Immune-mediated pathways in pathogenesis of abdominal aortic aneurysm

腹主动脉瘤发病机制中的免疫介导途径

• 批准号: 10087461
• 负责人: Christine T. Pham
• 金额: --
• 依托单位: ST. LOUIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10087461
• 关键词: Abdominal Aortic Aneurysm; Accounting; Affect; Age; Anaphylatoxins; Aneurysm; Antibodies; Antibody Response; Aorta; Appearance; Atherosclerosis; Attenuated; Autoantibodies; Autoantigens; Autoimmune Process; Autoimmunity; Behavior; Binding; Blood Circulation; Blood Vessels; CD8-Positive T-Lymphocytes; Caliber; Cause of Death; Cell physiology; Cessation of life; Chronic; Complement; Complement 3a; Complement 5a; Complement Activation; Complex; Coronary Arteriosclerosis; Dendritic Cells; Development; Dilatation - action; Disease; Disease Progression; Elastases; Elderly; Emergency Situation; Environmental Risk Factor; Epitopes; Event; Fibrinogen; Gender; General Population; Generations; Genetic Predisposition to Disease; Genetic Risk; Goals; High Prevalence; Human; Hypertension; Immune; Immune Targeting; Immunoglobulin G; Immunotherapeutic agent; In Vitro; Individual; Inflammatory; Interferons; Intervention; Investigation; Lectin; Link; Mannose Binding Lectin; Mediating; Medical; Metalloproteases; Molecular; Mus; Neutrophil Infiltration; Operative Surgical Procedures; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pharmacology; Phenotype; Population; Post-Translational Protein Processing; Postoperative Period; Prevalence; Process; Production; Proteins; Risk; Risk Factors; Rupture; Ruptured Aneurysm; Sampling; Serum; Shapes; Signal Transduction; Site; Smoking; Structure; Survival Rate; T cell response; T-Lymphocyte; Testing; Tissues; Ultrasonography; Uncertainty; United States; Veterans; Work; adaptive immune response; base; biomarker validation; cigarette smoke; cigarette smoking; citrullinated protein; design; extracellular; human old age (65+); insight; macrophage; male; mortality; mortality risk; mouse model; neutrophil; older patient; operation; prevent; public health relevance; recruit; repaired; therapeutic target; Abdominal Aortic Aneurysm; Accounting; Affect; Age; Anaphylatoxins; Aneurysm; Antibodies; Antibody Response; Aorta; Appearance; Atherosclerosis; Attenuated; Autoantibodies; Autoantigens; Autoimmune Process; Autoimmunity; Behavior; Binding; Blood Circulation; Blood Vessels; CD8-Positive T-Lymphocytes; Caliber; Cause of Death; Cell physiology; Cessation of life; Chronic; Complement; Complement 3a; Complement 5a; Complement Activation; Complex; Coronary Arteriosclerosis; Dendritic Cells; Development; Dilatation - action; Disease; Disease Progression; Elastases; Elderly; Emergency Situation; Environmental Risk Factor; Epitopes; Event; Fibrinogen; Gender; General Population; Generations; Genetic Predisposition to Disease; Genetic Risk; Goals; High Prevalence; Human; Hypertension; Immune; Immune Targeting; Immunoglobulin G; Immunotherapeutic agent; In Vitro; Individual; Inflammatory; Interferons; Intervention; Investigation; Lectin; Link; Mannose Binding Lectin; Mediating; Medical; Metalloproteases; Molecular; Mus; Neutrophil Infiltration; Operative Surgical Procedures; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pharmacology; Phenotype; Population; Post-Translational Protein Processing; Postoperative Period; Prevalence; Process; Production; Proteins; Risk; Risk Factors; Rupture; Ruptured Aneurysm; Sampling; Serum; Shapes; Signal Transduction; Site; Smoking; Structure; Survival Rate; T cell response; T-Lymphocyte; Testing; Tissues; Ultrasonography; Uncertainty; United States; Veterans; Work; adaptive immune response; base; biomarker validation; cigarette smoke; cigarette smoking; citrullinated protein; design; extracellular; human old age (65+); insight; macrophage; male; mortality; mortality risk; mouse model; neutrophil; older patient; operation; prevent; public health relevance; recruit; repaired; therapeutic target

