Air pollution as a potential contributor to the ‘epidemic’ of autoimmune disease

Medical Hypotheses 74 (2010) 110–117

Contents lists available at ScienceDirect

Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy

Air pollution as a potential contributor to the ‘epidemic’ of autoimmune disease Stacey A. Ritz * Medical Sciences Division, Northern Ontario School of Medicine, East Campus – Laurentian University, 935 Ramsey Lake Road, Sudbury, ON, Canada P3C 2C9

a r t i c l e

i n f o

Article history: Received 15 July 2009 Accepted 16 July 2009

s u m m a r y There has been remarkable progress over the past 20 years in pushing forward our understanding of many facets of autoimmune disease. Indeed, knowledge of the genetic basis of autoimmunity and the molecular and cellular pathways involved in its pathogenesis has reached an unprecedented level. Yet this knowledge has not served to prevent autoimmune disease nor to curtail the dramatic rise in its incidence over the same interval. Population-level genetic changes cannot explain this trend; thus, environmental factors are strongly implicated. Among the possible environmental contributors to autoimmune disease, air pollution exposure has received very little attention. Although there is only a small amount of published data directly examining a possible causal relationship between air pollution exposure and autoimmunity, data from related fields suggests that it could facilitate autoimmunity as well. If correct, this hypothesis could prove to have sizeable public health implications. Ó 2009 Elsevier Ltd. All rights reserved.

Introduction The adverse health effects of exposure to air pollution have been recognized for decades, beginning especially with the occurrence of the famous ‘‘London Fogs” of the 1950s; during the most severe incident, the smog resulted in a mortality rate 3 times greater than normal [1]. Although regulation of emissions has led to improvements in air quality, epidemiological data indicates clearly that air pollution continues to have widespread effects on human health. Literally dozens of studies have demonstrated that poor air quality is associated with increased morbidity and mortality due to numerous causes; air pollution is thought to be responsible for approximately 3 million deaths per year worldwide [2]. Of course, death represents only a fraction of the likely impact. While it is obvious how air pollution could affect the lungs, its potential for effects on other body systems is not immediately evident, and for many years the epidemiological associations between poor air quality and non-respiratory health effects were puzzling. Seaton et al. are widely credited with introducing the hypothesis that the systemic effects of air pollution exposure are mediated through the induction of pulmonary oxidative stress and inflammation, the mediators from which can spill over into the circulation and influence distant events [3]. This framework has inspired much research over the past 15 years, and shed light on the mechanistic pathways linking air pollution exposure with diverse effects throughout the body, particularly with respect to cardiovascular morbidity and mortality. * Tel.: +1 705 662 7253; fax: +1 705 675 4858. E-mail address: [email protected] 0306-9877/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2009.07.033

With respect to the immune system, air pollution has attracted significant research attention as a factor that could influence allergic disease, but virtually none has been directed to its potential role in autoimmune disease. Allergic and autoimmune diseases have both been described as ‘epidemics’ in the literature, with dramatic increases in incidence observed over the span of several decades [4]. Genetic factors influence susceptibility to these diseases significantly. However, population-level genetic changes cannot explain the steep rises in incidence that have been observed epidemiologically over the span of only a few generations; thus, environmental factors are strongly implicated. Autoimmune diseases are an eclectic group of disorders that can target a wide variety of tissues and organs, with the common thread being that the immune system is inappropriately activated to produce destructive responses against self antigens. Relatively common autoimmune diseases include pernicious anaemia, coeliac disease, Crohn’s disease, type 1 diabetes, Graves’ disease, Hashimoto’s thyroiditis, idiopathic thrombocytopenia purpura, systemic lupus erythematosus, multiple sclerosis, and rheumatoid arthritis; many more autoimmune diseases are recognized but are relatively rare. In addition, a number of common disorders causing significant morbidity and mortality are suspected to be related to autoimmunity, including such diverse conditions as chronic obstructive pulmonary disease [5–7], endometriosis [8–10], and schizophrenia [11–13]. To date, there have been astonishingly few population-based or experimental investigations of the possible influence of air pollution on autoimmune diseases. The small amount of existing data on air pollution and autoimmunity (along with extrapolations from relevant studies in other areas) are suggestive, and lead to the

S.A. Ritz / Medical Hypotheses 74 (2010) 110–117

speculation that air pollution could be one environmental factor that is contributing to the ‘epidemic’ of autoimmunity. The hypothesis Studies have repeatedly demonstrated that air pollution can affect lung development and promote respiratory morbidity and mortality [14,15]. Emerging more recently is evidence that exposure to relatively low levels of air pollution might contribute to the development of other diseases, including those without an obvious connection to the respiratory tract. Experimental and epidemiological studies have demonstrated associations of air pollution exposure with a wide variety of negative health effects, including myocardial infarction and other cardiovascular events [16–21], atherosclerosis [22–24], altered haemostasis [25–28], adverse birth outcomes [29–32], otitis media [33], neuroinflammation and accumulation of proteins associated with neurodegenerative disease (such as Abeta42 and alpha-synuclein) [34], and even suicide [35]. With respect to immunological disorders, current thinking recognizes a likely role for air pollution in the development of allergy [36–39], but the possibility that it might be involved in other kinds of hypersensitivity disorders has been almost completely overlooked. Although there are clear genetic predispositions to many autoimmune disorders, and gender is known to be a significant influence, environmental factors undoubtedly play a critical role in determining whether that genetic potential is manifested. The vast majority of study in this area has concentrated on nutritional factors, smoking, and infection. We hypothesize that air pollution exposure could contribute to the development of autoimmunity by enhancing antigen presentation and by augmenting autoimmune responses. The respiratory tract is the largest body surface exposed to the external environment, and inflammatory responses in the lungs are highly prevalent. Soluble mediators generated during immune–inflammatory processes in the respiratory tract are known to have systemic sequelae, as detailed below. These kinds systemic effects can influence nascent and ongoing immune responses, as has been well-established for allergic disorders; there is no a priori reason to expect that these events would have any lesser effect on the development of autoimmune responses. Thus, we speculate that inhalation of air pollution could be a significant pathway through which susceptibility to autoimmune disorders could be modified. Prospective mechanisms linking air pollution exposure and autoimmunity Air pollution is a heterogeneous mixture, including gaseous, liquid, and solid components, each of which has unique potential for effects on biological systems. In general terms, the adverse effects of air pollution are thought to be due primarily to the induction of the NF-jB and MAP kinase pathways in response to oxidative stress [40–46]. Volatile chemicals and reactive metals can directly generate free radicals; in the case of particulate air pollution, oxidative stress can be produced even by relatively inert particles because they provide a reaction surface upon which redox cycling can take place [43]. There is also evidence that air pollution can stimulate neurogenic inflammation [47–49]. These effects do not remain localized to the respiratory microenvironment, but have systemic sequelae as well, including evidence of systemic oxidative stress [22,28,50], bone marrow stimulation [51–53], and increased leucocyte numbers and cytokine levels in the blood [25,53,54]. Of special relevance here is the observation that oxidative stress and air pollution exposure

