Protein kinase CK2 enables regulatory T cells to suppress excessive TH2 responses in vivo.

The quality of the adaptive immune response depends on the differentiation of distinct CD4(+) helper T cell subsets, and the magnitude of an immune response is controlled by CD4(+)Foxp3(+) regulatory T cells (Treg cells). However, how a tissue- and cell type-specific suppressor program of Treg cells is mechanistically orchestrated has remained largely unexplored. Through the use of Treg cell-specific gene targeting, we found that the suppression of allergic immune responses in the lungs mediated by T helper type 2 (TH2) cells was dependent on the activity of the protein kinase CK2. Genetic ablation of the ß-subunit of CK2 specifically in Treg cells resulted in the proliferation of a hitherto-unexplored ILT3(+) Treg cell subpopulation that was unable to control the maturation of IRF4(+)PD-L2(+) dendritic cells required for the development of TH2 responses in vivo.

Association between copy-number variation on metabolic phenotypes and HDL-C levels in patients with polycystic ovary syndrome.

Polygenic diseases with a broad phenotypic spectrum, such as polycystic ovary syndrome (PCOS), present a particular challenge in terms of identifying the underlying genetic mechanisms, nevertheless genetic variants have impact on the individual phenotype. We aimed to determine if next to genetic variations like SNPs further mechanisms might play a role in the pathogenesis of PCOS. We examined the effect of copy-number variations (CNVs) on metabolic phenotypes in PCOS. The intragenic rs1244979, rs2815752 in NEGR1 gene, and rs780094 in GCKR gene were genotyped and CNVs were determined by droplet digital polymerase chain reaction (ddPCR) in PCOS patients (n = 153) and controls without metabolic syndrome (n = 142). The study indicated that SNPs are not associated with the pathogenesis of PCOS but affect metabolic phenotypes. The CNVs investigated show a lower variability in PCOS than in CON. Furthermore, we provided direct evidence that the copy number, but not the genotype of the CNV in the genomic regions of rs780094(GCKR) is associated with low level of high-density lipoprotein cholesterol in PCOS. This study supports the hypothesis that not only genetic variants, but also CNVs in metabolically relevant genes, have an effect on metabolic phenotypes in our group of PCOS patients.

Soluble GARP has potent antiinflammatory and immunomodulatory impact on human CD4⁺ T cells.

Glycoprotein A repetitions predominant (GARP) is expressed on the surface of activated human regulatory T cells (Treg) and regulates the bioavailability of transforming growth factor-ß (TGF-ß). GARP has been assumed to require membrane anchoring. To investigate the function of GARP in more detail, we generated a soluble GARP protein (sGARP) and analyzed its impact on differentiation and activation of human CD4⁺ T cells. We demonstrate that sGARP efficiently represses proliferation and differentiation of naïve CD4⁺ T cells into T effector cells. Exposure to sGARP induces Foxp3, decreases proliferation and represses interleukin (IL)-2 and interferon-γ production, resulting in differentiation of naïve T cells into induced Treg. This is associated with Smad2/3 phosphorylation and partially inhibited by blockade of TGF-ß signaling. Furthermore, in the presence of the proinflammatory cytokines IL-6 and IL-23, sGARP facilitates the differentiation of naïve T cells into Th17 cells. More important, in a preclinical humanized mouse model of xenogeneic graft-versus-host disease (GVHD), sGARP prevents T cell-mediated destructive inflammation by enhancing Treg and inhibiting T effector cell activity. These results demonstrate a crucial role of sGARP in modulation of peripheral tolerance and T effector cell function, opening the possibility to use sGARP as a potent immunomodulator of inflammatory diseases including transplant rejection, autoimmunity, and allergy.

Genetic variations in SREBP-1 and LXRα are not directly associated to PCOS but contribute to the physiological specifics of the syndrome.

