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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
J Immunol. Author manuscript; available in PMC 2017 April 15.
Published in final edited form as:
PMCID: PMC4824550
NIHMSID: NIHMS762021

Environmental Immunology: Lessons learned from exposure to a select panel of immunotoxicants

Abstract

Exposure to environmental contaminants can produce profound effects on the immune system. Many different classes of xenobiotics can significantly suppress or enhance immune responsiveness depending on the levels (i.e. dose) and context (i.e. timing, route) of exposure. While defining the effects that toxicants can have on the immune system is a valuable component to improving public health, environmental immunology has greatly enhanced our understanding of how the immune system functions and explore new immunotherapies. This Brief Review focuses on three different examples of how immunotoxicology has benefitted the field of immunology, presenting information on (A) the aryl hydrocarbon receptor (AhR) signaling pathway, (B) the immunomodulatory effects of nanomaterials, and (C) the impact of xenobiotic exposure on the developing immune system. Collectively, contributions from immunotoxicology have significantly enhanced public health and spurred seminal advances in both basic and applied immunology.

Keywords: aryl hydrocarbon receptor, TCDD, nanomaterials, MWCNT, immunomodulation, developmental immunology, immunotoxicology, endocrine disruptor, heavy metals

INTRODUCTION

It is widely accepted that human health is a product of both genetics and the environment; a premise that also holds true for the immune system. While our genetic make up is essentially set at birth, the environment we experience is constantly changing, presenting novel challenges in the development, regulation and function of immunity. Assessing the consequences of exposure to environmental compounds within the immune system is not a straightforward process. Toxicants can enter the human body through four primary routes: inhalation (respiratory tract), ingestion (gastrointestinal tract), dermal contact (skin), and parenteral (circulation/muscles) as a result of intentional or accidental exposure (Figure 1). Therefore, the study of how xenobiotics influence the immune system, also known as immunotoxicology or environmental immunology, is a critical component of immunology. Understanding how environmental contaminants impact immune responsiveness not only helps in the effective regulation of pollutants and improving public health, but also provides novel insights into basic functions of the immune system. Therefore, the intent of this article is not to present an overview of the immunotoxic effects of environmental toxicants as it pertains to human health (as this information is much too extensive for a Brief Review) but instead to emphasize recent contributions that environmental immunology has made to advance the field of immunology. Consequently, this Brief Review focuses exclusively on three cutting-edge areas of research that are providing critical insights into basic immune function, the effects of environmental compounds on immune function and the development of potentially novel immunotherapies.

Figure 1
Exposure to and effects of environmental toxicants

Discovering the Aryl hydrocarbon Receptor

While multiple scientific advances coalesced into the discovery of the aryl hydrocarbon receptor, a common theme existed among them: the necessity to understand mechanisms of xenobiotic toxicity. Specifically, the observation in the 1970's that polycyclic aromatic hydrocarbons (PAHs) appeared to induce their own metabolism drove the ultimate discovery of a receptor that could bind these compounds. (1-3). A prodigious contribution to AhR research came with the discovery that 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD), a halogenated aromatic hydrocarbon and ubiquitous environmental contaminant, could bind the AhR, and in fact could do so in mammalian hepatocytes with 30,000 times the affinity of other environmental compounds including PAHs (4). With this discovery, AhR research and its impacts across multiple physiological systems, including immunology, were just beginning.

In the years following identification of the AhR, characterizing its expression in non-hepatic tissues became a key focus. In 1984, thymic expression of the AhR in Sprague-Dawley rats was determined to occur at high levels for twice as long (42 days vs. 21 days) after parturition compared to non-immune tissues such as liver and lungs (5). These observations led to further investigation of AhR activity in immune organs, and the pivotal discovery that AhR activation had adverse effects on thymic function. In 1985, PCBs acting through the AhR were found to cause severe thymic atrophy and humoral immune suppression (6). The succession of rapid discoveries throughout the 1980s broadened the expanse of AhR-mediated suppression within the immune system to include: thymic atrophy, reduced cell-mediated immunity, diminished humoral antibody responses, and an overall reduction in the ability to respond to and resist infectious diseases (5-9).

