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

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.

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β (CCL2) and α (CXCL10) chemokine modulations by cytokines and peroxisome proliferator-activated receptor-α agonists in Graves' ophthalmopathy

Journal of Endocrinology ◽

10.1530/joe-11-0488 ◽

2012 ◽

Vol 213 (2) ◽

pp. 183-191 ◽

Cited By ~ 8

Author(s):

Alessandro Antonelli ◽

Silvia Martina Ferrari ◽

Silvia Frascerra ◽

Ilaria Ruffilli ◽

Cinzia Pupilli ◽

...

Keyword(s):

Interferon Γ ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Graves Ophthalmopathy ◽

Primary Fibroblasts ◽

Pparγ Agonists ◽

Factor Α ◽

Orbital Fibroblasts ◽

Ifnγ And Tnfα

No data are present in the literature about the effect of cytokines on the prototype β chemokine (C-C motif) ligand 2 (CCL2) or of peroxisome proliferator-activated receptor α (PPARα (PPARA)) activation on CCL2 and CXCL10 chemokines secretion in fibroblasts or preadipocytes in Graves' ophthalmopathy (GO). We have tested the effect of interferon γ (IFNγ (IFNG)) and tumor necrosis factor α (TNFα) on CCL2, and for comparison on the prototype α chemokine (C-X-C motif) ligand 10 (CXCL10), and the possible modulatory role of PPARα activation on secretion of these chemokines in normal and GO fibroblasts or preadipocytes in primary cell cultures. This study shows that IFNγ alone, or in combination with TNFα, stimulates the secretion of CCL2 in primary orbital fibroblasts or preadipocytes from patients with GO at levels similar to those observed in controls. IFNγ and TNFα also stimulated CXCL10 chemokine secretion as expected. The presence of PPARα and PPARγ (PPARG) in primary fibroblasts or preadipocytes of patients with GO has been confirmed. PPARα activators were able to inhibit the secretion of CXCL10 and CCL2, while PPARγ activators were confirmed to be able to inhibit CXCL10 but had no effect on CCL2. PPARα activators were stronger inhibitors of chemokine secretions than PPARγ agonists. In conclusion, CCL2 and CXCL10 are modulated by IFNγ and TNFα in GO. PPARα activators inhibit the secretion of the main prototype α (CXCL10) and β (CCL2) chemokines in GO fibroblasts or preadipocytes, suggesting that PPARα may be involved in the modulation of the immune response in GO.

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Cytokines as Targets of Novel Therapies for Graves’ Ophthalmopathy

Frontiers in Endocrinology ◽

10.3389/fendo.2021.654473 ◽

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.

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Regulation of host-microbe interactions at oral mucosal barriers by type 17 immunity

Science Immunology ◽

10.1126/sciimmunol.aau4594 ◽

2020 ◽

Vol 5 (43) ◽

pp. eaau4594 ◽

Cited By ~ 14

Author(s):

Sarah L. Gaffen ◽

Niki M. Moutsopoulos

Keyword(s):

Oral Mucosa ◽

Oral Microbiome ◽

T Cell Subsets ◽

Interleukin 17 ◽

T Helper 17 ◽

Microbe Interactions ◽

Host Microbe Interactions ◽

Clinically Significant ◽

And Function

The oral mucosa is a primary barrier site and a portal for entry of microbes, food, and airborne particles into the gastrointestinal tract. Nonetheless, mucosal immunity at this barrier remains understudied compared with other anatomical barrier sites. Here, we review basic aspects of oral mucosal histology, the oral microbiome, and common and clinically significant diseases that present at oral mucosal barriers. We particularly focus on the role of interleukin-17 (IL-17)/T helper 17 (TH17) responses in protective immunity and inflammation in the oral mucosa. IL-17/TH17 responses are highly relevant to maintaining barrier integrity and preventing pathogenic infections by the oral commensal fungus Candida albicans. On the other hand, aberrant IL-17/TH17 responses are implicated in driving the pathogenesis of periodontitis and consequent bone and tooth loss. We discuss distinct IL-17–secreting T cell subsets, emphasizing their regulation and function in oropharyngeal candidiasis and periodontitis.