111

have been shown to cause maturation of antigen-presenting cells [55–61], equipping them with the costimulatory molecules required for the activation of T lymphocytes. Experimental studies have clearly demonstrated that air pollutants (especially airborne particulates) can act as adjuvants, stimulating the development of active immune responses against otherwise innocuous antigens. Injection of particles significantly enhances the production of cytokines and antigen-specific immunoglobulins in a variety of mouse models [62–64]. Based on these data, we speculate that air pollution could influence autoimmunity by facilitating presentation of self-antigens in a context that would cause activation of self-reactive lymphocytes (Fig. 1). Air pollution exposure creates oxidative stress in the airways, causing airway epithelial cells and alveolar macrophages to express pro-inflammatory cytokines that trigger the maturation of airway-resident dendritic cells, which in turn migrate to the local lymph nodes. In an individual in whom self-reactive lymphocytes had escaped the mechanisms of central tolerance in the bone marrow and thymus, these activated dendritic cells present self-antigens in the context of costimulatory molecules, activating the lymphocytes instead of tolerizing them, and triggering the development of a full-blown autoimmune response. Once such an autoimmune response is established (even in cases where air pollution exposure was not a factor in the initiation steps), the pro-inflammatory cytokines generated upon air pollution exposure will act to consolidate and exacerbate the ongoing response. Although the mechanisms involved in this chain of events have all been demonstrated in principle, whether or not they operate in the context of autoimmunity has not been definitively established. Studies that directly examine the relationship between air pollution and autoimmunity are sparse, but there are many others that indirectly support this hypothesis.

Direct investigations of air pollution and autoimmunity Air pollution has been considered in only a handful of studies as a factor that could induce or exacerbate autoimmunity. The most compelling of the epidemiologic investigations are two retrospective case-control studies of the relationship between air pollution exposure and the development of type 1 diabetes (T1D) published by Hathout et al.; in both instances, the authors found significant associations between ambient air pollution levels and the risk of T1D [65,67]. The first study demonstrated that children with T1D had significantly higher exposure to ozone or particulate air pollution prior to diagnosis compared to healthy controls, with odds ratios of 4.22 [1.96–9.10] and 2.37 [1.11–5.03] respectively [65]. Exposure to particulate air pollution was specifically associated with the development of T1D before 5 years of age (OR = 3.32 [1.10–10.08]) [65]; this is notable because epidemiological studies of the incidence of T1D among children has indicated that such early onset is increasing especially rapidly [68–75]. The second study showed that cumulative exposure to ozone and sulfate was significantly associated with the development of T1D, with odds ratios of 2.89 [1.80–4.62] and 1.65 [1.20–2.28], respectively [67]. Children with diabetes were also significantly more likely to have been exposed to second-hand smoke than healthy controls [67]. Dahlgren et al. conducted a community comparison study examining the prevalence of rheumatic disease and systemic lupus erythematosus in individuals living in a subdivision exposed to high levels of airborne petroleum products and mercury, compared to those living in another community with no such known exposures [76]. They observed a significantly increased risk of rheumatic disease (OR = 10.87, [4.14–28.12]) and lupus (OR = 19.33, [1.96–190.72]). There was also evidence of immunological aberration among exposed individuals without overt disease. Of course,

112

S.A. Ritz / Medical Hypotheses 74 (2010) 110–117

Fig. 1. The putative mechanisms through which air pollution exposure could influence autoimmune diseases are illustrated. Inhalation of gaseous and particulate air pollution brings these substances in contact with the airway epithelium and alveolar macrophages. Oxidative stress caused by the pollutants elicits the production of proinflammatory cytokines. These cytokines can have local effects, including the stimulation of resting dendritic cells. Cytokines generated in the airways by exposure to air pollution can also spill over into the systemic circulation and have effects on distant tissues, thereby consolidating nascent or ongoing autoimmune responses.

the methodological limitations in exposure assessment and the potential confounding by other environmental contaminants are significant shortcomings of the study, but the magnitude of the increased risk for autoimmune diseases suggests that further investigation is warranted. Poor air quality has also been associated with exacerbations of existing autoimmune disease. Oikonen et al. demonstrated a four fold increase in the risk of multiple sclerosis relapse during periods when the concentration of coarse particulate air pollution was in the highest quartile [77]. They speculated that increased exposure to particulate air pollution enhanced susceptibility to transmissible infections, thereby triggering the exacerbation. Other mechanisms (including the pro-inflammatory effects of the pollution itself) could potentially explain this relationship. Examination of the literature on cigarette smoking and autoimmunity also provides a form of evidence that inhalation of toxic particulates and gases and influence the development of these diseases. Although there is not complete consistency, the balance of evidence from both epidemiological and experimental studies sup-

port the notion that smokers, those exposed to second-hand smoke, and those exposed to smoking in utero tend to have a higher risk of developing autoimmune diseases (including multiple sclerosis, rheumatoid arthritis, type 1 diabetes, and systemic lupus erythematosus) [78–89], although some forms of autoimmune thyroid disease appear to be decreased with smoke exposure [89–91]. Of course, cigarette smoking is an imperfect proxy for exposure to ambient air pollution, since the doses involved are vastly different, as are the temporal patterns of exposure over the lifespan. Even given these limitations, the data from these studies are informative because they illustrate the principle that inhalation of toxic gases and particulates can indeed influence autoimmune responses. Experimentally, there are few published papers investigating the effect of air pollution exposure on autoimmunity. In two papers examining the effect of diesel exhaust particles (DEPs) on rheumatoid arthritis, the authors used DEPs or their extracts, administered intranasally over the course of 20 days, in a mouse model of collagen-induced arthritis [92,93]. They showed that exposure to DEPs (or chemicals contained in them) during the development of

S.A. Ritz / Medical Hypotheses 74 (2010) 110–117

arthritis enhanced both incidence and severity [92,93]. In another paper, investigators injected n-hexadecane (a chemical contained in oil mist, jet fuel, or diesel exhaust) intraperitoneally in normal Balb/c mice, and observed a pattern of autoantibody production similar to systemic lupus erythematosus 3 months later [94]. The relevance for real-life exposures to air pollutants is unclear given the doses and routes of administration used by these investigators. However, they clearly serve as a ‘proof-of-principle’ that these materials can influence the development of autoimmune disorders, at least under experimental conditions. Our laboratory has conducted pilot studies examining the effect of chronic respiratory exposure to ambient urban particulate matter (Ottawa dust, EHC-93) [95] in the non-obese diabetic (NOD) mouse model of type 1 diabetes. Beginning at 4 weeks of age, NOD mice were exposed 2x-weekly to an aerosolized suspension of EHC-93 particles, and the development of frank diabetes monitored. The preliminary data suggest that although exposure to EHC-93s did not affect the cumulative incidence of autoimmune diabetes after 5 months, it appeared to accelerate the onset of disease (median time-to-onset of 84 days in EHC-93-exposed mice, vs. 105 days in saline-exposed mice). EHC-93-exposed mice were also more likely to have high titres of anti-insulin autoantibodies (unpublished data). Although the pilot study was not powered to detect statistically significant differences, the fact that our observations are fully consistent with the observations of Hathout et al. [65] is suggestive. Although these studies indicate a possible relationship between air pollution exposure and autoimmune disease, a great deal more investigation is required to substantiate these findings. Until such studies are conducted, we must look elsewhere for indirect evidence of the ability of air pollution to affect such responses.

