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The genetics of innate immunity
1Pulmonary and Critical Care Division, Department of Medicine, Department of Veterans Affairs Medical Center and Duke University Medical Center, Durham, NC 27710, USA. david.schwartz@duke.edu
Chest
|March 15, 2002
Summary
Genetic variations in the toll-like receptor 4 (TLR4) gene are linked to differing responses to inhaled lipopolysaccharide (LPS) in humans. This suggests TLR4 plays a role, but other genes also influence LPS biological responses.
Area of Science:
- Immunology
- Genetics
- Toxicology
Background:
- Interindividual variability in toxin response is poorly understood.
- The toll-like receptor 4 (TLR4) gene influences lipopolysaccharide (LPS) responsiveness in mice.
Purpose of the Study:
- Investigate if TLR4 gene variations explain differing airway responsiveness to inhaled LPS in humans.
- Identify genetic factors contributing to variable biological responses to LPS.
Main Methods:
- Studied common, cosegregating missense mutations (Asp299Gly and Thr399Ile) in the TLR4 receptor in 83 humans.
- Conducted in vitro experiments to confirm in vivo observations.
- Analyzed genetically diverse and recombinant inbred mouse strains to explore additional genetic influences.
Main Results:
- Specific TLR4 mutations (Asp299Gly and Thr399Ile) were associated with a blunted airway response to inhaled LPS in humans.
- In vitro findings supported the in vivo human observations.
- Mouse studies confirmed TLR4's importance but also revealed involvement of additional genes in LPS response.
Conclusions:
- Common TLR4 gene variants contribute to variability in human airway responsiveness to LPS.
- While TLR4 is significant, other genes also play a crucial role in the mammalian biological response to LPS.
- Further research is needed to fully elucidate the genetic architecture of LPS response variability.