With a potential link made between the AhR and observed suppression of the immune system, immunologists entered into a field, which to this point had predominantly been pioneered by toxicologists and biochemists. The interweaving of discoveries from these disciplines has both expanded our understanding of the AhR signaling pathway and its role in innate and adaptive immune responses as recently reviewed by Stockinger and colleagues (10). Because several recent reviews have focused on AhR activation in T cells, our focus will be on what we consider three key areas of ongoing investigation: the role of the AhR in the innate immune system, the crusade to identify endogenous ligands, and the development of novel AhR-mediated immunotherapies.

Innate immune cells vary widely in their expression of the AhR (Figure 2), ranging from high, constitutive expression, to low, conservatively inducible expression. It should be noted that most reports describing AhR expression in immune cells rely solely on mRNA levels and not protein expression, representing a potential important gap in information as recently highlighted by Esser and Rannug (11). The outcome of AhR activation on the promotion or regulation of immune responses appears to vary by cell type and maturational state. Interestingly, both inflammatory and regulatory genes have an abundance of AhR responsive elements (DREs or XREs) within their promoter/enhancer regions (12, 13), and it has been shown that cross-talk between AhR and NF-κB can significantly impact multiple pro-inflammatory signals (14). Neutrophils, and most granulocytes, do not express the AhR at significant levels and appear to be predominantly influenced by AhR activation through indirect mechanisms (15).

Figure 2
AhR expression in immune cells

Professional antigen presenting cells (e.g. macrophages and dendritic cells) constitutively express the AhR at relatively high levels, and play a significant role in AhR-mediated immune suppression. AhR activation in dendritic cells increases the expression of regulatory genes including indoleamine 2,3-dioxygenase-1, and -2 (Ido1 and Ido2), retinaldehyde dehydrogenase 1 (aldh1a1), and transforming growth factor beta 3 (TGFβ3). Consequently, AhR-activated regulatory DCs can be potent inducers of Foxp3+ regulatory T cells (16-20). On the other hand, the AhR functions as a regulator of innate/inflammatory responses in macrophages as illustrated by the negative regulation of LPS-induced inflammation and subsequent enhanced sensitivity to lethal shock (21). Also, AhR activation in monocytes/macrophages results in dysregulated cytokine and chemokine production, a consistent effect observed in both murine and human cells (22, 23). Lastly, the differentiation and/or maturation of both monocytes/macrophages and dendritic cells is affected by the AhR, an effect that contributes to immune dysregulation (24-26).

Human NK cells, which express the AhR in stage 3 immature NK cells and “NK-22” cells, play an important role in innate immune responses to mucosal infections that may be altered by environmental AhR ligands (27, 28). Indeed, the AhR regulates cytolytic activity in murine NK cells as represented by reduced bacterial clearance, and tumor cell recognition capacity in AhR null mice. These studies also suggest that NK cell function is potentiated following AhR activation (29). Conversely, other reports demonstrate that AhR activation can suppress NK cell function, suggesting additional environmental, or maturational components may also contribute to AhR-mediated effects in NK cells (14). Likewise, innate lymphoid cells (ILCs), which play an important role in mucosal immunity, were shown to have compromised bacterial clearance and reduced IL-22 expression when ILCs lack the AhR (30). While investigations into the role of the AhR in ILCs are relatively recent, existing studies indicate AhR activation in ILC subsets effectively regulate transcriptional activation, and consequently the clearance of mucosal infections, immune tissue development, and regulation of chronic inflammatory diseases such as IBD (31). Collectively, the AhR plays a prominent role in the development and function of the innate immune system, and future studies are warranted to further elucidate the health implications of this relationship.