The polycystic ovary syndrome (PCOS) is a complex endocrine-metabolic disorder consisting of reproductive disturbances associated with all aspects of the metabolic syndrome and genetic components in the pathology of this complex disease is very likely. Accordingly, variations in single genes might affect specific features of PCOS and thereby help to define different subgroups. SREBP-1 or LXRα have been shown to be genetically linked to lipid metabolism or insulin sensitivity. As these are two major aspects of the PCOS phenotype, we evaluated both genes in a cohort of 153 PCOS patients. Analyses of both genes revealed in SREBF-1, i.e. SREBP-1a and SREBP-1c, not any variation and in the LXRα gene no novel sequence variations. Common variants of LXRα (rs2279238:G; all:0.8658; PCOS:0.8627; controls: 0.8686 or A: all:0.13412; PCOS:0.1373; controls:0.1314; (OR (95% CI) 0.9508 (0.4226-2.1385); rs11039155: G: all:0.8767; PCOS:0.8663; controls:0.8857 and A all:0.1233; PCOS:0.1337; controls:0.1143; (OR (95% CI) 0.8383 (0.3618-1.9371)) were also not directly associated to PCOS. Combined analyses of both polymorphism revealed that there was no difference of distribution between the groups. In contrast, analyses of the impact of these polymorphisms on metabolic parameters of the syndrome indicated significant differences related to genotypes. The data indicated that rs11039155 increases metabolic risk, whereas rs2279238 has a protective effect on the overall metabolic risk. The investigation of the PCOS group presented indicates that the combined analyses of variations in putative candidate genes allowed a genotype-phenotype correlation for metabolic features.

A functional GNAQ promoter haplotype is associated with altered Gq expression and with insulin resistance and obesity in women with polycystic ovary syndrome.

OBJECTIVES: The G-protein Gq, encoded by GNAQ, is involved in glucose metabolism. The GNAQ promoter harbours three polymorphisms. The TT(-695/-694)GC polymorphism was already shown to affect Gq transcription. Accordingly, we (i) characterized the GNAQ promoter polymorphisms G(-173)A and G(-168)A, (ii) investigated potential influences upon the TT(-695/-694)GC polymorphism and (iii) studied the associations with metabolic abnormalities in polycystic ovary syndrome (PCOS). METHODS: Characterization of the polymorphisms was performed with electrophoretic mobility shift assays and reporter assays. Inhibition of lipolysis and Gq expression were measured in adipocytes isolated from female mammary tissue. We genotyped 266 healthy Caucasians, 265 women with PCOS, and 293 healthy, age-matched female controls to associate GNAQ promoter polymorphisms and haplotypes with anthropometric and metabolic variables. RESULTS: The A(-168) allele was associated with significantly decreased transcriptional activity and altered transcription factor binding, whereas the G(-173)A polymorphism appeared functionally silent. Linkage and haplotype frequencies analysis resulted in four common haplotypes. In adipose tissue, a 44% higher Gq mRNA concentration was observed in homozygous GC(-695/-694)-G(-168) haplotypes compared with homozygous TT(-695/-694)-G(-168) haplotypes (P=0.046). This was associated with increased insulin inhibition of lipolysis in isolated adipocytes. In PCOS patients, the homozygous GC-G haplotype was associated with decreased insulin resistance and body mass index (BMI) compared with the homozygous TT-G haplotype (homeostatic model assessment of insulin resistance: 3.4+/-0.4 vs. 5.6+/-0.7 mmol/l x mmol/l2, P=0.001; fasting insulin: 86.6+/-11.9 vs. 128.8+/-16.5 pmol/l, P=0.003; BMI: 29.3+/-1.2 vs. 33.9+/-1.3 kg/m2, P=0.002). No association with BMI was found in healthy women. CONCLUSION: G(-168)A is functionally relevant and in linkage with TT(-695/-694)GC. GNAQ promoter diplotypes are associated with insulin resistance and obesity in PCOS.

Large effects on body mass index and insulin resistance of fat mass and obesity associated gene (FTO) variants in patients with polycystic ovary syndrome (PCOS).

