The role of Burkholderia in giant cell arteritis

描述(由申请人提供)： 巨细胞动脉炎(GCA)是一种老年人的全身性炎症性疾病，可引起大中型血管的炎症。它与风湿性多发性肌痛(PMR)高度相关，PMR是一种导致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肉芽肿性动脉炎。GCA的诊断基于临床怀疑，但经颞动脉活检证实。GCA的病因尚不清楚，但被认为是由于一种侵入大中型动脉壁的抗原所致。分子证据支持感染性有机体引起GCA。我们发现海普西丁，一种铁调节激素，在GCA患者的颞动脉壁上表达。众所周知，海普西丁是在细菌感染时分泌的。这导致我们对GCA患者的颞动脉壁进行了分析，以寻找一种感染微生物。我们通过遗传分析发现，在GCA患者的颞动脉壁中存在一株伯克霍尔德氏菌。进一步的研究证实，该菌株为假鼻疽杆菌样菌株(BpGCA)，缺乏III型分泌因子，使其无毒。用血清学方法检测感染患者血清中的BpGCA内毒素。BpGCA在GCA发病机制中的作用是这一应用的重点。我们将分析更多患有GCA的患者是否存在这种微生物。我们还将分析PMR和TAK患者是否存在有机体，以确定这些疾病是否可能有相似的病因。我们的研究表明，这种微生物会感染GCA患者的颞动脉。我们将确定是否可以从患有GCA的受试者的血液中分离出这种微生物，以及它是否可以在人源化的小鼠嵌合模型中诱导多核巨细胞的形成和引起血管炎。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细胞的缺陷，从而阻止生物体的根除。我们将确定血清学检测的敏感性和特异性。 用于诊断GCA，以及该检测方法和一种检测海普西丁的ELISA是否可以作为疾病活动性的生物标志物。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还知之甚少。更好地了解感染性生物在GCA中所起的作用，可能有助于更好地理解更常见的炎症性血管疾病的发病机制，如动脉粥样硬化。我们的发现BpGCA感染GCA患者的颞动脉和血液，可能会导致一种新的疾病诊断方法，从而避免手术活检的需要。它还可能为风湿性多发性肌痛和TAK的发病机制提供进一步的见解，这两种疾病与GCA具有共同的临床和显微特征。最后，这项研究可能会彻底改变GCA的治疗方法，导致使用抗生素作为治疗这种疾病的潜在方法。

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.