1) During this FY, the Neutrophil Monitoring Laboratory (NML), our clinical laboratory collaboration managed by Douglas Kuhns, has performed molecular diagnostic studies on 56 patients suspected of having CGD. A total of 29 new X-linked CGD patients were identified as well as 11 autosomal CGD patients. Diagnosis was confirmed by nucleic acid sequencing of a total of 57 CGD patients or carriers. The NML has performed 1,262 superoxide assays and 740 DHR assays to support active clinical protocols relating to CGD. 2) Our group continues its clinical and laboratory studies of the novel Gram-negative CGD pathogen, Granulibacter bethesdensis. During FY13, we continued screening for MDH seropositivity in CGD and other disorders. We have identified additional seropositive CGD patients and are evaluating the progression of seropositivity during convalescence. In collaboration with Joseph Fontana (NIH/NHLBI) we examined Granulibacter seropositivity in patients with sarcoidosis. A study of the antimicrobial activities of monocytes and macrophages from CGD patients and normal subjects against G.bethesdensis has been published (Chu et al., 2013, J Immunology). 3) During FY2013, we analyzed data from NIH Protocol #10-I-0029 Non-invasive Assessment of Atherosclerosis in Patients with CGD and other Disorders of the Immune System (current total = 74 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 hypothesized 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 was 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. We found significant differences in the incidences of pre-clinical signs of atherosclerosis in CGD patients and have submitted a manuscript describing these findings. 4) This year we studied B-cell function in CGD patients. We reported in Matharu et al. (2013, Clinical Immunology), a significant elevation in the concentrations of B-cell Activating Factor (BAFF) in the serum of CGD patients as well as in normal patients treated intravenously with lipopolysaccharide (LPS). This study also demonstrated the correlations of BAFF with acute phase reactants. Since BAFF is elevated in CGD, we collaborated with James Cimino (NIH Laboratory for Informatics Development) to perform an extensive clinical data-mining study to characterize both total and autoimmune immunoglobulin levels and in the NIH Clinical Center CGD cohort as well as correlate these parameters with other genotypic and phenotypic data. Further analysis is pending. 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 have submitted this paper for publication.

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Kuhns, Douglas B; Fink, Danielle L; Choi, Uimook et al. (2016) Cytoskeletal abnormalities and neutrophil dysfunction in WDR1 deficiency. Blood 128:2135-2143
De Ravin, Suk See; Wu, Xiaolin; Moir, Susan et al. (2016) Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency. Sci Transl Med 8:335ra57
Khangura, Sajneet K; Kamal, Natasha; Ho, Nancy et al. (2016) Gastrointestinal Features of Chronic Granulomatous Disease Found During Endoscopy. Clin Gastroenterol Hepatol 14:395-402.e5
De Ravin, Suk See; Reik, Andreas; Liu, Pei-Qi et al. (2016) Targeted gene addition in human CD34(+) hematopoietic cells for correction of X-linked chronic granulomatous disease. Nat Biotechnol 34:424-9
Feingold, Paul L; Quadri, Humair S; Steinberg, Seth M et al. (2016) Thoracic Surgery in Chronic Granulomatous Disease: a 25-Year Single-Institution Experience. J Clin Immunol 36:677-83
Marciano, Beatriz E; Spalding, Christine; Fitzgerald, Alan et al. (2015) Common severe infections in chronic granulomatous disease. Clin Infect Dis 60:1176-83
Greenberg, David E; Sturdevant, Daniel E; Marshall-Batty, Kimberly R et al. (2015) Simultaneous Host-Pathogen transcriptome analysis during Granulibacter bethesdensis infection of normal and chronic granulomatous disease neutrophils. Infect Immun :
Merling, Randall K; Sweeney, Colin L; Chu, Jessica et al. (2015) An AAVS1-targeted minigene platform for correction of iPSCs from all five types of chronic granulomatous disease. Mol Ther 23:147-57
Sibley, Christopher T; Estwick, Tyra; Zavodni, Anna et al. (2014) Assessment of atherosclerosis in chronic granulomatous disease. Circulation 130:2031-9
Chu, Jessica; Song, Helen H; Zarember, Kol A et al. (2013) Persistence of the bacterial pathogen Granulibacter bethesdensis in chronic granulomatous disease monocytes and macrophages lacking a functional NADPH oxidase. J Immunol 191:3297-307

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