Innate Immunity in Myocarditis

心肌炎的先天免疫

• 批准号: 7658608
• 负责人: Sally A Huber
• 金额: $ 18.81万
• 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 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7658608
• 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）： 心肌炎是一种通常由微生物感染引起的心肌炎症。肠道病毒（小核糖核酸病毒）和腺病毒最常与临床疾病有关。我们开发了柯萨奇病毒 B3 (CVB3) 心肌炎小鼠模型。致病性需要病毒诱导强烈的抗原特异性 CD4+Th1 (IFN+) 细胞反应，而促进 CD4+Th2 (IL-4+) 反应的条件可预防心肌炎。表达 V4 T 细胞受体的 T 细胞对于 CD4+Th1 免疫的产生至关重要。人们普遍认为，先天效应细胞（例如 + 细胞）调节适应性免疫反应。这种调节的公认机制取决于先天效应器释放的细胞因子，这提供了有利于特定 Th 反应的环境环境；对抗原呈递细胞的先天效应影响导致抗原呈递细胞辅助分子或细胞因子表达的变化，从而导致 CD4+ 细胞反应的改变。据我们所知，我们是唯一假设 + 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+细胞选择性地杀死CD4+Th2细胞，而留下CD4+Th1细胞完整。目前，几乎所有研究都表明CD4+Th1细胞对Fas依赖性细胞凋亡选择性敏感，而CD4+Th2细胞则显着抵抗。我们的数据与公认的知识截然相反。主要问题是为什么在我们的 CVB3 模型中，CD4+Th2 细胞对凋亡敏感，以及 + 细胞选择性消除 Th2 细胞对 CVB3 感染小鼠中 CD4+Th1 的优势有多大贡献。我们假设 CD4+ Th1 和 Th2 细胞之间的 CD1d、Fas 或抗凋亡因子（例如 c-FLIPL）存在差异，并且这些差异允许选择性杀死 Th2 细胞。在抗原刺激结束时消除效应 CD4+ 细胞可以节省造血室中的资源和空间，但免疫收缩应适用于 CD4+Th1 和 Th2 细胞。仅 CD4+Th1 细胞的收缩可能导致 CD4+Th2 逐渐积累，最终导致免疫系统失衡。先天效应细胞如 + 细胞可能在消除活化的 CD4+Th2 细胞中发挥重要作用。该提议的核心问题是先天效应器如何区分 Th1 和 Th2 细胞，杀死后者而不杀死前者。具体目标是： 1) 确定 + 细胞是否仅需要用于激活 CD4+ 细胞或在体内维持激活的细胞； (2)确定CD4+细胞上的CD1d表达是否是体内CD4+反应的+细胞免疫调节所必需的以及V4+细胞产生IFN的作用； (3) 确定 CD4+ Th1 或 Th2 细胞克隆上的 CD1d 或 Fas 表达是否不同，并解释 Th2 克隆对 V4+ 细胞诱导的细胞凋亡的敏感性增加。 (4) 确定 CD4+Th1 和 Th2 细胞之间的 c-FLIPL 表达是否不同，以及 Th1 细胞中升高的水平是否可以保护它们免受 V4+ 细胞介导的杀伤。 。公共健康相关性：这项资助将研究 Vgamma4+ T 细胞通过 Fas 依赖性机制选择性杀死活化的 CD4+Th2 细胞的作用，作为免疫反应后免疫收缩的一种方法。具体目标是 1) 确定 + 细胞是否仅需要用于激活 CD4+ 细胞或在体内维持激活的细胞。 2) 确定 CD4+ 细胞上的 Fas 或 CD1d 表达是否是体内 CD4+ 反应的细胞免疫调节所必需的，以及 V4+ 细胞产生 IFN 的作用。 3) 确定 CD4+ Th1 或 Th2 细胞克隆上的 CD1d 或 Fas 表达是否不同，并解释 Th2 克隆对 V4+ 细胞诱导的细胞凋亡的敏感性增加。 4) 确定 CD4+Th1 和 Th2 细胞之间的 c-FLIPL 表达是否不同，以及 Th1 细胞中升高的水平是否可以保护它们免受 V4+ 细胞介导的杀伤。