Coxsackievirus B3 infection leads to the generation of cardiac myosin heavy chain-α-reactive CD4 T cells in A/J mice

Gangaplara, Arunakumar; Massilamany, Chandirasegaran; Brown, Deborah M.; Delhon, G.; Pattnaik, Asit K.; Chapman, Nora M.; Rose, Noel R.; Steffen, David; Reddy, N R Jayagopala

doi:10.1016/j.clim.2012.07.003

Cited by 69 publications

(105 citation statements)

References 51 publications

(73 reference statements)

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“…Long-term effects of MAV-1 infection on cardiac remodeling could be due to chronic inflammation induced by persistence of virus in the absence of active replication. Long-term effects of infection on cardiac function can be caused by an autoimmune process, as occurs with autoreactive T cells that arise following CV3B infection (59). To our knowledge, no reports document this type of response during HAdV or MAV-1 infection, but we are in the process of characterizing virus-specific and autoreactive T cells in the context of MAV-1 myocarditis.…”

Section: Discussionmentioning

confidence: 98%

Proinflammatory Effects of Interferon Gamma in Mouse Adenovirus 1 Myocarditis

McCarthy

Procario

Twisselmann

et al. 2015

J Virol

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Adenoviruses are frequent causes of pediatric myocarditis. Little is known about the pathogenesis of adenovirus myocarditis, and the species specificity of human adenoviruses has limited the development of animal models, which is a significant barrier to strategies for prevention or treatment. We have developed a mouse model of myocarditis following mouse adenovirus 1 (MAV-1) infection to study the pathogenic mechanisms of this important cause of pediatric myocarditis. Following intranasal infection of neonatal C57BL/6 mice, we detected viral replication and induction of interferon gamma (IFN-␥) in the hearts of infected mice. MAV-1 caused myocyte necrosis and induced substantial cellular inflammation that was composed predominantly of CD3 ؉ T lymphocytes. Depletion of IFN-␥ during acute infection reduced cardiac inflammation in MAV-1-infected mice without affecting viral replication. We observed decreased contractility during acute infection of neonatal mice, and persistent viral infection in the heart was associated with cardiac remodeling and hypertrophy in adulthood. IFN-␥ is a proinflammatory mediator during adenovirus-induced myocarditis, and persistent adenovirus infection may contribute to ongoing cardiac dysfunction. IMPORTANCEStudying the pathogenesis of myocarditis caused by different viruses is essential in order to characterize both virus-specific and generalized factors that contribute to disease. Very little is known about the pathogenesis of adenovirus myocarditis, which is a significant impediment to the development of treatment or prevention strategies. We used MAV-1 to establish a mouse model of human adenovirus myocarditis, providing the means to study host and pathogen factors contributing to adenovirus-induced cardiac disease during acute and persistent infection. The MAV-1 model will enable fundamental studies of viral myocarditis, including IFN-␥ modulation as a therapeutic strategy.

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Section: Discussionmentioning

confidence: 98%

Proinflammatory Effects of Interferon Gamma in Mouse Adenovirus 1 Myocarditis

McCarthy

Procario

Twisselmann

et al. 2015

J Virol

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“…Despite experiments clearly implicating DCs in the regulation of peripheral tolerance and induction of autoimmunity, the precise triggers that cause DC activation and possibly break self-tolerance are incompletely understood (Ganguly et al., 2013). Certain organ-directed infections trigger tissue-specific autoimmunity by promoting DC activation either through direct infection or release of cytokines that cause full DC maturation (Gangaplara et al., 2012, Torchinsky et al., 2009). Endogenous danger signals like uric acid or HMGB1 lead to DC maturation in response to sterile tissue injury (Scaffidi et al., 2002).…”

Section: Introductionmentioning

confidence: 99%

Myocardial Infarction Primes Autoreactive T Cells through Activation of Dendritic Cells

et al. 2017

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SummaryPeripheral tolerance is crucial for avoiding activation of self-reactive T cells to tissue-restricted antigens. Sterile tissue injury can break peripheral tolerance, but it is unclear how autoreactive T cells get activated in response to self. An example of a sterile injury is myocardial infarction (MI). We hypothesized that tissue necrosis is an activator of dendritic cells (DCs), which control tolerance to self-antigens. DC subsets of a murine healthy heart consisted of IRF8-dependent conventional (c)DC1, IRF4-dependent cDC2, and monocyte-derived DCs. In steady state, cardiac self-antigen α-myosin was presented in the heart-draining mediastinal lymph node (mLN) by cDC1s, driving the proliferation of antigen-specific CD4+ TCR-M T cells and their differentiation into regulatory cells (Tregs). Following MI, all DC subsets infiltrated the heart, whereas only cDCs migrated to the mLN. Here, cDC2s induced TCR-M proliferation and differentiation into interleukin-(IL)-17/interferon-(IFN)γ-producing effector cells. Thus, cardiac-specific autoreactive T cells get activated by mature DCs following myocardial infarction.

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“…To enumerate the frequencies of antigen-specific cells, LNC obtained from wild type or SOD1-KO mice immunized with MOG 35–55 were stimulated with MOG 35–55 (20 µg/ml) for two days, and the cultures were maintained in growth medium containing interleukin (IL)-2, hereafter called as IL-2 medium (eBioscience; Advanced Biotechnologies, Columbia, MD). On day six poststimulation, viable lymphoblasts were stained with IA b /MOG 35–55 and IA s /TMEV 70–86 (control) dextramers, anti-CD4 (eBioscience), and 7-AAD (Massilamany et al, 2011c; Gangaplara et al, 2012). Cells were acquired by flow cytometry, and the percentages of dextramer-positive (dext + ) cells were then determined in the live (7-AAD − ) CD4 + population.…”

Section: Methodsmentioning

confidence: 99%

Copper–zinc superoxide dismutase-deficient mice show increased susceptibility to experimental autoimmune encephalomyelitis induced with myelin oligodendrocyte glycoprotein 35–55

Massilamany

Gangaplara

Kim

et al. 2013

Journal of Neuroimmunology

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In this report, we have addressed the role of copper–zinc superoxide dismutase (SOD1) deficiency in the mediation of central nervous system autoimmunity. We demonstrate that SOD1-deficient C57Bl/6 mice develop more severe autoimmune encephalomyelitis induced with myelin oligodendrocyte glycoprotein (MOG) 35–55, compared with wild type mice. This alteration in the disease phenotype was not due to aberrant expansion of MOG-specific T cells nor their ability to produce inflammatory cytokines; rather lymphocytes generated in SOD1-deficient mice were more prone to spontaneous cell death when compared with their wild type littermate controls. The data point to a role for SOD1 in the maintenance of self-tolerance leading to the suppression of autoimmune responses.

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Coxsackievirus B3 infection leads to the generation of cardiac myosin heavy chain-α-reactive CD4 T cells in A/J mice

Cited by 69 publications

References 51 publications

Proinflammatory Effects of Interferon Gamma in Mouse Adenovirus 1 Myocarditis

Proinflammatory Effects of Interferon Gamma in Mouse Adenovirus 1 Myocarditis

Myocardial Infarction Primes Autoreactive T Cells through Activation of Dendritic Cells

Copper–zinc superoxide dismutase-deficient mice show increased susceptibility to experimental autoimmune encephalomyelitis induced with myelin oligodendrocyte glycoprotein 35–55

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