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 gastrointestinal manifestations of CGD, since almost 50% of patients develop inflammatory bowel disease. We have characterized the gastrointestinal histopathology and the role of surgery in the world's largest cohort of cases. We have also identified an unexpectedly high frequency of diabetes, kidney and heart diseases in the most common autosomal recessive variant of CGD due to defects in p47phox. We have also performed a retrospective study CGD retinitis in autopsy and biopsy specimens. We found evidence of bacterial DNA in ocular lesions in CGD eyes. 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.

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Jing, Huie; Zhang, Qian; Zhang, Yu et al. (2014) Somatic reversion in dedicator of cytokinesis 8 immunodeficiency modulates disease phenotype. J Allergy Clin Immunol 133:1667-75
Chien, Wade Wei-De; Leiding, Jennifer W; Hsu, Amy P et al. (2014) Auditory and vestibular phenotypes associated with GATA3 mutation. Otol Neurotol 35:577-81
Elloumi, Houda Zghal; Holland, Steven M (2014) Diagnostic assays for chronic granulomatous disease and other neutrophil disorders. Methods Mol Biol 1124:517-35
Lionakis, Michail S; Netea, Mihai G; Holland, Steven M (2014) Mendelian genetics of human susceptibility to fungal infection. Cold Spring Harb Perspect Med 4:
Steward-Tharp, Scott M; Laurence, Arian; Kanno, Yuka et al. (2014) A mouse model of HIES reveals pro- and anti-inflammatory functions of STAT3. Blood 123:2978-87
Zhu, Shiguo; Phatarpekar, Prasad V; Denman, Cecele J et al. (2014) Transcription of the activating receptor NKG2D in natural killer cells is regulated by STAT3 tyrosine phosphorylation. Blood 124:403-11
Medical Advisory Committee of the Immune Deficiency Foundation; Shearer, William T; Fleisher, Thomas A et al. (2014) Recommendations for live viral and bacterial vaccines in immunodeficient patients and their close contacts. J Allergy Clin Immunol 133:961-6
Sowerwine, Kathryn J; Shaw, Pamela A; Gu, Wenjuan et al. (2014) Bone density and fractures in autosomal dominant hyper IgE syndrome. J Clin Immunol 34:260-4
Moutsopoulos, Niki M; Konkel, Joanne; Sarmadi, Mojgan et al. (2014) Defective neutrophil recruitment in leukocyte adhesion deficiency type I disease causes local IL-17-driven inflammatory bone loss. Sci Transl Med 6:229ra40
Lionakis, Michail S; Holland, Steven M (2014) Human Invasive Mycoses: Immunogenetics on the Rise. J Infect Dis :

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