Relationship between smoking and serum levels of eye muscle and orbital connective tissue antibodies in patients with Graves ophthalmopathy.

Over the past three decades, several studies have quantified the risk of smoking in the development of ophthalmopathy in patients with Graves' hyperthyroidism, with an overall odds ratio of approximately 3.0. Smokers also have a greater risk of more advanced ophthalmopathy than non-smokers. We studied 30 patients with Graves' ophthalmopathy (GO) and 10 patients with upper eyelid signs as the only manifestation of ophthalmopathy, whose eye signs were assessed using the clinical activity score (CAS), NOSPECS classes and upper eyelid retraction (UER) score, half of whom were smokers and half of whom were non-smokers. Serum levels of eye muscle (CSQ, Fp2, G2s) and orbital connective tissue type XIII collagen (Coll XIII) antibodies are valuable markers of ophthalmopathy in patients with Graves' disease. Still, their relationship to smoking has not been investigated. These antibodies were measured by enzyme-linked immunosorbent assay (ELISA) in all patients as a component of their clinical management. Mean serum antibody levels of all four antibodies were significantly greater in smokers than in non-smokers in patients with ophthalmopathy but not in those with upper eyelid signs only. As determined using one-way ANOVA and Spearman's correlation test, there was a significant correlation between smoking severity, assessed as pack-years, with mean Coll XIII antibody level, but not with levels of the 3 eye muscle antibodies. These results suggest that in patients with Graves' hyperthyroidism who smoke, the orbital inflammatory reactions are more advanced than in those with Graves' hyperthyroidism who do not smoke. The mechanism of this enhanced Autoimmunity against orbital antigens in smokers is unclear and worthy of further study.

Breast cancer immunotherapy: a comprehensive review.

Cancer remains a major health problem despite numerous new medical interventions that have been introduced in recent years. One of the major choices for cancer therapy is so-called adoptive cell therapy (ACT). ACT can be performed using both innate immune cells, including dendritic cells (DCs), natural killer (NK) cells, and γδ T cells and acquired immune T cells. It has become possible to utilize these cells in both their native and modified states in clinical studies. Because of considerable success in cancer treatment, ACT now plays a role in advanced therapy protocols. Genetic engineering of autologous and allogeneic immune cells (T lymphocytes, NK cells, macrophages, etc.) with chimeric antigen receptors (CAR) is a powerful new tool to target specific antigens on cancer cells. The Food and Drug Administration (FDA) in the US has approved certain CAR-T cells for hematologic malignancies and it is hoped that their use can be extended to incorporate a variety of cells, in particular NK cells. However, the ACT method has some limitations, such as the risk of rejection in allogeneic engrafts. Accordingly, numerous efforts are being made to eliminate or minimize this and other complications. In the present review, we have developed a guide to breast cancer (BC) therapy from conventional therapy, through to cell-based approaches, in particular novel technologies including CAR with emphasis on NK cells as a new and safer candidate in this field as well as the more recent aptamer technology, which can play a major role in BC immunotherapy.

The cardiac calsequestrin gene (CASQ2) is up-regulated in the thyroid in patients with Graves' ophthalmopathy--support for a role of autoimmunity against calsequestrin as the triggering event.