Population-based studies of air pollution and immune– inflammatory responses Although the literature on air pollution an autoimmunity per se is sparse, there is little question that air pollution exposure has immunological effects, with the specific nature of those effects varying depending on pollutant, dose, chronicity of exposure, age, and other factors. Population-based studies have clearly indicated that air pollution exposure affects the immune system. In a cross-sectional study of 17 European cities, exposure to particulate air pollution was associated with increased numbers of lymphocytes and total IgG [96]. Compared to children living in a less polluted environment, those living in Mexico City had significantly reduced interferon-c (IFN-c), granulocyte-macrophage colony-stimulating factor (GM-CSF), and natural killer cells, but increased levels of monocytes, CD8 + T cells, and systemic inflammation [97]. Other population-based studies have also demonstrated alterations in numerous immunological markers related to air pollution exposure [98,99]. In addition to measureable effects on immune cells and mediators, significant epidemiological associations between air pollution exposure and the development of overt immune–inflammatory disorders have been demonstrated, including allergy [100–104], asthma [105–112], and atherosclerosis [24]. However, not all studies have found robust associations [113,114]. The discordance in the literature is most likely due to some very difficult practical impediments to epidemiological investigation of the influence of air pollution on disease, all of which are likely to result in exposure misclassification bias and thereby underestimate the effect size. There has been significant progress in the development of more sophisticated approaches to exposure assessment, and studies utilizing more nuanced modeling strategies have tended to find more

113

robust associations [109,115]. Although the current literature in population-based studies of air pollution and immunological disorders is somewhat conflicting, the experimental literature is much more consistent.

Experimental evidence that air pollution exposure influences immune responses Although some of the studies cited previously have used contrived models of immune responses with questionable physiological relevance, there are a large number of experimental studies using a variety of disease models that more directly demonstrate the clinical relevance of these effects. Probably the largest and most persuasive literature in this regard has looked at the influence of air pollution on allergy. Experimental investigations have consistently demonstrated that air pollution can both exacerbate existing allergic disease [116–119], and also cause allergic sensitization, at least under experimental conditions. Whitekus et al. reported that daily exposure to aerosolized DEPs along with the innocuous protein ovalbumin resulted in the production of ovalbumin-specific antibodies of the IgE and IgG1 classes, which are molecular hallmarks of allergy in mice [120]. Inhalation of ambient urban particulate pollution has been shown to elicit specific antibody responses and airway inflammation characteristic of allergy in mouse models [121–123]; other groups have shown similar results using other types of particulates [124–129]. Gaseous air pollutants such as ozone and SO2 can also potentiate allergic responses in experimental settings [130–133]. Thus it is clear that air pollution exposure can cause allergy, at least under experimental conditions. It has been questioned whether findings from these animal models can be extrapolated to humans, and whether the pollutant doses used are relevant to human exposures. Notably, Diaz-Sanchez et al. have demonstrated that particulate air pollution can cause allergic sensitization in human subjects: exposure to the model antigen keyhole limpet haemocyanin (KLH) in the context of intranasal administration of DEPs elicited KLH-specific IgE production, whereas KLH exposure without DEPs did not [134]. The dose of DEPs used in this study were roughly equivalent to approximately 40 h of normal breathing in a city like Los Angeles, or to the acute exposure that might be experience by a person standing in proximity to the exhaust of a diesel engine for 30 s, and so are well within the bounds of what might be expected under everyday conditions [134]. These findings decisively demonstrate the ability of particulate air pollution to cause allergic sensitization in human beings. The link between air pollution exposure and the development of allergic disease has been treated more intensively than that with autoimmunity or other immunological disorders, probably in part because air pollution is broadly characterized as primarily promoting a profile of cytokine production (Th2) that favours the development of allergic responses. However, this seems to be an overgeneralization, as many of the mediators generated by exposure to air pollution are broadly pro-inflammatory, and some are also associated with non-allergic (Th1) types of immune responses [53,54,135]. For example, experimental data looking at air pollution and atherosclerosis (a disorder driven by inflammation) indicates that exposure to particulate matter enhances plaque formation in experimental animal models [22,136], consistent with the epidemiological findings [24]. Air pollution exposure also appears to alter pulmonary immunity in complex ways that undermine host defense. For example, exposure to ozone increases levels of pro-inflammatory cytokines, but reduced leucocyte infiltration into the airways [137]. Exposure to particulates has been shown to diminish the ability to clear bacteria in a mouse model

114

S.A. Ritz / Medical Hypotheses 74 (2010) 110–117

of infection [138]. Given that air pollution has been shown to have diverse effects on many immune–inflammatory indices and disorders, one would expect it to influence autoimmune disease as well.

Importance and implications Admittedly, it is unlikely that air pollution is the most important factor in the development of autoimmune disease, but it is a plausible contributor. Genetic susceptibility plays a significant role, accounting for about one third of the risk of developing autoimmune disease, with the remainder attributed to environmental influences [139]. Other environmental and lifestyle factors that have been implicated include chemical and metal exposure, nutritional deficiencies, some drugs, ultraviolet radiation, infectious agents, dietary composition, consumption of antioxidants, and smoking, among others [139]. Air pollution exposure has been under-investigated in this context, but the available data is suggestive; moreover, the body of literature showing that air pollution can influence the immune system and trigger other hypersensitivity disorders (such as allergy) indicates that this question deserves further attention. A great deal of research will be required to address this hypothesis. Further work in experimental animal models of autoimmune disease would establish in principle whether a role for air pollution exposure in the development of autoimmune disease is consistently demonstrable, and delineate the mechanisms through which this occurs. These experiments would be most useful if the models used approximated real-world exposures in humans (via the respiratory tract), using realistic doses. Epidemiological research that examines incident autoimmune disease is crucial to resolve the issue in human populations; such studies are fraught with complexity. First, because air pollution is not a homogeneous entity, it is not immediately evident which constituents are the most relevant to assess. Moreover, the interactions upon co-exposure to multiple pollutants are largely uncharacterized, and could hypothetically be additive, synergistic, or counter-regulatory. Second, it is difficult to account for temporal and spatial variability in air pollution exposures. Most epidemiological investigations involving air pollution base their estimates on outdoor pollutant levels at the subjects’ home address (which may be as simple as assigning levels measured at central monitoring sites, or more sophisticated models that interpolate between these sites, or account for land use and other factors). However, most people spend only a fraction of their day at home (and much of that indoors), so this method of estimating exposure does not account for exposures that occur in transit, and in schools or workplaces. Although some studies have used personal monitors worn on the body to measure actual exposures in real-time, this is an extremely expensive and resource-intensive enterprise that makes it impractical for large prospective studies. Finally, the time period during which such exposures may have been relevant is difficult to ascertain. Cumulative exposure is not necessarily the correct metric; a crucial period of exposure could theoretically be at any point prior to the onset of disease, including even the pre-natal period [140–144]. Indeed, there are particular developmental periods of increased susceptibility to air pollution; children are especially vulnerable, due to their higher baseline ventilation rates, the increased time spent in physical activity outdoors compared to adults, and the relative developmental immaturity of the lungs and immune system [31,145–148]. Prospective studies that address these issues would be ideal, but retrospective, case-control, and community comparison studies would be helpful in beginning to fill the enormous gap in the literature. Research (both experimental and epidemiological) looking at gene-environment interactions could be very informative in this