BACKGROUND: The polycystic ovary syndrome (PCOS), a common endocrine disorder in women of child-bearing age, mainly characterised by chronic anovulation and hyperandrogenism, is often associated with insulin resistance (IR) and obesity. Its etiology and the role of IR and obesity in PCOS are not fully understood. We examined the influence of validated genetic variants conferring susceptibility to obesity and/or type 2 diabetes mellitus (T2DM) on metabolic and PCOS-specific traits in patients with PCOS. METHODS: We conducted an association study in 386 patients with PCOS (defined by the Rotterdam-criteria) using single nucleotide polymorphisms (SNPs) in or in proximity to the fat mass and obesity associated gene (FTO), insulin-induced gene-2 (INSIG2), transcription factor 7-like 2 gene (TCF7L2) and melanocortin 4 receptor gene (MC4R). To compare the effect of FTO obesity risk alleles on BMI in patients with PCOS to unselected females of the same age range we genotyped 1,971 females from the population-based KORA-S4 study (Kooperative Gesundheitsforschung im Raum Augsburg, Survey 4). RESULTS: The FTO risk allele was associated with IR traits and measures of increased body weight. In addition, the TCF7L2 SNP was associated with body weight traits. For the SNPs in the vicinity of INSIG2 and MC4R and for the other examined phenotypes there was no evidence for an association. In PCOS the observed per risk allele effect of FTO intron 1 SNP rs9939609 on BMI was +1.56 kg/m2, whereas it was +0.46 kg/m2 in females of the same age range from the general population as shown previously. CONCLUSION: The stronger effect on body weight of the FTO SNP in PCOS might well have implications for the etiology of the disease.

Regulation of the expression of inducible nitric oxide synthase.

Nitric oxide (NO) generated by the inducible isoform of nitric oxide synthase (iNOS) is involved in complex immunomodulatory and antitumoral mechanisms and has been described to have multiple beneficial microbicidal, antiviral and antiparasital effects. However, dysfunctional induction of iNOS expression seems to be involved in the pathophysiology of several human diseases. Therefore iNOS has to be regulated very tightly. Modulation of expression, on both the transcriptional and post-transcriptional level, is the major regulation mechanism for iNOS. Pathways resulting in the induction of iNOS expression vary in different cells or species. Activation of the transcription factors NF-kappaB and STAT-1alpha and thereby activation of the iNOS promoter seems to be an essential step for the iNOS induction in most human cells. However, at least in the human system, also post-transcriptional mechanisms involving a complex network of RNA-binding proteins build up by AUF1, HuR, KSRP, PTB and TTP is critically involved in the regulation of iNOS expression. Recent data also implicate regulation of iNOS expression by non-coding RNAs (ncRNAs).

Mood and sexual function in polycystic ovary syndrome.

Women with polycystic ovary syndrome (PCOS) fail to conform with societal norms for outer appearance. Many PCOS patients thus feel stigmatized in the sense of a loss of "feminine identity." In addition to somatic impairment, mood disturbances such as depression and limitations in emotional well-being, quality of life, and life satisfaction, the diagnosis of PCOS also has a negative impact on sexual self-worth and sexual satisfaction. Both obesity and hirsutism are major determinants of the physical component of quality of life in affected women. However, its psychological aspect appears to be inherent and specific for PCOS. Confirmation of the diagnosis and provision of detailed information to affected women, together with the availability of interdisciplinary treatment aimed at improving PCOS-related symptoms, such as hirsutism, obesity, menstrual irregularity, and infertility, will also reduce psychological distress and improve sexual self-worth. New treatment options, including insulin sensitizers, psychological counseling, and participation in a PCOS support group, are likely to further improve life satisfaction and coping of affected women.

Medical treatment of hirsutism.

Hirsutism is usually the result of an underlying adrenal, ovarian, or central endocrine abnormality mainly due to polycystic ovary syndrome but may also be idiopathic or drug induced. The aim of medical treatment of hirsutism is to rectify any causal hormonal balance, slow down or stop excessive hair growth, and improve the aesthetic appearance of hirsutism, thereby positively affecting the patient's quality of life. Today, for the majority of women, a monotherapy with oral contraceptives that have antiandrogenic activity is recommended as a first-line treatment for hirsutism. Combining an oral contraceptive pill with an antiandrogen is recommended if clinical improvement of hirsutism is insufficient after 6-9 months' monotherapy. In women who present with hirsutism, hyperandrogenism, and insulin resistance, insulin sensitizers are effective for the hirsutism as well as the hyperinsulinemia, hyperandrogenism, and infertility but there is no convincing evidence that they are effective for hirsutism alone. Topical eflornithine is a medical therapy that can be a useful adjuvant for hirsutism when used in conjunction with systemic medications or with laser/photoepilation.

Retinol-binding protein 4 levels are elevated in polycystic ovary syndrome women with obesity and impaired glucose metabolism.

