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Sidong Xiong - One of the best experts on this subject based on the ideXlab platform.
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Dpep2 Emerging as a Modulator of Macrophage Inflammation Confers Protection Against CVB3-Induced Viral Myocarditis
Frontiers Media S.A., 2019Co-Authors: Xiaoli Yang, Yan Yue, Sidong XiongAbstract:Overwhelming cardiac inflammation has been reported to be the pathogenic mechanism of Coxsackievirus B3 (CVB3)-induced Viral Myocarditis (VMC), while the detailed molecular mechanisms remain unknown. Membrane-bound dipeptidases (MBD, also known as Dpep) have been shown to be involved in inflammatory diseases. However, the clear and direct evidence of their impacts on inflammation is still lacking. In this study, our results revealed that Dpep2 expression was remarkably increased during CVB3 infection, and primarily produced by the cardiac tissue-infiltrating macrophages instead of constitutive cardiomyocytes. Macrophages have been reported to play an important pathological role in driving VMC. Interestingly, macrophage-specific Dpep2 deletion robustly aggravated CVB3-induced cardiac inflammation, evidenced by augmented expression of TNF-α, IL-6, and MCP-1 in heart tissue. In addition, Dpep2-deficient bone-marrow derived macrophages (BMDMs) generated more TNF-α, IL-6, and MCP-1 after CVB3 stimulation compared with the control BMDMs. Moreover, this suppressive effect of Dpep2 on macrophages relied on its repression on NF-κB signaling pathway, but not on its conventional hydrolysate LTE4. Taken together, this study revealed that Dpep2 could protect against CVB3-induced VMC by acting as a suppressor of macrophage inflammation. Better understanding how macrophage Dpep2 dampened the cardiac inflammation would provide us with insights for the efficient control of CVB3-induced VMC
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intein mediated backbone cyclization of vp1 protein enhanced protection of cvb3 induced Viral Myocarditis
Scientific Reports, 2017Co-Authors: Sidong XiongAbstract:CVB3 is a common human pathogen to be highly lethal to newborns and causes Viral Myocarditis and pancreatitis in adults. However, there is no vaccine available for clinical use. CVB3 capsid protein VP1 is an immunodominant structural protein, containing several B- and T-cell epitopes. However, immunization of mice with VP1 protein is ineffective. Cyclization of peptide is commonly used to improve their in vivo stability and biological activity. Here, we designed and synthesizd cyclic VP1 protein by using engineered split Rma DnaB intein and the cyclization efficiency was 100% in E. coli. As a result, the cyclic VP1 was significantly more stable against irreversible aggregation upon heating and against carboxypeptidase in vitro and the degradation rate was more slowly in vivo. Compared with linear VP1, immunization mice with circular VP1 significantly increased CVB3-specific serum IgG level and augmented CVB3-specific cellular immune responses, consequently afforded better protection against CVB3-induced Viral Myocarditis. The cyclic VP1 may be a novel candidate protein vaccine for preventing CVB3 infection and similar approaches could be employed to a variety of protein vaccines to enhance their protection effect.
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il 33 enhances macrophage m2 polarization and protects mice from cvb3 induced Viral Myocarditis
Journal of Molecular and Cellular Cardiology, 2017Co-Authors: Chao Wang, Chunsheng Dong, Sidong XiongAbstract:Viral Myocarditis is the inflammation caused by myocardial virus infection, and the coxsackievirus group B3 virus (CVB3) is the most common pathogen. An efficient therapeutic agent against Viral Myocarditis is currently unavailable. IL-33, a new member of the IL-1 cytokine superfamily, exhibits potential immunotherapeutic effect against inflammatory and autoimmune diseases. However, the functional role of IL-33 in Viral Myocarditis has not been investigated. To examine the therapeutic role of IL-33 in Viral Myocarditis, an IL-33 overexpression plasmid (pDisplay-IL-33) and IL-33 knockdown plasmid (pLL3.7-IL-33) were packaged with polyethylenimine and delivered intravenously at the orbital area of BALB/c male mice after CVB3 infection. Then, Myocarditis severity was assessed 7days after infection. Results showed that IL-33 up-regulation significantly alleviated the severity of Viral Myocarditis with an increased cardiac contractive function and survival rate. Mechanistic studies demonstrated that IL-33 can stimulate ST2L+F4/80+ macrophages and ST2L+CD4+T cells in cardiac tissue to express IL-4, which is a potent inducer for macrophage M2 polarization. Mice with adoptive transfer of M2 macrophages exhibited less cardiac inflammation and attenuated Myocarditis, suggesting the protective role of M2 macrophage in Viral Myocarditis. Additionally, IL-4 neutralization abolished the IL-33-mediated cardiac functional improvement in Myocarditis mice. Collectively, our findings provide a novel therapeutic role for IL-33 in CVB3-induced Myocarditis.