BACKGROUND: Graves' Ophthalmopathy (GO) is a complex eye and orbital disorder that is uniquely linked to Graves' Hyperthyroidism (GH) and has traditionally been considered a cross-reactive immune response against the thyroid stimulating hormone receptor (TSHR) in orbital tissue. However, because there is no direct evidence, such as specific TSHR antibodies or T lymphocytes targeting the orbital tissues in patients with GO compared to those without eye disease, it is important to consider alternative hypotheses for the pathogenesis of GO. The aim of this study was to identify differentially expressed genes within the thyroid of patients with GO and GH as a possible explanation for a thyroid initiated orbital autoimmunity. METHODS: RNA was extracted from thyroid glands of patients with GO (n = 10) and GH (n = 8) post-total thyroidectomy. RNA samples were arrayed on Illumina® Human Ref-8 Expression BeadChips™ representing 20,589 genes. Microarray results of selected genes were validated by quantitative PCR (qPCR) and levels of protein translation measured by Western blot analysis. FINDINGS: Two hundred and ninety-five genes were differentially expressed between patients with GO and GH. Of these, the cardiac calsequestrin gene (CASQ2) was the most highly expressed gene in GO (2.2-fold increase, P < 0.05). The succinate dehydrogenase flavoprotein subunit gene (SDHA) was also significantly up-regulated in GO (P < 0.05), 1.4-fold, while genes encoding the thyroid antigens thyroglobulin, thyroid peroxidase and TSHR were not differentially expressed. qPCR verified up-regulation of CASQ2 and down-regulation BMP7, CD80, IGFBP5, and MYD88 genes in GO. Western blot analysis showed that the average CASQ/GAPDH protein expression ratios for GH and GO were 1.04 and 1.03, respectively. t-Test analysis of data generated a P-value of 0.26, therefore no significant difference was found for CASQ protein expression in thyroid tissue between GH and GO. INTERPRETATION: The skeletal and cardiac calsequestrin proteins share 68.4% amino acid homology. Previous work has shown that RNA levels of skeletal muscle calsequestrin are 4.7 times higher in extraocular muscle (EOM) than in masticatory skeletal muscle (jaw), and cardiac calsequestrin is expressed 2.7 times more in EOM. We postulate that up-regulation of casq2 gene in the thyroid of patients with GH may lead to the production of autoantibodies and sensitized T-lymphocytes, which cross-react with calsequestrin in the EOM of patients who develop ophthalmopathy.

Association between radioiodine therapy for Graves' hyperthyroidism and thyroid-associated ophthalmopathy.

To investigate the role of radioactive iodine (RAI) in the onset and progression of thyroid-associated ophthalmopathy (TAO). Forty-six Graves' disease patients with mild or no ophthalmopathy were prospectively treated with carbimazole (CBZ) (n = 22) or RAI (n = 24). Treatment effects were evaluated clinically over 12 months, and with orbital MRI-measured extra-ocular muscle (EOM) volumes at baseline and at 6 months. The diagnosis of TAO was based on the clinical activity score (CAS) system. There were 11/22 CBZ and 10/24 RAI patients with active ophthalmopathy at baseline. Despite greater mean TSH levels post-RAI (P = 0.003), there was no increase in the likelihood of developing active ophthalmopathy (OR 0.95; 95% CI 0.56-1.61, P = 0.9) or EOM dysfunction (OR 0.52; 95% CI 0.26-1.06, P = 0.074). The increased mean palpebral aperture post-RAI (P = 0.023) and greater mean proptosis in the CBZ group (P = 0.005) were not confirmed when the absolute values of these measurements were examined. There was no association between the treatment received and MRI-measured EOM volumes. In this study, RAI therapy for Graves' disease did not increase the risk of progression or development of ophthalmopathy in patients with mild or no eye disease at baseline.

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.

Can autoimmunity against calsequestrin explain the eye and eyelid muscle inflammation of thyroid eye disease?

Extra-ocular and upper eyelid (levator) muscle damage in thyroid orbitopathy may be due to autoimmunity against eye muscle auto antigens. The main antigen appears to be the calcium binding protein calsequestrin. In this study we have tested for T lymphocyte sensitization to calsequestrin in patients with Graves' disease, with and without orbitopathy, in standard proliferation assay. We have also tested total RNA prepared from thyroid tissue of patients with Graves' disease with and without orbitopathy for expression across 20,589 genes using micro array analysis technology. We were looking for differences in gene expression between the two groups which might provide information about the early thyroid events that lead to the development of eye muscle autoimmunity. Positive lymphocyte reactivity to calsequestrin was demonstrated in 59% of Graves' patients with orbitopathy, 33% without evident ophthalmopathy and in 43% of patients with Hashimoto's thyroiditis and upper eyelid retraction (UER). Two hundred and ninety six genes were identified to be differentially expressed between in patients with Graves' disease with and without orbitopathy. Of these, the cardiac calsequestrin gene CASQ2 was the most highly up regulated, 2.2-fold. The closely related skeletal muscle calsequestrin gene CASQ1 was also up-regulated, 4.1 fold, but this was not significant, while genes encoding the thyroid antigens thyroglobulin, thyroid peroxidase and the TSH-receptor were not differentially expressed. These findings provide further evidence for a prominent role of autoimmunity against calsequestrin in the pathogenesis of the eye muscle components of thyroid orbitopathy.

