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 characterized the molecular and functional aspects of newly diagnosed cases of Granulibacter bethesdensis, including an isolate from Portugal, which appears to be more pathogenic both in human reports and in CGD mice. We have also defined the microbiomic aspects of CGD bowel disease, which are important in the induction of inflammation. 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 being due to 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. Further, the infections in these mice are driven in part by the proinflammatory molecule tumor necrosis factor, offering new avenues for therapy. 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. With NCI investigators we have developed a comprehensive and successful bone marrow transplantation program for DOCK8 deficiency. 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.
| Bousfiha, Aziz; Jeddane, Leïla; Picard, Capucine et al. (2018) The 2017 IUIS Phenotypic Classification for Primary Immunodeficiencies. J Clin Immunol 38:129-143 |
| van de Geer, Annemarie; Nieto-Patlán, Alejandro; Kuhns, Douglas B et al. (2018) Inherited p40phox deficiency differs from classic chronic granulomatous disease. J Clin Invest 128:3957-3975 |
| Drummond, Rebecca A; Zahra, Fatema Tuz; Natarajan, Mukil et al. (2018) GM-CSF Therapy in Human CARD9 Deficiency. J Allergy Clin Immunol : |
| Natarajan, Mukil; Hsu, Amy P; Weinreich, Michael A et al. (2018) Aspergillosis, eosinophilic esophagitis, and allergic rhinitis in signal transducer and activator of transcription 3 haploinsufficiency. J Allergy Clin Immunol 142:993-997.e3 |
| Myles, Ian A; Anderson, Erik D; Earland, Noah J et al. (2018) TNF overproduction impairs epithelial staphylococcal response in hyper IgE syndrome. J Clin Invest 128:3595-3604 |
| Henrickson, Sarah E; Walter, Jolan E; Quinn, Colin et al. (2018) Adult-Onset Myopathy in a Patient with Hypomorphic RAG2 Mutations and Combined Immune Deficiency. J Clin Immunol 38:642-645 |
| Wingfield, L R; Liu, J; Hu, M et al. (2018) Nine patients with chronic granulomatous disease having selective neck dissection for severe cervical lymphadenitis. Clin Otolaryngol 43:335-340 |
| Forbes, Lisa R; Vogel, Tiphanie P; Cooper, Megan A et al. (2018) Jakinibs for the treatment of immune dysregulation in patients with gain-of-function signal transducer and activator of transcription 1 (STAT1) or STAT3 mutations. J Allergy Clin Immunol : |
| Abusleme, Loreto; Diaz, Patricia I; Freeman, Alexandra F et al. (2018) Human defects in STAT3 promote oral mucosal fungal and bacterial dysbiosis. JCI Insight 3: |
| Gernez, Yael; Freeman, Alexandra F; Holland, Steven M et al. (2018) Autosomal Dominant Hyper-IgE Syndrome in the USIDNET Registry. J Allergy Clin Immunol Pract 6:996-1001 |
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