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endoplasmic reticulum stress aggravates Viral Myocarditis by raising inflammation through the ire1 associated nf κb pathway
Canadian Journal of Cardiology, 2015Co-Authors: Xi Zha, Yan Yue, Ning Dong, Sidong XiongAbstract:Abstract Background Viral Myocarditis, which is mostly caused by coxsackievirus infection, is characterized by myocardial inflammation. Abnormal endoplasmic reticulum (ER) stress participates in many heart diseases, but its role in Viral Myocarditis remains unsolved. Methods We investigated the influence of ER stress in coxsackievirus B3 (CVB3)-induced Viral Myocarditis by dynamically detecting its activation in CVB3-infected hearts, analyzing its association with Myocarditis severity, and exploring its impact on disease development by modulating the strength of ER stress with the chemical activator tunicamycin (Tm) or the inhibitor tauroursodeoxycholic acid (TUDCA). The underlying signal pathway of ER stress in CVB3-induced Myocarditis was also deciphered. Results We found that myocardial expression of Grp78 and Grp94, 2 ER stress markers, was significantly increased after CVB3 infection and positively correlated with Myocarditis severity. Consistently, Tm-augmented ER stress obviously aggravated Myocarditis, as shown by more severe myocardial inflammation, reduced cardiac function, and a lower survival rate, whereas TUDCA decreased ER stress and obviously alleviated Myocarditis. This pathologic effect of ER stress could be attributed to increased levels of proinflammatory cytokine (interleukin [IL]-6, IL-12, tumor necrosis factor-alpha, and monocyte chemoattractant protein-1) production through the IRE1-associated nuclear factor-κB (NF-kB) pathway. Conclusions ER stress accentuated CVB3-induced myocardial inflammation through the IRE1-associated NF-κB pathway. This study may help us understand the role of ER stress in Viral Myocarditis and promote the development of corresponding therapeutic strategies based on manipulating ER stress.
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involvement of nlrp3 inflammasome in cvb3 induced Viral Myocarditis
American Journal of Physiology-heart and Circulatory Physiology, 2014Co-Authors: Yan Wang, Bo Gao, Sidong XiongAbstract:Viral Myocarditis, which is most prevalently caused by coxsackievirus B3 (CVB3) infection, is a serious clinical condition characterized by cardiac inflammation. Inflammasome plays an essential rol...
Shigetake Sasayama - One of the best experts on this subject based on the ideXlab platform.
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therapeutic effects of fty720 a new immunosuppressive agent in a murine model of acute Viral Myocarditis
Journal of the American College of Cardiology, 2001Co-Authors: Tadashi Miyamoto, Akira Matsumori, Myungwoo Hwang, Ryosuke Nishio, Haruyasu Ito, Shigetake SasayamaAbstract:OBJECTIVES This study examines the efficacy of FTY720 (FTY), a new immunosuppressor, in the treatment of acute Viral Myocarditis in a murine model. BACKGROUND Immunosuppressive agents have no proven therapeutic efficacy in experimental or clinical Myocarditis. METHODS EncephaloMyocarditis virus was inoculated i.p. in DBA/2 mice on day 0. Postinoculation treatment consisted of FTY 10 mg/kg/day p.o. (FTY group), or cyclosporine A (CsA) 40 mg/kg/day p.o. (CsA group) or distilled water p.o. only (control group). Survival until day 14, as well as cardiac histopathology, virus concentrations, cytokines (interleukin [IL]-2, IL-12, interferon [IFN]-gamma and tumor necrosis factor [TNF]-alpha) and nitric oxide (NO) on day 5 were examined. RESULTS In the control and CsA groups, all mice died within 10 and 7 days, respectively. However, in the FTY group, 27% of the animals survived up to day 14. Compared with the control group, 1) histological scores were significantly lower in the FTY group but unchanged in the CsA group; 2) virus concentration was significantly higher in the CsA group but not in the FTY group; 3) expressions of IL-2, IL-12 and IFN-gamma in the heart were suppressed in both the FTY and CsA groups, though suppression was weaker in the FTY group; 4) TNF-alpha and NO were significantly increased in the CsA group but not in the FTY group. CONCLUSIONS FTY720 had a significant therapeutic effect in acute experimental Myocarditis without inducing excessive virus replication. This report is the first to describe a beneficial effect by an immunosuppressive agent in the treatment of acute Viral Myocarditis.
