Autoimmunity in the Mediation of Infectious Myocarditis

自身免疫介导感染性心肌炎

基本信息

批准号：
9069029
负责人：
Jay Reddy
金额：
$ 35.42万
依托单位：
UNIVERSITY OF NEBRASKA LINCOLN
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-14 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9069029
关键词：
A/J Mouse Active Immunization Acute Address Adolescent Adoptive Transfer Adrenergic Receptor Affect Antibodies Antigens Appearance Autoimmune Diseases Autoimmune Process Autoimmune Responses Autoimmunity Bacteria Biological Assay CD4 Positive T Lymphocytes Ca(2+)-Transporting ATPase Cardiac Cardiac Myosins Cardiomyopathies Cardiovascular system Cause of Death Cells Chemicals Chronic Coxsackie Viruses Defective Viruses Dilated Cardiomyopathy Disease Epitopes Etiology Evaluation Exposure to Future Generations Goals Health Heart Heart Diseases Heart Transplantation Heart failure Histocompatibility Antigens Class II Histologic Histology Human Immune response Immunization Immunodominant Epitopes Immunotherapy Individual Infection Infectious Agent Inflammation Inflammatory Injury Investigation Keto Acids Knowledge Ligands Link Magnetic Resonance Measurement Mediating Mediation Metals Microbe Microscopy Mission Modality Molecular Mimicry Mus Myocardial Myocarditis Myosin Heavy Chains Oxidoreductase Parasites Pathogenesis Patients Peptides Pharmaceutical Preparations Phase Process Proteome Protocols documentation Public Health Research Resistance Rickettsia Role SLC25A4 gene Sarcoplasmic Reticulum Specificity Staining method Stains Survival Rate T cell response T-Cell Proliferation T-Lymphocyte T-Lymphocyte Epitopes Testing Tissues Tolerogen Troponin I United States National Institutes of Health Viral Virus Virus Replication Work autoreactive T cell base chronic myocarditis combat cytokine human disease innovation microscopic imaging mimicry pathogen personalized medicine research study response therapy development viral myocarditis

项目摘要

DESCRIPTION (provided by applicant): Heart disease is the leading cause of death in humans, and myocarditis is a predominant cause of heart failure in young adolescents. Patients affected with myocarditis can develop dilated cardiomyopathy (DCM), a common reason for heart transplantation, which to date is the only viable option for combating DCM. Myocarditis/DCM patients show antibodies to coxsackievirus B3 (CVB) and cardiac antigens, suggesting a role for CVB-mediated autoimmunity in the disease pathogenesis, but a direct causal link remains to be determined clinically. The long-term goal is to determine the autoimmune mechanisms of pathogens that commonly infect the cardiovascular system and initiate heart autoimmunity. The objective of this application is to determine whether chronic myocarditis that occurs in CVB infection due to an autoimmune response to cardiac antigens. The central hypothesis is that cardiac-specific CD4 T cells generated by mechanisms that involve molecular mimicry and epitope spreading mediate postinfectious myocarditis induced by CVB. This hypothesis will be tested in A/J mice that are highly susceptible to both autoimmune and viral myocarditis, the histologic features of which resemble those in human disease. The project's two specific aims are to: 1) Delineate the role of cross-reactive CD4 T cells in the mediation of CVB myocarditis. Panel of mimicry epitopes identified from the CVB proteome are capable of inducing pathogenic cross-reactive T cells for three cardiac antigens as evaluated by T cell proliferation assay and cytokine responses. [2) Investigate epitope spreading as an autoimmune mechanism of postinfectious myocarditis induced by CVB. Using major histocompatibility complex (MHC) class II dextramers for cardiac myosin heavy chain (Myhc)-� 334-352, the team has demonstrated that myocarditis-susceptible A/J mice, show the generation of Myhc-�-specific T cells that transfer disease to naive mice. These observations provide a compelling rationale to test the hypothesis that CVB infection induces the generation of cardiac-reactive T cells with multiple antigen specificities through epitope spreading. The specific aims will be achieved by measurement of T cell responses, MHC class II dextramer staining, cytokine analysis, magnetic resonance microscopy imaging, active immunization and adoptive transfer experiments, and histology. The proposed approach is innovative, as it addresses the fundamental question of whether autoimmune response contributes to postinfectious myocarditis induced by CVB at the level of antigen specificity. The proposed research is significant, as it may provide a basis for future investigations into the role of cardic-reactive T cells that might be generated in cardiomyopathy patients as a result of exposure to CVB. These studies may then create opportunities to derive immunotherapies in the form of altered peptide ligands and tolerogens as antigen-specific treatment modalities, including personalized therapies, for DCM patients.]

