scholarly journals Cytokines as Targets of Novel Therapies for Graves’ Ophthalmopathy

2021 ◽  
Vol 12 ◽  
Author(s):  
Poupak Fallahi ◽  
Silvia Martina Ferrari ◽  
Giusy Elia ◽  
Francesca Ragusa ◽  
Sabrina Rosaria Paparo ◽  
...  
Keyword(s):  
Autoimmune Disorder ◽  
Intravenous Immunoglobulins ◽  
Novel Therapies ◽  
Autoimmune Process ◽  
Blocking Antibody ◽  
Graves Ophthalmopathy ◽  
Tnf Α ◽  
Organ Specific ◽  
Orbital Fibroblasts ◽  
B And T Lymphocytes

Graves’ disease (GD) is an organ-specific autoimmune disorder of the thyroid, which is characterized by circulating TSH-receptor (TSH-R) stimulating antibodies (TSAb), leading to hyperthyroidism. Graves’ ophthalmopathy (GO) is one of GD extra-thyroidal manifestations associated with the presence of TSAb, and insulin-like growth factor-1 receptor (IGF-1R) autoantibodies, that interact with orbital fibroblasts. Cytokines are elevated in autoimmune (i.e., IL-18, IL-6) and non-autoimmune hyperthyroidism (i.e., TNF-α, IL-8, IL-6), and this could be associated with the chronic effects of thyroid hormone increase. A prevalent Th1-immune response (not related to the hyperthyroidism per se, but to the autoimmune process) is reported in the immune-pathogenesis of GD and GO; Th1-chemokines (CXCL9, CXCL10, CXCL11) and the (C-X-C)R3 receptor are crucial in this process. In patients with active GO, corticosteroids, or intravenous immunoglobulins, decrease inflammation and orbital congestion, and are considered first-line therapies. The more deepened understanding of GO pathophysiology has led to different immune-modulant treatments. Cytokines, TSH-R, and IGF-1R (on the surface of B and T lymphocytes, and fibroblasts), and chemokines implicated in the autoimmune process, are possible targets of novel therapies. Drugs that target cytokines (etanercept, tocilizumab, infliximab, adalimumab) have been tested in GO, with encouraging results. The chimeric monoclonal antibody directed against CD20, RTX, reduces B lymphocytes, cytokines and the released autoantibodies. A multicenter, randomized, placebo-controlled, double-masked trial has investigated the human monoclonal blocking antibody directed against IGF-1R, teprotumumab, reporting its effectiveness in GO. In conclusion, large, controlled and randomized studies are needed to evaluate new possible targeted therapies for GO.

scholarly journals Simvastatin Inhibits CYR61 Expression in Orbital Fibroblasts in Graves’ Ophthalmopathy through the Regulation of FoxO3a Signaling

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Yi-Hsuan Wei ◽  
Shu-Lang Liao ◽  
Chia-Chun Wang ◽  
Sen-Hsu Wang ◽  
Wan-Chun Tang ◽  
...  
Keyword(s):  
Inflammatory Diseases ◽  
Protective Effects ◽  
Cellular Mechanisms ◽  
Graves Ophthalmopathy ◽  
Potential Biomarker ◽  
Tnf Α ◽  
Orbital Tissue ◽  
Proinflammatory Role ◽  
And Migration ◽  
Orbital Fibroblasts