context, given that there are distinct heritable susceptibilities to both autoimmunity and air pollution. Genetic loci with confirmed associations to human autoimmune disorders include proteins involved in immunoregulation at multiple levels: intracellular signaling, pattern-recognition, transcription factors, cytokines, costimulation, and the major histocompatibility complex [149]. Susceptibility to the adverse effects of air pollution also has a genetic component [150]. Individuals with null polymorphisms in enzymes that respond to oxidative stress (including NQO1, GSTM1, and GSTP1) have been shown to have more severe respiratory effects when exposed to air pollution [102,151–154]. Polymorphisms in some immune–inflammatory genes (TNF and TLR4) have also been associated with enhanced responses to air pollutants [150]. Thus, if air pollution exposure was able to influence the development of autoimmunity, one would expect that there would be an additive or even synergistic effect of these genetic susceptibilities. This possibility is supported by a study showing that NQO1 and NQO2 knock-out mice demonstrated an enhanced predisposition to collagen-induced arthritis [155]. It remains to establish definitively whether there is a causal connection between air pollution exposure and autoimmune disease, determine the magnitude of the problem, and ultimately take action to intervene. If air pollution can promote autoimmune disease, further research into the molecular and cellular pathways involved will continue to be important, but this should be complemented by social and political efforts to reduce exposure. Implementation of personal-level environmental controls would be unlikely to be feasible or cost-effective, and development of pharmacological interventions would be impractical. However, changes in public policy relating to air pollution would likely prove to be a more viable approach, as the public health implications of the hypothesis are potentially sizeable. There is a lack of rigorous quantitative estimates for morbidity, mortality, and economic impact of autoimmune diseases as a category. The best available estimates from the National Institutes of Health in the United States are that autoimmune diseases collectively affect 5–8% of the American population [139]; moreover, the incidence of many autoimmune diseases is increasing and the reasons for this increase are unknown. The cost of treating autoimmune diseases is also substantial: the Director of the Canadian Institute of Infection and Immunity estimates that Canada spends ‘‘about 20% of [the Canadian] healthcare budget on the treatment of autoimmune diseases and their complications” [156]. In Canada alone (a country with a population of 33 million people), that amounts to approximately $25 billion annually [156]. Autoimmune disorders also cause significant mortality: in 2000, Walsh and Rau reported that ‘‘autoimmune diseases constitute a leading cause of death among young and middle-aged women”, ranking among the top ten causes of death for this population [157]. Based on this information, autoimmune disorders likely affect tens of millions of individuals worldwide, with economic costs in the hundreds of billions of dollars. Thus, if air pollution has even a minor influence on the development of these diseases, the impact at the population level would be considerable. Conflicts of interest statement The author declares that there are no conflicts of interest. Acknowledgements My research is currently funded by grants from the Canadian Institutes of Health Research and the National Science and Engineering Research Council (Canada); I have previously held funds from the Ontario Thoracic Society and the Banting Research

S.A. Ritz / Medical Hypotheses 74 (2010) 110–117

Foundation. These funders had no involvement in the writing or decision to submit this manuscript for publication. I would also like to acknowledge Catherine Brummer for her work on the pilot studies referred to in this article. References [1] Bell ML, Davis DL. Reassessment of the lethal London fog of 1952: novel indicators of acute and chronic consequences of acute exposure to air pollution. Environ Health Perspect 2001;109(Suppl. 3):389–94. [2] World Health Organization (WHO), Reducing risks, promoting healthy life; 2002. [3] Seaton A, MacNee W, Donaldson K, Godden D. Particulate air pollution and acute health effects. Lancet 1995;345(8943):176–8. [4] Bach JF. The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 2002;347(12):911–20. [5] Curtis JL, Freeman CM, Hogg JC. The immunopathogenesis of chronic obstructive pulmonary disease: insights from recent research. Proc Am Thorac Soc 2007;4(7):512–21. [6] Taraseviciene-Stewart L, Douglas IS, Nana-Sinkam PS, et al. Is alveolar destruction and emphysema in chronic obstructive pulmonary disease an immune disease? Proc Am Thorac Soc 2006;3(8):687–90. [7] Voelkel N, Taraseviciene-Stewart L. Emphysema: an autoimmune vascular disease? Proc Am Thorac Soc 2005;2(1):23–5. [8] Matarese G, De Placido G, Nikas Y, Alviggi C. Pathogenesis of endometriosis: natural immunity dysfunction or autoimmune disease? Trends Mol Med 2003;9(5):223–8. [9] Yeaman GR, Collins JE, Lang GA. Autoantibody responses to carbohydrate epitopes in endometriosis. Ann NY Acad Sci 2002;955:174–82 [Discussion 199–200, 396–406]. [10] Nothnick WB. Treating endometriosis as an autoimmune disease. Fertil Steril 2001;76(2):223–31. [11] Ortega-Hernandez OD, Kivity S, Shoenfeld Y. Olfaction, psychiatric disorders and autoimmunity: is there a common genetic association? Autoimmunity 2009;42(1):80–8. [12] Strous RD, Shoenfeld Y. Schizophrenia, autoimmunity and immune system dysregulation: a comprehensive model updated and revisited. J Autoimmun 2006;27(2):71–80. [13] Jones AL, Mowry BJ, Pender MP, Greer JM. Immune dysregulation and selfreactivity in schizophrenia: do some cases of schizophrenia have an autoimmune basis? Immunol Cell Biol 2005;83(1):9–17. [14] Gehring U, Cyrys J, Sedlmeir G, et al. Traffic-related air pollution and respiratory health during the first 2 yrs of life. Eur Respir J 2002;19(4):690–8. [15] Joad JP, Sekizawa S, Chen CY, Bonham AC. Air pollutants and cough. Pulm Pharmacol Ther 2007;20(4):347–54. [16] Sullivan J, Sheppard L, Schreuder A, Ishikawa N, Siscovick D, Kaufman J. Relation between short-term fine-particulate matter exposure and onset of myocardial infarction. Epidemiology 2005;16(1):41–8. [17] D’Ippoliti D, Forastiere F, Ancona C, et al. Air pollution and myocardial infarction in Rome: a case-crossover analysis. Epidemiology 2003;14(5):528–35. [18] Engstrom G, Stavenow L, Hedblad B, et al. Inflammation-sensitive plasma proteins, diabetes, and mortality and incidence of myocardial infarction and stroke: a population-based study. Diabetes 2003;52(2):442–7. [19] Fung KY, Luginaah I, Gorey KM, Webster G. Air pollution and daily hospital admissions for cardiovascular diseases in Windsor, Ontario. Can J Public Health 2005;96(1):29–33. [20] Pope 3rd CA, Burnett RT, Thurston GD, et al. Cardiovascular mortality and long-term exposure to particulate air pollution: epidemiological evidence of general pathophysiological pathways of disease. Circulation 2004;109(1):71–7. [21] Goldberg MS, Burnett RT, Yale JF, Valois MF, Brook JR. Associations between ambient air pollution and daily mortality among persons with diabetes and cardiovascular disease. Environ Res 2005. [22] Araujo JA, Barajas B, Kleinman M, et al. Ambient particulate pollutants in the ultrafine range promote early atherosclerosis and systemic oxidative stress. Circ Res 2008;102(5):589–96. [23] Yamawaki H, Iwai N. Mechanisms underlying nano-sized air-pollutionmediated progression of atherosclerosis: carbon black causes cytotoxic injury/inflammation and inhibits cell growth in vascular endothelial cells. Circ J 2006;70(1):129–40. [24] Kunzli N, Jerrett M, Mack WJ, et al. Ambient air pollution and atherosclerosis in Los Angeles. Environ Health Perspect 2005;113(2):201–6. [25] Liao D, Heiss G, Chinchilli VM, et al. Association of criteria pollutants with plasma hemostatic/inflammatory markers: a population-based study. J Expo Anal Environ Epidemiol 2005;15(4):319–28. [26] Nemmar A, Hoylaerts MF, Nemery B. Effects of particulate air pollution on hemostasis. Clin Occup Environ Med 2006;5(4):865–81. [27] Nemmar A, Hoylaerts MF, Hoet PH, et al. Ultrafine particles affect experimental thrombosis in an in vivo hamster model. Am J Respir Crit Care Med 2002;166(7):998–1004. [28] Barregard L, Sallsten G, Gustafson P, et al. Experimental exposure to woodsmoke particles in healthy humans: effects on markers of inflammation, coagulation, and lipid peroxidation. Inhal Toxicol 2006;18(11):845–53.

