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1 Division of Intramural Research, and 2 National Institute of Environmental Health Sciences, Department of Health and Human Services, National Institutes of Health, Research Triangle Park, North Carolina
Correspondence and requests for reprints should be addressed to Donald N. Cook, Ph.D., Group Leader, Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, 111 T.W. Alexander Drive, Building 101, E244, Research Triangle Park, NC 27709. E-mail: cookd{at}niehs.nih.gov
The 22nd annual Transatlantic Airway Conference (TAC) was convened in January of 2007 to review and discuss the latest developments in airway biology and the impact of innate immune responses on environmental airway disease. This topic was approached from several different directions, including epidemiologic, genetic, pathogenic, and therapeutic studies. The goal of this conference was to identify common themes emerging from various methodological approaches, and at the same time, promote cross-fertilization of ideas. Although this goal is frequently stated, it is not always achieved, perhaps because the investigative approaches are either too divergent or too similar. The 2007 TAC was an exception, and revealed unifying themes from presentations based on fundamentally different investigative approaches.
A major theme that emerged from this conference was the interdependence of factors that predispose to airway disease. Epidemiologic studies were presented by Erica von Mutius of the University Children's Hospital in Munich, Germany. Dr. von Mutius described several studies showing that exposure to a farming environment protects against developing allergic asthma. However, the impact of this effect depends on multiple factors, including the geographical location of the farm, and the types of animals and agriculture that are present on it. In addition, she showed that individuals living on farms have increased levels of innate immune genes, such as the Toll-like receptor 4 (TLR4). Because TLR4 is required for signaling responses to endotoxin or lipopolysaccharide (LPS), this finding strengthens the notion that the LPS associated with farm animals and fodder influences the development of airway disease. LPS is not the only environmental agent affecting levels of TLR4; John Hollingsworth of Duke University showed that the biologic response to ozone is dependent on intact TLR4 and that exposure to ozone can modify subsequent response to inhaled LPS. Such relationships between environmental exposures and innate immune genes are likely to be the focus of much investigation over the next several years.
The theme of gene–environment interrelationships was echoed and extended in a presentation by Fernando Martinez of the University of Arizona. Using the CD14 gene as an example, Dr. Martinez showed that the impact of specific genetic polymorphisms on disease susceptibility can vary, depending on the environmental conditions to which these individuals are exposed. CD14, which is part of a protein complex that includes TLR4, is required for effective intracellular signaling responses to LPS. Interestingly, a CC polymorphism at position –159 of the CD14 gene is associated with a higher incidence of airway disease in individuals exposed to an environment with low levels of endotoxin, but is protective in an environment with high levels of endotoxin. Conversely, this finding might be viewed as evidence that the ability to identify environmental risk factors sometimes depends on the genotypes of the individuals under study. This emerging understanding might help to explain some of the disparate findings seen in seemingly similar studies of environmental or genetic associations with airway disease. For example, in the reported study, if the effect of genotype had not been considered, it is unlikely that environmental levels of endotoxin would have been found to have a significant impact on disease.
Another additional factor complicating the gene–environment issue was provided by Stephanie London (National Institute of Environmental Health Sciences [NIEHS], National Institutes of Health [NIH]). Dr. London showed that the effect of environmental ozone on asthma depends not only on genotype and environment but also on diet. Thus, individuals having a particular polymorphism in the glutathione S-transferase M1 gene (GSTM1) had an increased risk of ozone-associated asthma, and that within this population, individuals with inadequate levels of antioxidant in their diet were at even more risk. Thus, diet, genotype, and environmental ozone all combine to confer a disease susceptibility phenotype that might not be evident in individuals lacking one or more of these risk factors. Esteban González Burchard (University of California at San Francisco) pointed out that the situation can be even further complicated by factors such as socioeconomic status, cultural heritage, gender, and age.
Just as extragenetic factors such as environment and diet can influence the impact of particular polymorphisms on disease susceptibility, so too can specific polymorphisms of other genes. Using an unbiased Bayesian analysis, Scott Weiss (Harvard Medical School) showed that certain genetic polymorphisms impact disease susceptibility only in individuals who also carry specific polymorphisms in other genes. David Schwartz of the NIEHS expanded on this notion, showing that levels of methylating agents in the diet can affect the methylation and transcription patterns of specific genes, which in turn affect responses to allergens, not only in the diet-treated mice but also in their offspring. Thus, unpredicted interrelationships between genetic and epigenetic factors can combine to render some individuals particularly susceptible to environmental risk factors.
