We seek to understand the role of phagocytes in immune function through examination of the consequences of immune defects. Our major focus is on chronic granulomatous disease (CGD), which is caused by defects in the enzyme NADPH oxidase. The NADPH oxidase is involved in the generation and control of inflammation, protection from infection, and cell-cell signaling. We have a comprehensive portfolio involving patients, animals, and laboratory specimens. We have continued our exploration of the seroepidemiology of Granulibacter bethesdensis, a novel Gram negative organism with a host range limited to CGD. We have confirmed a seropositivity rate of almost 75% in CGD patients, but an impressive 25% in normal individuals (J Infect Dis. 2012 Sep;206(6):943-51). Identification of the genetic and cellular basis of hyper-IgE recurrent infection syndrome (HIES or Job's syndrome), an autosomal dominant disease characterized by extremely elevated IgE, recurrent sino-pulmonary infections, osteopenia, kyphoscoliosis, pulmonary cysts, and dental abnormalities, as STAT3 has informed broad areas of investigation. With NIAID, NIAMS and extramural collaborators we have identified abnormalities in other cytokines downstream of STAT3, most notably IL-17, which is profoundly low in cells from Job's syndrome patients. Collaborating with investigators in NIAMS we have created a mouse model of STAT3 deficiency which has impaired wound healing and staphylococcal control. Collaborating with investigators in NHLBI we continue to study vascular endothelial cells from patients with STAT3 deficeincy in vitro, deriving endothelial and muscle cells from STAT3 deficient patients that have shown impaired chemokine production. Recently we identified novel defects in the scaffolding protein WDR1/AIP1. Interestingly enough, we have found the same defect in children seen here over the last 25 years with identified mutations in the same gene. These combined approaches continue to be productive and help us understand innate immunity and inflammation. These studies will help us understand several different infections, including filamentous fungal infections, at a molecular genetic and functional level.

Project Start
Project End
Budget Start
Budget End
Support Year
21
Fiscal Year
2012
Total Cost
$1,711,994
Indirect Cost
City
State
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Zip Code
Zerbe, Christa S; Marciano, Beatriz E; Katial, Rohit K et al. (2016) Progressive Multifocal Leukoencephalopathy in Primary Immune Deficiencies: Stat1 Gain of Function and Review of the Literature. Clin Infect Dis 62:986-94
Falcone, E Liana; Petts, Jennifer R; Fasano, Mary Beth et al. (2016) Methylotroph Infections and Chronic Granulomatous Disease. Emerg Infect Dis 22:404-9
Lawrence, Monica G; Leiding, Jennifer W; Lyons, Jonathan J et al. (2016) GATA3 haploinsufficiency does not block allergic sensitization or atopic disease. J Allergy Clin Immunol 137:627-629.e2
Myles, Ian A; Zhao, Ming; Nardone, Glenn et al. (2016) CD8+ T cells produce a dialyzable antigen-specific activator of dendritic cells. J Leukoc Biol :
Chandrasekaran, Prabha; Zimmerman, Ofer; Paulson, Michelle et al. (2016) Distinct mutations at the same positions of STAT3 cause either loss or gain of function. J Allergy Clin Immunol 138:1222-1224.e2
Falcone, E Liana; Abusleme, Loreto; Swamydas, Muthulekha et al. (2016) Colitis susceptibility in p47(phox-/-) mice is mediated by the microbiome. Microbiome 4:13
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
Lovell, Jana P; Foruraghi, Ladan; Freeman, Alexandra F et al. (2016) Persistent nodal histoplasmosis in nuclear factor kappa B essential modulator deficiency: Report of a case and review of infection in primary immunodeficiencies. J Allergy Clin Immunol 138:903-5
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
Thomsen, Isaac P; Smith, Meaghan A; Holland, Steven M et al. (2016) A Comprehensive Approach to the Management of Children and Adults With Chronic Granulomatous Disease. J Allergy Clin Immunol Pract :

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