Given the opposing effects of endotoxin, it is perhaps not unexpected that some studies have not revealed an effect of the common TLR4 polymorphism (D299G) on the overall incidence of asthma [116-118]. Individuals having this polymorphism have a blunted airway response  and reduced systemic inflammation  in response to inhaled endotoxin. Consistent with these observations, a study of asthma specifically associated with endotoxin in house dust showed that people with the TLR4 polymorphism (D299G) had a decreased risk of bronchoreactivity . These observations are consistent with the hypothesis that endotoxin can exacerbate existing airway inflammation and that individuals with the D299G polymorphism have diminished pulmonary responses to endotoxin. However, other studies found that asthmatic individuals with the D299G polymorphism have an increased severity of atopy  and an increased incidence of atopic asthma . Each of these associations with common polymorphisms of TLR4 is consistent with the ability of LPS to exacerbate existing asthma and to decrease atopy respectively, and suggest that the D299G polymorphism could be predictive of airway and atopic responses in a specific subset of the population.
Genetic approaches to identify associations between airway disease and activation of the innate immune system are not limited to TLR4. Polymorphisms of the TLR4 co-receptor CD14 are associated with increased levels of soluble CD14 and an enhanced biological response to endotoxin. Polymorphisms of CD14 have been associated with both a decrease in total serum IgE in asthmatic children  and a decrease in lung function among endotoxin exposed farmers . The observation among children is consistent with the hygiene hypothesis concerning attenuation of allergic symptoms with enhanced response to endotoxin. The enhanced biologic response among farmers with exposure to high levels of occupational endotoxin would be expected to demonstrate decreased lung function, as was observed. In another study, common polymorphisms of TLR2 among European farmers were associated with protection from asthma, atopy and hay fever . This observation would suggest that a blunted response to TLR2 agonists is protective against the subsequent development of allergic asthma. While this is inconsistent with the hygiene hypothesis, the exposure dose to ligands of TLR2 among farmers as well as the func tional significance of this polymorphism of human TLR2 remains poorly understood. Similarly, polymorphisms of TLR6 have been associated with a decreased risk of asthma in African Americans . Finally, polymorphisms of TLR10 have been associated with an increase risk of asthma in two separate cohorts .
It has become clear that TLR-dependent signaling is critical for the activation of the adaptive immune response. Given the complexity and broad range of environmental challenges which lead to the clinical diagnosis of asthma, it is not surprising that apparent divergent phenotypes are observed with attenuation of TLR-depen-dent signaling associated with many polymorphisms. Little is known about the lig-ands of many TLRs, including TLR6 and TLR10. Furthermore, it remains unknown if polymorphisms of TLRs affect interactions between other accessory molecules required to maintain unaltered signaling. Despite limitations of genetic association studies, these observations provide insight into the role of TLRs in the development and progression of human airways disease.
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