OBJECTIVE: Insulin resistance and obesity are common features of the polycystic ovary syndrome (PCOS). Retinol-binding protein 4 (RBP4), a new fat-derived adipokine, has been described to be elevated in obesity and type 2 diabetes. The aim of the present study was to investigate whether serum RBP4 levels are correlated with metabolic parameters, indices of insulin resistance, and endocrine variables in German PCOS women. DESIGN: We assessed the correlation between metabolic and endocrine parameters with RBP4 levels in 200 PCOS patients and 64 healthy controls. METHODS: Serum RBP4 was measured by enzyme-linked immunosorbent assay (Immundiagnostik AG, Bensheim, Germany). In addition, anthropometric variables, clinical signs of hyperandrogenism, and body fat were evaluated, and a glucose tolerance test was performed to assess parameters of insulin resistance and glucose metabolism. RESULTS: Taking the entire PCOS cohort, RBP4 levels were positively correlated with body mass index (BMI), body fat, waist circumference, fasting glucose, and area under the curve for glucose (all P<0.05), but not with indices of insulin resistance. On the other hand, PCOS women with impaired glucose metabolism had higher RBP4 levels than PCOS women with normal glucose metabolism (median 30.6, range 23.3-73.9 versus median 26.3, range 6.4-61.4, P<0.05). Furthermore, no differences were found in RBP4 levels between lean PCOS women and BMI-matched healthy controls. CONCLUSION: In German PCOS women, serum RBP4 levels are associated with obesity and parameters of glucose metabolism but not with PCOS per se.

Decreased soluble leptin receptor levels in women with polycystic ovary syndrome.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is associated with insulin resistance and a high incidence of obesity. Leptin, the product of the ob gene, is involved in the regulation of energy balance and obesity and circulates in both free and bound forms. The soluble leptin receptor (sOB-R) is the most important leptin-binding protein, thus influencing the biologically active free leptin level. DESIGN: We assessed the correlation of metabolic and endocrine parameters with leptin and sOB-R levels in 122 PCOS women (aged 27 +/- 5.7 years) and 81 healthy controls (aged 25 +/- 4.0 years). METHODS: Leptin and sOB-R levels were measured using ELISA kits. In addition, anthropometric variables, body fat and endocrine parameters were evaluated and a glucose tolerance test performed to assess indices of insulin resistance and glucose metabolism. RESULTS: In PCOS patients, no correlation was found between leptin or sOB-R and parameters of hyper-androgenism. However, as expected, body mass index (BMI), body fat, waist circumference and indices of insulin resistance were significantly correlated with leptin in PCOS subjects and controls. In a subgroup analysis of lean, overweight and obese PCOS patients, significant differences were found in leptin (29.7 +/- 20.7 vs 45.4 +/- 25.0 vs 67.7 +/- 28.8 ng/ml, P < 0.0001) and sOB-R (8.0 +/- 3.4 vs 6.4 +/- 2.5 vs 5.7 +/- 2.3 ng/ml, P < 0.05). Compared with BMI-matched controls, lean PCOS patients had lower sOB-R levels (8.0 +/- 3.4 vs 12.7 +/- 4.7 ng/ml, P < 0.0001) and higher free leptin indices (4.5 +/- 3.9 vs 2.8 +/- 2.2, P = 0.0285). CONCLUSION: Taking into account that low sOB-R levels supposedly compensate diminished leptin action, PCOS per se might cause leptin resistance.

The CC genotype of the GNAS T393C polymorphism is associated with obesity and insulin resistance in women with polycystic ovary syndrome.

OBJECTIVE: Variants in the Gs protein alpha subunit gene (GNAS1) are known to be involved in the pathogenesis of several endocrine and metabolic disorders. To understand genetic determinants of androgen excess, insulin resistance, and obesity in polycystic ovary syndrome (PCOS), we investigated the effect of the common GNAS1 T393C polymorphism on the phenotype of German PCOS women. DESIGN: Two hundred and seventy-eight PCOS women and 820 Caucasian controls were genotyped for the common T393C polymorphism in GNAS1. To this end, genomic DNA was amplified by PCR with specific oligonucleotides and genotypes were determined using the restriction enzyme FokI. In addition, we evaluated whether the T393C polymorphism had an influence on the response to 6 months metformin treatment in a subgroup of 105 PCOS women. METHODS: Anthropometric variables, metabolic parameters including indices of insulin resistance measured by oral glucose tolerance testing, and endocrine biochemical as well as clinical parameters were measured in all PCOS subjects. RESULTS: GNAS1 genotype distributions were not significantly different between PCOS women and controls. In PCOS women, no significant differences in endocrine clinical and biochemical variables were found between the genotypes. However, the C-allele carrier group had significantly higher mean body weight, body mass index, leptin levels, and higher indices of insulin resistance compared with women with GNAS1 TT-genotype. Metformin treatment significantly improved hyperandrogenism, menstrual cyclicity, body weight, and insulin resistance independent of GNAS1 genotype. The major determinant of weight loss was body weight before treatment. CONCLUSION: The T393C polymorphism is not associated with PCOS in Caucasian women, but may represent a genetic marker for increased susceptibility for obesity in this cohort.