Graves’ ophthalmopathy (GO), which is characterized by orbital tissue inflammation, expansion, and fibrosis, is the ocular manifestation in 25% to 50% of patients with Graves’ disease. As the pathology of GO is driven by autoimmune inflammation, many proinflammatory cytokines/chemokines, including TNF-α, IL-1β, IL-6, and CCL20, are crucial in the pathogenesis of GO to activate the orbital fibroblasts. Cysteine-rich protein 61 (CYR61), which is known to regulate cell proliferation, adhesion, and migration, plays a proinflammatory role in the pathogenesis of many inflammatory diseases, such as rheumatoid arthritis. CYR61 was considered a potential biomarker of GO in recent studies. Statins, which are cholesterol-lowering drugs, were found to reduce the risk of GO, probably through their anti-inflammatory and immunomodulatory effects. In this study, we established a link between CYR61 and statins in the pathogenesis and potential treatment for GO. Firstly, our data showed the overexpression of CYR61 in the orbital tissue ( n = 4 ) and serum specimens ( n = 6 ) obtained from the patients with inactive GO. CYR61 could induce the production of IL-6 and CCL20 in cultured GO orbital fibroblasts. The expression of CYR61 in cultured GO orbital fibroblasts was upregulated via TNF-α stimulation. Secondly, we pretreated cultured GO orbital fibroblasts using simvastatin, a statin, followed by TNF-α stimulation. The data revealed that simvastatin could inhibit TNF-α-induced CYR61 expression by modulating the activity of transcription factor FoxO3a. Our results provided insights into some cellular mechanisms that may explain the possible protective effects of simvastatin against the development of GO.

scholarly journals Relative Overexpression of Macrophage-Derived Cytokines in Orbital Adipose Tissue from Patients with Graves’ Ophthalmopathy

2003 ◽  
Vol 88 (9) ◽  
pp. 4246-4250 ◽  
Author(s):  
Seema Kumar ◽  
Rebecca S. Bahn
Keyword(s):  
Adipose Tissue ◽  
Immune Responses ◽  
Autoimmune Disorder ◽  
Rt Pcr ◽  
Connective Tissues ◽  
Predominant Role ◽  
Graves Ophthalmopathy ◽  
Normal Individuals ◽  
Tnf Α ◽  
Ifn Γ

Graves’ ophthalmopathy (GO) is an autoimmune disorder involving the adipose and connective tissues of the orbit. The study of cytokines present in these tissues may reveal the nature of the cells and immune responses involved in GO pathogenesis. In the current study, we performed relative quantification of the expression of cytokine genes in orbital adipose tissue from patients with GO (n = 6) and normal individuals (n = 2). Real-time RT-PCR was performed using fluorescent probes and primers for cytokines including IL-1β, IL-2, IL-4, IL-5, IL-8, IL-10, IFN-γ, and TNF-α. Results showed IL-1β to be the gene having the greatest fold expression increase over normal in four of six patients. TNF-α was increased in all six GO patients. In addition, IL-8, IL-10, and IFN-γ were increased in five of six GO patients. We found no evidence of either IL-4 or IL-5 expression in any of the GO or normal samples. The increased expression of the macrophage-derived cytokines IL-1β, TNF-α, and IL-10 suggests the presence of macrophage activation and ongoing antigen presentation within the orbit in GO. In addition, the overexpression of IFN-γ, without evidence of IL-4 or IL-5 expression, supports the concept that cell-mediated, rather than humoral, immunity plays the predominant role in pathogenesis of this disorder.

scholarly journals Precision Medicine in Graves’ Disease and Ophthalmopathy

2021 ◽  
Vol 12 ◽  
Author(s):  
Giusy Elia ◽  
Poupak Fallahi ◽  
Francesca Ragusa ◽  
Sabrina Rosaria Paparo ◽  
Valeria Mazzi ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Active Phase ◽  
Graves Disease ◽  
Autoimmune Process ◽  
Blocking Antibody ◽  
Immune Pathogenesis ◽  
Tnf Α ◽  
Immune Therapies ◽  
Specific Antigens ◽  
Ifn Γ