Eye signs and serum eye muscle and collagen XIII antibodies in patients with transient and progressive thyroiditis.

BACKGROUND: There have been reports of the development of ophthalmopathy in patients with subacute thyroiditis (SAT) in the absence of Graves' disease and thyroid-stimulating hormone receptor (TSH-r) antibodies. OBJECTIVE: The aim of the study was to determine the prevalences of eye and eyelid signs and positive eye muscle and collagen XIII antibody tests in patients with SAT and silent thyroiditis (ST) and in patients with Hashimoto's thyroiditis (HT) as chronic thyroiditis controls. DESIGN: Ophthalmopathy was classified as Nunery type 1 (orbital inflammation, proptosis, without restrictive myopathy) or Nunery type 2 (with restrictive myopathy). We tested for antibodies against calsequestrin, flavoprotein (Fp), G2s, and collagen XIII in 5 patients with SAT, 6 with ST, and 11 with HT, and in 12 age- and sex-matched healthy subjects, using an optimized and standardized enzyme-linked immunosorbent assay (ELISA). MAIN OUTCOME: At the first visit, eye signs were found in two patients with SAT, one with type 1 ophthalmopathy and one with type 2 ophthalmopathy, and in three patients with ST, two with type 1 ophthalmopathy and one with dominant upper eyelid retraction only. Later in the course of their illness, one other patient with ST developed mild type 1 disease, giving an overall prevalence of any eye signs of 50% in patients with TT. Five patients with HT had mild type 1 ophthalmopathy and dominant upper eyelid retraction. One or more eye muscle antibodies were detected in three patients with SAT, four with ST, and seven with HT, of which calsequestrin and Fp antibodies were the most commonly found. TSH-r antibodies were detected in only one patient with ST, at the time when she developed Graves' hyperthyroidism following an episode of ST. CONCLUSION: The development of mild, but definite, ophthalmopathy or dominant upper eyelid retraction in patients with TT and chronic (Hashimoto's) thyroiditis in the absence of TSH-r antibodies or Graves' hyperthyroidism is an interesting observation that should be further addressed in larger groups of patients, including those with postpartum thyroiditis. These preliminary findings also raise questions about the mechanism for the link between ophthalmopathy and thyroid autoimmunity.

Antibodies against calsequestrin and type XIII collagen are good markers for chronic upper eyelid retraction.

PURPOSE: Chronic upper eyelid retraction is a common manifestation of thyroid-associated ophthalmopathy (TAO) but can occur as a dominant feature of ophthalmopathy in patients with Graves' hyperthyroidism and in association with Hashimoto's thyroiditis in the absence of other eye signs except mild proptosis. METHODS: We measured antibodies against calsequestrin, flavoprotein (Fp), G2s, and collagen XIII in an enzyme-linked immunosorbent assay (ELISA) in 15 patients with chronic upper eyelid retraction. RESULTS: Calsequestrin antibodies were detected in 67% of patients with upper eyelid retraction, Fp antibodies in 47%, G2s antibodies in 20%, and collagen XIII antibodies were detected in 40% of these patients at the first visit. These prevalences were significantly greater than normal for calsequestrin and collagen XIII, but not for Fp and G2s antibodies. On follow-up, calsequestrin antibodies were detected in two more patients, for an overall prevalence of 80%. Levels of the four antibodies remained fairly constant over the study period and generally correlated with the presence and severity of upper eyelid signs. CONCLUSIONS: These findings support the notion that autoimmune attack against calsequestrin and collagen XIII in the levator palpebrae superioris (LPS) muscle may play a role in the pathogenesis of upper eyelid retraction and that lid retraction may be the dominant feature of ophthalmopathy in patients with Hashimoto's thyroiditis and non-autoimmune thyroid disease. Because calsequestrin is an intracellular protein, the corresponding autoantibodies probably do not initiate LPS muscle inflammation but may contribute to its damage. The mix of antibodies against calsequestrin and collagen XIII may shed light on the diverse presentations found in thyroid-associated ophthalmopathy.

Single nucleotide polymorphism 1623 A/G (rs180195) in the promoter of the Thyroglobulin gene is associated with autoimmune thyroid disease but not with thyroid ophthalmopathy.

