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: 8967150
• 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/8967150
• 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; Health; Hormones; Immunoassay; Immunohistochemistry; Incidence; Infection; Infectious Agent; Infiltration; Inflammation; Inflammatory; Invaded; Iron; Jaw; Knowledge; Lead; Learning; Lipopolysaccharides; Lymphocyte; Microscopic; Modeling; Molecular; Mutation; Myalgia; Night Sweating; Operative Surgical Procedures; Organism; Pain; Pathogenesis; Pathway interactions; Patients; Peptides; Play; Polymyalgia Rheumatica; Population; Predisposition; Production; Property; RNA; 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; humanized mouse; improved outcome; insight; macrophage; muscle stiffness; novel diagnostics; older patient; peptide hormone; prevent; receptor binding; relapse patients; research study; response; 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）是一种全身性炎症性疾病的老年人，造成炎症的大，中型血管。它与风湿性多肌痛（PMR）高度相关，PMR是一种引起近端肌肉疼痛和僵硬的疾病。GCA也具有类似于Takayasu动脉炎（TAK）的组织学特征，TAK是一种影响年轻女性的大中型血管的肉芽肿性动脉炎。GCA的诊断是基于临床怀疑，但经颞动脉活检证实。GCA的原因尚不清楚，但被认为是由于侵入大中型动脉壁的抗原。分子证据支持感染性微生物导致GCA。我们发现铁调素，一种铁调节激素，在GCA患者的颞动脉壁中表达。已知铁调素响应于细菌感染而分泌。这促使我们分析GCA患者的颞动脉壁是否存在感染性微生物。我们通过基因分析发现，一株伯克霍尔德菌存在于GCA患者的颞动脉壁。进一步研究证实该菌株为一株B型。假鼻疽样菌株（BpGCA），它缺乏III型分泌因子，使其无毒力。通过血清学测定在受影响患者的血清中检测到BpGCA LPS。BpGCA在GCA发病机制中的作用是本申请的重点。我们将分析其他GCA患者是否存在微生物。我们还将分析PMR和TAK患者是否存在微生物，以确定这些疾病是否具有相似的病因。我们的研究表明，这种微生物感染了GCA患者的颞动脉。我们将确定该生物体是否可以从GCA受试者的血液中分离出来，以及它是否可以在人源化小鼠嵌合模型中诱导多核巨细胞的形成并引起血管炎。我们将确定Toll样受体和人类白细胞抗原突变在BpGCA发病机制中的作用。我们将确定衰老是否会导致T细胞缺陷，从而阻止生物体的根除。我们将确定血清学检测的灵敏度和特异性 用于诊断GCA，以及该测定和hepcidin的ELISA是否可用作疾病活动的生物标志物。炎症性血管疾病在退伍军人中很常见。这些疾病的发病机制知之甚少。更好地了解感染性微生物在GCA中的作用可能会更好地理解更常见的炎症性血管疾病（如动脉粥样硬化）的发病机制。我们发现BpGCA感染GCA患者的颞动脉和血液，这可能会导致一种新的诊断方法，以预防手术活检的需要。它还可以提供进一步了解风湿性多肌痛和TAK的发病机制，这两种疾病与GCA具有共同的临床和显微镜特征。最后，这项研究可能会彻底改变GCA的治疗方法，从而使用抗生素作为治疗这种疾病的潜在方法。

项目成果

Absence of Bacteria in the Temporal Arteries of Patients with Giant Cell Arteritis.

巨细胞动脉炎患者的颞动脉中没有细菌。

• DOI: 10.1097/rhu.0000000000000344
• 发表时间: 2016
• 期刊: Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases
• 作者: Koening,CurryL;Peterson,SpencerG;Podnecky,NicoleL;Schweizer,HerbertP;Li,DeanY;Katz,BradleyJ
• 通讯作者: Katz,BradleyJ