115

[29] Wang L, Pinkerton KE. Air pollutant effects on fetal and early postnatal development. Birth Defects Res C Embryo Today 2007;81(3):144–54. [30] Slama R, Morgenstern V, Cyrys J, et al. Traffic-related atmospheric pollutants levels during pregnancy and offspring’s term birth weight: a study relying on a land-use regression exposure model. Environ Health Perspect 2007;115(9):1283–92. [31] Heinrich J, Slama R. Fine particles, a major threat to children. Int J Hyg Environ Health 2007;210(5):617–22. [32] Wang L, Joad JP, Abel K, et al. Effects of environmental tobacco smoke on the developing immune system of infant monkeys. J Allergy Clin Immunol 2007;120(2):445–51. [33] Brauer M, Gehring U, Brunekreef B, et al. Traffic-related air pollution and otitis media. Environ Health Perspect 2006;114(9):1414–8. [34] Calderon-Garciduenas L, Solt AC, Henriquez-Roldan C, et al. Long-term air pollution exposure is associated with neuroinflammation, an altered innate immune response, disruption of the blood–brain barrier, ultrafine particulate deposition, and accumulation of amyloid beta-42 and alpha-synuclein in children and young adults. Toxicol Pathol 2008;36(2):289–310. [35] Biermann T, Stilianakis N, Bleich S, Thurauf N, Kornhuber J, Reulbach U. The hypothesis of an impact of ozone on the occurrence of completed and attempted suicides. Med Hypotheses 2009;72(3):338–41. [36] Heinrich J, Wichmann HE. Traffic related pollutants in Europe and their effect on allergic disease. Curr Opin Allergy Clin Immunol 2004;4(5):341–8. [37] Wills-Karp M, Santeliz J, Karp CL. The germless theory of allergic disease: revisiting the hygiene hypothesis. Nat Rev Immunol 2001;1(1):69–75. [38] Gershwin LJ. Effects of air pollutants on development of allergic immune responses in the respiratory tract. Clin Dev Immunol 2003;10(2–4): 119–26. [39] Wong GW, Lai CK. Outdoor air pollution and asthma. Curr Opin Pulm Med 2004;10(1):62–6. [40] Williams MA, Rangasamy T, Bauer SM, et al. Disruption of the transcription factor Nrf2 promotes pro-oxidative dendritic cells that stimulate Th2-like immunoresponsiveness upon activation by ambient particulate matter. J Immunol 2008;181(7):4545–59. [41] Pourazar J, Mudway IS, Samet JM, et al. Diesel exhaust activates redoxsensitive transcription factors and kinases in human airways. Am J Physiol Lung Cell Mol Physiol 2005;289(5):L724–30. [42] Matos TJ, Duarte CB, Goncalo M, Lopes MC. Role of oxidative stress in ERK and p38 MAPK activation induced by the chemical sensitizer DNFB in a fetal skin dendritic cell line. Immunol Cell Biol 2005;83(6):607–14. [43] Nel AE, Diaz-Sanchez D, Li N. The role of particulate pollutants in pulmonary inflammation and asthma: evidence for the involvement of organic chemicals and oxidative stress. Curr Opin Pulm Med 2001;7(1):20–6. [44] Reibman J, Hsu Y, Chen LC, et al. Size fractions of ambient particulate matter induce granulocyte macrophage colony-stimulating factor in human bronchial epithelial cells by mitogen-activated protein kinase pathways. Am J Respir Cell Mol Biol 2002;27(4):455–62. [45] Hashimoto S, Gon Y, Takeshita I, et al. Diesel exhaust particles activate p38 MAP kinase to produce interleukin 8 and RANTES by human bronchial epithelial cells and N-acetylcysteine attenuates p38 MAP kinase activation. Am J Respir Crit Care Med 2000;161(1):280–5. [46] Baeza-Squiban A, Bonvallot V, Boland S, Marano F. Airborne particles evoke an inflammatory response in human airway epithelium. Activation of transcription factors. Cell Biol Toxicol 1999;15(6):375–80. [47] Verones B, Oortgiesen M. Neurogenic inflammation and particulate matter (PM) air pollutants. Neurotoxicology 2001;22(6):795–810. [48] Campese VM, Ye S, Zhong H, Yanamadala V, Ye Z, Chiu J. Reactive oxygen species stimulate central and peripheral sympathetic nervous system activity. Am J Physiol Heart Circ Physiol 2004;287(2):H695–703. [49] Tin-Tin-Win-Shwe, Yamamoto S, Nakajima D, et al. Modulation of neurological related allergic reaction in mice exposed to low-level toluene. Toxicol Appl Pharmacol 2007;222(1):17–24. [50] Folkmann JK, Risom L, Hansen CS, Loft S, Moller P. Oxidatively damaged DNA and inflammation in the liver of dyslipidemic ApoE / mice exposed to diesel exhaust particles. Toxicology 2007;237(1–3):134–44. [51] Goto Y, Ishii H, Hogg JC, et al. Particulate matter air pollution stimulates monocyte release from the bone marrow. Am J Respir Crit Care Med 2004;170(8):891–7. [52] Fujii T, Hayashi S, Hogg JC, et al. Interaction of alveolar macrophages and airway epithelial cells following exposure to particulate matter produces mediators that stimulate the bone marrow. Am J Respir Cell Mol Biol 2002;27(1):34–41. [53] van Eeden SF, Hogg JC. Systemic inflammatory response induced by particulate matter air pollution: the importance of bone-marrow stimulation. J Toxicol Environ Health A 2002;65(20):1597–613. [54] van Eeden SF, Tan WC, Suwa T, et al. Cytokines involved in the systemic inflammatory response induced by exposure to particulate matter air pollutants (PM(10)). Am J Respir Crit Care Med 2001;164(5):826–30. [55] Verstraelen S, Van Den Heuvel R, Nelissen I, Witters H, Verheyen G, Schoeters G. Flow cytometric characterisation of antigen presenting dendritic cells after in vitro exposure to diesel exhaust particles. Toxicol In Vitro 2005;19(7):903–7. [56] Becker S, Soukup J. Coarse(PM(2.5-10)), fine(PM(2.5)), and ultrafine air pollution particles induce/increase immune costimulatory receptors on human blood-derived monocytes but not on alveolar macrophages. J Toxicol Environ Health A 2003;66(9):847–59.