BACKGROUND: Our studies over recent years have focused on some new ideas concerning the pathogenesis for the orbital reaction that characterizes Graves' ophthalmopathy namely, that there are antigens expressed by thyroid tissue and orbital tissue where they are targeted by autoantibodies and/or sensitized T cells, leading to orbital inflammation. While this has been well studied for the thyroid stimulating hormone-receptor, the possible role of another major thyroid antigen, Thyroglobulin (TG), has been largely ignored. METHODS: We identified novel variant 1623 A/G single nucleotide polymorphism (SNP) (rs180195) in the promoter of TG gene associated with autoimmune thyroid disorders. We genotyped the TG SNPs rs2069566, rs2076739, rs121912646, rs121912647, rs121912648, rs121912649, rs121912650, rs137854433, rs137854434, and rs180195 by MassARRAY SNP analysis using iPLEX technology in a cohort of 529 patients with thyroid autoimmunity with and without ophthalmopathy, and controls. RESULTS: We showed that variant 1623 A/G SNP (rs180195) in the promoter of TG gene is a marker for thyroid autoimmunity, but not for ophthalmopathy. We showed that there was a significant difference in the distribution of the major allele (G) vs minor allele (A) in patients with Hashimoto's thyroiditis (HT). In HT the wild-type (GG) genotype was less common. We showed that the genotypes homozygous AA and heterozygous GA rs180195 SNP in the promoter of TG gene were more closely associated with thyroid autoimmunity than the wild-type (GG) polymorphism, and are thus, markers of autoimmunity. CONCLUSION: rs180195 SNP was previously identified by Stefan et al independently of us, who showed that this TG SNP predisposed to autoimmune thyroid diseases. However, this is the first study to explore the association between TG SNPs and HT. Our findings support the notion that the thyroid and orbital disorders are not part of the same disease, ie, "Graves' disease" or "Hashimoto's disease", but separate autoimmune disorders.

Acute delirium in the setting of primary hypothyroidism: the role of thyroid hormone replacement therapy.

Psychiatric illness, mostly mania and psychosis, are reported to occur after rapid normalization of thyroid function in patients with primary hypothyroidism. It is generally believed that the gradual restoration of thyroid function may reduce the risk of psychiatric complications. This case report describes the occurrence of acute delirium in a 67-year-old man with primary hypothyroidism shortly after the initiation of thyroid hormone replacement. The use of low-dose thyroxine initially and persistent severe biochemical hypothyroidism on presentation with psychiatric symptoms illustrate that psychiatric illness can still occur despite unaggressive thyroid hormone replacement. A temporal relationship with the initiation of thyroxine and rapid recovery of mental state over 1 to 2 weeks differentiate this condition from hypothyroidism-related psychopathology, which tends to have a more prolonged course.

Relationship between Clinical and Immunological Features of Thyroid Autoimmunity and Ophthalmopathy during Pregnancy.

Problem. Clinical features of Graves' hyperthyroidism (GH) generally improve during pregnancy and rebound in the postpartum period. It is unclear whether the ophthalmopathy that is associated with GH and, less often, Hashimoto's thyroiditis (HT) changes in parallel with the thyroid associated antibody reactions and clinical features or runs a different course. Method of Study. We retrospectively studied 19 patients with autoimmune thyroid disease over 22 pregnancies: 9 pregnancies with GH and 13 with HT. Ophthalmopathy was defined by NOSPECS class. Results. Thyroid peroxidase (TPO) and thyroglobulin (Tg) antibody titres decreased during pregnancy and rose in the postpartum period. During pregnancy, 5 patients with GH and 4 patients with HT developed mild ophthalmopathy and two patients with GH and HT developed new upper eyelid retraction (UER). In the postpartum period, eye scores improved in 3 patients with GH and 3 with HT, remained stable in two and 5 patients, respectively, and worsened in 2 patients with GH and one with HT. Conclusions. In patients with mild to moderate eye signs associated with GH and HT, the orbital and thyroid reactions ran different courses during pregnancy. Since no patient had severe ophthalmopathy, we cannot draw definitive conclusions from this preliminary study.

Does autoimmunity against thyroglobulin play a role in the pathogenesis of Graves' ophthalmopathy: a review.