描述（由申请人提供）：心脏病是人类死亡的主要原因，心肌炎是青少年心力衰竭的主要原因。患有心肌炎的患者可能会发展为扩张型心肌病（DCM），这是心脏移植的常见原因。迄今为止，这是对抗 DCM 的唯一可行选择。心肌炎/DCM 患者表现出针对柯萨奇病毒 B3 (CVB) 和心脏抗原的抗体，表明其具有一定作用。 CVB 介导的自身免疫在疾病发病机制中，但临床上仍有待确定直接的因果关系。长期目标是确定通常感染心血管系统并引发心脏自身免疫的病原体的自身免疫机制。确定 CVB 感染中发生的慢性心肌炎是否是由于对心脏抗原的自身免疫反应引起的，核心假设是通过涉及分子拟态和表位扩散的机制产生的心脏特异性 CD4 T 细胞介导感染后。该假设将在对自身免疫性和病毒性心肌炎高度敏感的 A/J 小鼠中进行测试，其组织学特征类似于人类疾病的组织学特征，该项目的两个具体目标是：1）描述其作用。交叉反应性 CD4 T 细胞在介导 CVB 心肌炎中的作用通过 T 细胞增殖和细胞因子反应评估抗原 [2) 研究表位扩散测定作为 CVB 诱导的感染后心肌炎的自身免疫机制。 -352，研究小组已经证明，心肌炎易感的 A/J 小鼠会产生 Myhc-� 特异性 T 细胞，将疾病转移到这些观察结果为检验 CVB 感染通过表位扩散诱导产生具有多种抗原特异性的心脏反应性 T 细胞的假设提供了令人信服的理由。具体目标将通过测量 T 细胞反应、MHC II 类右聚体来实现。染色、细胞因子分析、磁共振显微镜成像、主动免疫和过继转移实验以及组织学所提出的方法是创新的，因为它解决了自身免疫反应是否有助于感染后的基本问题。这项研究具有重要意义，因为它可能为未来研究心肌病患者因暴露于 CVB 而产生的心脏反应性 T 细胞的作用奠定基础。这些研究可能会创造机会，以改变的肽配体和耐受原的形式衍生出免疫疗法，作为 DCM 患者的抗原特异性治疗方式，包括个性化疗法。]

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Major Histocompatibility Complex Class II Dextramers: New Tools for the Detection of antigen-Specific, CD4 T Cells in Basic and Clinical Research.

DOI：
10.1111/sji.12344
发表时间：
2015-11
期刊：
Scandinavian journal of immunology
影响因子：
3.7
作者：
Massilamany C;Krishnan B;Reddy J
通讯作者：
Reddy J

Mutations in the 5' NTR and the Non-Structural Protein 3A of the Coxsackievirus B3 Selectively Attenuate Myocarditogenicity.

DOI：
10.1371/journal.pone.0131052
发表时间：
2015
期刊：
PloS one
影响因子：
3.7
作者：
Massilamany C;Gangaplara A;Basavalingappa RH;Rajasekaran RA;Vu H;Riethoven JJ;Steffen D;Pattnaik AK;Reddy J
通讯作者：
Reddy J

Noninvasive assessment of cardiac abnormalities in experimental autoimmune myocarditis by magnetic resonance microscopy imaging in the mouse.