John I. Gallin, M.D.

Chief, Clinical Pathophysiology Section
Director, Clinical Center NIH

The long-term focus of the Clinical Pathophysiology Section (CPS) is on phagocyte dysfunction in human primary immunodeficiencies such as chronic granulomatous disease (CGD), Job's syndrome, leukocyte adhesion deficiency, Secondary Granule deficiency, IRAK-4 deficiency, and NEMO deficiency. CPS emphasizes studies of the etiology, pathogenesis, and therapy of granulomatous disorders caused by an inherited defect in the ability of phagocytes (neutrophils and monocytes) to produce superoxide. This defect leads to recurrent, life-threatening bacterial and fungal infections, as well as tissue granuloma formation. CPS is also interested in evaluating novel therapeutic approaches for treating CGD patients (e.g., interferon-y, itraconazole).

Douglas Kuhns, Ph.D., of Science Applications International Corporation (SAIC)-Frederick, heads the Neutrophil Monitoring Laboratory (NML), a CLIA-certified laboratory that supports the clinical and basic research of the NIAID Laboratory of Host Defenses (LHD) and the NIAID Laboratory of Clinical Infectious Diseases (LCID). NML provides assays (O2- generation, staphylocidal activity, adherence to plastic/coated surfaces, chemotaxis, degranulation, Western blot analysis, and surface antigen expression by flow cytometric analysis) that assess the functional responses of phagocytic cells isolated from patients with recurrent bacterial, mycobacterial, and fungal infections, as well as patients with abnormal inflammatory responses.

In addition, NML analyzes biological specimens for various inflammatory mediators/cytokines using ELISA and a multi-array cytokine platform. NML also maintains an extensive repository (~70,000 vials) of patient plasma, cryopreserved peripheral blood mononuclear cells (PBMCs), Epstein-Barr virus (EBV)-transformed B-cell lines, DNA, and RNA. All have proven to be a valuable resource to LHD and LCID investigators. Dr. Kuhns also studies the function and intracellular signaling pathways of neutrophils, leading to the production of reactive oxygen species and the chemokine interleukin-8.

(left to right) Karen Lau, Laura Coffin, Dara Riva, Dani Fink, Debra Long Priel, Douglas Kuhns

E-mail: dkuhns@mail.nih.gov

Kol Zarember, Ph.D., Staff Scientist, studies human innate immunity against pathogenic organisms, particularly those infecting CGD patients (e.g., Aspergillus fumigatus, Granulibacter bethesdensis). Dr. Zarember’s long-term interests have focused on how microbes are detected by the immune system—for example, through toll-like receptors—and how the immune system attacks the invading pathogen (e.g., production of toxic oxygen radicals, antimicrobial peptides, and complement). Parallel studies examining how the microbe attempts to counter the immune system’s attacks provide potential targets for novel immunotheraputics to enhance host defenses. Another major project involves the study of the human inflammatory response in vivo using the suction blister technique.

Kol Zarember, Ph.D., Staff Scientist

Email: kzarember@niaid.nih.gov

Anjali Singh, Ph.D., supports some of the lab functions and studies the assembly and activation of the NADPH oxidase in neutrophils from normal donors and patients with immune dysfunction.

Anjali Singh, Ph.D.

Benjamin Soule, M.D., Clinical Fellow, is studying mechanisms underlying the development and progression of chronic inflammation and free radical signaling in neutrophils.

Benjamin Soule, M.D., Clinical Fellow

The following are clinical protocols in CPS that are actively recruiting patients:

Comparison of Inflammatory Responses in Normal Volunteers and Patients with Abnormal Phagocyte Function Using the Suction Blister Technique (90-I-0120)

Selected Recent Publications

To view a complete listing, visit PubMed.

Kuhns DB, Priel DA, Gallin JI. Induction of human monocyte interleukin (IL)-8 by fibrinogen through the toll-like receptor pathway. Inflammation. 2007 Oct; 30(5):178-88.

Zarember KA, Sugui JA, Chang YC, Kwon-Chung KJ, Gallin JI. Human polymorphonuclear leukocytes inhibit Aspergillus fumigatus conidial growth by lactoferrin-mediated iron depletion. J Immunol. 2007 May 15;178(10):6367-73.

Lekstrom-Himes JA, Kuhns DB, Alvord WG, Gallin JI. Inhibition of human neutrophil IL-8 production by hydrogen peroxide and dysregulation in chronic granulomatous disease. J Immunol. 2005 Jan 1;174(1):411-7.

Medvedev AE, Lentschat A, Kuhns DB, Blanco JC, Salkowski C, Zhang S, Arditi M, Gallin JI, Vogel SN. Distinct mutations in IRAK-4 confer hyporesponsiveness to lipopolysaccharide and interleukin-1 in a patient with recurrent bacterial infections. J Exp Med. 2003 Aug 18;198(4):521-31.

Gallin JI, Alling DW, Malech HL, Wesley R, Koziol D, Marciano B, Eisenstein EM, Turner ML, DeCarlo ES, Starling JM, Holland SM. Itraconazole to prevent fungal infections in chronic granulomatous disease. N Engl J Med. 2003 Jun 12;348(24):2416-22.

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