116

S.A. Ritz / Medical Hypotheses 74 (2010) 110–117

[57] Bleck B, Tse DB, Jaspers I, Curotto de Lafaille MA, Reibman J. Diesel exhaust particle-exposed human bronchial epithelial cells induce dendritic cell maturation. J Immunol 2006;176(12):7431–7. [58] Hamilton Jr RF, Holian A, Morandi MT. A comparison of asbestos and urban particulate matter in the in vitro modification of human alveolar macrophage antigen-presenting cell function. Exp Lung Res 2004;30(2):147–62. [59] Kantengwa S, Jornot L, Devenoges C, Nicod LP. Superoxide anions induce the maturation of human dendritic cells. Am J Respir Crit Care Med 2003;167(3): 431–7. [60] Alderman CJ, Shah S, Foreman JC, Chain BM, Katz DR. The role of advanced oxidation protein products in regulation of dendritic cell function. Free Radic Biol Med 2002;32(5):377–85. [61] Rutault K, Alderman C, Chain BM, Katz DR. Reactive oxygen species activate human peripheral blood dendritic cells. Free Radic Biol Med 1999;26(1– 2):232–8. [62] Granum B, Gaarder PI, Groeng E, Leikvold R, Namork E, Lovik M. Fine particles of widely different composition have an adjuvant effect on the production of allergen-specific antibodies. Toxicol Lett 2001;118(3):171–81. [63] Takano H, Yoshikawa T, Ichinose T, Miyabara Y, Imaoka K, Sagai M. Diesel exhaust particles enhance antigen-induced airway inflammation and local cytokine expression in mice. Am J Respir Crit Care Med 1997;156(1):36–42. [64] van Zijverden M, van der Pijl A, Bol M, et al. Diesel exhaust, carbon black, and silica particles display distinct Th1/Th2 modulating activity. Toxicol Appl Pharmacol 2000;168(2):131–9. [65] Hathout EH, Beeson WL, Nahab F, Rabadi A, Thomas W, Mace JW. Role of exposure to air pollutants in the development of type 1 diabetes before and after 5 yr of age. Pediatr Diabetes 2002;3(4):184–8. [67] Hathout EH, Beeson WL, Ischander M, Rao R, Mace JW. Air pollution and type 1 diabetes in children. Pediatr Diabetes 2006;7(2):81–7. [68] Harjutsalo V, Sjoberg L, Tuomilehto J. Time trends in the incidence of type 1 diabetes in Finnish children: a cohort study. Lancet 2008;371(9626):1777–82. [69] Green A, Patterson CC, EURODIAB TIGER study group. Europe and Diabetes. Trends in the incidence of childhood-onset diabetes in Europe 1989–1998. Diabetologia 2001;44(Suppl. 3):B3–8. [70] Cinek O, Lanska V, Kolouskova S, et al. Type 1 diabetes mellitus in Czech children diagnosed in 1990–1997: a significant increase in incidence and male predominance in the age group 0–4 years. Collaborators of the Czech Childhood Diabetes Registry. Diabet Med 2000;17(1):64–9. [71] Zhao HX, Stenhouse E, Soper C, et al. Incidence of childhood-onset type 1 diabetes mellitus in Devon and Cornwall, England, 1975–1996. Diabet Med 1999;16(12):1030–5. [72] Charkaluk ML, Czernichow P, Levy-Marchal C. Incidence data of childhoodonset type I diabetes in France during 1988–1997: the case for a shift toward younger age at onset. Pediatr Res 2002;52(6):859–62. [73] Pundziute-Lycka A, Dahlquist G, Nystrom L, et al. The incidence of Type I diabetes has not increased but shifted to a younger age at diagnosis in the 0– 34 years group in Sweden 1983–1998. Diabetologia 2002;45(6):783–91. [74] Weets I, De Leeuw IH, Du Caju MV, et al. The incidence of type 1 diabetes in the age group 0–39 years has not increased in Antwerp (Belgium) between 1989 and 2000: evidence for earlier disease manifestation. Diabetes Care 2002;25(5):840–6. [75] Schoenle EJ, Lang-Muritano M, Gschwend S, et al. Epidemiology of type I diabetes mellitus in Switzerland: steep rise in incidence in under 5 year old children in the past decade. Diabetologia 2001;44(3):286–9. [76] Dahlgren J, Takhar H, Anderson-Mahoney P, Kotlerman J, Tarr J, Warshaw R. Cluster of systemic lupus erythematosus (SLE) associated with an oil field waste site: a cross sectional study. Environ Health 2007;6:8. [77] Oikonen M, Laaksonen M, Laippala P, et al. Ambient air quality and occurrence of multiple sclerosis relapse. Neuroepidemiology 2003;22(1): 95–9. [78] Mikaeloff Y, Caridade G, Tardieu M, Suissa S, KIDSEP study group. Parental smoking at home and the risk of childhood-onset multiple sclerosis in children. Brain 2007;130(Pt 10):2589–95. [79] Jaakkola JJ, Gissler M. Maternal smoking in pregnancy as a determinant of rheumatoid arthritis and other inflammatory polyarthropathies during the first 7 years of life. Int J Epidemiol 2005;34(3):664–71. [80] Klareskog L, Stolt P, Lundberg K, et al. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA–DR (shared epitope)restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum 2006;54(1):38–46. [81] Costenbader KH, Karlson EW. Cigarette smoking and systemic lupus erythematosus: a smoking gun? Autoimmunity 2005;38(7):541–7. [82] Rubin RL, Hermanson TM, Bedrick EJ, et al. Effect of cigarette smoke on autoimmunity in murine and human systemic lupus erythematosus. Toxicol Sci 2005;87(1):86–96. [83] Olsson AR, Skogh T, Wingren G. Aetiological factors of importance for the development of rheumatoid arthritis. Scand J Rheumatol 2004;33(5):300–6. [84] Stene LC, Barriga K, Norris JM, et al. Perinatal factors and development of islet autoimmunity in early childhood: the diabetes autoimmunity study in the young. Am J Epidemiol 2004;160(1):3–10. [85] Brix TH, Hansen PS, Kyvik KO, Hegedus L. Cigarette smoking and risk of clinically overt thyroid disease: a population-based twin case-control study. Arch Intern Med 2000;160(5):661–6. [86] Zifman E, Amital H, Gilburd B, Shoenfeld Y. Antioxidants and smoking in autoimmune disease–opposing sides of the seesaw? Autoimmun Rev 2008;8(2):165–9.