Graves’ disease (GD) is a condition caused by an autoimmune process involving the thyroid gland, whose main outcome is hyperthyroidism. TSAb start the autoimmune process stimulating the overproduction of thyroid hormones. In addition, TSAb can stimulate TSH-R expressed in fibroblasts and orbital pre-adipocytes leading to the manifestation of Graves’ ophtalmopathy (GO). Also, autoantibodies directed against IGF-1R have an important role in immune-pathogenesis of GO. Fundamental is the role played by cytokines (IFN-γ, TNF-α, Il-6), and Th1 chemokines in the immune-pathogenesis of both disorders, particularly in the active phase. Novel discoveries in the field led to the investigation of promising therapies, such as immune-therapies towards specific antigens (for example against TSH-R), aiming in restoring the immune tolerance versus the immune dominant epitopes associated with autoimmunity in GD. Moreover, Etanercept (that blocks the TNF-mediated inflammatory responses), TCZ (that acts against the IL-6 receptor), and RTX (that acts against CD20) have proven to be useful and safe therapeutic options in refractory GO treatment. Furthermore, teprotumumab (a human monoclonal anti-IGF-1R blocking antibody), have been revealed effective in the treatment of patients with moderate-severe GO and it is now approved for GO therapy in United States. Molecules able to act as antagonists of CXCR3, or to block CXCL10, are also under study. More extensive researches are needed to deepen out these drugs as well as to identify new targeted and effective therapies, that will permit a more precise identification of GD, or GO, patients able to respond to specific targeted therapies.

scholarly journals Emerging Insights Into the Role of Epigenetics and Gut Microbiome in the Pathogenesis of Graves’ Ophthalmopathy

2022 ◽  
Vol 12 ◽  
Author(s):  
Yan Wang ◽  
Xiao-Min Ma ◽  
Xin Wang ◽  
Xin Sun ◽  
Ling-Jun Wang ◽  
...  
Keyword(s):  
Gut Microbiome ◽  
Single Gene ◽  
T Helper 17 ◽  
Risk Alleles ◽  
Graves Ophthalmopathy ◽  
Thyrotropin Receptor Antibody ◽  
Organ Specific ◽  
Clinically Significant ◽  
Orbital Fibroblasts

Graves’ Ophthalmopathy (GO) is an organ-specific autoimmune disease that is often characterized by infiltration of orbital tissues and is considered as the most common extra-thyroid manifestation of Graves’ disease (GD). Although genetic susceptibility has been found to be critical for the phenotype of GO, the associated risk alleles in a single gene are generally insufficient to cause the disease. Accruing evidence has shown that epigenetic disorders can act as the potentially missing link between genetic risk and clinically significant disease development. Abnormal epigenetic modifications can lead to pro-inflammatory cascades and activation of orbital fibroblasts (OFs) by promoting the various inflammatory response pathways and regulating the diverse signaling molecules that are involved in the fibrogenesis and adipogenesis, thereby leading to the significant expansion of orbital tissues, fibrosis and inflammation infiltration. Additionally, emerging evidence has shown that the gut microbiome can possibly drive the pathogenesis of GO by influencing the secretion of Thyrotropin receptor antibody (TRAb) and T-helper 17 (Th17)/regulatory T cells (Treg) imbalance. This paper describes the latest epigenetic research evidence and progress made in comprehending the mechanisms of GO development, such as DNA methylation, histone modification, non-coding RNAs, and the gut microbiome.

scholarly journals The Rheumatology Drugs for COVID-19 Management: Which and When?

2021 ◽  
Vol 10 (4) ◽  
pp. 783
Author(s):  
Fabiola Atzeni ◽  
Ignazio Francesco Masala ◽  
Javier Rodríguez-Carrio ◽  
Roberto Ríos-Garcés ◽  
Elisabetta Gerratana ◽  
...  
Keyword(s):  
English Language ◽  
Multidisciplinary Approach ◽  
Intravenous Immunoglobulins ◽  
Cochrane Library ◽  
Immunomodulatory Drugs ◽  
Antiviral Therapies ◽  
Tnf Α ◽  
Large Heterogeneity ◽  
Necrosis Factor ◽  
Game Changer

