The role of Burkholderia in giant cell arteritis

伯克霍尔德杆菌在巨细胞动脉炎中的作用

• 批准号: 8595162
• 负责人: Curry L Koening
• 金额: --
• 依托单位: VA SALT LAKE CITY HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8595162
• 关键词: Abate; Affect; Age; Aging; Anemia; Antibiotics; Antigens; Arteries; Atherosclerosis; Bacteria; Bacterial Antigens; Bacterial Infections; Biological Assay; Biological Markers; Biopsy; Blindness; Blood; Blood Tests; Blood Vessels; Burkholderia; Burkholderia pseudomallei; C-reactive protein; Cells; Characteristics; Clinical; DNA; Defect; Diagnosis; Diagnostic; Diagnostic tests; Disease; Elderly; Enzyme-Linked Immunosorbent Assay; Etiology; Fever; Genetic Polymorphism; Genetic screening method; Genomics; Giant Cells; Glucocorticoids; Goals; Granulomatous; Granulomatous Arteritis; HLA Antigens; Headache; Hormones; Immunoassay; Immunohistochemistry; Incidence; Infection; Infectious Agent; Infiltration; Inflammation; Inflammatory; Invaded; Iron; Jaw; Knowledge; Lead; Learning; Lipopolysaccharides; Lymphocyte; Microscopic; Modeling; Molecular; Mus; Mutation; Myalgia; Night Sweating; Operative Surgical Procedures; Organism; Outcome; Pain; Pathogenesis; Pathway interactions; Patients; Peptides; Play; Polymyalgia Rheumatica; Population; Predisposition; Production; Property; RNA; Relapse; Role; Scalp structure; Sedimentation process; Sensitivity and Specificity; Serological; Serum; Stimulus; Stroke; Symptoms; Systemic disease; T-Lymphocyte; TLR4 gene; Takayasu' s Arteritis; Temporal Arteries; Temporal Arteritis; Thoracic aorta; Toll-like receptors; Vascular Diseases; Vasculitis; Veterans; Work; antimicrobial; aortic arch; base; claudication; design; genetic analysis; hepcidin; improved; insight; macrophage; novel diagnostics; older patient; peptide hormone; prevent; public health relevance; receptor binding; research study; response; toll-like receptor 4; young woman

DESCRIPTION (provided by applicant): Giant cell arteritis (GCA) is a systemic inflammatory disease of the elderly that causes inflammation of large- and medium-sized blood vessels. It is highly associated with polymyalgia rheumatica (PMR), a disease that causes proximal muscle pain and stiffness. GCA also has similar histological features similar to Takayasu's arteritis (TAK), a granulomatous arteritis of large and medium-sized blood vessels that affects young women. The diagnosis of GCA is based upon clinical suspicion but confirmed by temporal artery biopsy. The cause of GCA is not known but is thought to be due to an antigen that invades the wall of large and medium-sized arteries. Molecular evidence supports that an infectious organism causes GCA. We showed hepcidin, an iron-regulatory hormone, is expressed in the temporal artery wall of patients with GCA. It is known that hepcidin is secreted in response to bacterial infections. This led us to analyze the temporal artery wall of GCA patients for an infectious organism. We discovered by genetic analysis that a strain of Burkholderia was present in the temporal artery wall of patients with GCA. Further studies confirmed that this strain was a B. pseudomallei-like strain (BpGCA) and that it lacked type III secretion factors rendering it avirulent. BpGCA LPS was detected in the sera of affected patients by a serologic assay. The role of BpGCA in the pathogenesis of GCA is the focus of this application. We will analyze additional patients with GCA for the presence of the organism. We will also analyze patients with PMR and TAK for the presence of the organism to determine if these diseases could have similar etiologies. Our studies show the organism infects the temporal arteries of patients with GCA. We will determine if the organism can be isolated from the blood of subjects with GCA and whether it can induce the formation of multinucleated giant cells and cause vasculitis in a humanized-mouse chimeric model. We will determine the role of Toll like receptors and human leukocyte antigen mutations in the pathogenesis of BpGCA. We will determine if aging causes a defect in T cells that prevents eradication of the organism. We will determine the sensitivity and specificity of a serologic assay for diagnosing GCA and whether this assay and an ELISA for hepcidin can be used as biomarkers of disease activity. Inflammatory blood vessel disorders are common in the veteran population. The pathogenesis of these diseases is poorly understood. Better insight into the role that infectious organisms play in GCA may provide a better understanding of the pathogenesis of more common inflammatory blood vessel diseases such as atherosclerosis. Our finding that BpGCA infects the temporal arteries and blood of GCA patients may lead to a new diagnostic test for the disease preventing the need for surgical biopsy. It may also provide further insight into the pathogenesis of polymyalgia rheumatica and TAK, two diseases that share common clinical and microscopic characteristics with GCA. Finally, this study could revolutionize the treatment for GCA leading to the use of antibiotics as a potential cure for the disease.

描述（由申请人提供）： 巨细胞动脉炎（GCA）是老年人的全身性炎症性疾病，会引起大型和中大小的血管发炎。它与多肌痛性风湿病高度相关（PMR），这种疾病会导致近端肌肉疼痛和僵硬。 GCA还具有类似的组织学特征，类似于Takayasu的动脉炎（TAK），Takayasu的动脉炎是一种影响年轻女性的大型和中型血管的肉芽肿性动脉炎。 GCA的诊断是基于临床怀疑，但通过颞动脉活检证实。 GCA的原因尚不清楚，但被认为是由于抗原侵入大型和中型动脉的壁。分子证据支持传染性生物会导致GCA。我们显示在GCA患者的颞动脉壁中表达肝素调节激素。众所周知，肝素是针对细菌感染而分泌的。这导致我们分析了GCA患者的颞动脉壁的感染生物。我们通过遗传分析发现，GCA患者的颞动脉壁中存在伯克霍尔德菌菌株。进一步的研究证实，该菌株是假子芽孢杆菌样菌株（BPGCA），并且缺乏III型分泌因子，使其无毒。通过血清学测定，在患者的血清中检测到BPGCA LPS。 BPGCA在GCA发病机理中的作用是该应用的重点。我们将分析其他GCA患者的生物存在。我们还将分析PMR和TAK患者的存在，以确定这些疾病是否具有类似的病因。我们的研究表明，生物体感染了GCA患者的时间动脉。我们将确定是否可以从具有GCA的受试者的血液中分离出生物体，以及它是否可以诱导多核巨细胞的形成并在人源化鼠类嵌合模型中引起血管炎。我们将确定像受体和人类白细胞抗原突变在BPGCA发病机理中的作用。我们将确定衰老是否导致T细胞中的缺陷，以防止根除生物体。我们将确定血清学测定的灵敏度和特异性 为了诊断GCA以及该测定法和肝素的ELISA是否可以用作疾病活动的生物标志物。炎症血管疾病在退伍军人人群中很常见。这些疾病的发病机理知之甚少。更好地了解传染性生物在GCA中发挥的作用可能会更好地理解更常见的炎症血管疾病（如动脉粥样硬化）。我们的发现，BPGCA感染GCA患者的时间动脉和血液可能会导致对疾病进行新的诊断测试，从而阻止了手术活检。它还可以进一步了解多肌痛风湿病和TAK的发病机理，这两种疾病与GCA具有共同的临床和显微镜特征。最后，这项研究可以彻底改变GCA的治疗方法，从而导致使用抗生素作为对疾病的潜在治疗方法。