[87] Harel-Meir M, Sherer Y, Shoenfeld Y. Tobacco smoking and autoimmune rheumatic diseases. Nat Clin Pract Rheumatol 2007;3(12):707–15. [88] Galanti MR, Cnattingius S, Granath F, Ekbom-Schnell A, Ekbom A. Smoking and environmental iodine as risk factors for thyroiditis among parous women. Eur J Epidemiol 2007;22(7):467–72. [89] Krassas GE, Wiersinga W. Smoking and autoimmune thyroid disease: the plot thickens. Eur J Endocrinol 2006;154(6):777–80. [90] Belin RM, Astor BC, Powe NR, Ladenson PW. Smoke exposure is associated with a lower prevalence of serum thyroid autoantibodies and thyrotropin concentration elevation and a higher prevalence of mild thyrotropin concentration suppression in the third National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2004;89(12): 6077–86. [91] Pedersen IB, Laurberg P, Knudsen N, et al. Smoking is negatively associated with the presence of thyroglobulin autoantibody and to a lesser degree with thyroid peroxidase autoantibody in serum: a population study. Eur J Endocrinol 2008;158(3):367–73. [92] Yoshino S, Sagai M. Enhancement of collagen-induced arthritis in mice by diesel exhaust particles. J Pharmacol Exp Ther 1999;290(2):524–9. [93] Yoshino S, Hayashi H, Taneda S, Sagai M, Mori Y. Effect of diesel exhaust particle extracts on collagen-induced arthritis in mice. Autoimmunity 2002;35(1):57–61. [94] Kuroda Y, Ono N, Akaogi J, et al. Induction of lupus-related specific autoantibodies by non-specific inflammation caused by an intraperitoneal injection of n-hexadecane in BALB/c mice. Toxicology 2006;218(2– 3):186–96. [95] Vincent R, Goegan P, Johnson G, et al. Regulation of promoter-CAT stress genes in HepG2 cells by suspensions of particles from ambient air. Fundam Appl Toxicol 1997;39(1):18–32. [96] Leonardi GS, Houthuijs D, Steerenberg PA. Et al. Immune biomarkers in relation to exposure to particulate matter: a cross-sectional survey in 17 cities of Central Europe. Inhal Toxicol 2000;12(Suppl. 4):1–14. [97] Calderon-Garciduenas L, Macias-Parra M, Hoffmann HJ, et al. Immunotoxicity and environment: immunodysregulation and systemic inflammation in children. Toxicol Pathol 2009. [98] Stiller-Winkler R, Idel H, Leng G, Spix C, Dolgner R. Influence of air pollution on humoral immune response. J Clin Epidemiol 1996;49(5):527–34. [99] Hadnagy W, Stiller-Winkler R, Idel H. Immunological alterations in sera of persons living in areas with different air pollution. Toxicol Lett 1996;88(1– 3):147–53. [100] de Marco R, Poli A, Ferrari M, et al. The impact of climate and traffic-related NO2 on the prevalence of asthma and allergic rhinitis in Italy. Clin Exp Allergy 2002;32(10):1405–12. [101] Kramer U, Koch T, Ranft U, Ring J, Behrendt H. Traffic-related air pollution is associated with atopy in children living in urban areas. Epidemiology 2000;11(1):64–70. [102] Melen E, Nyberg F, Lindgren CM, et al. Interactions between glutathione Stransferase P1, tumor necrosis factor, and traffic-related air pollution for development of childhood allergic disease. Environ Health Perspect 2008;116(8):1077–84. [103] Nordling E, Berglind N, Melen E, et al. Traffic-related air pollution and childhood respiratory symptoms, function and allergies. Epidemiology 2008;19(3):401–8. [104] Morgenstern V, Zutavern A, Cyrys J, et al. Atopic diseases, allergic sensitization, and exposure to traffic-related air pollution in children. Am J Respir Crit Care Med 2008;177(12):1331–7. [105] Morgenstern V, Zutavern A, Cyrys J, et al. Respiratory health and individual estimated exposure to traffic-related air pollutants in a cohort of young children. Occup Environ Med 2007;64(1):8–16. [106] McConnell R, Berhane K, Gilliland F, et al. Asthma in exercising children exposed to ozone: a cohort study. Lancet 2002;359(9304):386–91. [107] Lindgren A, Stroh E, Montnemery P, Nihlen U, Jakobsson K, Axmon A. Trafficrelated air pollution associated with prevalence of asthma and COPD/chronic bronchitis. A cross-sectional study in Southern Sweden. Int J Health Geogr 2009;8:2. [108] Wichmann FA, Muller A, Busi LE, et al. Increased asthma and respiratory symptoms in children exposed to petrochemical pollution. J Allergy Clin Immunol 2009;123(3):632–8. [109] Jerrett M, Shankardass K, Berhane K, et al. Traffic-related air pollution and asthma onset in children: a prospective cohort study with individual exposure measurement. Environ Health Perspect 2008;116(10):1433–8. [110] Jacquemin B, Sunyer J, Forsberg B, et al. Home outdoor NO2 and new onset of self-reported asthma in adults. Epidemiology 2009;20(1):119–26. [111] Kim JJ, Huen K, Adams S, et al. Residential traffic and children’s respiratory health. Environ Health Perspect 2008;116(9):1274–9. [112] Liebhart J, Malolepszy J, Wojtyniak B, et al. Prevalence and risk factors for asthma in Poland: results from the PMSEAD study. J Investig Allergol Clin Immunol 2007;17(6):367–74. [113] Rosenlund M, Forastiere F, Porta D, De Sario M, Badaloni C, Perucci CA. Traffic-related air pollution in relation to respiratory symptoms, allergic sensitization, and lung function in school children. Thorax 2008. [114] Mortimer K, Neugebauer R, Lurmann F, Alcorn S, Balmes J, Tager I. Earlylifetime exposure to air pollution and allergic sensitization in children with asthma. J Asthma 2008;45(10):874–81. [115] Jerrett M, Burnett RT, Ma R, et al. Spatial analysis of air pollution and mortality in Los Angeles. Epidemiology 2005;16(6):727–36.