How Soluble GARP Enhances TGFß Activation.

GARP (glycoprotein A repetitions predominant) is a cell surface receptor on regulatory T-lymphocytes, platelets, hepatic stellate cells and certain cancer cells. Its described function is the binding and accommodation of latent TGFß (transforming growth factor), before the activation and release of the mature cytokine. For regulatory T cells it was shown that a knockdown of GARP or a treatment with blocking antibodies dramatically decreases their immune suppressive capacity. This confirms a fundamental role of GARP in the basic function of regulatory T cells. Prerequisites postulated for physiological GARP function include membrane anchorage of GARP, disulfide bridges between the propeptide of TGFß and GARP and connection of this propeptide to αvß6 or αvß8 integrins of target cells during mechanical TGFß release. Other studies indicate the existence of soluble GARP complexes and a functionality of soluble GARP alone. In order to clarify the underlying molecular mechanism, we expressed and purified recombinant TGFß and a soluble variant of GARP. Surprisingly, soluble GARP and TGFß formed stable non-covalent complexes in addition to disulfide-coupled complexes, depending on the redox conditions of the microenvironment. We also show that soluble GARP alone and the two variants of complexes mediate different levels of TGFß activity. TGFß activation is enhanced by the non-covalent GARP-TGFß complex already at low (nanomolar) concentrations, at which GARP alone does not show any effect. This supports the idea of soluble GARP acting as immune modulator in vivo.

Kinome Profiling of Regulatory T Cells: A Closer Look into a Complex Intracellular Network.

Regulatory T cells (Treg) are essential for T cell homeostasis and maintenance of peripheral tolerance. They prevent activation of auto-reactive T effector cells (Teff) in the context of autoimmunity and allergy. Otherwise, Treg also inhibit effective immune responses against tumors. Besides a number of Treg-associated molecules such as Foxp3, CTLA-4 or GARP, known to play critical roles in Treg differentiation, activation and function, the involvement of additional regulatory elements is suggested. Herein, kinase activities seem to play an important role in Treg fine tuning. Nevertheless, our knowledge regarding the complex intracellular signaling pathways controlling phenotype and function of Treg is still limited and based on single kinase cascades so far. To gain a more comprehensive insight into the pathways determining Treg function we performed kinome profiling using a phosphorylation-based kinome array in human Treg at different activation stages compared to Teff. Here we have determined intriguing quantitative differences in both populations. Resting and activated Treg showed an altered pattern of CD28-dependent kinases as well as of those involved in cell cycle progression. Additionally, significant up-regulation of distinct kinases such as EGFR or CK2 in activated Treg but not in Teff not only resemble data we obtained in previous studies in the murine system but also suggest that those specific molecular activation patterns can be used for definition of the activation and functional state of human Treg. Taken together, detailed investigation of kinome profiles opens the possibility to identify novel molecular mechanisms for a better understanding of Treg biology but also for development of effective immunotherapies against unwanted T cell responses in allergy, autoimmunity and cancer.

A key role of GARP in the immune suppressive tumor microenvironment.

