Health disparities: Intracellular consequences of social determinants of health.

Health disparities exist dependent on socioeconomic status, living conditions, race/ethnicity, diet, and exposures to environmental pollutants. Herein, the various exposures contributing to a person's exposome are collectively considered social determinants of health (SDOH), and the SDOH-exposome impacts health more than health care. This review discusses the extent of evidence of the physiologic consequences of these exposures at the intracellular level. We consider how the SDOH-exposome, which captures how individuals live, work and age, induces cell processes that modulate a conceptual "redox rheostat." Like an electrical resistor, the SDOH-exposome, along with genetic predisposition and age, regulate reductive and oxidative (redox) stress circuits and thereby stimulate inflammation. Regardless of the source of the SDOH-exposome that induces chronic inflammation and immunosenescence, the outcome influences cardiometabolic diseases, cancers, infections, sepsis, neurodegeneration and autoimmune diseases. The endogenous redox rheostat is connected with regulatory molecules such as NAD+/NADH and SIRT1 that drive redox pathways. In addition to these intracellular and mitochondrial processes, we discuss how the SDOH-exposome can influence the balance between metabolism and regulation of immune responsiveness involving the two main molecular drivers of inflammation, the NLRP3 inflammasome and NF-κB induction. Mitochondrial and inflammasome activities play key roles in mediating defenses against pathogens and controlling inflammation before diverse cell death pathways are induced. Specifically, pyroptosis, cell death by inflammation, is intimately associated with common disease outcomes that are influenced by the SDOH-exposome. Redox influences on immunometabolism including protein cysteines and ion fluxes are discussed regarding health outcomes. In summary, this review presents a translational research perspective, with evidence from in vitro and in vivo models as well as clinical and epidemiological studies, to outline the intracellular consequences of the SDOH-exposome that drive health disparities in patients and populations. The relevance of this conceptual and theoretical model considering the SARS-CoV-2 pandemic are highlighted. Finally, the case of asthma is presented as a chronic condition that is modified by adverse SDOH exposures and is manifested through the dysregulation of immune cell redox regulatory processes we highlight in this review.

The Exposome and Immune Health in Times of the COVID-19 Pandemic.

Growing evidence supports the importance of lifestyle and environmental exposures-collectively referred to as the 'exposome'-for ensuring immune health. In this narrative review, we summarize and discuss the effects of the different exposome components (physical activity, body weight management, diet, sun exposure, stress, sleep and circadian rhythms, pollution, smoking, and gut microbiome) on immune function and inflammation, particularly in the context of the current coronavirus disease 2019 (COVID-19) pandemic. We highlight the potential role of 'exposome improvements' in the prevention-or amelioration, once established-of this disease as well as their effect on the response to vaccination. In light of the existing evidence, the promotion of a healthy exposome should be a cornerstone in the prevention and management of the COVID-19 pandemic and other eventual pandemics.

Environmental pollutants and the immune response.

Environmental pollution is one of the most serious challenges to health in the modern world. Pollutants alter immune responses and can provoke immunotoxicity. In this Review, we summarize the major environmental pollutants that are attracting wide-ranging concern and the molecular basis underlying their effects on the immune system. Xenobiotic receptors, including the aryl hydrocarbon receptor (AHR), sense and respond to a subset of environmental pollutants by activating the expression of detoxification enzymes to protect the body. However, chronic activation of the AHR leads to immunotoxicity. KEAP1-NRF2 is another important system that protects the body against environmental pollutants. KEAP1 is a sensor protein that detects environmental pollutants, leading to activation of the transcription factor NRF2. NRF2 protects the body from immunotoxicity by inducing the expression of genes involved in detoxification, antioxidant and anti-inflammatory activities. Intervening in these sensor-response systems could protect the body from the devastating immunotoxicity that can be induced by environmental pollutants.

Histological mucous cell quantification and mucosal mapping reveal different aspects of mucous cell responses in gills and skin of shorthorn sculpins (Myoxocephalus scorpius).

