Slam Haplotype 2 Promotes NKT But Suppresses Vγ4+ T-Cell Activation in Coxsackievirus B3 Infection Leading to Increased Liver Damage But Reduced Myocarditis
Department of Pathology, University of Vermont, Burlington, Vermont. Electronic address: .American Journal Of Pathology (Impact Factor: 4.59). 11/2012; 182(2). DOI: 10.1016/j.ajpath.2012.10.019
There are two major haplotypes of signal lymphocytic activation molecule (Slam) in inbred mouse strains, with the Slam haplotype 1 expressed in C57Bl/6 mice and the Slam haplotype 2 expressed in most other commonly used inbred strains, including 129 mice. Because signaling through Slam family receptors can affect innate immunity [natural killer T cell (NKT) and γ-δ T-cell receptor], and innate immunity can determine susceptibility to coxsackievirus B3 (CVB3) infection, the present study evaluated the response of C57Bl/6 and congenic B6.129c1 mice (expressing the 129-derived Slam locus) to CVB3. CVB3-infected C57Bl/6 male mice developed increased myocarditis but reduced hepatic injury compared with infected B6.129c1 mice. C57Bl/6 mice also had increased γδ(+) and CD8(+)interferon-γ(+) cells but decreased numbers of NKT (T-cell receptor β chain + mCD1d tetramer(+)) and CD4(+)FoxP3(+) cells compared with B6.129c1 mice. C57Bl/6 mice were infected with CVB3 and treated with either α-galactosylceramide, an NKT cell-specific ligand, or vehicle (dimethyl sulfoxide/PBS). Mice treated with α-galactosylceramide showed significantly reduced myocarditis. Liver injuries, as determined by alanine aminotransferase levels in plasma, were increased significantly, confirming that NKT cells are protective for myocarditis but pathogenic in the liver.
Article: Autoimmunity in viral myocarditis[Show abstract] [Hide abstract]
ABSTRACT: Purpose of review: To review how autoimmunity is induced in viral myocarditis. Recent findings: Clinical and experimental myocarditis follows microbial infections, but autoimmunity to cardiac antigens leads to heart failure since infected myocytes are sparse and virus clearance is rapid. In mice, CD4+ T cells specific for cardiac alpha myosin heavy chain (αMYHC) cause myocarditis and mice tolerized to αMYHC are protected from virus challenge proving pathogenesis depends upon autoimmunity. Most importantly, multiple microbes share the same mimicking epitope with αMYHC. Serial infections with very different microbes could result in memory responses to the shared epitope leading to aggressive and severe heart failure. A similar phenomenon may explain autoimmune diseases with suspected infectious causes, where specific pathogens have not been identified. Production of the relevant cardiac epitope for antigen presentation requires more than myosin release from dead myocytes. Otherwise, myocarditis would commonly follow myocardial infarcts. The inherent nature of the innate immune response associated with viral infections in the heart is crucial to cardiac epitope expression. Summary: Antigenic mimicry between microbes and cardiac proteins causes autoimmunity in myocarditis. Characteristics of innate immunity associated with cardiac infection determine relevant epitope expression (cryptic epitopes).Current opinion in rheumatology 05/2013; 25(4). DOI:10.1097/BOR.0b013e3283620036 · 4.89 Impact Factor
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ABSTRACT: Abstract Invariant natural killer T cells (iNKT) perform different functions in different diseases. The cells were reported to protect myocarditis. However, the detail relationships between iNKT and Coxsackievirus B3 (CVB3)-induced myocarditis remain unclear. In order to investigate the correlation between the severity of CVB3-induced inflammation infiltration and the proportion of iNKT in the spleen and circulating blood, BALB/c mice were grouped into three groups according to the inflammation infiltration area of heart sections. The proportion of iNKT in CD3-positive cells in the spleen correlated negatively with the inflammation area (linear fit; R(2)=0.93) and virus capsid protein VP1 (linear fit; R(2)=0.84) in the myocardial tissue, while the proportion of iNKT in CD3-positive cells in the PBMC positively correlated with the inflammation area (linear fit; R(2)=0.91) and virus capsid protein VP1 (linear fit; R(2)=0.93) in the myocardial tissue. The results imply that iNKT might be used as a parameter for the diagnosis of myocarditis in clinical practice.Viral immunology 04/2014; 27(3). DOI:10.1089/vim.2013.0078 · 1.45 Impact Factor
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