Innate Immunity in Myocarditis

心肌炎的先天免疫

• 批准号: 7780450
• 负责人: Sally A Huber
• 金额: $ 22.58万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7780450
• 关键词: Adenoviruses; Antigen-Presenting Cells; Antigens; Apoptosis; Apoptotic; Binding; CD4 Positive T Lymphocytes; Cardiac; Cells; Clinical; Coxsackie Viruses; Data; Disease; Enterovirus; Family Picornaviridae; Generations; Goals; Grant; Heart; Immune; Immune response; Immune system; Immunity; Infection; Inflammation; Injury; Interferons; Interleukin-4; Knowledge; Laboratories; Left; Mediating; Methods; Modeling; Mus; Myocarditis; Myocardium; Natural Immunity; Pathogenicity; Phenotype; Play; Population; Predisposition; Production; Publishing; Reporting; Resistance; Resources; Role; T-Cell Receptor; T-Lymphocyte; Th1 Cells; Th2 Cells; Viral; Virus; Virus Activation; Virus Diseases; cell killing; cytokine; immunoregulation; in vivo; killings; microbial; novel; prevent; public health relevance; response

DESCRIPTION (provided by applicant): Myocarditis is an inflammation of the myocardium which often follows microbial infections. Enteroviruses (picornaviruses) and adenoviruses are most frequently implicated in clinical disease. We have developed a murine model of coxsackievirus B3 (CVB3) myocarditis. Pathogenicity requires virus induction of a strong antigen-specific CD4+Th1 (IFN+) cell response while conditions which promote a CD4+Th2 (IL-4+) response prevent myocarditis. T cells expressing the V4 T cell receptor are crucial to generation of CD4+Th1 immunity. It is well accepted that innate effectors such as + cells modulate adaptive immune responses. The accepted mechanisms for this modulation depend upon cytokine release by the innate effectors which provides an environmental milieu favorable to a specific Th response; and innate effector impact on antigen presenting cells resulting in changes in accessory molecule or cytokine expression by the antigen presenting cells leading to alterations in CD4+ cell responses. To the best of our knowledge, we are the only laboratory hypothesizing that + cells directly bind to CD4+ cells modulating the Th phenotype. We have shown that + cells selectively kill CD4+Th2 cells leaving the CD4+Th1 cells intact. Currently, nearly all studies show that CD4+Th1 cells are selectively susceptible to Fas-dependent apoptosis while CD4+Th2 cells are remarkably resistant. Our data is diametrically opposite of accepted knowledge. The major question is why in our CVB3 model, CD4+Th2 cells are apoptosis susceptible and how much the selective elimination of Th2 cells by + cells contributes to the CD4+Th1 dominance in CVB3 infected mice. We hypothesize that there would be differences in CD1d, Fas or anti-apoptotic factors, such as c-FLIPL, between CD4+ Th1 and Th2 cells and that these differences allow the selective killing of the Th2 cells. Elimination of effector CD4+ cells at the end of antigenic stimulation conserves resources and space in the hemopoietic compartment, but immune contraction should apply to both CD4+Th1 and Th2 cells. Contraction of only CD4+Th1 cells could allow progressive accumulation of CD4+Th2 and ultimate imbalance of the immune system. Innate effectors such as + cells may play an important role in eliminating activated CD4+Th2 cells. The question central to this proposal is how innate effectors distinguish between Th1 and Th2 cells, killing the latter but not the former. The Specific Aims are: 1) Determine if + cells are only required for activating CD4+ cells or for maintaining the activated cells in vivo; (2) Determine if CD1d expression on CD4+ cells is required for + cell immunomodulation of the CD4+ response in vivo and the role of IFN production by V4+ cells; (3) Determine whether CD1d or Fas expression on CD4+ Th1 or Th2 cell clones differs and explains the increased susceptibility of Th2 clones to V4+ cell induced apoptosis.; and (4) Determine if c-FLIPL expression differs between CD4+Th1 and Th2 cells and elevated levels in Th1 cells protects them from V4+ cell mediated killing. . PUBLIC HEALTH RELEVANCE: This grant will investigate the role of Vgamma4+ T cells in selectively killing activated CD4+Th2 cells by Fas-dependent mechanisms, as a method for immune contraction after an immune response. The Specific Aims are to 1) Determine if + cells are only required for activating CD4+ cells or for maintaining the activated cells in vivo. 2) Determine if Fas or CD1d expression on CD4+ cells is required for + cell immunomodulation of the CD4+ response in vivo and the role of IFN production by V4+ cells. 3) Determine whether CD1d or Fas expression on CD4+ Th1 or Th2 cell clones differs and explains the increased susceptibility of Th2 clones to V4+ cell induced apoptosis. 4) Determine if c-FLIPL expression differs between CD4+Th1 and Th2 cells and whether elevated levels in Th1 cells protects them from V4+ cell mediated killing.