Because the most well-studied AhR ligands are ubiquitous environmental pollutants, studies aimed at defining the impacts of AhR activation within the immune system often have had dual roles: (A) to identify the immunomodulatory effects of AhR signaling in immune cells, and (B) to assess the breadth of immunotoxicity following exposure to large classes of xenobiotics. Early discoveries by toxicologists and biochemists have provided several decades of highly insightful AhR research within the immune system. However, now that AhR research has gained considerable traction among immunologists, future studies on this ligand-activated transcription factor are expected to continue to bolster our understanding of immune function and regulation. To this end, recent discovery of putative endogenous AhR ligands have yielded several compounds that can bind and activate the AhR with relatively high affinity (32). For example, 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) from porcine lung tissue (33), and the tryptophan derivatives 6-formylindolo[3,2-b]carbazole (FICZ) and L-kynurenine are “natural” AhR-activating compounds that can significantly impact the generation of immunity (34-38). However, importantly, although these chemicals activate the AhR and can induce similar transcriptional responses to TCDD such as the induction of signature cytochrome P450s (CYP1A1, CYP1A2, CYP1B1), they are highly susceptible to metabolism by these xenobiotic-metabolizing enzymes thereby limiting their effective half-life and associated toxicities (38). At present, at least one of these compounds (ITE) is currently being evaluated for potential therapeutic use in humans (discussed below). Notably, we currently have a limited understanding of the specific biomolecular interactions that occur between ligands and the AhR due to the lack of a defined crystal structure for this receptor. Therefore, it is difficult to accurately predict what the clinical outcomes will be if/when AhR-binding compounds are eventually tested in humans who are generally considered to express a ten-fold lower-affinity AhR when compared to (most) rodents, a relationship that remains to be confirmed in significantly larger human cohorts thereby representing a prominent gap in our understanding of AhR biology.

With the AhR now recognized as a potent immune regulator, it has become an attractive target for immunotherapy. However, there are many factors that must be fully considered when intentionally targeting the AhR to achieve specific immune regulation. It is well documented that the effects of AhR activation during an immune response vary based on the target cell (10, 11, 32, 38). AhR activation can increase inflammatory responses, or alternatively, promote immune regulation or tolerance (39). Recently, nanoparticles containing ITE, an AhR agonist, were utilized successfully to treat experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. In these studies, gold nanoparticles (NPs) were used for parenteral delivery of both ITE, and an antigenic self-peptide, myelin oligodendrocyte glycoprotein (MOG)35–55 (40). Within six hours of administration, splenic DCs, which internalized ITE-loaded NPs, significantly upregulated AhR-responsive genes including aldh1a1 and cytochrome P450 1a1, the prototypical AhR target gene. Ultimately, a marked reduction of EAE disease scores were observed following administration of ITE-loaded and ITE/MOG35-55-loaded NPs, an outcome that was attributed to a significant induction of disease-specific regulatory T cells (40).

While parenteral administration of AhR agonist-loaded NPs (AhR/NPs) showed significant amelioration of EAE in mice, gold NP uptake was not isolated to DCs in these animals, but was observed in several immune and non-immune cells (40). Because unguided NPs can often yield off target adverse effects, we hypothesize that utilizing delivery systems that directly target specific immune cells such as DCs will increase the efficacy of AhR/NP therapy, lower the concentration of AhR/NPs necessary to reach therapeutic levels, and reduce or eliminate potential adverse responses that may occur from non-specific uptake of AhR/NPs by bystander cells. Ultimately, intentional modulation of the AhR holds great promise for the development of novel immunotherapeutics to treat patients suffering from MS and potentially other devastating immune-mediated diseases.