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high doses of digitalis increase the myocardial production of proinflammatory cytokines and worsen myocardial injury in Viral Myocarditis a possible mechanism of digitalis toxicity
Japanese Circulation Journal-english Edition, 1999Co-Authors: Akira Matsumori, Tadashi Miyamoto, Ryosuke Nishio, Atsushi Iwasaki, Hideki Igata, Shigetake SasayamaAbstract:Results of recent studies suggest that proinflammatory cytokines cause myocardial contractile dysfunction, and that the drugs used to treat heart failure modulate the production of cytokines. This study was designed to examine the effects of digoxin in a murine model of heart failure induced by Viral Myocarditis. Four-week-old inbred DBA/2 mice were inoculated intraperitoneally with encephaloMyocarditis virus (EMCV). Digoxin was given orally in doses of 0.1, 1 or 10 mg/kg daily from the day of virus inoculation. Interleukin (IL)-1 β, IL-6 and tumor necrosis factor (TNF)-α production in the heart were measured on day 5 after EMCV inoculation by enzyme-linked immunosorbent assay. The 14-day mortality tended to be increased in mice treated with 1 mg/kg, and was significantly increased in the group treated with 10 mg/kg per day. Myocardial necrosis and cellular infiltration on day 6 were significantly more severe in the high-dose digoxin group than in the control group. In the animals treated with 1 mg/kg digoxin, IL-1β was significantly higher than in the control group. Intracardiac TNF-α levels were increased in a dose-dependent manner. These results suggest that digoxin worsens Viral Myocarditis, and that its use in high doses should be avoided in patients suffering from heart failure due to Viral Myocarditis. (Jpn Circ J 1999; 63: 934 - 940)
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treatment of experimental Viral Myocarditis with interleukin 10
Circulation, 1999Co-Authors: Ryosuke Nishio, Akira Matsumori, Tetsuo Shioi, Hiroshi Ishida, Shigetake SasayamaAbstract:Background —The T helper cell type 2–associated cytokine interleukin (IL)-10 has a variety of immunomodulatory properties. However, the effects of the cytokine on Viral Myocarditis remain unclear. Methods and Results —We studied the effects of recombinant human IL-10 (rhIL-10) fully active on mouse cells in a murine experimental model of acute Viral Myocarditis caused by the encephaloMyocarditis virus (EMCV). Four-week-old DBA/2 mice were inoculated with EMCV (day 0). rhIL-10 (10 μg/mouse) was administered once daily, starting on day 0, and control mice received vehicle only. Survival rates were determined on day 14. Myocardial histopathology, cytokine levels in the heart by ELISA assay, and myocardial virus concentration were examined on day 6, and the expression levels of myocardial inducible nitric oxide synthase (iNOS) mRNA were measured by competitive polymerase chain reaction. The 14-day survival in mice treated with rhIL-10 was significantly higher (80%) than in the control group (30%, n=10 in each, P <0.05). rhIL-10 treatment significantly attenuated myocardial lesions and suppressed tumor necrosis factor-α and IL-2 in the heart. rhIL-10 treatment had little effect on myocardial virus concentration. The expression levels of myocardial iNOS mRNA were significantly decreased in the group treated with rhIL-10 (8.6±4.7 amol/mg total RNA in treated versus 26.5±7.1 amol/mg total RNA in control mice, P <0.05). Conclusions —These findings provide new insights into the in vivo effects of IL-10 on Viral infection and suggest a therapeutic effect of IL-10 on Viral Myocarditis.