Introduction: While waiting for the development of specific antiviral therapies and vaccines to effectively neutralize the SARS-CoV2, a relevant therapeutic strategy is to counteract the hyperinflammatory status, characterized by an increase mainly of interleukin (IL)-1β, IL-2, IL-6, IL-7, IL-8, and tumor necrosis factor (TNF)-α, which hallmarks the most severe clinical cases. ‘Repurposing’ immunomodulatory drugs and applying clinical management approved for rheumatic diseases represents a game-changer option. In this article, we will review the drugs that have indication in patients with COVID-19, including corticosteroids, antimalarials, anti-TNF, anti-IL-1, anti-IL-6, baricitinib, intravenous immunoglobulins, and colchicine. The PubMed, Medline, and Cochrane Library databases were searched for English-language papers concerning COVID-19 treatment published between January 2020 and October 2020. Results were summarized as a narrative review due to large heterogeneity among studies. In the absence of specific treatments, the use of immunomodulatory drugs could be advisable in severe COVID-19 patients, but clinical outcomes are still suboptimal. An early detection and treatment of the complications combined with a multidisciplinary approach could allow a better recovery of these patients.

scholarly journals Emerging Therapies in Immune Thrombocytopenia

2021 ◽  
Vol 10 (5) ◽  
pp. 1004
Author(s):  
Sylvain Audia ◽  
Bernard Bonnotte
Keyword(s):  
Tyrosine Kinase ◽  
Immune Thrombocytopenia ◽  
Plasma Cells ◽  
Autoimmune Disorder ◽  
Intravenous Immunoglobulins ◽  
Therapeutic Interventions ◽  
Autoimmune Response ◽  
Platelet Destruction ◽  
Classical Complement Pathway ◽  
Splenic Macrophages

Immune thrombocytopenia (ITP) is a rare autoimmune disorder caused by peripheral platelet destruction and inappropriate bone marrow production. The management of ITP is based on the utilization of steroids, intravenous immunoglobulins, rituximab, thrombopoietin receptor agonists (TPO-RAs), immunosuppressants and splenectomy. Recent advances in the understanding of its pathogenesis have opened new fields of therapeutic interventions. The phagocytosis of platelets by splenic macrophages could be inhibited by spleen tyrosine kinase (Syk) or Bruton tyrosine kinase (BTK) inhibitors. The clearance of antiplatelet antibodies could be accelerated by blocking the neonatal Fc receptor (FcRn), while new strategies targeting B cells and/or plasma cells could improve the reduction of pathogenic autoantibodies. The inhibition of the classical complement pathway that participates in platelet destruction also represents a new target. Platelet desialylation has emerged as a new mechanism of platelet destruction in ITP, and the inhibition of neuraminidase could dampen this phenomenon. T cells that support the autoimmune B cell response also represent an interesting target. Beyond the inhibition of the autoimmune response, new TPO-RAs that stimulate platelet production have been developed. The upcoming challenges will be the determination of predictive factors of response to treatments at a patient scale to optimize their management.

Anti-inflammatory and Antioxidant Effects of Selenium on Orbital Fibroblasts of Patients With Graves Ophthalmopathy

2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Bo-Yeon Kim ◽  
Sun-Young Jang ◽  
Dug-Hyun Choi ◽  
Chan-Hee Jung ◽  
Ji-Oh Mok ◽  
...  
Keyword(s):  
Graves Ophthalmopathy ◽  
Anti Inflammatory ◽  
Orbital Fibroblasts ◽  
Antioxidant Effects

scholarly journals Cytokine expression in the duodenal mucosa of patients with visceral leishmaniasis

2010 ◽  
Vol 43 (4) ◽  
pp. 393-395 ◽  
Author(s):  
Kleber Giovanni Luz ◽  
Felipe Francisco Tuon ◽  
Maria Irma Seixas Duarte ◽  
Guilherme Mariz Maia ◽  
Paulo Matos ◽  
...  
Keyword(s):  
Immune Response ◽  
Gastrointestinal Tract ◽  
Visceral Leishmaniasis ◽  
Intestinal Bacteria ◽  
Duodenal Mucosa ◽  
Control Group ◽  
Tnf Α ◽  
Organ Specific ◽  
Ifn Γ