While most authors believe that autoimmunity against the TSH receptor expressed in the orbital connective tissue cells is the main reaction that leads to the development of ophthalmopathy in patients with Graves' hyperthyroidism, an older hypothesis that deserves fresh consideration is based on the notion that thyroglobulin (Tg) in the thyroid gland passes in a retrograde fashion to the orbit where it is recognized by Tg autoantibodies, leading to inflammation. Here, we review new evidence that supports a role of Tg and propose a new hypothesis based on the notion that Tg is targeted in the orbit leading to a complex cascade of reactions that leads to Graves' ophthalmopathy.

Novel single-nucleotide polymorphisms in the calsequestrin-1 gene are associated with Graves' ophthalmopathy and Hashimoto's thyroiditis.

BACKGROUND: The eye disorder associated with Graves' disease, called Graves' ophthalmopathy (GO), greatly reduces the quality of life in affected patients. Expression of the calsequestrin (CASQ1) protein in thyroid tissue may be the trigger for the development of eye muscle damage in patients with GO. We determined the prevalence of rs74123279, rs3747673, and rs2275703 single-nucleotide polymorphism (SNPs) in patients with autoimmune thyroid disorders, GO, Graves' hyperthyroidism (GH), or Hashimoto's thyroiditis (HT) and control subjects with no personal or family history of autoimmune thyroid disorders. Furthermore, we measured the concentration of the CASQ1 protein in normal and Graves' thyroid tissue, correlating levels with parameters of the eye signs, CASQ1 antibody levels, and the CASQ1 gene polymorphism rs74123279 and rs2275703. METHODS: High-quality genomic DNA was isolated from fresh blood samples, assayed for identification of rs74123279, rs3747673, and rs2275703 SNPs in CASQ1 gene by MassARRAY SNP analysis using iPLEX technology of SEQUENOM. RESULTS: DNA samples from 300 patients and 106 control subjects (100 males, 306 females) with GO (n=74), GH (n=130), HT (n=96) and control subjects (n=106) were genotyped for the SNPs rs74123279, rs3747673 (n=405), and rs2275703 (n=407). The SNP rs74123279, rs3747673, and rs2275703 were identified as 1) common homozygous or wild type, 2) heterozygote, and 3) rare homozygous. Minor allele frequency for rs74123279, rs3747763, and rs2275703 were 21%, 40%, and 44%, respectively. Multiple comparisons of genotype frequency for rs74123279, rs3747763, and rs2275703 in the GO, GH, HT, and control groups showed P=0.06, 0.641, and 0.189, respectively. These results were substantiated by multiple comparison of alleles frequency for rs74123279, rs3838216, rs3747763, and rs2275703 in the GO, GH, HT, and control groups showed, P=0.36, 0.008, 0.66, and 0.05, respectively. Pairwise analysis of alleles frequency distribution in patients with GO showed significant probability for rs2275703, P=0.008. CONCLUSION: Based on their evolutionary conservation and their significant prevalence, we suggest that CASQ1 gene SNPs rs74123279, rs3838216, and rs2275703 may be considered as genetic markers for GO.

Experimental model for ophthalmopathy in BALB/c and outbred (CD-1) mice genetically immunized with G2s and the thyrotropin receptor.