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pimobendan inhibits the production of proinflammatory cytokines and gene expression of inducible nitric oxide synthase in a murine model of Viral Myocarditis
Journal of the American College of Cardiology, 1999Co-Authors: Atsushi Iwasaki, Akira Matsumori, Ryosuke Nishio, Takehiko Yamada, Tetsuo Shioi, Weizhong Wang, Koh Ono, Masaharu Okada, Shigetake SasayamaAbstract:Abstract OBJECTIVES This study was designed to examine the effects of pimobendan in a murine model of Viral Myocarditis in relation to proinflammatory cytokine production and nitric oxide (NO) synthesis by inducible NO synthase (iNOS) in the heart. BACKGROUND Pimobendan has been recently confirmed to improve both acute and chronic heart failure. Since the modulation of myocardial necrosis and contractile dysfunction by various proinflammatory cytokines may be partially mediated by the production of nitric oxide, the effects of pimobendan on the production of proinflammatory cytokines and NO were investigated in an animal model of Viral Myocarditis involving heart failure. METHODS DBA/2 mice were inoculated with the encephaloMyocarditis virus. To observe its effect on survival up to 14 days, pimobendan (0.1 mg/kg or 1 mg/kg) or vehicles were given from the day of virus inoculation (day 0) orally once daily. The effects of pimobendan on histological changes, cytokine production, NO production and iNOS gene expression in the heart were studied in mice treated either with pimobendan, 1 mg/kg or with vehicles only, and sacrificed seven days after virus inoculation. RESULTS The survival of mice improved in a dose-dependent fashion such that a significant difference (p CONCLUSIONS These findings suggest that the beneficial effects of pimobendan in Viral Myocarditis are partially mediated by the inhibition of both proinflammatory cytokine production and NO synthesis by iNOS.
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persistent expression of cytokine in the chronic stage of Viral Myocarditis in mice
Circulation, 1996Co-Authors: Tetsuo Shioi, Akira Matsumori, Shigetake SasayamaAbstract:Background Dilated cardiomyopathy (DCM) is one of the most frequent causes of heart failure of unknown origin. One possible cause of DCM is considered to be a sequel to Myocarditis. However, the mechanism of progression from Viral Myocarditis to DCM is still not clear. Methods and Results The expression of the immunoregulatory cytokines interferon (IFN)-γ and interleukin (IL)-2 and the proinflammatory cytokines IL-1β and tumor necrosis factor (TNF)-α in the heart tissue was studied in a murine model of postMyocarditis DCM induced by encephaloMyocarditis virus. IFN-γ, IL-1β, and TNF-α mRNA increased 3 days after virus inoculation. IL-2 mRNA was detectable 7 days after inoculation. The peak expression of all cytokine genes examined was seen 7 days after inoculation. The expression of these cytokine genes decreased thereafter but persisted 80 days after inoculation. IL-1β gene expression in the chronic stage was relatively high compared with other cytokines and was correlated with the ratio of heart weight t...
Stephane Heymans - One of the best experts on this subject based on the ideXlab platform.
