Cardiac injury in myocarditis induced by coxsackievirus group B, type 3 in Balb/c mice is mediated by Lyt 2+ cytolytic lymphocytes

Guthrie, Maureen; Lodge, Patricia A.; Huber, Sally A.

doi:10.1016/0008-8749(84)90188-6

Cited by 86 publications

(40 citation statements)

References 12 publications

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“…Disease induction is strongly associated with infection by Coxsackie virus B3 (CVB3) 3 (2). Local tissue damage is believed to be primarily T cell mediated (3,4) and to result from both the antiviral immune response and an autoimmune response against cardiac myosin.…”

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confidence: 99%

TLR Ligands Act Directly upon T Cells to Restore Proliferation in the Absence of Protein Kinase C-θ Signaling and Promote Autoimmune Myocarditis

Marsland

Nembrini

Grün

et al. 2007

The Journal of Immunology

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The serine/threonine kinase, protein kinase C-θ (PKC-θ), plays a central role in the activation and differentiation of Th2 cells while being redundant in CD4+ and CD8+ antiviral responses. Recent evidence indicates that PKC-θ may however be required for some T cell-driven autoimmune responses. We have investigated the role of PKC-θ in the induction of autoimmune myocarditis induced by either Coxsackie B3 virus infection or immunization with α-myosin/CFA (experimental autoimmune myocarditis (EAM)). PKC-θ-deficient mice did not develop EAM as shown by impaired inflammatory cell infiltration into the heart, reduced CD4+ T cell IL-17 production, and the absence of a myosin-specific Ab response. Comparatively, PKC-θ was not essential for both early and late-phase Coxsackie virus-induced myocarditis. We sought to find alternate pathways of immune stimulation that might reconcile the differential requirements for PKC-θ in these two disease models. We found systemic administration of the TLR ligand CpG restored EAM in PKC-θ-deficient mice. CpG could act directly upon TLR9-expressing T cells to restore proliferation and up-regulation of Bcl-xL, but exogenous IL-6 and TGF-β was required for Th17 cell differentiation. Taken together, these results indicate that TLR-mediated activation of T cells can directly overcome the requirement for PKC-θ signaling and, combined with the dendritic cell-derived cytokine milieu, can promote the development of autoimmunity.

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confidence: 99%

TLR Ligands Act Directly upon T Cells to Restore Proliferation in the Absence of Protein Kinase C-θ Signaling and Promote Autoimmune Myocarditis

Marsland

Nembrini

Grün

et al. 2007

The Journal of Immunology

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“…[15][16][17][18][19] For example, anticardiac antibodies and sensitized T lymphocytes have been detected in patients with acute MI. 20 Lymphocytes have also been implicated in cardiomyocyte injury during autoimmune myocarditis, [21][22][23][24][25] Here we established the presence of T cells in the hearts of dKO mice. We explored the roles of lymphocytes in murine CHD 1,3 by generating and analyzing B and T cell-deficient SR-BI/apoE/RAG2 triple KO (tKO) and corresponding dKO control mice.…”

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confidence: 99%

“…[15][16][17][18][19] For example, anticardiac antibodies and sensitized T lymphocytes have been detected in patients with acute MI. 20 Lymphocytes have also been implicated in cardiomyocyte injury during autoimmune myocarditis, [21][22][23][24][25] and spontaneous RAG2-dependent, lymphocyte-mediated immune responses in mice lacking the negative immunoregulatory receptor PD-1 cause dilated cardiomyopathy and death from congestive heart failure. 26 Here we established the presence of T cells in the hearts of dKO mice.…”

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confidence: 99%

Lymphocytes Are Not Required for the Rapid Onset of Coronary Heart Disease in Scavenger Receptor Class B Type I/Apolipoprotein E Double Knockout Mice