Nanomaterials and the immune system

Nanotechnology represents the merging of science, engineering, and technology at the next great industrial revolution: control of matter at the nanoscale. At this level, matter exhibits unique physical, chemical, and biological properties, which differ from the canonical properties of bulk materials, and single atoms or molecules. These unique properties, while enabling novel applications and technological advances, also give rise to safety concerns that cannot be ignored. Several of those same characteristics that make nanomaterials (NM) so promising from a technological standpoint, also make their interactions with biological systems difficult to anticipate and critically important to methodically investigate.

Over the last decade, researchers from industry, academia, and federal agencies have been collaborating to establish specific assays and NM criteria that will assess the impact of NM on immune function. Currently, no comprehensive guidelines exist. Because NM represent such physically and chemically diverse materials, classical immunotoxicological methods cannot always be applied, and novel approaches may be required to overcome challenges inherent to NM research. For example, many NM absorb in the UV–Vis range and may even catalyze enzyme reactions or quench fluorescent dyes commonly used in common end-point and kinetic assays. Similarly, while exposure to a particular NM may result in no change in immune function when delivered via the oral and dermal route, it may induce sensitization after intradermal injection. Lastly, risk to human health is not entirely linked to NM production volume and probability of exposure, but rather to reactivity and potency of impact on specific organs. Consequently, NM produced in lower quantities that have potent and selective effects on the immune system (e.g. nickel, gold, and cobalt NM) may exhibit greater immunotoxicity. Thus, we must as semble a comprehensive understanding of the relationship between diverse NM and specific components of the immune response resulting from different testing scenarios.

Due to NM size and unique properties, the immune system efficiently recognizes engineered NM as foreign bodies resulting in multilevel responses that can range from acute to chronic, and immunostimulatory, or immunosuppressive (41). While NM-induced immune activation may increase the incidence of allergic reactions, inflammatory responses, or autoimmunity, NM-induced suppression may reduce maturation and proliferation of immune cells, resulting in increased susceptibility to infectious diseases or tumor growth. While a desirable interaction between NM and the immune system may lead to beneficial outcomes such as vaccines or therapeutics for inflammatory and autoimmune disorders, an undesirable interaction may result in adverse outcomes such as hypersensitivity reactions and inflammation, or lowered response to infection and cancerous cells. Moreover, inadvertent recognition of NM as foreign by immune cells may result in host toxicity and/or reduced therapeutic efficacy of conventional pharmaceuticals.

Carbon nanotubes are a family of NMs made up entirely of carbon. Within this family, multi-walled carbon nanotubes (MWCNT) are of special interest to the industry due to the broad applications of MWCNT in electronics, cosmetics, cleaning materials, coatings, food packaging, and medicines. Concerns over MWCNT-induced toxicity have emerged in part due to their high production volume, but also to their structural similarity to asbestos. Numerous studies have since scrutinized the effects of MWCNT length and diameter, purity, aspect ratio or rigidity, and functionalization in relation to in vitro and in vivo toxicity, inflammation, and fibrosis—particularly in the lungs (42-44). Numerous studies clearly demonstrate that MWCNT induce lung injury through acute and chronic inflammation, granuloma formation, substantial interstitial lung fibrosis, as well as exacerbate asthma-like conditions in mice (45-47). This section surveys recent efforts to define the effects of MWCNT on the innate immune system. Once NM deposit in the lungs, alveolar macrophages are responsible for their uptake and processing through phagocytosis, macropinocytosis, and clathrin/caveolin dependent and independent endocytosis (48-50). A number of studies have similarly linked MWCNT-induced oxidant stress, phagolysomal permeabilization, cathepsin B release, Nlrp3 inflammasome assembly, and caspase-1 activation, with secretion of important regulatory cytokines (e.g. IL-1β and IL-18) (51-56). Activation of the NLRP3 inflammasome by MWCNT is consistent with reports showing that other inhaled particles (e.g. silica and asbestos) cause lung injury through NLRP3 inflammasome activation (57). Upon internalization, MWCNT induce lysosomal dysfunction and autophagosome accumulation, which may disrupt autophagy (58, 59). In turn, disruption of autophagy may enhance NLRP3 inflammasome accumulation, resulting in exaggerated IL-1β production and lung fibrosis (60). Interestingly, variation of the dimensions and surface properties of NM affects the autophagic responses of cells (61, 62). Similarly, variation of MWCNT surface structure activates alternate autophagy signaling pathways (mTOR-dependent to mTOR-independent) (63). Agents that can selectively induce autophagic cell death in tumor cells are promising tools to treat or supplement current cancer therapies. Thus, modulation of autophagy by NM may be a potential therapeutic strategy. Taken together, these studies provide novel insights on how NM such as MWCNT, contribute to inflammasome activation, autophagic cell death, and induction of the stress response, and the role of NM surface chemistry in the modulation of these signaling processes for therapeutic benefit. These findings are particularly relevant given that dysfunction or dysregulation of inflammasome activation and autophagy is associated with several immune mediated diseases.