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a novel 72 kda leukocyte derived osteoglycin enhances the activation of toll like receptor 4 and exacerbates cardiac inflammation during Viral Myocarditis
Cellular and Molecular Life Sciences, 2017Co-Authors: Marieke Rienks, Rick Van Leeuwen, Paolo Carai, Dirk Westermann, Wouter Verhesen, Anna Papageorgiou, Kristiaan Wouters, Georg Summer, Stephane HeymansAbstract:Viral Myocarditis can severely damage the myocardium through excessive infiltration of immune cells. Osteoglycin (OGN) is part of the small leucine-rich repeat proteoglycan (SLRP) family. SLRP’s may affect inflammatory and fibrotic processes, but the implication of OGN in cardiac inflammation and the resulting injury upon Viral Myocarditis is unknown. This study uncovered a previously unidentified 72-kDa variant of OGN that is predominant in cardiac human and mouse samples of Viral Myocarditis. Its absence in mice significantly decreased cardiac inflammation and injury in Coxsackievirus-B3-induced Myocarditis. It also delayed mortality in lipopolysaccharide-induced endotoxemia going along with a reduced systemic production of pro-inflammatory cytokines. This 72-kDa OGN is expressed in the cell membrane of circulating and resident cardiac macrophages and neutrophils. Co-immunoprecipitation and OGN siRNA experiments revealed that this 72-kDa variant activates the toll-like receptor-4 (TLR4) with a concomitant increase in IL-6, TNF-α, IL-1β, and IL-12 expression. This immune cell activation by OGN occurred via MyD88 and increased phosphorylation of c-jun. Finally, the 72-kDa chondroitin sulfate is the result of O-linked glycosylation of the 32-kDa protein core of OGN. In contrast, the 34-kDa dermatan sulfate-OGN, involved in collagen cross linking, was also the result of O-linked glycosylation. The current study discovered a novel 72-kDa chondroitin sulfate-OGN that is specific for innate immune cells. This variant is able to bind and activate TLR4. The absence of OGN decreases cytokine production by both circulating and cardiac leukocytes upon (systemic) LPS exposure, and reduces cardiac inflammation and injury in Viral Myocarditis.
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inflammation in Viral Myocarditis friend or foe
Trends in Molecular Medicine, 2012Co-Authors: Maarten F Corsten, Blanche Schroen, Stephane HeymansAbstract:Viral Myocarditis is an important cause of heart failure for which no specific treatments are available. Direct Viral injury to cardiac cells provokes an inflammatory response that significantly contributes to cardiac damage and ensuing morbidity. Despite the central pathogenic role of autoimmune injury, broad inhibition of the inflammatory response does not result in patient benefit. Many preclinical studies collectively emphasize that modulating distinct inflammatory signaling pathways may yield effective Viral clearance while preserving cardiac structure. This review aims to provide an overview of the sometimes contrasting observations from experimental Viral Myocarditis models and to translate the lessons learned into opportunities for future investigations and therapies.
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acute Viral Myocarditis
European Heart Journal, 2008Co-Authors: Robert Dennert, Harry J G M Crijns, Stephane HeymansAbstract:Acute Myocarditis is one of the most challenging diagnosis in cardiology. At present, no diagnostic gold standard is generally accepted, due to the insensitivity of traditional diagnostic tests. This leads to the need for new diagnostic approaches, which resulted in the emergence of new molecular tests and a more detailed immunohistochemical analysis of endomyocardial biopsies. Recent findings using these new diagnostic tests resulted in increased interest in inflammatory cardiomyopathies and a better understanding of its pathophysiology, the recognition in overlap of virus-mediated damage, inflammation, and autoimmune dysregulation. Novel results also pointed towards a broader spectrum of Viral genomes responsible for acute Myocarditis, indicating a shift of enterovirus and adenovirus to parvovirus B19 and human herpes virus 6. The present review proposes a general diagnostic approach, focuses on the Viral aetiology and associated autoimmune processes, and reviews treatment options for patients with acute Viral Myocarditis.
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inhibition of urokinase type plasminogen activator or matrix metalloproteinases prevents cardiac injury and dysfunction during Viral Myocarditis
Circulation, 2006Co-Authors: Stephane Heymans, Susanne Rutschow, Melissa Swinnen, Davy Vanhoutte, Matthias Pauschinger, Armando M De Palma, Angela Kallwellisopara, Fangye Gao, Raimund Torpai, Andy BakerAbstract:Background— Acute Viral Myocarditis is an important cause of cardiac failure in young adults for which there is no effective treatment apart from general heart failure therapy. The present study tested the hypothesis that increased expression of the proteinases urokinase-type plasminogen activator (uPA) and matrix metalloproteinases (MMPs) is implicated in cardiac inflammation, injury, and subsequent failure during Coxsackievirus-B3 (CVB3)–induced Myocarditis. Methods and Results— First, we showed increased expression and activity of uPA and MMP-9 in wild-type mice at 7 days of CVB3-induced Myocarditis. Targeted deletion of uPA, which resulted in reduced MMP activity and cytokine expression or inhibition of MMPs by adenoViral gene overexpression of tissue inhibitor of metalloproteinases-1, decreased cardiac inflammation and reduced myocardial necrosis at 7 days and decreased cardiac fibrosis at 35 days after CVB3 infection. Importantly, loss of uPA or MMP activity prevented CVB3-induced cardiac dilatation...