In teleosts, the mucosal epithelial barriers represent the first line of defence against environmental challenges such as pathogens and environmental contaminants. Mucous cells (MCs) are specialised cells providing this protection through mucus production. Therefore, a better understanding of various MC quantification methods is critical to interpret MC responses. Here, we compare histological (also called traditional) quantification of MCs with a novel mucosal mapping method to understand the differences between the two methods' assessment of MC responses to parasitic infections and pollution exposure in shorthorn sculpins (Myoxocephalus scorpius). Overall, both methods distinguished between the fish from stations with different levels of pollutants and detected the links between MC responses and parasitic infection. Traditional quantification showed relationship between MC size and body size of the fish whereas mucosal mapping detected a link between MC responses and Pb level in liver. While traditional method gave numerical density, mucosal mapping gave volumetric density of the mucous cells in the mucosa. Both methods differentiated MC population in skin from those in the gills, but only mucosal mapping pointed out the consistent differences between filament and lamellar MC populations within the gills. Given the importance of mucosal barriers in fish, a better understanding of various MC quantification methods and the linkages between MC responses, somatic health and environmental stressors is highly valuable.

Early life exposures shape the CD4+ T cell transcriptome, influencing proliferation, differentiation, and mitochondrial dynamics later in life.

Early life environmental exposures drive lasting changes to the function of the immune system and can contribute to disease later in life. One of the ways environmental factors act is through cellular receptors. The aryl hydrocarbon receptor (AHR) is expressed by immune cells and binds numerous xenobiotics. Early life exposure to chemicals that bind the AHR impairs CD4+ T cell responses to influenza A virus (IAV) infection in adulthood. However, the cellular mechanisms that underlie these durable changes remain poorly defined. Transcriptomic profiling of sorted CD4+ T cells identified changes in genes involved in proliferation, differentiation, and metabolic pathways were associated with triggering AHR during development. Functional bioassays confirmed that CD4+ T cells from infected developmentally exposed offspring exhibit reduced proliferation, differentiation, and cellular metabolism. Thus, developmental AHR activation shapes T cell responsive capacity later in life by affecting integrated cellular pathways, which collectively alter responses later in life. Given that coordinated shifts in T cell metabolism are essential for T cell responses to numerous challenges, and that humans are constantly exposed to many different types of AHR ligands, this has far-reaching implications for how AHR signaling, particularly during development, durably influences T cell mediated immune responses across the lifespan.

Shared epitope-aryl hydrocarbon receptor crosstalk underlies the mechanism of gene-environment interaction in autoimmune arthritis.

The susceptibility to autoimmune diseases is affected by genetic and environmental factors. In rheumatoid arthritis (RA), the shared epitope (SE), a five-amino acid sequence motif encoded by RA-associated HLA-DRB1 alleles, is the single most significant genetic risk factor. The risk conferred by the SE is increased in a multiplicative way by exposure to various environmental pollutants, such as cigarette smoke. The mechanism of this synergistic interaction is unknown. It is worth noting that the SE has recently been found to act as a signal transduction ligand that facilitates differentiation of Th17 cells and osteoclasts in vitro and in vivo. Intriguingly, the aryl hydrocarbon receptor (AhR), a transcription factor that mediates the xenobiotic effects of many pollutants, including tobacco combustion products, has been found to activate similar biologic effects. Prompted by these similarities, we sought to determine whether the SE and AhR signaling pathways interact in autoimmune arthritis. Here we uncovered a nuclear factor kappa B-mediated synergistic interaction between the SE and AhR pathways that leads to markedly enhanced osteoclast differentiation and Th17 polarization in vitro. Administration of AhR pathway agonists to transgenic mice carrying human SE-coding alleles resulted in a robust increase in arthritis severity, bone destruction, overabundance of osteoclasts, and IL17-expressing cells in the inflamed joints and draining lymph nodes of arthritic mice. Thus, this study identifies a previously unrecognized mechanism of gene-environment interaction that could provide insights into the well-described but poorly understood amplification of the genetic risk for RA upon exposure to environmental pollutants.

Epidermal Overexpression of Xenobiotic Receptor PXR Impairs the Epidermal Barrier and Triggers Th2 Immune Response.