Given the rapid growth of nanotechnology and the myriad of potential physico-chemical properties, NM will influence and advance emerging medical technologies in both therapeutics and diagnostic applications. Scientists are engineering NM-based approaches to either specifically target and/or circumvent the immune system. The resulting treatments may be more precise, may diagnose or treat disease earlier, and may exhibit fewer adverse side effects. Nanotechnology platforms are being investigated as vaccine carriers, adjuvants, and drug delivery systems to target inflammation and inflammatory-associated disorders. Some formulations are already in clinical trials, whereas many others are in various phases of preclinical development. Nanomaterial-based delivery systems offer the following potential advantages: (A) site-specific delivery of drugs, peptides, and genes; (B) improved in vitro and in vivo stability; and (C) reduced side effects. Although in recent years our understanding of NM interaction with components of the immune system has improved, many questions remain.

It is now well accepted that NM size, surface charge, hydrophobicity/hydrophilicity, and the steric effects of particle coating can dictate NM compatibility with the immune system. For example, NM can be designed by attaching to polyethylene glycol (PEG) of other types of polymers to create a hydrophobic environment, thus shielding them from immune recognition (64). Although these polymers may shield NM from most immune surveillance, some data suggests the formation of PEG-specific antibodies (65, 66) and accelerated clearance of PEG-liposomes from the blood, thus changing the pharmacokinetic profiles (67-69). Therefore, generation of NM-specific antibodies may affect the efficacy and safety of NM-based therapeutics. In contrast, NM can be designed to elicit an immune response by either direct activation of antigen presenting cells, or delivering Ag to specific cellular compartments (70). One of the most heavily researched areas in nanomedicine is nanoparticle (NP) based drug delivery (71, 72). While this research is producing effective reagents and making poorly soluble drugs useful through encapsulation, controlled release, and targeting, the NP themselves are usually not therapeutic.

In this final section, we will briefly review the effects of gold nanoparticles (AuNPs) on immune function. Due to their fairly simple preparation and functionalization with drugs or other ligands, unique optical properties, and tune-ability with regards to a desired size or shape (73-75), AuNP-based immunotherapies have been a promising carrier for immune therapies in cancer antigen and immune adjuvant delivery (76-78), as well as in photothermal ablation and light triggered drug delivery (79-81). However, because AuNP can accumulate in the immune system and exhibit many toxic side effects, they should be used cautiously as a delivery system.