Toshitaka Yajima - One of the best experts on this subject based on the ideXlab platform.
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Viral Myocarditis potential defense mechanisms within the cardiomyocyte against virus infection
Future Microbiology, 2011Co-Authors: Toshitaka YajimaAbstract:Virus infection can inflict significant damage on cardiomyocytes through direct injury and secondary immune reactions, leading to Myocarditis and dilated cardiomyopathy. While Viral Myocarditis or cardiomyopathy is a complication of systemic infection of cardiotropic viruses, most individuals infected with the viruses do not develop significant cardiac disease. However, some individuals proceed to develop severe virus-mediated heart disease. Recent studies have shown that Viral infection of cardiomyocytes is required for the development of Myocarditis and subsequent cardiomyopathy. This suggests that Viral infection of cardiomyocytes can be an important step that determines the pathogenesis of Viral Myocarditis during systemic infection. Accordingly, this article focuses on potential defense mechanisms within the cardiomyocyte against virus infection. Understanding of the cardiomyocyte defense against invading viruses may give us novel insights into the pathophysiology of Viral Myocarditis, and enable us ...
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Viral Myocarditis potential defense mechanisms within the cardiomyocyte against virus infection
Future Microbiology, 2011Co-Authors: Toshitaka YajimaAbstract:Virus infection can inflict significant damage on cardiomyocytes through direct injury and secondary immune reactions, leading to Myocarditis and dilated cardiomyopathy. While Viral Myocarditis or cardiomyopathy is a complication of systemic infection of cardiotropic viruses, most individuals infected with the viruses do not develop significant cardiac disease. However, some individuals proceed to develop severe virus-mediated heart disease. Recent studies have shown that Viral infection of cardiomyocytes is required for the development of Myocarditis and subsequent cardiomyopathy. This suggests that Viral infection of cardiomyocytes can be an important step that determines the pathogenesis of Viral Myocarditis during systemic infection. Accordingly, this article focuses on potential defense mechanisms within the cardiomyocyte against virus infection. Understanding of the cardiomyocyte defense against invading viruses may give us novel insights into the pathophysiology of Viral Myocarditis, and enable us to develop innovative strategies of diagnosis and treatment for this challenging clinical entity.
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Viral Myocarditis from the perspective of the virus
Circulation, 2009Co-Authors: Toshitaka Yajima, Kirk U KnowltonAbstract:Viral Myocarditis has been recognized as a cause of congestive heart failure for >50 years, but it is still a challenging disease to diagnose and treat.1,2 The history and clinical features are often nonspecific, and practical serological markers are not available during the acute phase of the disease. Even after proper diagnosis, no clinically proven treatment exists to inhibit the development of subsequent dilated cardiomyopathy (DCM) and, in some cases, death. Accordingly, to facilitate future scientific work into this difficult clinical entity, this review proposes a clinical paradigm that focuses on the phases of Viral infection and the molecular insights that are important for these phases of the infectious process with a focus on interactions between the virus and the cardiac myocyte. Myocarditis is defined as inflammation of the heart muscle. The gold standard for diagnosis has been the Dallas criteria based on histopathology from an endomyocardial biopsy.3 It is now recognized that the Dallas criteria are not sensitive for Myocarditis because they do not consider the presence of Viral genome in the heart.4 Furthermore, an invasive procedure is required to obtain a sample of the myocardium. Many viruses have been implicated as causes of Myocarditis. These most commonly include adenoviruses and enteroviruses such as the coxsackieviruses. Recently, parvovirus B19 has been associated with a significant percentage of patients diagnosed with Myocarditis and DCM.5 However, a growing body of data indicates that parvovirus is present in a large percentage of patients who do not have Myocarditis.6–8 Of the viruses that cause Myocarditis, the cellular and molecular mechanisms associated with coxsackieViral infection of the heart have been most thoroughly investigated with murine models. Therefore, the mechanistic experiments described in this review focus primarily, but not exclusively, on coxsackieViral Myocarditis. It is important to note that coxsackieviruses …
Yuhua Liao - One of the best experts on this subject based on the ideXlab platform.