The skin is in daily contact with environmental pollutants, but the long-term effects of such exposure remain underinvestigated. Many of these toxins bind and activate the pregnane X receptor (PXR), a ligand-activated transcription factor that regulates genes central to xenobiotic metabolism. The objective of this work was to investigate the effect of constitutive activation of PXR in the basal layer of the skin to mimic repeated skin exposure to noxious molecules. We designed a transgenic mouse model that overexpresses the human PXR gene linked to the herpes simplex VP16 domain under the control of the keratin 14 promoter. We show that transgenic mice display increased transepidermal water loss and elevated skin pH, abnormal stratum corneum lipids, focal epidermal hyperplasia, activated keratinocytes expressing more thymic stromal lymphopoietin, a T helper type 2/T helper type 17 skin immune response, and increased serum IgE. Furthermore, the cutaneous barrier dysfunction precedes development of the T helper type 2/T helper type 17 inflammation in transgenic mice, thereby mirroring the time course of atopic dermatitis development in humans. Moreover, further experiments suggest increased PXR signaling in the skin of patients with atopic dermatitis when compared with healthy skin. Thus, PXR activation by environmental pollutants may compromise epidermal barrier function and favor an immune response resembling atopic dermatitis.

Sample processing approach for detection of ricin in surface samples.

With several ricin contamination incidents reported over the past decade, rapid and accurate methods are needed for environmental sample analysis, especially after decontamination. A sample processing method was developed for common surface sampling devices to improve the limit of detection and avoid false negative/positive results for ricin analysis. Potential assay interferents from the sample matrix (bleach residue, sample material, wetting buffer), including reference dust, were tested using a Time-Resolved Fluorescence (TRF) immunoassay. Test results suggested that the sample matrix did not cause the elevated background fluorescence sometimes observed when analyzing post-bleach decontamination samples from ricin incidents. Furthermore, sample particulates (80mg/mL Arizona Test Dust) did not enhance background fluorescence or interfere with ricin detection by TRF. These results suggested that high background fluorescence in this immunoassay could be due to labeled antibody quality and/or quantity issues. Centrifugal ultrafiltration devices were evaluated for ricin concentration as a part of sample processing. Up to 30-fold concentration of ricin was observed by the devices, which serve to remove soluble interferents and could function as the front-end sample processing step to other ricin analytical methods. The procedure has the potential to be used with a broader range of environmental sample types and with other potential interferences and to be followed by other ricin analytical methods, although additional verification studies would be required.

Arsenic and Immune Response to Infection During Pregnancy and Early Life.

PURPOSE OF REVIEW: Arsenic, a known carcinogen and developmental toxicant, is a major threat to global health. While the contribution of arsenic exposure to chronic diseases and adverse pregnancy and birth outcomes is recognized, its ability to impair critical functions of humoral and cell-mediated immunity-including the specific mechanisms in humans-is not well understood. Arsenic has been shown to increase risk of infectious diseases that have significant health implications during pregnancy and early life. Here, we review the latest research on the mechanisms of arsenic-related immune response alterations that could underlie arsenic-associated increased risk of infection during the vulnerable periods of pregnancy and early life. RECENT FINDINGS: The latest evidence points to alteration of antibody production and transplacental transfer as well as failure of T helper cells to produce IL-2 and proliferate. Critical areas for future research include the effects of arsenic exposure during pregnancy and early life on immune responses to natural infection and the immunogenicity and efficacy of vaccines.

Accumulation of coal combustion residues and their immunological effects in the yellow-bellied slider (Trachemys scripta scripta).

Anthropogenic activities such as industrial processes often produce copious amounts of contaminants that have the potential to negatively impact growth, survival, and reproduction of exposed wildlife. Coal combustion residues (CCRs) represent a major source of pollutants globally, resulting in the release of potentially harmful trace elements such as arsenic (As), cadmium (Cd), and selenium (Se) into the environment. In the United States, CCRs are typically stored in aquatic settling basins that may become attractive nuisances to wildlife. Trace element contaminants, such as CCRs, may pose a threat to biota yet little is known about their sublethal effects on reptiles. To assess the effects of CCR exposure in turtles, we sampled 81 yellow-bellied sliders (Trachemys scripta scripta) in 2014-2015 from CCR-contaminated and uncontaminated reference wetlands located on the Savannah River Site (Aiken, SC, USA). Specific aims were to (1) compare the accumulation of trace elements in T. s. scripta claw and blood samples between reference and CCR-contaminated site types, (2) evaluate potential immunological effects of CCRs via bacterial killing assays and phytohaemagglutinin (PHA) assays, and (3) quantify differences in hemogregarine parasite loads between site types. Claw As, Cd, copper (Cu), and Se (all p ≤ 0.001) and blood As, Cu, Se, and strontium (Sr; p ≤ 0.015) were significantly elevated in turtles from CCR-contaminated wetlands compared to turtles from reference wetlands. Turtles from reference wetlands exhibited lower bacterial killing (p = 0.015) abilities than individuals from contaminated sites but neither PHA responses (p = 0.566) nor parasite loads (p = 0.980) differed by site type. Despite relatively high CCR body burdens, sliders did not exhibit apparent impairment of immunological response or parasite load. In addition, the high correlation between claw and blood concentrations within individuals suggests that nonlethal tissue sampling may be useful for monitoring CCR exposure in turtles.