INTRODUCTION: Visceral leishmaniasis (VL) is a neglected tropical disease with a complex immune response in different organs. This pattern of organ-specific immune response has never been evaluated in the gastrointestinal tract. The aim of this study was to determine the in situ immune response in duodenal biopsies on patients with VL. METHODS: A case-control study was conducted on 13 patients with VL in comparison with nine controls. The immune response was evaluated using immunohistochemistry, for CD4, CD8, CD68, IL-4, IFN-γ, TNF-α and IL-10. Histological findings from the villi, crypts and inflammatory process were analyzed. RESULTS: All the cases of VL presented Leishmania antigens. No antigen was detected in the control group. The villus size was greater in the VL patients (p < 0.05). CD68 (macrophages) and CD4 levels were higher in the VL patients (p < 0.05). No differences in the expression of CD8, TNF-α, IL-10 or IL-4 were demonstrated. The number of cells expressing IFN-γ was lower in the VL patients (p < 0.05). CONCLUSIONS: Low levels of cytokines were found in the gastrointestinal tract of patients with VL. This pattern was not found in other organs affected by the disease. Immunotolerance of this tissue against Leishmania could explain these findings, as occurs with intestinal bacteria.

scholarly journals Integrative Analysis of Proteomics and DNA Methylation in Orbital Fibroblasts From Graves’ Ophthalmopathy

2021 ◽  
Vol 11 ◽  
Author(s):  
Sita Virakul ◽  
Poorichaya Somparn ◽  
Trairak Pisitkun ◽  
Peter J. van der Spek ◽  
Virgil A. S. H. Dalm ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Extracellular Matrix ◽  
Rna Polymerase Ii ◽  
Cellular Proliferation ◽  
Effector Function ◽  
Inactive Disease ◽  
Poor Correlation ◽  
Graves Ophthalmopathy ◽  
Orbital Fibroblast ◽  
Orbital Fibroblasts

BackgroundGraves’ ophthalmopathy (GO) is a frequent extrathyroidal complication of Graves’ hyperthyroidism. Orbital fibroblasts contribute to both orbital tissue inflammation and remodeling in GO, and as such are crucial cellular elements in active GO and inactive GO. However, so far it is largely unknown whether GO disease progression is associated with functional reprogramming of the orbital fibroblast effector function. Therefore, the aim of this study was to compare both the proteome and global DNA methylation patterns between orbital fibroblasts isolated from active GO, inactive GO and healthy controls.MethodsOrbital fibroblasts from inactive GO (n=5), active GO (n=4) and controls (n=5) were cultured and total protein and DNA was isolated. Labelled and fractionated proteins were analyzed with a liquid chromatography tandem-mass spectrometer (LC-MS/MS). Data are available via ProteomeXchange with identifier PXD022257. Furthermore, bisulphite-treated DNA was analyzed for methylation pattern with the Illumina Infinium Human Methylation 450K beadchip. In addition, RNA was isolated from the orbital fibroblasts for real-time quantitative (RQ)-PCR. Network and pathway analyses were performed.ResultsOrbital fibroblasts from active GO displayed overexpression of proteins that are typically involved in inflammation, cellular proliferation, hyaluronan synthesis and adipogenesis, while various proteins associated with extracellular matrix (ECM) biology and fibrotic disease, were typically overexpressed in orbital fibroblasts from inactive GO. Moreover, orbital fibroblasts from active GO displayed hypermethylation of genes that linked to inflammation and hypomethylated genes that linked to adipogenesis and autoimmunity. Further analysis revealed networks that contained molecules to which both hypermethylated and hypomethylated genes were linked, including NF-κB, ERK1/2, Alp, RNA polymerase II, Akt and IFNα. In addition, NF-κB, Akt and IFNα were also identified in networks that were derived from the differentially expressed proteins. Generally, poor correlation between protein expression, DNA methylation and mRNA expression was observed.ConclusionsBoth the proteomics and DNA methylation data support that orbital fibroblasts from active GO are involved in inflammation, adipogenesis, and glycosaminoglycan production, while orbital fibroblasts from inactive disease are more skewed towards an active role in extracellular matrix remodeling. This switch in orbital fibroblast effector function may have therapeutic implications and further studies into the underlying mechanism are thus warranted.

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