描述(由申请人提供)：心肌炎是一种心肌炎，通常伴随着微生物感染。肠道病毒(微小核糖核酸病毒)和腺病毒最常与临床疾病有关。我们建立了柯萨奇B3病毒(CVB3)心肌炎的小鼠模型。病原性需要病毒诱导强烈的抗原特异性CD4+Th1(干扰素+)细胞反应，而促进CD4+Th2(IL-4+)反应的条件可以预防心肌炎。表达V4T细胞受体的T细胞对产生CD4+Th1免疫至关重要。众所周知，先天效应物，如+细胞，可调节适应性免疫反应。这种调节的公认机制依赖于先天效应器释放的细胞因子，这为特定的Th应答提供了有利的环境；以及先天效应器对抗原提呈细胞的影响导致抗原提呈细胞辅助分子或细胞因子表达的变化，从而导致CD4+细胞应答的改变。就我们所知，我们是唯一一个假设+细胞直接与调节Th表型的CD4+细胞结合的实验室。我们已经证明，+细胞选择性地杀伤CD4+Th2细胞，而不影响CD4+Th1细胞。目前，几乎所有的研究都表明，CD4+Th1细胞对Fas依赖的细胞凋亡具有选择性易感性，而CD4+Th2细胞对Fas依赖的细胞凋亡具有显著的抵抗力。我们的数据与公认的知识截然相反。主要的问题是为什么在我们的CVB3模型中，CD4+Th2细胞是易凋亡的，以及在CVB3感染的小鼠中，+细胞选择性地消除Th2细胞对CD4+Th1优势有多大贡献。我们推测，在CD4+Th1和Th2细胞中，CD1d、Fas或c-flipl等抗凋亡因子可能存在差异，这些差异允许选择性杀伤Th2细胞。在抗原刺激结束时消除效应的CD4+细胞可以节省造血室的资源和空间，但免疫收缩应该同时适用于CD4+Th1和Th2细胞。只有CD4+Th1细胞的收缩可能会导致CD4+Th2的逐渐积累，最终导致免疫系统的失衡。先天效应细胞如+细胞可能在消除活化的CD4+Th2细胞方面发挥重要作用。这一提议的核心问题是，先天效应者如何区分Th1和Th2细胞，杀死后者，而不是前者。其具体目的是：1)确定在体内是否只需要+细胞来激活CD4+细胞或维持激活的细胞；(2)确定在体内CD4+细胞上CD1d的表达是否是+细胞免疫调节所必需的，以及V4+细胞产生干扰素的作用；(3)确定CD1d或Fas在CD4+Th1或Th2细胞克隆上的表达是否不同，并解释Th2克隆对V4+细胞诱导的凋亡的易感性增加；以及(4)确定c-Flipl在CD4+Th1和Th2细胞中的表达是否不同，Th1细胞中升高的c-Flipl表达水平是否保护它们免受V4+细胞介导的杀伤。。公共卫生相关性：这项拨款将调查VGamma4+T细胞在通过Fas依赖的机制选择性地杀死激活的CD4+Th2细胞中的作用，作为免疫反应后免疫收缩的一种方法。其具体目的是：1)确定+细胞是否仅用于激活体内的CD4+细胞或维持激活的细胞。2)确定体内CD4+细胞免疫调节是否需要CD4+细胞表面Fas或CD1d的表达，以及V4+细胞产生干扰素的作用。3)确定CD1d或Fas在CD4+Th1或Th2细胞克隆上的表达是否不同，并解释Th2克隆对V4+细胞诱导的凋亡的易感性增加。4)确定c-FLIPL在CD4+Th1和Th2细胞中的表达是否不同，以及Th1细胞中升高的水平是否保护它们免受V4+细胞介导的杀伤。