Although many cell types function in the development of airway disease, dendritic cells (DCs) might be particularly sensitive to environmental cues. These cells reside in the pulmonary mucosa, and migrate to draining lymph nodes where they present inhaled antigen to naive T cells. The nature of the immune responses conferred by this antigen presentation depends largely on the inflammatory conditions in the lung. This was nicely illustrated in work presented by Kim Bottomly (Yale University), who showed that levels of LPS in the lung can determine whether allergen delivery to the airway results in T helper (Th)1 or Th2 immune responses. She further showed that TLR4 and MyD88, both proteins that mediate innate immune responses, are important in this response. The use of an animal model to demonstrate a link between levels of LPS and different types of immune responses was satisfying in view of previously presented epidemiologic studies showing that levels of LPS in the environment, and polymorphisms in genes that mediate responsiveness to LPS, can affect the incidence of allergic asthma in humans. Several presentations highlighted the growing understanding that pulmonary DCs likely differ from their counterparts in the bone marrow or peritoneum, and that model systems should take account of these differences. Thus, Dr. Bottomly showed that pulmonary DC signaling properties can differ from those in other tissues; Donald Cook (NIEHS, NIH) showed that chemokine receptor requirements for the trafficking of pulmonary DCs to draining lymph nodes differ from peritoneal DCs; and Joe Rae Wright (Duke University) showed that the interaction of surfactant proteins with DCs depends on the source of these important cells. Based on these observations, it seems likely that the mechanisms by which pulmonary DCs signal immunogenic or tolerogenic immune responses might differ from DCs of other tissues. Allergen-specific tolerogenic responses are normally conferred by exposing mice to aerosolized ovalbumin, but Marsha Wills-Karp (Cincinnati Children's Hospital Medical Center) showed that complement 5a can prevent this tolerance. Richard Flavell (Yale University) showed that levels of Foxp3 are critical to the function of regulatory T cells (Tregs), which function to establish and maintain immune tolerance. The role of intracellular proteins, such as the CATERPILLAR family of gene products and the high-mobility group (HMG) B1 molecule, were identified by Jenny Ting (University of North Carolina) and David Pisetsky (Duke University), respectively, as key molecules in regulating inflammatory responses. It will be interesting to learn whether genetic polymorphisms in these genes can predispose to airway disease.
During the final section of the meeting, Sebastian Johnston (Imperial College of London) and Homer Boushey (University of California at San Francisco) presented compelling evidence that viral infections, and immune responses to them, can predispose to asthma, or even cause the disease in susceptible individuals. Because Th2 immune responses are associated with allergic asthma, it is reasonable to investigate therapeutic approaches capable of blocking such responses. Toward this end, Dr. Boushey proposed the use of probiotic therapy, and Joel Kline (University of Iowa) and Arthur Krieg (Coley Pharmaceutical Group) presented data showing the potential of DNA containing unmethylated CpG motifs as a therapeutic reagent either alone or in conjunction with allergen. This therapy is based on the ability of CpG DNA to bind and activate TLR9 on plasmacytoid DCs, thereby leading to a Th1-biased immune response.
By the conclusion of the meeting, it was clear that a comprehensive understanding of environmental airway disease requires a multidisciplinary approach. The theme of interrelationships between multiple risk factors echoed through discussions of environmental exposures, diet, genetic polymorphisms, epistatic interactions, epigenetics, and intracellular and extracellular signaling among immune cells. In some ways, the final discussion on therapeutics came full circle because the principle underlying their use first emerged from associative studies of environmental exposures and disease outcomes. It is likely that, with an improved understanding of the environmental, genetic, and epigenetic factors that confer susceptibility to airway disease, novel therapies will eventually be tailored to intervene in the specific molecular pathway(s) relevant to an individual's disease. Based on the data presented at the 2007 TAC, that day is closer than ever before.
FOOTNOTES
Supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences.
Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
(Received in original form March 8, 2007; accepted in final form March 8, 2007)
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