In melanoma patients, one of the main reasons for tumor immune escape and therapy failure is the immunosuppressive tumor microenvironment. Herein, suppressive immune cells and inhibitory factors secreted by the tumor itself play a central role.In the present study we show that the Treg activation marker GARP (glycoprotein A repetitions predominant), known to induce peripheral tolerance in a TGF-ß dependent way, is also expressed on human primary melanoma. Interestingly, membrane bound GARP is shed from the surface of both, activated Treg and melanoma cells, and, in its soluble form (sGARP), not only induces peripheral Treg but also a tumor associated (M2) macrophage phenotype. Notably, proliferation of cytotoxic T cells and their effector function is inhibited in the presence of sGARP. GARP expression on Treg and melanoma cells is significantly decreased in the presence of agents such as IFN-α, thus explaining at least in part a novel mechanism of action of this adjuvant therapy.In conclusion, GARP in its soluble and membrane bound form contributes to peripheral tolerance in a multipronged way, potentiates the immunosuppressive tumor microenvironment and thus acts as a negative regulator in melanoma patients. Therefore, it may qualify as a promising target and a new checkpoint for cancer immunotherapy.

Clinical and psychological correlates of quality-of-life in polycystic ovary syndrome.

OBJECTIVE: Polycystic ovary syndrome (PCOS) has been shown to cause a reduction in quality of life. This study examines the extent of different PCOS symptoms on quality-of-life, psychosocial well-being and sexual satisfaction. METHODS: Complete metabolic, hormonal, clinical and psychosocial data were obtained from a total of 120 women with PCOS. Patients were compared with 50 healthy women to establish reductions in quality-of-life and emotional well-being. In addition, the correlation between psychosocial variables and the major clinical PCOS features obesity (body mass index (BMI)), excessive body hair (hirsutism score), acne, hyperandrogenism (serum testosterone levels), disturbed insulin regulation (area under the insulin response curve and homeostasis model assessment of insulin resistance), menstrual cycle disturbances and infertility were analyzed. RESULTS: PCOS patients showed significant reductions in quality-of-life, increased psychological disturbances, and decreased sexual satisfaction when compared with healthy controls. BMI and hirsutism scores, but not the presence of acne, were associated with physical aspects of quality-of-life and sexual satisfaction. No clear effect of androgens or insulin resistance on psychosocial variables was detected. Similarly, the type of menstrual cycle disturbances or infertility had no impact on psychological well-being. CONCLUSION: In PCOS, changes in appearance, particularly obesity and hirsutism, reduce physical dimensions of quality-of-life and decrease sexual satisfaction. The role of biochemical, endocrine and metabolic parameters as well as menstrual irregularities and infertility appeared to be less important. Clinicians should pay attention to the psychosocial dimensions of PCOS on an individual basis, regardless of symptom severity or treatment response.

Sensitive thyrotropin and thyrotropin-receptor antibody determinations one month after discontinuation of antithyroid drug treatment as predictors of relapse in Graves' disease.

OBJECTIVE: After primary successful antithyroid drug treatment (ATDT), Graves' disease has a relapse rate of 30% to 50%. Previous studies have evaluated age, gender, goiter volume, smoking habits, and the presence of thyrotropin-receptor antibodies (TRAb) as predictive markers to facilitate an individualized patient management. Despite higher sensitivity and specificity of the new second generation human TSH-receptor assay, the predictive value of TRAb for relapse of hyperthyroidism is still controversial. In a recent prospective multicenter study we have previously shown that suppressed or low TSH values predict both early (persistence) and late relapse of Graves' disease. We now present a more detailed analysis of the predictive value of TSH and TRAb for recurrent hyperthyroidism. METHODS: Four weeks after withdrawal of ATDT, 96 patients were available for thyroid function tests, including a sensitive third-generation TSH assay and a second-generation recombinant TSH receptor assay. Relapse of Graves' disease was evaluated for a total follow-up of 2 years. RESULTS: Within 2 years, 47 of 96 patients (49%) developed relapse of hyperthyroidism. Nine patients relapsed within the first 4 weeks after withdrawal of ATDT and were thus considered to have persistent Graves' disease. Ten of 15 other patients with TSH levels below 0.3 mU/L without overt hyperthyroidism relapsed within 2 years. Twenty-five of 65 patients with normal TSH (0.3-3.0 mU/L) and 3 of 4 patients with TSH values above 3 mU/L also had recurrent hyperthyroidism. After ATDT cessation, TSH had a positive predictive value of 70% and a negative predictive value of 62% (specificity 85%) for relapse of Graves 'disease. Mean TRAb levels in the group of patients with relapse were significantly higher (11.1 IU/L +/- 0.17) than TRAb values in the remission group (4.5 IU/L +/- 0.6), p < 0.001. Using a cutoff value of 1.5 IU/L, TRAb had low positive and negative predictive values of 49% and 54%, respectively (specificity, 14%), but with a cutoff level of 10 IU/L, predictive values improved to 83% and 62%, respectively (specificity, 92%). Combination of TSH and TRAb determinations did not further improve prediction of relapse. Other factors such as gender, age, goiter volume, smoking habits, presence of thyroid-associated ophthalmopathy, and urinary iodine excretion did not show a significant influence on relapse rate. CONCLUSION: Low TSH values 4 weeks after ATDT withdrawal predict relapse of Graves' disease, both early (persistence) and, to a lesser extend, within 2 years of follow-up. Also, TRAb above 10 IU/L found in a small subset of patients, correlated with a higher relapse rate.