S.A. Ritz / Medical Hypotheses 74 (2010) 110–117 [116] Gilliland FD, Li YF, Saxon A, Diaz-Sanchez D. Effect of glutathione-Stransferase M1 and P1 genotypes on xenobiotic enhancement of allergic responses: randomised, placebo-controlled crossover study. Lancet 2004;363(9403):119–25. [117] Nel AE, Diaz-Sanchez D, Ng D, Hiura T, Saxon A. Enhancement of allergic inflammation by the interaction between diesel exhaust particles and the immune system. J Allergy Clin Immunol 1998;102(4 Pt 1):539–54. [118] Diaz-Sanchez D, Tsien A, Fleming J, Saxon A. Combined diesel exhaust particulate and ragweed allergen challenge markedly enhances human in vivo nasal ragweed-specific IgE and skews cytokine production to a T helper cell 2-type pattern. J Immunol 1997;158(5):2406–13. [119] Diaz-Sanchez D, Tsien A, Casillas A, Dotson AR, Saxon A. Enhanced nasal cytokine production in human beings after in vivo challenge with diesel exhaust particles. J Allergy Clin Immunol 1996;98(1):114–23. [120] Whitekus MJ, Li N, Zhang M, et al. Thiol antioxidants inhibit the adjuvant effects of aerosolized diesel exhaust particles in a murine model for ovalbumin sensitization. J Immunol 2002;168(5):2560–7. [121] Steerenberg PA, Withagen CE, van Dalen WJ, et al. Dose dependency of adjuvant activity of particulate matter from five European sites in three seasons in an ovalbumin-mouse model. Inhal Toxicol 2005;17(3):133–45. [122] Steerenberg PA, Withagen CE, van Dalen WJ, et al. Adjuvant activity of ambient particulate matter of different sites, sizes, and seasons in a respiratory allergy mouse model. Toxicol Appl Pharmacol 2004;200(3): 186–200. [123] Steerenberg PA, van Dalen WJ, Withagen CE, Dormans JA, van Loveren H. Optimization of route of administration for coexposure to ovalbumin and particle matter to induce adjuvant activity in respiratory allergy in the mouse. Inhal Toxicol 2003;15(13):1309–25. [124] Samuelsen M, Nygaard UC, Lovik M. Allergy adjuvant effect of particles from wood smoke and road traffic. Toxicology 2008;246(2–3):124–31. [125] Steerenberg PA, Withagen CE, Dormans JA, van Dalen WJ, van Loveren H, Casee FR. Adjuvant activity of various diesel exhaust and ambient particles in two allergic models. J Toxicol Environ Health A 2003;66(15):1421–39. [126] Nygaard UC, Samuelsen M, Aase A, Lovik M. The capacity of particles to increase allergic sensitization is predicted by particle number and surface area, not by particle mass. Toxicol Sci 2004;82(2):515–24. [127] Moerloose KB, Robays LJ, Maes T, Brusselle GG, Tournoy KG, Joos GF. Cigarette smoke exposure facilitates allergic sensitization in mice. Respir Res 2006;7:49. [128] Rumold R, Jyrala M, Diaz-Sanchez D. Secondhand smoke induces allergic sensitization in mice. J Immunol 2001;167(8):4765–70. [129] Fujimaki H, Saneyoshi K, Shiraishi F, Imai T, Endo T. Inhalation of diesel exhaust enhances antigen-specific IgE antibody production in mice. Toxicology 1997;116(1–3):227–33. [130] Osebold JW, Zee YC, Gershwin LJ. Enhancement of allergic lung sensitization in mice by ozone inhalation. Proc Soc Exp Biol Med 1988;188(3):259–64. [131] Osebold JW, Gershwin LJ, Zee YC. Studies on the enhancement of allergic lung sensitization by inhalation of ozone and sulfuric acid aerosol. J Environ Pathol Toxicol 1980;3(5–6):221–34. [132] Riedel F, Kramer M, Scheibenbogen C, Rieger CH. Effects of SO2 exposure on allergic sensitization in the guinea pig. J Allergy Clin Immunol 1988;82(4): 527–34. [133] Matsumura Y. The effects of ozone, nitrogen dioxide, and sulfur dioxide on the experimentally induced allergic respiratory disorder in guinea pigs. I. The effect on sensitization with albumin through the airway. Am Rev Respir Dis 1970;102(3):430–7. [134] Diaz-Sanchez D, Garcia MP, Wang M, Jyrala M, Saxon A. Nasal challenge with diesel exhaust particles can induce sensitization to a neoallergen in the human mucosa. J Allergy Clin Immunol 1999;104(6):1183–8.

117

[135] Riechelmann H, Deutschle T, Grabow A, Heinzow B, Butte W, Reiter R. Differential response of Mono Mac 6, BEAS-2B, and Jurkat cells to indoor dust. Environ Health Perspect 2007;115(9):1325–32. [136] Suwa T, Hogg JC, Quinlan KB, Ohgami A, Vincent R, van Eeden SF. Particulate air pollution induces progression of atherosclerosis. J Am Coll Cardiol 2002;39(6):935–42. [137] Hollingsworth JW, Maruoka S, Li Z, et al. Ambient ozone primes pulmonary innate immunity in mice. J Immunol 2007;179(7):4367–75. [138] Sigaud S, Goldsmith CA, Zhou H, et al. Air pollution particles diminish bacterial clearance in the primed lungs of mice. Toxicol Appl Pharmacol 2007;223(1):1–9. [139] NIH Autoimmune Diseases Coordinating Committee. Progress in autoimmune diseases research. U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Allergy and Infectious Diseases. Report to Congress, March 2005. [140] Hertz-Picciotto I, Herr CE, Yap PS, et al. Air pollution and lymphocyte phenotype proportions in cord blood. Environ Health Perspect 2005;113(10): 1391–8. [141] Jedrychowski W, Galas A, Pac A, et al. Prenatal ambient air exposure to polycyclic aromatic hydrocarbons and the occurrence of respiratory symptoms over the first year of life. Eur J Epidemiol 2005;20(9):775–82. [142] Lehmann I, Thoelke A, Rehwagen M, et al. The influence of maternal exposure to volatile organic compounds on the cytokine secretion profile of neonatal T cells. Environ Toxicol 2002;17(3):203–10. [143] Fedulov AV, Leme A, Yang Z, et al. Pulmonary exposure to particles during pregnancy causes increased neonatal asthma susceptibility. Am J Respir Cell Mol Biol 2008;38(1):57–67. [144] Penn AL, Rouse RL, Horohov DW, Kearney MT, Paulsen DB, Lomax L. In utero exposure to environmental tobacco smoke potentiates adult responses to allergen in BALB/c mice. Environ Health Perspect 2007;115(4):548–55. [145] Sly PD, Flack F. Susceptibility of children to environmental pollutants. Ann NY Acad Sci 2008;1140:163–83. [146] van Leeuwen DM, Pedersen M, Hendriksen PJ, et al. Genomic analysis suggests higher susceptibility of children to air pollution. Carcinogenesis 2008;29(5):977–83. [147] Bateson TF, Schwartz J. Children’s response to air pollutants. J Toxicol Environ Health A 2008;71(3):238–43. [148] Schwartz J. Air pollution and children’s health. Pediatrics 2004;113(Suppl. 4):1037–43. [149] Gregersen PK, Olsson LM. Recent advances in the genetics of autoimmune disease. Annu Rev Immunol 2009;27:363–91. [150] Yang IA, Fong KM, Zimmerman PV, Holgate ST, Holloway JW. Genetic susceptibility to the respiratory effects of air pollution. Thorax 2008;63(6): 555–63. [151] London SJ. Gene-air pollution interactions in asthma. Proc Am Thorac Soc 2007;4(3):217–20. [152] Kleeberger SR. Genetic aspects of pulmonary responses to inhaled pollutants. Exp Toxicol Pathol 2005;57(Suppl. 1):147–53. [153] Kleeberger SR. Genetic aspects of susceptibility to air pollution. Eur Respir J Suppl 2003;40:52s–6s. [154] Kleeberger SR, Reddy S, Zhang LY, Jedlicka AE. Genetic susceptibility to ozone-induced lung hyperpermeability: role of toll-like receptor 4. Am J Respir Cell Mol Biol 2000;22(5):620–7. [155] Iskander K, Li J, Han S, Zheng B, Jaiswal AK. NQO1 and NQO2 regulation of humoral immunity and autoimmunity. J Biol Chem 2006;281(41):30917–24. [156] Pinock S. The trials of keeping track. The Scientist 2007;(Suppl.):17–26. [157] Walsh SJ, Rau LM. Autoimmune diseases: a leading cause of death among young and middle-aged women in the United States. Am J Public Health 2000;90(9):1463–6.