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.

Public Health Relevance

Our ability to detect the LPS of a B. pseudomallei-like bacterium (BpGCA) in the blood of patients with giant cell arteritis (GCA) may lead to a diagnostic blood test that would obviate the need for surgical biopsy and could be used as a biomarker of disease activity. This work could revolutionize the treatment of GCA and improve outcomes for patients affected with this disorder. Results from this work will assist us in learning the cause of GCA and will influence our knowledge of how vasculitis and other inflammatory blood vessel diseases develop. The experiments described will explore the role of BpGCA in the pathogenesis of other similar diseases related to GCA and will aid in determining why elderly patients are afflicted with this disorder.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Hematology (HEMA)
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VA Salt Lake City Healthcare System
Salt Lake City
United States
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