In an attempt to develop an animal model for thyroid-associated ophthalmopathy (TAO) we have genetically immunized BALB/c and outbred (CD-1) mice with cDNAs encoding the thyroid and eye muscle shared protein G2s and full length human thyrotropin receptor (TSHr). Firstly, BALB/c mice were immunized with cDNAs for G2s and the TSHr, alone or in tandem with cDNAs for interleukin (IL)4 or IL12. Control mice were immunized with empty vehicle only. Sera from the great majority of experimental mice contained antibodies against a G2s fusion protein and the flavoprotein (Fp) subunit of mitochondrial succinate dehydrogenase, the "64 kDa protein", with the greatest levels being found at sacrifice (17 wk). Antibody levels in mice immunized with G2s + TSHr or G2s + IL12 were generally higher than those in mice immunized with G2s only. TSHr antibodies (TRAb), measured as TSH binding inhibition, were detected in only two mice. On histological examination of the orbits, mild edema, eye muscle fiber separation and mast cell infiltration in and around the eye muscles were found in the majority of experimental mice, but not in control mice. Splenocytes were transferred from selected G2s-immunized mice to normal syngeneic litter mates. None of the transfer mice had serum antibodies against G2s, Fp or TSHr but their orbital tissue showed the same degree of mast cell infiltration as primary mice. No major histological changes were observed in the thyroid or other skeletal muscle in either primary or transfer mice. Similar results were observed in CD-1 mice although, overall, the model was better expressed than in BALB/c mice. In these mice, serum anti-G2s antibody levels were not significantly different between the various experimental groups except at 16 wk, when they were slightly greater than in control animals. Anti-Fp antibodies were detected at 12, 14 and 16 wk, in all experimental groups, including those immunized with G2s only, and were greatest in mice immunized with TSHr alone. TRAb levels were greatest in mice immunized with both G2s and the TSHr in the presence of TL4, but not IL12. The finding of negative anti-G2s but positive anti-Fp antibodies in some CD-1 mice suggests that eye muscle damage and Fp release must have been mediated by T lymphocytes, rather than antibodies, targeting G2s or some other as yet unidentified cell membrane antigen. Histological changes in the orbit were similar to those observed in BALB/c mice although mast cell numbers were greater, in both primary and transfer mice. Overall, the greatest histological changes were observed in CD-1 mice immunized with both G2s + TSHr + IL4. None of the animals became overtly hyperthyroid or hypothyroid during the course of the study although several of the CD-1 mice had abnormal TSH or T4 levels. These results indicate that we have established a valid model for human ophthalmopathy using the novel thyroid and eye muscle expressed protein G2s, now recognized as a fragment of the winged-helix transcription factor Foxp1, and TSHr, and that G2s and the TSHr are both primary antigens in TAO. Reactivity against a TSHr-like protein may be the first event leading to ophthalmopathy in humans with TAO and experimental mice and eye muscle damage may result from autoimmunity against G2s and Fp as a result of "antigen spreading".

Stress and thyroid autoimmunity.

While many studies have shown a connection between stress and autoimmune disease, most of the evidence for stress contributing to the onset and course of autoimmune disease is circumstantial and the mechanisms by which stress affects autoimmune disease are not fully understood. The best circumstantial evidence for an effect of stress on autoimmune thyroid disease is the well-known relationship between the onset of Graves' hyperthyroidism and major stress but even this is debated. However, most of the recent case-control studies have supported stress as a factor that affects the onset and clinical course of Graves' disease. On the other hand, there have been few reports concerning the possible relationship between stress and Hashimoto's thyroiditis. Because the onset and course of Hashimoto's thyroiditis is generally insidious, the effect of stress on Hashimoto's thyroiditis might be overlooked. Numerous human and animal studies have demonstrated that psychological and physiologic stressors induce various immunologic changes. Stress affects the immune system either directly or indirectly through the nervous and endocrine systems. These immune modulations may contribute to the development of autoimmunity as well as the susceptibility to autoimmune disease in genetically predisposed individuals. Stress can be one of the environmental factors for thyroid autoimmunity.

T-cell-mediated immunity in thyroid-associated ophthalmopathy.

Thyroid-associated ophthalmopathy (TAO) is considered to be an autoimmune inflammatory disorder of the extraocular muscles and the orbital fat/connective tissue. Recent studies analyzing T cells infiltrating retrobulbar tissues generated important insights into the immunopathogenesis of TAO. The present review focuses on advances in our understanding of mechanisms responsible for the autoimmune inflammation in TAO, especially T cell migration to the inflammatory site, T cell activation by autoantigens and costimulatory signals and their cytokine profile. The elucidation of these processes might lead to the development of novel therapeutic strategies directed against autoreactive T cells.

Thyroid function. Pathogenesis of Graves ophthalmopathy--a role for TSH-R?

A new study highlights the complexities of anti-TSH-receptor antibody function and the differences between adult and paediatric patients with Graves disease, adding to the controversy regarding the possible role of these antibodies in the development of ophthalmopathy.

Thyroid-stimulating immunoglobulins as measured in a reporter bioassay are not detected in patients with Hashimoto's thyroiditis and ophthalmopathy or isolated upper eyelid retraction.