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to elucidate the pathophysiological mechanisms underlying abdominal aortic aneurysm (AAA) formation and progression. AAA is a common and potentially fatal vascular condition affecting up to 9% of individiuals age 65 and older. AAA is a complex disease associated with male gender, hypertension, atherosclerosis, coronary artery disease, and cigarette smoking. It is among the top twenty leading causes of death in the United States, accounting for approximately 15,000 deaths per year. It is estimated that as many as 1 in 20 U.S. veterans over the age of 50 have AAA. Treatment option for AAA is currently limited to surgical intervention. Open surgical repair of large AAA (greater than 5.5 cm in diameter) is an effective option in preventing death from ruptures. Although effective, open surgical repair can be associated with high post-operative mortality (up to 6%). Given the limited treatment options, the advanced age of patients with AAA-which may preclude them from undergoing surgery- medical treatment to slow progression thus represents an attractive alternative. The objective of this application is to further the understanding of immune-mediated pathways involved in AAA. Increasing evidence suggests that AAA is an inflammatory, immune-mediated disease. Using an elastase-induced AAA mouse model that recapitulates many key features of human AAA, we previously established that an autoantibody directs aneurysm development through complement activation. We subsequently cloned a pathogenic IgG autoantibody specific for fibrinogen that binds to elastase-perfused aortic wall tissues in the mouse, activates the complement lectin pathway (LP) upstream of the alternative pathway (AP), and induces AAA formation. Additionally we demonstrate that, in human AAA tissues, fibrinogen colocalizes with mannan-binding lectin (MBL), an essential component of the LP, suggesting that recognition of fibrinogen may initiate complement activation in humans as well. Moreover, we found that circulating autoantibodies in a subset of individuals with AAA react against purified fibrinogen in vitro and fibrinogen- associated epitopes in human aneurysmal tissues, further enhancing the relevance of our experimental findings. Complement activation leads to the generation of anaphylatoxins (C3a and C5a) that attract neutrophils to the aortic wall. Once recruited neutrophils release neutrophil extracellular traps (NETs) that likely modulate the adaptive (T cell) response. Lastly, we established that CD8+ T cells are critically involved in aneurysm genesis downstream of neutrophil recruitment. Several outstanding questions remain: 1) what is the mechanism that triggers autoimmunity against a protein (fibrinogen) abundantly found in the circulation; 2) what are the events that link neutrophils and NETs to the chronic, adaptive immune (T cell) responses, and 3) how do T cells propagate the inflammatory cascade that leads to the eventual aneurysmal dilatation. We posit that a thorough investigation of the immune processes in AAA will provide new insights into mechanisms that govern aneurysm genesis and identify potential therapeutic targets for immune-based medical therapies.

描述（由申请人提供）： 该建议的长期目标是阐明腹主动脉瘤（AAA）形成和进展的病理生理机制。 AAA是一种常见且潜在的致命血管疾病，影响65岁及以上的个体人口9％。 AAA是一种与男性性别，高血压，动脉粥样硬化，冠状动脉疾病和吸烟有关的复杂疾病。它是美国二十主要死亡原因之一，每年约有15,000人死亡。据估计，50岁以上的美国退伍军人中有多达1名中有1名AAA。 AAA的治疗选择目前仅限于手术干预。大型AAA的开放手术修复（直径大于5.5 cm）是防止破裂死亡的有效选择。尽管有效，但开放手术修复可能与高术后死亡率有关（高达6％）。鉴于治疗方案有限，AAA患者的高龄 - 可能排除他们接受手术治疗而降低进展，因此代表了一种有吸引力的替代方法。 该应用的目的是进一步了解AAA中涉及的免疫介导的途径。越来越多的证据表明，AAA是一种炎症，免疫介导的疾病。使用弹性酶诱导的AAA小鼠模型，该模型概括了人AAA的许多关键特征，我们先前确定自身抗体通过补体激活来指导动脉瘤的发育。随后，我们克隆了针对纤维蛋白原特异性的致病性IgG自身抗体，该纤维蛋白原与小鼠中的弹性蛋白酶饱满的主动脉壁组织结合，激活 替代途径（AP）上游的补体凝集素途径（LP），并诱导AAA形成。此外，我们证明，在人AAA组织中，纤维蛋白原与LP的必不可少的成分与Mannan结合凝集素（MBL）共定位，这表明对纤维蛋白原的识别也可能引发人类的补体激活。此外，我们发现，在一部分AAA的个体中循环自身抗体反应于纯化的纤维蛋白原 人动脉瘤组织中的体外和纤维蛋白原相关的表位，进一步增强了我们的实验发现的相关性。补体激活导致产生过敏毒素（C3A和C5A），这些过敏毒素吸引中性粒细胞到主动脉壁。一旦招募中性粒细胞释放出可能调节适应性（T细胞）反应的细胞外陷阱（NET）。最后，我们确定CD8+ T细胞与嗜中性粒细胞募集的下游至关重要。 仍然存在几个杰出问题：1）触发自身免疫性与循环中大量发现的蛋白质（纤维蛋白原）的机制是什么？ 2）将中性粒细胞和网与慢性免疫（T细胞）反应联系起来的事件是什么，3）T细胞如何传播导致最终动脉瘤扩张的炎症性级联反应。我们认为，对AAA中免疫过程的彻底研究将为控制动脉瘤起源的机制提供新的见解，并确定基于免疫的医疗疗法的潜在治疗靶标。