Shining a light on thyroid eye disease

Effective medical treatment for thyroid eye disease, a debilitating condition which may cause sight-loss, has been lacking. A recent phase III trial of Teprotumumab, an IGF1R antagonist, reports most encouraging results – may be a game-changer? The trial is put in the context of current management strategies to address this question

Fibrosis in dysthyroid eye disease

Dysthyroid eye disease is a rare condition, mainly found in people with Graves’ hyperthyroidism. Autoimmune responses to thyroid/orbit shared antigens drive extensive tissue remodelling. This includes excess adipogenesis and over-production of extra-cellular matrix, which both tend to occur in the earlier ‘active’ inflammatory stages of disease. With time these give way to fibrosis, which has a profound impact on eye motility and may be life-long. Progress has been made in identifying the shared autoantigen(s) and the role of specific T cells and autoantibodies in remodelling, which have facilitated development of novel therapies. However relatively little is known of the autoimmune processes under-pinning fibrosis and currently there are no adequate medical treatments

The thyroid, the eyes and the gut: a possible connection

Graves’ disease (GD) is an autoimmune disorder responsible for 60–90% of thyrotoxicosis, with an incidence of 1 to 2 cases per 1000 population per year in England. Graves’ orbitopathy (GO) is the most frequent extrathyroidal manifestation, not provoked directly by abnormal thyroid hormone levels, but by the consequence of the underlying autoimmune process. The aetiology of autoimmune disorders is due to an interplay between susceptibility genes and environmental factors, such as infections and stress. What triggers the autoimmune reaction to a specific site of the body is not yet clearly understood. The lack of knowledge in GD and GO pathogenesis implicates therapies that only limit damage but do not prevent disease onset

Effect of iodine on early stage thyroid autonomy

AbstractThyroid autonomy is a frequent cause of thyrotoxicosis in regions with iodine deficiency. Epidemiological data suggest that iodide may influence the course of pre-existing thyroid autonomy.Making use of FRTL-5 cells stably expressing a constitutively activating TSH receptor mutation as an in vitro model of thyroid autonomy, we investigated the impact of iodide on proliferation, function and changes in global gene expression.We demonstrate that iodine inhibits growth in TSHR WT and L629F mutant FRTL-5 cells and downregulates e.g. protocadherin cluster (Pcdha1–13) and thyroid responsive element (Thrsp). In addition functional genes e.g. iodotyrosine deiodinase (iyd) and oncogen junB are upregulated, while sodium-iodide-symporter (Nis) and thyroid peroxidase (Tpo) are downregulated by iodide.Iodide tunes down the biological activity of autonomous thyrocytes and may thus be of therapeutic benefit not only to prevent the occurrence of somatic TSHR mutations, causing thyroid autonomy, but also to slow down the development of clinically relevant disease

Gsα signalling suppresses PPARγ2 generation and inhibits 3T3L1 adipogenesis

Since TSH receptor (TSHR) expression increases during adipogenesis and signals via cAMP/phospho-cAMP-response element binding protein (CREB), reported to be necessary and sufficient for adipogenesis, we hypothesised that TSHR activation would induce preadipocyte differentiation. Retroviral vectors introduced constitutively active TSHR (TSHR*) into 3T3L1 preadipocytes; despite increased cAMP (RIA) and phospho-CREB (western blot) there was no spontaneous adipogenesis (assessed morphologically, using oil red O and QPCR measurement of adipogenesis markers). We speculated that Gβγ signalling may be inhibitory but failed to induce adipogenesis using activated Gsα (gsp*). Inhibition of phosphodiesterases did not promote adipogenesis in TSHR* or gsp* populations. Furthermore, differentiation induced by adipogenic medium with pioglitazone was reduced in TSHR* and abolished in gsp* expressing 3T3L1 cells. TSHR* and gsp* did not inactivate PPARγ (PPARG as listed in the HUGO database) by phosphorylation but expression of PPARγ1 was reduced and PPARγ2 undetectable in gsp*. FOXO1 phosphorylation (required to inactivate this repressor of adipogenesis) was lowest in gsp* despite the activation of AKT by phosphorylation. PROF is a mediator that facilitates FOXO1 phosphorylation by phospho-Akt. Its transcript levels remained constantly low in the gsp* population. In most measurements, the TSHR* cells were between the gsp* and control 3T3L1 preadipocytes. The enhanced down-regulation of PREF1 (adipogenesis inhibitor) permits retention of some adipogenic potential in the TSHR* population. We conclude that Gsα signalling impedes FOXO1 phosphorylation and thus inhibits PPARγ transcription and the alternative promoter usage required to generate PPARγ2, the fat-specific transcription factor necessary for adipogenesis