Although ophthalmopathy is mainly associated with Graves' hyperthyroidism, milder eye changes are also found in about 25% of patients with Hashimoto's thyroiditis (HT). The recent finding of negative thyrotropin receptor (TSHR) antibodies, as measured in the Thyretain™ thyroid-stimulating immunoglobulin (TSI) reporter bioassay, in patients with euthyroid Graves' disease raises the possibility that TSHR antibodies are not the cause of ophthalmopathy in all situations. Here, we have tested serum from patients with HT with and without ophthalmopathy or isolated upper eyelid retraction (UER) for TSHR antibodies, using the TSI reporter bioassay and collagen XIII as a marker of autoimmunity against the orbital fibroblast. Study groups were 23 patients with HT with ophthalmopathy, isolated UER, or both eye features and 17 patients without eye signs. Thyretain™ TSI results were expressed as a percentage of the sample-to-reference ratio, with a positive test being taken as a sample-to-reference ratio of more than 140%. Serum collagen XIII antibodies were measured in standard enzyme-linked immunosorbent assay. TSI tests were positive in 22% of patients with HT with no eye signs but in no patient with eye signs. In contrast, TSI tests were positive in 94% of patients with Graves' ophthalmopathy. Tests were negative in all normal subjects tested. Collagen XIII antibodies were detected in 83% of patients with ophthalmopathy, UER, or both eye features, but in only 30% of patients with no eye signs. Our findings suggest that TSHR antibodies do not play a major role in the pathogenesis of ophthalmopathy or isolated UER in patients with HT. Moreover, the role of TSHR antibodies in the development of ophthalmopathy in patients with Graves' disease remains to be proven. In contrast, collagen XIII antibodies appear to be a good marker of eye disease in patients with HT.

Relationship between thyroid dysfunction and chronic kidney disease in community-dwelling older adults.

OBJECTIVES: Renal function has been shown to be influenced by thyroid status in animal models and human studies. We aimed to assess the cross-sectional association between thyroid hormones and function with prevalence of chronic kidney diseases (CKD) in older adults. STUDY DESIGN: 1571 Blue Mountains Eye Study participants aged ≥ 60 years were analyzed in 2002-4. Thyroid dysfunction was defined using serum thyrotropin (TSH) screen, followed by serum free T4 (FT4) assessment. Baseline biochemistry including serum creatinine was measured. Moderate CKD was defined as estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2). RESULTS: After adjusting for age, sex, receipt of pension payment, body mass index, smoking, hypertension and diabetes, persons with any thyroid dysfunction (hyperthyroidism or hypothyroidism) had 84% higher likelihood of having CKD, odds ratio, OR, 1.84 (95% confidence intervals, CI, 1.03-3.31). Participants in the highest versus lowest quartile (reference) of serum TSH and FT4 had a significantly greater odds of prevalent CKD, OR 1.82 (95% CI 1.22-2.71), and OR 1.64 (95% CI 1.10-2.45), respectively. Similarly, among participants not receiving treatment for their thyroid dysfunction (n=1329), those in the third and fourth quartiles of serum TSH had significantly greater odds of having prevalent CKD, OR 1.83 (95% CI 1.15-2.92) and OR 1.96 (95% CI 1.23-3.13), respectively, Ptrend=0.001. Significant associations were not observed between type of thyroid dysfunction (hyperthyroidism or hypothyroidism) and prevalent CKD. CONCLUSIONS: Increasing serum TSH was associated with a greater likelihood of prevalent CKD among older adults, independent of the influence of age, diabetes and hypertension.

Targeting the thyrotropin receptor in thyroid disease.

INTRODUCTION: The thyrotropin receptor (TSHR) is essential for thyroid growth and for the production of thyroid hormones. It is unique among the glycoprotein hormone receptors, in that some of the TSHRs undergo cleavage and shedding of the alpha subunit. AREAS COVERED: This review discusses the structure and function of the TSHR, followed by an evaluation of its role in thyroid disease. Possible limitations of the TSHR as a therapeutic target are also discussed. EXPERT OPINION: The TSHR is involved in a number of hereditary and acquired disorders of the thyroid making it of potential importance as a therapeutic target in thyroid disease. Expression of the TSHR in several non-thyroidal tissues and the development of systemic manifestations of thyroid disease suggest that the TSHR is also of interest as a therapeutic target outside the thyroid.