As with other NM, the size, shape, and electrical charge alters the recognition and uptake of AuNP in both phagocytic and non-phagocytic cells. Interestingly, in non-phagocytic cells, positively charged AuNP appear to be taken up to a much higher extent than negatively charged ones; whereas in phagocytic cells, particle charge has little effect on uptake. Furthermore, in non-phagocytic cells, AuNP were take up via clathrin-mediated endocytosis and localized to secondary lysosomes; while in phagocytic cells, AuNP were taken up through phagocytosis and located in phagosomes (82). Later studies showed that phagocytosis of 30 nm vs. 150 nm diameter AuNP occurred via different mechanisms (e.g. clathrin mediated pinocytosis and scavenger receptor mediated phagocytosis, respectively) (83). In vitro AuNPs induce proinflammatory cytokine expression in macrophages in a size dependent manner (84). In contrast, other labs showed that AuNPs can inhibit IL-1β-mediated inflammatory responses and toll like receptor 9 (TLR9) responses, also in a size dependent manner (85, 86). While these studies also suggested that particles < 5 nm had the highest impact on immune response, others determined that more hydrophobic ~2 nm AuNP exhibit greatest expression of inflammatory cytokines by mouse splenocytes (87). Oligonucleotide conjugated 13 nm AuNPs increased expression of inflammatory and defense responses genes in human peripheral blood mononuclear cells, yet similar responses were not observed in the 293 T cell line (88), suggesting that assessing immunotoxicity of AuNPs on immortalized cell lines as opposed to primary cells may yield differing results. Therefore, the immune response to AuNPs may be tissue and context dependent, as well as particle size and shape dependent. Finally, because AuNP inevitably accumulate in high concentrations in the liver and spleen in the liver and spleen for extended periods of time (89, 90), it is important to better understand how AuNPs interact with the immune system before developing them as a therapeutic delivery platform. It appears that therapeutic AuNP may be similar to chemotherapeutics’ double-edged sword because they can be therapeutic, yet can also be toxic. Additionally, the differing results regarding the inflammatory or anti-inflammatory effects of AuNPs merit further consideration. Although the distribution and immune modulatory activity of AuNP in vivo may cause either inflammatory or anti-inflammatory side effects, these properties might also be manipulated for therapeutic applications, such as vaccine and immune adjuvant delivery. These studies highlight the need to design NM that do not adversely affect the biological systems where they will be used and demonstrate that it is crucial to simultaneously ascertain both therapeutic and toxic properties of any metal containing NP.

Nanotechnology has generated, and will continue to generate, a wide spectrum of novel NM that will revolutionize many fields. Existing studies have demonstrated that nanotechnology offers advantages over traditional medicines, such as improved stability, favorable biodistribution profiles, slower drug release kinetics, lower immunotoxicity, and targeting to specific immune cell populations. However, it is essential to address the potential adverse health risks that NM poses in occupational, medicinal, consumer, or environmental exposure settings because of their unpredictable chemical and biological nature. Immune reactions are a key concern for potential adverse effects of NM. While certain predictions can be made regarding the immunotoxicity of NM, the unique nature of these structures make it difficult, if not impossible, to predict how some NM will interact with intracellular structures such as DNA, cell membranes, and cytoskeletal proteins. NM exposure has not yet been linked to human disease due to the relatively recent emergence of nanotechnology and the lack of epidemiologic data. Thus, future research into nanomaterials is both highly relevant from a public health perspective but also for the novel insights it will yield on the basic functions of the immune system.

Effects of xenobiotics on the developing immune system

To develop novel and safe therapies that provide efficient protection against infectious, or immune-mediated diseases in children or that develop during childhood, it is necessary to understand immune system ontogeny. Because immunological development is dependent on both genetic and environmental influences, investigations into both fields advance our understanding of immune function, and provide the foundation for development of novel immunotherapeutics. Notably, the generation of research tools such as genetically altered animals and targeted gene modulation has greatly enhanced our understanding of the impact that genetic abnormalities have on the developing immune system. However, over the last two decades, the effects of pollutants have been systematically evaluated, further adding to our understanding of how the environment affects the developing immune system. These studies revolve around two central tenets: (A) the developing immune system may be more sensitive to environmental chemical exposures than the adult immune system, and (B) the environment significantly impacts developmental origins of health and disease. Disruption of the developing immune system by early-life environmental insults may not only adversely affect the health of the exposed offspring later in life, but also potentially extend to additional generations through epigenetic changes. Therefore, uncovering the effects of environmental insults on the developing immune system is expected to not only benefit public health, but also provide novel insights into immune system ontogeny. The increased risk of injury to the developing immune system has been seen across several categories of drugs and chemicals, as well as heavy metals and mold toxins. Moreover, prenatal and early postnatal exposures are more likely to produce a broader array of immune parameters affected, and an increased risk of adverse immune outcomes persisting into later life (91). These differential immune effects can take many forms, which are briefly described below for a select few toxicants.

