Major Areas of Research
- Phagocyte dysfunction
The mission of the Clinical Pathophysiology Section is to study the genetic causes and the biological consequences of inborn diseases of phagocytic blood cells.
Infection leads to the production of chemoattractants that promote white blood cell migration into the tissues where they interact with pathogens, normally resulting in killing of the microbe. Diseases studied by our group include STAT3-, NEMO-, and IRAK4-deficiencies which tend to reduce activation of white cells by inflammatory signals; Leukocyte Adhesion Deficiency, and WDR1/AIP1-deficiency that reduce the ability of white blood cells to enter tissues; Secondary Granule Deficiency and Chediak-Higashi Syndrome that alter granule formulation or function; and Chronic Granulomatous Disease (CGD) that decrease the production of microbicidal reactive oxygen species such as hydrogen peroxide and bleach.
Chronic granulomatous disease (CGD) is our major focus. CGD occurs in patients whose phagocytes (neutrophils and monocytes) are unable to generate antimicrobial levels of reactive oxygen species (e.g. superoxide anion) due to mutations in components of the NADPH oxidase (NOX2). Without sufficient production of superoxide anion, a key mediator of host defense, these patients suffer from life-threatening bacterial and fungal infections as well as tissue granuloma formation and other inflammatory diseases. Our section is particularly interested in Granulibacter bethesdensis, a recently described species that can cause lethal infections in patients with CGD. We are studying phenotypic and genotypic attributes of this organism to understand microbial pathogenesis of this emerging pathogen.
Genetic immunodeficiencies such as CGD also provide unique opportunities to study the roles of specific elements of the immune system in human health. For example, our clinical study employing non-invasive radiologic imaging of the cardiovascular system of CGD patients demonstrated a contribution of reactive oxygen species to the pathogenesis of atherosclerosis. Further studies are underway to evaluate the role of the NADPH oxidase in atherosclerosis and other important human diseases.
Dr. Gallin received his medical training at Cornell University Medical College in New York City followed by residency in internal medicine at Bellevue Hospital. In 1971, he first came to NIH as a clinical associate in Sheldon Wolff’s Laboratory of Clinical Investigation. In 1974, he was the senior chief resident in medicine at Bellevue Hospital before returning to NIH in 1976 as a senior investigator. Dr. Gallin served as the director of the NIAID Intramural Research Program (1985–1994), the chief of the Laboratory of Host Defenses (1991–2003), and the director of the NIH Clinical Center (1994–2017). Currently, Dr. Gallin is the chief scientific officer of the NIH Clinical Center and the NIH associate director for clinical research. Among his honors are membership of the National Academy of Medicine (formally the Institute of Medicine) of the National Academy of Sciences, and he is a master of the American College of Physicians.
Closely associated with CPS is the Neutrophil Monitoring Laboratory (NML), located on the Fort Detrick campus in Frederick, MD. NML is headed by Douglas Kuhns, Ph.D. (contractor, Leidos Biomedical Research, Inc.), and performs genetic and functional studies on materials from patients CGD and other primary immunodeficiencies in support of several NIAID laboratories.
Contact: Douglas B. Kuhns
Chu J, Smelkinson MG, Dorward DW, Zarember KA, Gallin JI. Early intracellular trafficking of granulibacter bethesdensis in human macrophages. Infect Immun. 2017 May 23;85(6). pii: e00847-16.
Kuhns DB, Fink DL, Choi U, Sweeney C, Lau K, Priel DL, Riva D, Mendez L, Uzel G, Freeman AF, Oliver KN, Anderson VL, Currens R, Mackley V, Kang A, Al-Adeli M, Mace E, Orange JS, Kang E, Lockett SJ, Chen, Steinbach PJ, Hsu AP, Zarember KA, Malech HL, Gallin JI, Holland SM. Cytoskeletal abnormalities and neutrophil dysfunction in WDR1 deficiency. Blood. 2016 Oct 27;128(17):2135-2143.
Greenberg DE, Sturdevant DE, Marshall-Batty KR, Chu J, Pettinato AM, Virtaneva K, Lane J, Geller BL, Porcella SF, Gallin JI, Holland SM, Zarember KA. Simultaneous host-pathogen transcriptome analysis during Granulibacter bethesdensis infection of neutrophils from healthy subjects and patients with chronic granulomatous disease.(link is external) Infect Immun. 2015 Nov;83(11):4277-92.
Sibley CT, Estwick T, Zavodni A, Huang CY, Kwan AC, Soule BP, Long Priel DA, Remaley AT, Rudman Spergel AK, Turkbey EB, Kuhns DB, Holland SM, Malech HL, Zarember KA, Bluemke DA, Gallin JI. Assessment of Atherosclerosis in Chronic Granulomatous Disease. Circulation. 2014 Dec 2;130(23):2031-2039.
Kuhns DB, Alvord WG, Heller T, Feld JJ, Pike KM, Marciano BE, Uzel G, DeRavin SS, Priel DA, Soule BP, Zarember KA, Malech HL, Holland SM, Gallin JI. Residual NADPH oxidase and survival in chronic granulomatous disease(link is external). N Engl J Med. 2010 Dec 30;363(27):2600-10.