Biological effects of thyrotropin receptor activation on human orbital dreadipocytes

purpose. Thyrotropin receptor (TSHR) expression is upregulated in the orbits of patients with Graves ophthalmopathy (GO), most of whom have TSHR-stimulating antibodies. The authors investigated the biological effects of TSHR activation in vitro in adipose tissue, the site of orbital TSHR expression. methods. Activating mutant TSHR (TSHR*) or wild-type (WT) was introduced into human orbital preadipocytes using retroviral vectors. Their proliferation (Coulter counting), basal cAMP accumulation (radioimmunoassay), and spontaneous and peroxisome proliferator-activated receptor (PPARγ)-induced adipogenesis (quantitative oil red O staining) were assessed and compared with those of nonmodified cells. QRT-PCR was used to measure transcripts of CCAT/enhancer binding protein (C/EBP)β, PPARγ, and lipoprotein lipase (LPL; early, intermediate, and late markers of adipogenesis) and for uncoupling protein (UCP)-1 (brown adipose tissue [BAT]). results. Expression of TSHR* significantly inhibited the proliferation of preadipocytes and produced an increase in unstimulated cAMP of 200% to 600%. Basal lipid levels were significantly increased in TSHR* (127%–275%) compared with nonmodified (100%) or WT-expressing (104%–187%) cells. This was accompanied by 2- to 10-fold increases in early-intermediate markers and UCP-1 transcripts (2- to 8-fold); LPL was at the limit of detection. In nonmodified cells, adipogenesis produced significant increases in transcripts of all markers, including LPL (approximately 30-fold). This was not the case in TSHR*-expressing cells, which also displayed 67% to 84% reductions in lipid levels. conclusions. TSHR activation stimulates early differentiation (favoring BAT formation?) but renders preadipocytes refractory to PPARγ-induced adipogenesis. In neither case did lipid-containing vacuoles accumulate, suggesting that terminal stages of differentiation were inhibited

The microbiota and autoimmunity: their role in thyroid autoimmune diseases

Since the 1970s, the role of infectious diseases in the pathogenesis of Graves' disease (GD) has been an object of intensive research. The last decade has witnessed many studies on Yersinia enterocolitica, Helicobacter pylori and other bacterial organisms and their potential impact on GD. Retrospective, prospective and molecular binding studies have been performed with contrary outcomes. Until now it is not clear whether bacterial infections can trigger autoimmune thyroid disease. Common risk factors for GD (gender, smoking, stress, and pregnancy) reveal profound changes in the bacterial communities of the gut compared to that of healthy controls but a pathogenetic link between GD and dysbiosis has not yet been fully elucidated. Conventional bacterial culture, in vitro models, next generation and high-throughput DNA sequencing are applicable methods to assess the impact of bacteria in disease onset and development. Further studies on the involvement of bacteria in GD are needed and may contribute to the understanding of pathogenetic processes. This review will examine available evidence on the subject

Moderate-intensity exercise alters markers of alternative activation in circulating monocytes in females: a putative role for PPARγ

Monocytes may be primed towards differentiation into classically activated M1 macrophages or alternatively activated M2 macrophages. M1 macrophages greatly contribute to the inflammation which promotes insulin resistance, whereas M2 macrophages resolve inflammation. We have previously shown that exercise increases M2 marker expression in mixed mononuclear cells, possibly via activation of the nuclear transcription factor PPARγ. However, these effects have not been demonstrated specifically within monocytes. Thus, we aimed to investigate whether moderate-intensity exercise elicited similar effects on monocytic M1/M2 marker expression and PPARγ activity to those reported previously in mononuclear cells, so as to further elucidate the mechanisms by which exercise may alter inflammatory status and, accordingly, prevent insulin resistance

Orbital signaling in Graves’ orbitopathy

Graves’ orbitopathy (GO) is a complex and poorly understood disease in which extensive remodeling of orbital tissue is dominated by adipogenesis and hyaluronan production. The resulting proptosis is disfiguring and underpins the majority of GO signs and symptoms. While there is strong evidence for the thyrotropin receptor (TSHR) being a thyroid/orbit shared autoantigen, the insulin-like growth factor 1 receptor (IGF1R) is also likely to play a key role in the disease. The pathogenesis of GO has been investigated extensively in the last decade with further understanding of some aspects of the disease. This is mainly derived by using in vitro and ex vivo analysis of the orbital tissues. Here, we have summarized the features of GO pathogenesis involving target autoantigens and their signaling pathways