To date, perhaps one of the more comprehensive datasets for developmental immunotoxicity exists for TCDD and TCDD-like chemicals. To this end, developmental exposure to AhR-activating chemicals such as TCDD perturbs immune cell development resulting in attenuated hematopoietic stem cell (HSC) differentiation and long-term self-renewal (92). These effects can contribute to increased incidence of autoimmunity and decreased responsiveness to infectious pathogens such as influenza A (93, 94). Furthermore, activation of AhR by TCDD induces epigenetic changes in lymphocytes, especially T cells, causing DNA hypermethylation and ultimately reducing CD8+ T cell antiviral immunity (95). Conversely, early life exposure to TCDD was recently demonstrated to enhance the CD4+ T cell response to viral infection in the lung, however, this response ultimately resulted in greater bronchopulmonary inflammation and consequently reduced anti-viral immunity (96, 97). Additionally, the AhR signaling pathway plays a requisite role in the development and function of HSCs and progenitor cells, and consequently AhR null mice possess abnormalities in these cellular populations (98-101). Moreover, recent reports have described a critical utility for AhR antagonists (along with Notch ligand agonists) in the regulation and generation of HSCs from cord blood, providing significant advances for allograft transplantation (98, 102). Taken together, the AhR is now recognized as a critical regulator of key cells in the developing immune system and consequently a greater understanding of its effects will benefit the development of novel immunotherapies and consequently improved human health.

Exposure to other chemicals in the environment such as pesticides, heavy metals and endocrine disruptors also impact the developing immune system. Several pesticides including organochlorines (i.e. Chlordane, DDT/DDE), organophosphates (ie Diazonin), and carbamates (i.e. Carbofuran) have been reported to induce developmental immunotoxicity in rodents (103). Additionally, prenatal exposure in humans to DDE is associated with reduced levels of IgG and recurrent respiratory infections in infants (104, 105). These results are intriguing due to reports that DDE can also enhance allergic responses in infants via induction of Th2 cytokines (106) but not via modulation of IgE, IL-33 or TSLP (107). Exposure of the developing immune system to heavy metals such as lead, a known developmental toxicant and heavy metal, can adversely affect the generation of innate immune cells such as macrophages and dendritic cells (108). Specifically, dysregulated macrophage and DC effector functions including reduced phagocytosis, lysosomal activation, excessive production of ROS and other inflammatory mediators (i.e. TNF-a, PGE2) contribute to Th2 biased immune responses in lead-exposed animals (109-111) ultimately contributing to imbalanced and inappropriate immune responses that can be persistent and increase the risk for inflammatory disorders and disease later in life (108). Thus, these studies have advanced our understanding of ontogeny of the innate immune system and support the hypothesis that early life exposure to these environmental stressors can program the immune system for subsequent dysfunction. Lastly, endocrine disruptors such as bisphenol A (BPA; found in plastics, food sources and many other consumer products) can alter various physiological systems by interfering with the activity or production of hormones. As expected, exposure to these types of chemicals, which occurs at the highest levels in fetuses, infants and children, is thought to adversely affect human development. It is not yet known if these environmental chemicals adversely affect the developing immune system; although, this has very recently been an area of intense investigation (112). For example, developmental exposure to BPA modulated innate immunity in adult offspring mice but did not impair the adaptive immune response to influenza A virus infection (113). Perinatal exposure to low doses of BPA rendered the neonatal immune system more susceptible to food intolerance (114), and prenatal, but not postnatal, BPA exposure can enhance the postnatal development of experimental allergic asthma (115). Because BPA has been shown to induce epigenetic regulation (ie DNA methylation, miRNA expression and histone acetylation) in reproductive tissues, it will be interesting to determine if similar effects exist in the developing immune system that may consequently affect the generation of inflammatory or immune-mediated disease (116). At the least, it is expected that further research on the potential immunotoxic effects of BPA and other endocrine disruptors will help us better understand how the immune system develops and is shaped by environmental insults.