Exposure to phthalates in house dust and associated allergies in children aged 6-12years.

Phthalates are widely used as plasticizers in household products. Several studies have reported an association between phthalate exposure and an increased risk of allergies. The present study estimated phthalate exposure in children aged 6-12years and assessed potential correlations with allergies. House dust samples were collected from floors and multi-surface objects >35cm above the floor. Urine samples were collected from the first morning void of the day. Daily phthalate intake (DIdust and DI) was estimated using both house dust and urinary metabolite concentrations. Exposure to di-2-ethylhexyl phthalate (DEHP) in floor dust was associated with parental-reported rhino-conjunctivitis. After stratification by gender, this trend was found to only occur in boys. Furthermore, urinary mono-isobutyl phthalate was inversely associated with parental-reported wheeze in boys. DIdust of benzyl butyl phthalate (BBzP) and DEHP were significantly correlated with DI_BBzP and DI_DEHP, respectively. These correlations were stronger with floor than with multi-surface dust. Our results suggest that, among Japanese children, house dust from low surfaces, such as living room floors, might play a meaningful role in the indoor environmental exposure pathway for BBzP and DEHP.

Tributyltin exposure alters cytokine levels in mouse serum.

Tributyltin (TBT), a toxic environmental contaminant, has been widely utilized for various industrial, agricultural and household purposes. Its usage has led to a global contamination and its bioaccumulation in aquatic organisms and terrestrial mammals. Previous studies suggest that TBT has debilitating effects on the overall immune function of animals, rendering them more vulnerable to diseases. TBT (at concentrations that have been detected in human blood) alters secretion of inflammatory cytokines from human lymphocytes ex vivo. Thus, it is important to determine if specified levels of TBT can alter levels of cytokines in an in vivo system. Mice were exposed to biologically relevant concentrations of TBT (200, 100 or 25 nM final concentrations). The quantitative determination of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL2, IL5, IL7, IL12ßp40, IL13, IL15, keratinocyte chemoattractant (KC), macrophage inflammatory protein 1ß (MIP), MIP2 and regulated on activation normal T-cell-expressed and secreted (RANTES) was performed in mouse sera by MAGPIX analysis and Western blot. Results indicated alterations (both decreases and increases) in several cytokines. The pro-inflammatory cytokines IFNγ, TNFα, IL-1ß, IL-2, IL5, IL12ßp40 and IL-15 were altered as were the chemokines MIP-1 and RANTES and the anti-inflammatory cytokine IL-13. Increases in IFNγ and TNFα were seen in the serum of mice exposed to TBT for less than 24 h. Levels of IL1ß, IL-12 ßp40, IL-5 and IL-15 were also modulated in mouse serum, depending on the specific experiment and exposure level. IL-2 was consistently decreased in mouse serum when animals were exposed to TBT. There were also TBT-induced increases in MIP-1ß, RANTES and IL-13. These results from human and murine samples clearly suggest that TBT exposures modulate the secretion inflammatory cytokines.

Immunomodulatory effects of exposure to polychlorinated biphenyls and perfluoroalkyl acids in East Greenland ringed seals (Pusa hispida).

To better elucidate the potential immune-related health effects of exposure to environmentally persistent organic pollutants (POP), such as polychlorinated biphenyls (PCBs) and perfluoroalkyl substances (PFASs), in ringed seals (Pusa hispida), a sentinel Arctic species, we assessed 1) associations between mitogen-induced lymphocyte proliferation and in vivo tissue contaminant burdens, and 2) the concentration-response effects of in vitro exposure to PFASs and PCB congeners on mitogen-induced lymphocyte proliferation. Upon in vitro contaminant exposure, the non-coplanar PCB congeners CB 138, 153, and 180, but not the coplanar CB 169, significantly reduced lymphocyte proliferation between 10 and 20µgg-1 ww. The respective in vitro EC50 values for these congeners were 13.3, 20.7, 20.8, and 54.6µgg-1 ww. No modulation of lymphocyte proliferation was observed upon in vitro exposure to two individual PFASs, perfluorooctane sulphonic acid (PFOS) and perfluorooctanoic acid (PFOA), at concentrations up to 1000ngg-1. In addition, no significant correlations were found between lymphocyte proliferation and any blood or blubber contaminant measured. Taken together, these data suggest this population of ringed seals is not currently at high risk of altered lymphocyte proliferation from exposure to the POPs or PFASs in this study.

