Genetic mechanisms of autoimmune myocarditis

自身免疫性心肌炎的遗传机制

基本信息

批准号：
7924263
负责人：
Noel R. Rose
金额：
$ 36.9万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7924263
关键词：
Affect Antibodies Antigens Autoantigens Autoimmune Diseases Autoimmune Process B-Lymphocytes Blocking Antibodies Bone Marrow Bone Marrow Cells CD4 Positive T Lymphocytes Candidate Disease Gene Cardiac Cardiac Myosins Cell Lineage Cells Chimera organism Chromosomes, Human, Pair 1 Coxsackie Viruses Development Diabetes Mellitus Dilated Cardiomyopathy Disease Disease Resistance Disease model Disease susceptibility Dissection Down-Regulation Early treatment Effector Cell Evaluation Figs - dietary Flow Cytometry Gene Chips Generations Genes Genetic Genetic Polymorphism Genetic Predisposition to Disease Goals Haplotypes Heart Heart Transplantation Heart failure Hematopoietic Hematopoietic System Human Immune response Immune system Immunization Immunologics In Vitro Infection Interleukin-10 Kinetics Knock-out Knockout Mice Laboratories Ligands Mediating Mediator of activation protein Modeling Molecular Profiling Mouse Strains Mus Myocarditis Myosin ATPase Natural Killer Cells Organ Other Genetics Pathway interactions Pericarditis Phase Population Predisposition Production Resistance Role Signal Pathway Signal Transduction Spleen Surface Susceptibility Gene T-Cell Proliferation T-Lymphocyte Testing Viral Virus Virus Diseases base chemokine cytokine design interleukin-23 lymph nodes macrophage mouse model plasma cell differentiation protein expression resistant strain trait young adult

项目摘要

Autoimmune myocarditis develops due to an immune response to cardiac-specific antigens expressed in the heart. The MHC is important in determining susceptibility to autoimmune myocarditis; however other genetic factors are also critical. We propose to study these genetic mechanisms using a mouse model, cardiac myosin-induced experimental autoimmune myocarditis (EAM). The goal of the present proposal is to further localize the genetic differences between susceptible and resistant mouse strains, and to distinguish the roles of several cell lineages in genetic susceptibility to autoimmune myocarditis. We will investigate two costimulatory candidate genes, ICOS (Specific aim 1) and CD27 (Specific aim 2). Both of these genes are located in susceptibility regions on chromosomes 1 and 6 respectively. Additionally, both ICOS and CD27 are differentially regulated following immunization with cardiac myosin in the susceptible and resistant mice. Specific aim 1 will examine in depth our preliminary finding that resistant B 10.S mice have higher ICOS expression on CD4+T cells after myosin immunization. This finding suggests that at least part of the ICOS expressing CD4+ T cells are regulatory in EAM. Therefore we will assess the expression of ICOS on subsets of CD4+ T cells and determine the role of ICOS in effector and regulatory T cells during EAM by adoptively transferring ICOS deficient and/or IL-10 deficient CD4+ T cells into Rag-/- mice. We will also identify polymorphism in the ICOS gene. Specific aim 2 CD27 is significantly down regulated in A.SW but not B10.S mice following immunization with cardiac myosin, suggesting that CD27 is a candidate gene influencing EAM susceptibility in the Eam2 region. We will first examine the CD27 gene for polymorphisms. Next, we will determine the kinetics and function of CD27 on T cells during EAM in A.SW and B10.S mice and test our hypothesis that down regulation of CD27 on T cells in early activation phase is essential for their differentiation to pathogenic effector cells. We have established that genetic control of EAM is mediated by cells of the hematopoietic lineage including T and/or B cells. Specific aim 3 will examine if genetic factors modulate Th17 cells, NK cells, macrophages, B cells and T regulatory cells in mediating EAM. We will transfer bone marrow from cell specific knockout mice of the susceptible strain into the irradiated resistant strain. We have found that IL-23 production was less in B10.S mice than AS.W mice during EAM, which suggest that B10.S mice might be resistant to myocarditis due to their decrease and ability to induce differentiation or sustain survival of Th17 cells in heart. Therefore we will identify polymorphisms and the protein expression profile of cytokines and chemokines related to Th17 pathway following immunization with cardiac myosin in A.SW and B10.S mice.

自身免疫性心肌炎是由于对心脏特异性抗原的免疫反应而发生的心脏。 MHC 对于确定自身免疫性心肌炎的易感性很重要；然而其他遗传因素也很重要。我们建议使用小鼠模型研究这些遗传机制，心肌肌球蛋白诱导的实验性自身免疫性心肌炎（EAM）。本提案的目标是进一步定位易感小鼠品系和耐药小鼠品系之间的遗传差异，并区分几种细胞谱系在自身免疫性心肌炎遗传易感性中的作用。我们将研究两个共刺激候选基因：ICOS（具体目标 1）和 CD27（具体目标 2）。两者都这些基因分别位于1号和6号染色体的易感区。此外，两者在易感人群中使用心肌肌球蛋白免疫后，ICOS 和 CD27 受到不同的调节和耐药小鼠。具体目标 1 将深入研究我们的初步发现，即耐药 B 10.S 小鼠肌球蛋白免疫后CD4+T细胞上ICOS表达较高。这一发现表明至少部分表达 CD4+ T 细胞的 ICOS 在 EAM 中受到调节。因此我们将评估表达式 ICOS 对 CD4+ T 细胞亚群的作用，并确定 ICOS 在效应 T 细胞和调节性 T 细胞中的作用 EAM 通过将 ICOS 缺陷和/或 IL-10 缺陷的 CD4+ T 细胞过继转移至 Rag-/- 小鼠中。我们将还鉴定了 ICOS 基因的多态性。具体目标 2 CD27 在 A.SW 中显着下调但用心肌肌球蛋白免疫后的 B10.S 小鼠则不然，表明 CD27 是候选基因影响 Eam2 区域的 EAM 敏感性。我们将首先检查 CD27 基因的多态性。接下来，我们将确定 A.SW 和 B10.S 小鼠 EAM 期间 CD27 在 T 细胞上的动力学和功能并检验我们的假设，即早期激活阶段 T 细胞上 CD27 的下调对于它们分化为致病效应细胞。我们已经确定 EAM 的遗传控制是由造血谱系细胞（包括 T 和/或 B 细胞）介导。具体目标 3 将检查是否遗传因素通过调节 Th17 细胞、NK 细胞、巨噬细胞、B 细胞和 T 调节细胞介导 EAM。我们将把易感品系的细胞特异性敲除小鼠的骨髓转移到辐照抗性菌株。我们发现 B10.S 小鼠的 IL-23 产量少于 AS.W 小鼠在 EAM 期间，这表明 B10.S 小鼠可能由于心肌炎的减少和诱导心脏中 Th17 细胞分化或维持存活的能力。因此我们将确定 Th17通路相关细胞因子和趋化因子多态性及蛋白表达谱 A.SW 和 B10.S 小鼠用心肌肌球蛋白免疫后。