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th17 cells contribute to Viral replication in coxsackievirus b3 induced acute Viral Myocarditis
Journal of Immunology, 2010Co-Authors: Jing Yuan, Qiongwen Lin, Ailin Cao, Jihua Dong, Jinping Wang, Jinghui Zhang, Min Wang, Heping Guo, Xiang Cheng, Yuhua LiaoAbstract:Acute Viral Myocarditis (AVMC) is characterized by virus-triggered myocardial inflammation, and Coxsackievirus B3 (CVB3) is the primary pathogen. We previously proved that Th17 cells, besides having proinflammatory effects, were involved in AVMC by enhancing humoral response. However, the relationship between Th17 cells and CVB3 replication remains unknown. In this experiment, we infected BALB/c mice with CVB3 for establishing AVMC models and then found that, with the increase of Viral replication, the expressions of splenic Th17 cells, serum IL-17, and cardiac IL-17 mRNA were elevated significantly, accompanied by the progressive cardiac injuries of AVMC. Furthermore, on day 5, the peak time for Viral replication, correlation was positive between cardiac IL-17 mRNA and CVB3 RNA (correlation index = 0.835; p < 0.01). Although the expressions of Th1 and CD8(+) T cells, which could secrete the antiViral cytokine IFN-γ and damage the heart, were also elevated, along with Th17 cells, in AVMC, the neutralization of IL-17 further upregulated the percentages of splenic Th1 and CD8(+) T cells and the levels of cardiac IFN-γ mRNA. The cardiac pathological changes were obviously improved after neutralization, with reduced Viral replication followed by decreases in the cardiac inflammatory cytokines IL-17, TNF-α, and IL-1β. These data suggest that Th17 cells contribute to CVB3 replication in AVMC, and that IL-17 might be an important target for regulating the balance of antiViral immunities.
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th17 cells facilitate the humoral immune response in patients with acute Viral Myocarditis
Journal of Clinical Immunology, 2010Co-Authors: Jing Yuan, Qiongwen Lin, Ailin Cao, Jinghui Zhang, Min Wang, Heping Guo, Yuhua LiaoAbstract:Recently, the Th17 cell, a newly determined CD4+Th subset, was reported to participate in the inflammation of Myocarditis combined with Th1 cells, and this study aimed to explore whether it was involved in the Th2 cell-mediated humoral immunity in Viral Myocarditis. A total of 34 patients, including 16 acute Viral Myocarditis (AVMC) and 18 dilated cardiomyopathy (DCM) having a history of AVMC, were enrolled for this study besides 18 healthy volunteers. The frequencies of Th17 and Th1 cells, especially Th17 cells in AVMC patients, while those of Th1 and Th2 cells, especially Th2 cells in DCM group, were all increased significantly compared with those in healthy volunteers (P < 0.01), with no changes of Th2 cells in AVMC and Th17 cells in DCM groups. The similar results were also observed in Th cell cytokines (IL-17, INF-γ, and IL-4) and key transcript factors (RORγt, T-bet, and GATA-3). Meanwhile, antiheart antibodies (AHA) of IgG type were found in 15 (93.8%) patients with AVMC and ten (55.6%) cases with DCM, accompanied by the higher expression of IL-17R on B cells and the frequencies of B cells than those in healthy controls (P < 0.01 in AVMC and P < 0.05 in DCM, respectively) who had no AHA. Furthermore, both of the B cell activities in AVMC and DCM groups were elevated and positively correlated to serum IL-17 (R = 0.66, P < 0.01) and IL-4 (R = 0.47, P < 0.05) respectively, with no correlation to INF-γ. It was Th17 cells but not Th2 cells that helped the B cells to produce AHA in AVMC and not until at the late phase of Viral Myocarditis could Th2 cells play the important role in mediating humoral response.