VHH antibodies: emerging reagents for the analysis of environmental chemicals.

A VHH antibody (or nanobody) is the antigen binding fragment of heavy chain only antibodies. Discovered nearly 25 years ago, they have been investigated for their use in clinical therapeutics and immunodiagnostics, and more recently for environmental monitoring applications. A new and valuable immunoreagent for the analysis of small molecular weight environmental chemicals, VHH will overcome many pitfalls encountered with conventional reagents. In the work so far, VHH antibodies often perform comparably to conventional antibodies for small molecule analysis, are amenable to numerous genetic engineering techniques, and show ease of adaption to other immunodiagnostic platforms for use in environmental monitoring. Recent reviews cover the structure and production of VHH antibodies as well as their use in clinical settings. However, no report focuses on the use of these VHH antibodies to detect small environmental chemicals (MW < 1500 Da). This review article summarizes the efforts made to produce VHHs to various environmental targets, compares the VHH-based assays with conventional antibody assays, and discusses the advantages and limitations in developing these new antibody reagents particularly to small molecule targets. Graphical Abstract Overview of the production of VHHs to small environmental chemicals and highlights of the utility of these new emerging reagents.

Arsenic Exposure and Immunotoxicity: a Review Including the Possible Influence of Age and Sex.

Increasing evidence suggests that inorganic arsenic, a major environmental pollutant, exerts immunosuppressive effects in epidemiological, in vitro, and animal models. The mechanisms, however, remain unclear, and little is known about variation in susceptibilities due to age and sex. We performed a review of the experimental and epidemiologic evidence on the association of arsenic exposure and immune diseases. The majority of the studies described arsenic as a potent immunosuppressive compound, though others have reported an increase in allergy and autoimmune diseases, suggesting that arsenic may also act as an immune system stimulator, depending on the dose or timing of exposure. Limited information, due to either the high concentrations of arsenic used in in vitro studies or the use of non-human data for predicting human risks, is available from experimental studies. Moreover, although there is emerging evidence that health effects of arsenic manifest differently between men and women, we found limited information on sex differences on the immunotoxic effects of arsenic. In conclusion, preliminary data show that chronic early-life exposure to arsenic might impair immune responses, potentially leading to increased risk of infections and inflammatory-like diseases during childhood and in adulthood. Further investigation to evaluate effects of arsenic exposure on the developing immune system of both sexes, particularly in human cells and using concentrations relevant to human exposure, should be a research priority.

The genetics of drug hypersensitivity reactions

Drug hypersensitivity reactions (DHRs) are a major problem for healthcare systems, regulatory agencies, and the pharmaceutical industry. DHRs are induced by various mechanisms and encompass a heterogeneous set of potentially life-threatening clinical entities. In addition to environmental effects, individual factors play a key role in this intricate puzzle. However, despite commendable efforts in recent years to identify individual predisposing factors, our knowledge of the genetic basis of these reactions remains incomplete. In this manuscript, we summarize current research on the genetics of DHRs, focusing on specific immune-mediated reactions (immediate and nonimmediate) and on pharmacologically mediated reactions (cross-intolerance to nonsteroidal anti-inflammatory drugs). We also provide some thoughts on potential technological approaches that would help us to decipher the molecular mechanisms underlying DHRs. We believe this manuscript will be of interest not only for allergists and basic researchers in the field, but also for clinicians from various areas of expertise who manage these reactions in their clinical practice (AU)