Disruption of the ordered process of immunological development by xenobiotics can generate several potential outcomes including immune deficiency, deviation, or dysregulation. While it is hypothesized that these e ffects manifest themselves during the course of development or maturation of an organism, it is also possible that immunotoxicity can be transgenerational although additional studies are necessary to firmly establish this potential outcome. If confirmed, these long-term effects could have profound implications on the immune system and its ability to respond effectively to infectious pathogens and tumor cells, or to regulate appropriately self-directed responses that underlie autoimmunity. It is expected, however, that with an increased understanding of immunological ontogeny, opportunities will develop for the generation of novel therapies to mitigate the effects of environmental stressors.

CONCLUSIONS

Environmental immunology/immunotoxicology is a relatively new and vital area of investigation in the field of immunology. Understanding how anthropogenic toxicants and natural toxins affect the development, maintenance and function of the immune system is critical for achieving optimal human health. Surprisingly perhaps, at present, the U.S. EPA is the only chemical regulatory agency to have specific immunotoxicity testing requirements, and these are primarily for assessing pesticides (117). In contrast, the pharmaceutical industry utilizes a weight of evidence approach that is only used for immunological evaluation if standard toxicological assays show cause for concern. Regardless, numerous examples exist demonstrating the potential adverse effects that exposure to environmental chemicals can and do have on the immune system. While xenobiotic exposure can come from environmental, occupational or recreational sources, more recently this list of potential threats has expanded to include symbiotic microbial exposure. Thus, it is extremely valuable for public health to fully understand the impact that environmental chemicals have on the immune system, the mechanisms underlying these effects, and how they might be mitigated.

Overall, environmental immunology has provided highly tangible benefits in the study of the immune system. To better understand how the aryl hydrocarbon receptor regulates immune development and function, the use of chemicals such as TCDD have been invoked not only as environmental stressors, but also as biological probes. From these studies, a greater understanding of the critical role of the AhR in HSC, progenitor cells, as well as innate and adaptive immune cells has resulted. In the study of nanomaterials, immunotoxicologists have been on the cutting-edge of discovery, identifying powerful biomedical uses and establishing necessary safety parameters for these xenobiotics. Experiments utilizing nanomaterials have also yielded novel, fundamental insights into inflammatory processes such as the generation and regulation of the inflammasome, and intracellular organelles (i.e. lysosomes, phagosomes) and their function (i.e. autophagy) in immune cells. Moreover, recent studies involving nanomedicines have ushered in a new era for discovery of biomedical probes and drug delivery systems that have the potential to revolutionize medicine in the coming years. Lastly, experiments aimed at defining the effects of xenobiotics on the developing immune system are beginning to expand our understanding of immunological ontogeny. Previously unknown or unappreciated molecular regulators of immune cell/tissue development such as the AhR signaling modulators (both agonists and antagonists), environmental pollutants (i.e. TCDD, PCBs) that induce epigenetic modifications, and endocrine disruption b y xenoestrogens (i.e. BPA) are expected to not only enhance public health, but also spur development of novel immunotherapeutics designed to improve childhood health. In this manner, environmental immunology provides innovation at the intersection of immunology and the environment in which we live.

Acknowledgments

This work was supported by NIEHS/NIGMS grant ES013784 and NIEHS grant ES025386 (to D.M.S.), and NIGMS grant GM103546 (to C.A.B.).

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