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The Role of Oxidative Stress on the Pathogenesis of Graves' Disease

Journal of Thyroid Research ◽

10.1155/2012/302537 ◽

2012 ◽

Vol 2012 ◽

pp. 1-5 ◽

Cited By ~ 28

Author(s):

Miloš Žarković

Keyword(s):

Oxidative Stress ◽

The Other ◽

Graves Disease ◽

Graves Ophthalmopathy ◽

Selenium Treatment ◽

Graves Orbitopathy ◽

Eye Involvement ◽

Orbital Fibroblasts

Graves' disease is a most common cause of hyperthyroidism. It is an autoimmune disease, and autoimmune process induces an inflammatory reaction, and reactive oxygen species (ROSs) are among its products. When balance between oxidants and antioxidants is disturbed, in favour of the oxidants it is termed “oxidative stress” (OS). Increased OS characterizes Graves' disease. It seems that the level of OS is increased in subjects with Graves' ophthalmopathy compared to the other subjects with Graves' disease. Among the other factors, OS is involved in proliferation of orbital fibroblasts. Polymorphism of the 8-oxoG DNA N-glycosylase 1 (hOGG1) involved in repair of the oxidative damaged DNA increases in the risk for developing Grave's disease. Treatment with glucocorticoids reduces levels of OS markers. A recent large clinical trial evaluated effect of selenium on mild Graves' ophthalmopathy. Selenium treatment was associated with an improved quality of life and less eye involvement and slowed the progression of Graves' orbitopathy, compared to placebo.

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Forkhead Transcription Factor FOXO1 Is Regulated by Both a Stimulatory Thyrotropin Receptor Antibody and Insulin-Like Growth Factor-1 in Orbital Fibroblasts from Patients with Graves' Ophthalmopathy

Thyroid ◽

10.1089/thy.2015.0254 ◽

2015 ◽

Vol 25 (10) ◽

pp. 1145-1150 ◽

Cited By ~ 4

Author(s):

Seema Kumar ◽

Michael Coenen ◽

Seethalakshmi Iyer ◽

Rebecca S. Bahn

Keyword(s):

Transcription Factor ◽

Growth Factor ◽

Insulin Like Growth Factor ◽

Thyrotropin Receptor ◽

Forkhead Transcription Factor ◽

Receptor Antibody ◽

Graves Ophthalmopathy ◽

Thyrotropin Receptor Antibody ◽

Orbital Fibroblasts

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Ingestible Osmotic Pill for In-vivo Sampling of Gut Microbiome

10.1101/690982 ◽

2019 ◽

Cited By ~ 1

Author(s):

Hojatollah Rezaei Nejad ◽

Bruno C. M. Oliveira ◽

Aydin Sadeqi ◽

Amin Dehkharghani ◽

Ivanela Kondova ◽

...

Keyword(s):

Gut Microbiome ◽

Spatial Diversity ◽

Microfluidic Channels ◽

Bacterial Populations ◽

Population Demographics ◽

Organ Specific ◽

3D Printed

AbstractTechnologies capable of non-invasively sampling different locations in the gut upstream of the colon will enable new insights into the role of organ-specific microbiota in human health. We present an ingestible, biocompatible, battery-less, 3D-printed micro-engineered pill with integrated osmotic sampler and microfluidic channels for in vivo sampling of the gut lumen and its microbiome upstream of the colon. The pill’s sampling performance was characterized using realistic in vitro models and validated in vivo in pigs and primates. Our results show that the bacterial populations recovered from the pills’ microfluidic channels closely resemble the bacterial population demographics of the microenvironment to which the pill was exposed. We believe such lab-on-a-pill devices will revolutionize our understanding of the spatial diversity of the gut microbiome and its response to medical conditions and treatments.

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