Translating Treg Therapy in Humanized Mice.

Regulatory T cells (Treg) control immune cell function as well as non-immunological processes. Their far-reaching regulatory activities suggest their functional manipulation as a means to sustainably and causally intervene with the course of diseases. Preclinical tools and strategies are however needed to further test and develop interventional strategies outside the human body. "Humanized" mouse models consisting of mice engrafted with human immune cells and tissues provide new tools to analyze human Treg ontogeny, immunobiology, and therapy. Here, we summarize the current state of humanized mouse models as a means to study human Treg function at the molecular level and to design strategies to harness these cells for therapeutic purposes.

Quality of life, psychosocial well-being, and sexual satisfaction in women with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by chronic anovulation and hyperandrogenism. PCOS is one of the leading causes of infertility and manifests with hirsutism, acne, and obesity. To investigate its impact on health-related quality of life and sexuality, 50 women with PCOS and 50 controls were evaluated with standardized questionnaires (36-item short-form health survey, symptom checklist revised, and life satisfaction questionnaire). The impact of hirsutism, obesity, and infertility was assessed using five-point rating scales, and sexual satisfaction was analyzed with visual analog scales. Patients showed greater psychological disturbances on the symptom checklist revised dimensions, obsessive-compulsive, interpersonal sensitivity, depression, anxiety, aggression, and psychoticism, along with a lower degree of life satisfaction in the life satisfaction questionnaire scales health, self, and sex. Health-related quality of life measured with the 36-item short-form health survey revealed significantly decreased scores for physical role function, bodily pain, vitality, social function, emotional role function, and mental health in patients with PCOS. Although patients had the same partner status and frequency of sexual intercourse, they were significantly less satisfied with their sex life and found themselves less attractive. Most of the differences were not affected by correction for body weight. In conclusion, PCOS causes a major reduction in the quality of life and severely limits sexual satisfaction.

High prevalence of autoimmune thyroiditis in patients with polycystic ovary syndrome.

OBJECTIVE: To investigate the prevalence of autoimmune thyroiditis (AIT) in patients with polycystic ovary syndrome (PCOS). DESIGN: Over a period of 30 months, 175 patients with PCOS were recruited to a prospective multicenter study to evaluate thyroid function and morphology; 168 age-matched women without PCOS were studied as a control group. METHODS: PCOS was defined as a- or oligomenorrhea, hyperandrogenism and exclusion of other disturbances of estrogen or androgen synthesis. All laboratory parameters were determined with automated immunoassays. Thyroid morphology was assessed by ultrasound. RESULTS: PCOS patients were characterized by an increased LH/FSH ratio, low progesterone, elevated testosterone and a high prevalence of hirsutism (PCOS 83%, control 3%; mean hirsutism score 12+/-5 and 3+/-2 respectively), but no differences in estrogen levels were found. Thyroid function and thyroid-specific antibody tests revealed elevated thyroperoxidase (TPO) or thyroglobulin (TG) antibodies in 14 of 168 controls (8.3%), and in 47 of 175 patients with PCOS (26.9%; P<0.001). On thyroid ultrasound, 42.3% of PCOS patients, but only 6.5% of the controls (P<0.001) had a hypoechoic tissue typical of AIT; while thyroid hormone levels were normal in all subjects, PCOS patients had a higher mean TSH level (P<0.001) and a higher incidence of TSH levels above the upper limit of normal (PCOS 10.9%, controls 1.8%; P<0.001). CONCLUSION: This prospective study demonstrates a threefold higher prevalence of AIT in patients with PCOS, correlated in part with an increased estrogen-to-progesterone ratio and characterized by early manifestation of the disease.