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.

自身免疫性心肌炎由于对心脏特异性抗原的免疫反应而发育心。 MHC在确定自身免疫性心肌炎的易感性方面很重要。但是其他遗传因素也很关键。我们建议使用小鼠模型研究这些遗传机制心脏肌球蛋白诱导的实验性自身免疫性心肌炎（EAM）。本提议的目的是进一步定位易感和抗性小鼠菌株之间的遗传差异，以及区分几个细胞谱系在遗传易感性自身免疫性心肌炎中的作用。我们将研究两个共刺激候选基因，ICO（特定目标1）和CD27（特定目标2）。两个这些基因分别位于染色体1和6上的易感区域。另外，两者兼而有之 ICOS和CD27在易感性的心脏肌球蛋白免疫后受到差异调节和抗性小鼠。具体目标1将深入研究我们的初步发现，即抗性B 10.S小鼠肌球蛋白免疫后，在CD4+T细胞上具有较高的ICOS表达。这一发现表明至少表达CD4+ T细胞的ICO的一部分在EAM中是调节性的。因此，我们将评估表达 ICO在CD4+ T细胞子集上的ICO，并确定ICO在效应子和调节性T细胞中的作用 EAM通过通过继而将ICOS缺乏和/或IL-10缺陷CD4+ T细胞转移到抹布 - / - 小鼠中。我们将还可以确定ICOS基因中的多态性。特定的AIM 2 CD27在A.SW中显着下调但不是通过心脏肌球蛋白免疫后的B10.S小鼠，这表明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，我们将在A.SW和B10.S小鼠中确定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的下调是必不可少的它们与致病效应细胞的分化。我们已经确定了EAM的遗传控制是由造血谱系的细胞介导，包括T和/或B细胞。特定目标3将检查是否是否遗传因子调节介导的Th17细胞，NK细胞，巨噬细胞，B细胞和T调节细胞 EAM。我们将从易感性菌株的细胞特异性敲除小鼠中转移骨髓辐照抗性应变。我们发现，B10.S小鼠的IL-23产生比AS.W小鼠少。在EAM期间，这表明B10.S小鼠由于其减少和能够诱导Th17细胞在心脏中的分化或维持生存的能力。因此，我们将确定与Th17途径相关的细胞因子和趋化因子的蛋白质表达谱在A.SW和B10.S小鼠中用心脏肌球蛋白免疫后。