Las reacciones de hipersensibilidad a fármacos (RHFs) son un problema preocupante para los sistemas de salud, las agencias reguladoras y la industria. Además de la diversidad de mecanismos implicados, las RHFs incluyen un conjunto heterogéneo de entidades clínicas que pueden amenazar la vida del paciente. A esta complejidad se añade el hecho de que, además de factores ambientales, en ellas participan factores individuales. A pesar del considerable esfuerzo desarrollado en los últimos años en la identificación de los factores individuales que predisponen a la aparición de estas reacciones, nuestro conocimiento sobre la base genética de las RHFs es todavía limitado. En esta revisión se presentan los datos disponibles sobre la genética de las RHFs, tomando como modelo las reacciones mediadas por mecanismos inmunológicos específicos (anticuerpos IgE y células T, reacciones inmediatas y no inmediatas) así como las mediadas por mecanismos farmacológicos (intolerancia cruzada a anti-inflamatorios no esteroideos). También se destacan las aproximaciones tecnológicas que pueden proporcionar información fundamental sobre los mecanismos moleculares que subyacen en estas reacciones. Creemos que este manuscrito será útil no solo para alergólogos e investigadores básicos en éste área, sino también para otros profesionales de la medicina que pueden encontrarse con este tipo de reacciones en su práctica clínica (AU)

[Immune System Reaction against Environmental Pollutants].

Environmental pollutants (such as diesel exhaust particles and silica) cause disorders ranging from bronchial asthma to malignant tumors. In recent years, it has been reported that some of the signaling pathways in which environmental contaminants act in vivo are associated with innate immunity. Innate immunity recognizes ligands and induces inflammation. Those ligands are pathogen-associated molecular patterns (PAMPs: e.g., lipopolysaccharide) and danger-associated molecular patterns (DAMPs: e.g., cholesterol crystallization or uric acid crystal). Activation of innate immunity stimulates the acquired immunity system. Therefore, innate immunity regulates the strength of the general immune system. Furthermore, crystal silica, which is an environmental pollutant, activates innate immunity as a ligand. Innate immunity involves the membrane-bound Toll-like receptors (TLR) and cytoplasm-localized nucleotide-binding oligomerization domain (NOD)-like receptors (NLR). We reported the innate immunity-system-related diseases such as Crohn's disease, Blau syndrome, myelogenous leukemia, and sarcoidosis. An inflammasome complex containing NLR has attracted attention owing to its correlation with the onset of several diseases. It is reported that the inflammasome activation is related to the development of lifestyle-related diseases such as myocardial infarction and fatty liver. It is also reported that the mechanism by which crystal silica and asbestos cause inflammation involves the inflammasome activation. Analyzing the genes of innate immunity contributes to the clarification of the mechanism of disease onset caused by environmental pollutants.

T helper cell 2 immune skewing in pregnancy/early life: chemical exposure and the development of atopic disease and allergy.

During the last 50 years there has been a significant increase in Western societies of atopic disease and associated allergy. The balance between functional subpopulations of T helper cells (Th) determines the quality of the immune response provoked by antigen. One such subpopulation - Th2 cells - is associated with the production of IgE antibody and atopic allergy, whereas, Th1 cells antagonize IgE responses and the development of allergic disease. In seeking to provide a mechanistic basis for this increased prevalence of allergic disease, one proposal has been the 'hygiene hypothesis', which argues that in Westernized societies reduced exposure during early childhood to pathogenic microorganisms favours the development of atopic allergy. Pregnancy is normally associated with Th2 skewing, which persists for some months in the neonate before Th1/Th2 realignment occurs. In this review, we consider the immunophysiology of Th2 immune skewing during pregnancy. In particular, we explore the possibility that altered and increased patterns of exposure to certain chemicals have served to accentuate this normal Th2 skewing and therefore further promote the persistence of a Th2 bias in neonates. Furthermore, we propose that the more marked Th2 skewing observed in first pregnancy may, at least in part, explain the higher prevalence of atopic disease and allergy in the first born.

Environmental effects on immune responses in patients with atopy and asthma.

Despite attempts and some successes to improve air quality over the decades, current US national trends suggest that exposure to outdoor and indoor air pollution remains a significant risk factor for both the development of asthma and the triggering of asthma symptoms. Emerging science also suggests that environmental exposures during the prenatal period and early childhood years increase the risk of asthma. Multiple mechanisms mediate this risk because a wide range of deleterious air pollutants contribute to the pathogenesis of asthma across a variety of complex asthma phenotypes. In this review we will consider the role of altered innate and adaptive immune responses, gene-environment interactions, epigenetic regulation, and possibly gene-environment-epigene interactions. Gaining a greater understanding of the mechanisms that underlie the effect of exposure to air pollution on asthma, allergies, and other airway diseases can identify targets for therapy. Such interventions will include pollutant source reduction among those most exposed and most vulnerable and novel pharmaceutical strategies to reduce asthma morbidity.