Karackattu

Picard

Krieger

2005

ATVB

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Objective-Scavenger receptor class B type I (SR-BI)/apolipoprotein E (apoE) double knockout (dKO) mice exhibit many features of human coronary heart disease (CHD), including occlusive coronary atherosclerosis, cardiac hypertrophy, myocardial infarctions, and premature death. Here we determined the influence of B and T lymphocytes, which can contribute to atherosclerosis, ischemia-reperfusion injury, and cardiomyocyte death, on pathology in dKO mice. Method and Results-The lymphocyte-deficient SR-BI/apoE/recombination activating gene 2 (RAG2) triple knockout mice and corresponding dKO controls generated for this study exhibited essentially identical lipid-rich coronary occlusions, myocardial infarctions, cardiac dysfunction, and premature death (average lifespans 41.6Ϯ0.6 and 42.0Ϯ0.5 days, respectively). Conclusions-B and T lymphocytes and associated immunoglobulin-mediated inflammation are not essential for the development and progression of CHD in dKO mice. Strikingly, the dKO mice bred for this study (mixed C57BL/6ϫSV129ϫBALB/c background; strain 2) compared with the previously described dKO mice (75:25 C57BL/6:SV129 background; strain 1) had a shorter mean lifespan and steeper survival curve, characteristics especially attractive for studying the effects of environmental, pharmacological, and genetic manipulations on cardiac pathophysiology. Key Words: atherosclerosis Ⅲ HDL receptor Ⅲ myocardial infarction Ⅲ RAG2 Ⅲ echocardiography M urine models of dyslipidemia, such as the apolipoprotein E (apoE) or low-density lipoprotein (LDL) receptor knockout (KO) mice, have been used extensively to study atherosclerosis. However, even when subjected to high-fat/highcholesterol diets, all but one of these hypercholesterolemia and atherosclerosis systems usually do not result in spontaneous development of occlusive coronary artery disease, myocardial infarction (MI), cardiac dysfunction, or the premature death that are hallmarks of human coronary heart disease (CHD). The exception, mice doubly deficient for the HDL receptor scavenger receptor class B type I (SR-BI) and apoE (double KO [dKO]) not only exhibit extensive aortic sinus and occlusive coronary arterial atherosclerosis (advanced plaques with fibrous caps, fibrin deposition, and cholesterol clefts), but they also experience severe CHD at a very young age (4 to 6 weeks). [1][2][3] The hearts of dKO mice are hypertrophic and exhibit left ventricular (LV) dilation and multiple, large MIs. Severe cardiac dysfunction is demonstrated by multiple ECG abnormalities (ST segment elevation and depression, anesthesia-induced conductance abnormalities [eg, bradyarrhythmias, atrioventricular blocks]), a 70% reduction in ϮdP/dT, and 50% reduced ejection fraction. The mice die between 5 and 8 weeks of age (mean 6 weeks). Thus, the many similarities in CHD of dKO mice and humans raised the possibility that these mice may help in the study of the pathophysiology of CHD and genetic, pharmacological, and environmental approaches for its prevention and treatment.B and T lymphocytes ...

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“…This enhanced expression was shown to be induced by the cytokines IFNy and TNFa. More importantly, treatment of the mice with F(ab'), fragments of an anti-ICAM-1 MAb significantly reduced myocardial inflammation, indicating that the expression of ICAM-1 plays a critical role in the cellmediated cytotoxicity involved in acute viral myocarditis (28)(29)(30). The LFA-l/ICAM-1 pathway has also been implicated in the rejection of cardiac allografts.…”

Section: Discussionmentioning

confidence: 99%

The role of cytokines in polymyositis

Kalovidouris¹,

Horn²,

Plotkin³

1994

Arthritis & Rheumatism

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Objective. To investigate the effect of interferon‐γ (IFNγ) on the adhesive interactions between human peripheral blood T cells and human skeletal muscle cells at various stages of muscle cell differentiation and maturation in vitro. Methods. Human muscle cell cultures were established from normal muscle biopsy material, using the explant technique. T cells were studied for their capacity to adhere to IFNγ‐treated and untreated myoblasts and myotubes. The role of intercellular adhesion molecule type 1 (ICAM‐1) in cell adhesion to muscle cells was examined in blocking studies, by enzyme‐linked immuno‐sorbent assay (ELISA), and by immunohistochemical staining using monoclonal antibodies (MAb). Results. Treatment of muscle cells (myoblasts and myotubes) with IFNγ resulted in a significant dose‐dependent increase in the number of adherent T cells. Adhesion of T cells to muscle cells was significantly inhibited by MAb to ICAM‐1 and to lymphocyte function–associated antigen type 1, but not by MAb to HLA–DR. There was no difference in the level of T cell adhesion to IFNγ‐treated allogeneic versus autologous muscle cells. By ELISA and immunohistochemical analysis, ICAM‐1 expression on the surface of cultured human muscle cells was either absent or barely detectable, but was strongly induced by treatment of muscle cells with IFNγ. Conclusion. Induction of cell adhesion molecules on muscle cells by IFNγ may be an important mechanism for the localization of T cells in the affected muscles of patients with autoimmune myositis.

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Cardiac injury in myocarditis induced by coxsackievirus group B, type 3 in Balb/c mice is mediated by Lyt 2+ cytolytic lymphocytes

Cited by 86 publications

References 12 publications

TLR Ligands Act Directly upon T Cells to Restore Proliferation in the Absence of Protein Kinase C-θ Signaling and Promote Autoimmune Myocarditis

TLR Ligands Act Directly upon T Cells to Restore Proliferation in the Absence of Protein Kinase C-θ Signaling and Promote Autoimmune Myocarditis

Lymphocytes Are Not Required for the Rapid Onset of Coronary Heart Disease in Scavenger Receptor Class B Type I/Apolipoprotein E Double Knockout Mice

The role of cytokines in polymyositis

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