy) and euthyroid goitre. In the four groups based on allergen seasonality, the month of the onset in Graves' disease was associated with the season of early tree and mugwort allergy (P < 0.019 between Graves' disease and Hashimoto's thyroiditis). The number of cases, in whom the onset of Graves' disease in a given month was similar to the month of allergic season, was 17 cases vs 7 cases with Hashimoto's thyroiditis (P < 0.028). CONCLUSIONS: The allergic sensitization was more frequent in Graves' disease, and the allergic seasonality may explain the fluctuation in the onset of Graves' disease.

The balance shift in Th1/Th2 related IL-12/IL-5 cytokines in Graves' disease during methimazole therapy.

Th1 and Th2-like cytokines are involved in the pathogenesis of Graves' disease. The shift in balance in IL-12/IL-5 cytokines was applied in judging the immunological events in 74 patients with Graves' disease (50 had ophthalmopathy) during methimazole therapy and in 15 controls. The serum levels of IL-12 and IL-5 were measured with enzyme-linked immunosorbent assay in all Graves' patients. Twelve cases for IL-5 and 20 cases for IL-12 were positive. In Graves' patients only those without ophthalmopathy had higher levels of IL-12 when compared to controls (192.66 +/- 29.19 vs. 85.09 +/- 8.95 pg/ml, P < 0.04). After 2 months of methimazole therapy in Graves' patients without ophthalmopathy an increase in the ratio of IL-12 to IL-5 was also observed as compared to those with eye symptoms (91.78 +/- 34.14 vs. 20.72 +/- 6.36, P < 0.015). Age-related difference in the serum level of IL-5 could be demonstrated between Graves' patients without and those with ophthalmopathy aged < or = 35 years (4.89 +/- 0.57 vs. 50.14 +/- 20.2 pg/ml, P < 0.002). No association was found among the serum levels of IL-5 or IL-12, thyroid hormones and TSH receptor antibodies. The results demonstrated a difference in the balance shift of IL-12/IL-5 between Graves' patients with and without ophthalmopathy. The increased ratio of IL-12 to IL-5 after methimazole therapy could be explained by the elevation of serum IL-12 due to methimazole therapy and the age-related decrease of serum IL-5.

Immunohistochemical studies using immunized Guinea pig sera with features of anti-human thyroid, eye and skeletal antibody and Graves' sera.

Type 2 5' deiodinase enzyme was observed in both thyroid and eye muscle tissues, highlighting its possible role as a common antigen in thyroid-associated ophthalmopathy. Sera of 105 Graves' patients and 40 controls, and immunized guinea pig sera against TCSS peptide, showing homology to the amino acid sequence from 132 to 152 of type 2 5' deiodinase, were investigated to demonstrate the binding effects to human thyroid, eye and skeletal muscle tissues. Twenty-two Graves' patients were positive for anti-TCSS peptide antibodies, of whom 18 cases had ophthalmopathy. The levels of anti-TCSS peptide antibodies were higher not only in Graves' patients with (P<0.0001) and without (P<0.036) eye symptoms compared to controls but also the difference was significant between patients with and without ophthalmopathy (P<0.049). In Western blot, immunized sera showed binding reactions to the supernatant fractions of human thyroid, eye and skeletal muscle tissues at the range of 29 kDa. Patient sera with Graves' ophthalmopathy resulted in positive reactions directed to membrane areas in thyroid follicular cells, and to fibers in eye and skeletal muscles using immunohistochemical method, while no positive staining was present after adding control sera. The binding features of immunized guinea pig sera exhibited similar staining in all human tissues but could be blocked with Graves' sera. Our results suggest that type 2 5' deiodinase enzyme protein could play a role as an antigen in Graves' disease. Immunized guinea pig sera against TCSS peptide exhibited similar binding reactions and stainings to human thyroid, eye and skeletal muscle tissues as patient sera with Graves' ophthalmopathy.

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.

[Cardiovascular consequences of thyroid diseases, their prevalence and treatment, particularly in cases with subclinical hyper- and hypothyroidism]. / Pajzsmirigybetegségek kardiológiai vonatkozásai, elofordulásuk és kezelésük, különös tekintettel a szubklinikus hyper- és hypothyreosisra.

Cardiovascular consequences of thyroid diseases, their prevalence and treatment, particularly in cases with subclinical hyper- and hypothyroidism. The aim of the study was to draw attention to an association between the thyroid and cardiovascular diseases. The main topic was to lay emphasis on the importance of cardiovascular diseases caused by subclinical hyper- and hypothyroidism in the relation to the practice. The subclinical states precede the overt hyper- and hypothyroidism, and they are often present during their treatments. The changes in the levels of thyrotropin demonstrating subclinical thyroid diseases, could be detected in different non-thyroid diseases and resulted from the effect of some drugs. Particularly, the subclinical thyroid diseases become more frequent in older age. In the background of the high prevalences of atrial fibrillation, hypertension and psychosomatic events subclinical hyperthyroidism could be revealed. Subclinical hypothyroidism is characterized by an increased prevalence of elevated serum lipid levels, atherosclerosis, ischemic heart disease and hypertension often associating with the presence of anti-thyroid antibodies. It is important to reveal subclinical thyroid diseases in time for the effective treatment and for stopping of the cardiovascular damages before manifestations of cardiovascular diseases. The paper gives advice for the practice and the rational management. At the end, a survey of the association between thyroid and heart diseases in own department of internal medicine at the last three years is given.

Inhibition of type 2,5'-deiodinase by tumor necrosis factor alpha, interleukin-6 and interferon gamma in human thyroid tissue.

The effects of tumor necrosis factor alpha (TNFalpha), interleukin-6 (IL-6) and interferon gamma (IFNgamma) were studied on the activity of type 2,5'-deiodinase and on the binding of [125I] T(4) to proteins in human thyroid cytosolic (supernatant) and membrane (pellet) fractions. The activity of thyroid type 2,5'-deiodinase was measured by iodothyronine outer ring deiodinase assay. The binding of [125I] T(4) to the proteins of thyroid cytosolic and membrane fractions was determined by autoradiography. The results showed that thyroid type 2,5'-deiodinase activity could be detected also in the cytosolic fraction, not only in the membrane. TNFalpha, IL-6 and IFNgamma could inhibit the type 2 deiodinase activity in vitro. The dose-dependent binding of [125I] T(4) to the proteins of 29, 66 and 200 kDa could be observed both in the cytosolic and membrane fractions. TNFalpha and IFNgamma inhibited the binding of [125I] T(4) to the two characteristic proteins of type 2,5'-deiodinase, to proteins of 29 and/or 200 kDa, both in the cytosolic and membrane fractions. We conclude that TNFalpha, IL-6 and IFNgamma can inhibit the activity of type 2,5'-deiodinase. Furthermore, TNFalpha and IFNgamma can still also decrease the binding of [125I] T(4) to the enzyme in vitro. It can be suggested that the increased level of these cytokines can be one of the reasons in the induction of the clinical symptoms in nonthyroidal illness associated with low levels of T(3).