Clinical Studies Of Abnormal Host Defense

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1) The Neutrophil Monitoring Laboratory (NML), our clinical laboratory collaboration managed by Douglas Kuhns, has characterized the molecular defects by western blotting of 38 subjects and identified 29 new CGD patients. Diagnosis was confirmed by nucleic acid sequencing of a total of 55 CGD patients or carriers. 2) Our group has been involved in the clinical and laboratory studies of the novel Gram-negative CGD pathogen, Granulibacter bethesdensis. During FY12, we have purified the dominant antigen recognized by patient sera, methanol dehydrogenase (MDH), and have begun the biochemical characterization of this enzyme. In collaboration with the LCID, we have participated in serologic studies of the CGD cohort using both immunoblotting and an ELISA based on MDH. These studies have identified several additional CGD patients with evidence of likely prior infections with Granulibacter and provide tools for larger-scale screening of other patient population in which this infection may be suspected. This project has been published in the Journal of Infectious Diseases. 3) During FY2012, we have studied 24 more patients on NIH Protocol #10-I-0029 Non-invasive Assessment of Atherosclerosis in Patients with CGD and other Disorders of the Immune System (current total = 73 subjects). Atherosclerosis, the major cause of heart disease, is thought to relate to dysregulated inflammation in the cardiac blood vessels and over production of reactive oxygen species (ROS) has been implicated. We hypothesize that CGD patients, who have deficient production of reactive oxygen species by their phagocytes and other cells, may be protected from developing atherosclerosis. The primary endpoint of this study is the assessment of atherosclerotic plaque formation/calcium deposition by CT, MRI and other imaging methodologies, in these and other patients with in-born disorders of immune function. Inflammatory bowel disease provides a group of patients with similar chronic inflammation but with intact ROS production for comparison. Importantly, this study may determine for the first time in humans, whether ROS indeed play a role in the pathogenesis of atherosclerosis, a finding that could have broad importance for the general population as it would provide a validated molecular target for therapeutic intervention. 4) This year we initiated a study of immunoglobulin production in CGD. One of the earliest reported phenotypes of CGD patients was the observation of abnormally high amounts of IgG and dysregulation of IgG production has been linked hypothetically to the increased frequency of autoimmune disorders in these subjects. We undertook, in collaboration with James Cimino (NIH Laboratory for Informatics Development), an extensive clinical data-mining study to characterize both total and autoimmune immunoglobulin levels and incidence in the NIH Clinical Center CGD cohort as well as correlate these parameters with other genotypic and phenotypic data. In vitro laboratory studies measuring B-cell function and immunoglobulin secretion have revealed potentially important differences between normal and CGD B-cells. This work has been submitted for publication. 5) Several years ago, two patients with an undiagnosed disease characterized by increased infections and neutropenia were seen at the NIH. These subjects bore similarities to 2 other families of patients seen over a time frame of 30 years by the LHD. Cellular studies indicated an abnormal neutrophil morphology with frequent nuclear herniations, subnormal chemotaxis, and aberrant cytoskeletal structure. We have identified by biochemical and molecular approaches the molecular defect in this disease and are currently preparing this publication for submission.