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Degranulation deconstructed
Robert L Baehner1, Morris J Karnovsky
1Keck School of Medicine, University of Southern California, Los Angeles, California, USA. rbaehner@hsc.usc.edu
Insights
Chronic granulomatous disease (CGD) involves a defect in the NADPH oxidase system of leukocytes, impairing pathogen fighting. Understanding this defect has led to advanced therapies for CGD patients.
Area of Science:
- Immunology
- Genetics
- Molecular Biology
Background:
- Chronic granulomatous disease (CGD) was first described in 1959, characterized by recurrent infections due to impaired immune responses.
- Early hypotheses suggested leukocyte degranulation defects were the primary cause of CGD's pathology.
Purpose of the Study:
- To elucidate the fundamental cellular defect underlying chronic granulomatous disease (CGD).
- To identify the specific molecular mechanisms responsible for the immunodeficiency in CGD.
Main Methods:
- Investigated the function of the NADPH oxidase system in phagocytizing leukocytes.
- Characterized the subunit components, structure, and translocation of NADPH oxidase during phagocytosis.
Main Results:
- Demonstrated that the primary defect in CGD resides within the NADPH oxidase system, not leukocyte degranulation.
- Identified the component genes of NADPH oxidase, mapped their chromosomal locations, and successfully cloned them.
Conclusions:
- The elucidation of NADPH oxidase defects has revolutionized the understanding and treatment of CGD.
- Advances in molecular genetics and cell biology have paved the way for effective therapies like bone marrow and gene therapy for CGD.
Abstract:
Pediatricians first described the clinical features of chronic granulomatous disease (CGD) in 1959. Almost a decade later, in a collaborative effort that crossed disciplines, we participated in the discoveries that defined the cellular deficiencies of CGD, specifically finding that improper degranulation of leukocytes did not explain their failure to fight pathogens, rather that the fundamental defect was due to problems in the unique NADPH oxidase system of phagocytizing leukocytes. In the years that followed, the subunit components and structure of NADPH oxidase and their translocation during leukocyte phagocytosis to form the active enzyme were well described, leading to the identification of the component genes, the mapping of their chromosomal locations, and their subsequent cloning. This remarkable progress has led to effective therapies, including bone marrow transplants and gene therapy, that would have been unimaginable when we began.
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