Environmental Immunology: Lessons

Learned from Exposure to a Select Panel of

This information is current as
of October 21, 2019.
Immunotoxicants
Joanna M. Kreitinger, Celine A. Beamer and David M.
Shepherd
J Immunol 2016; 196:3217-3225; ;
doi: 10.4049/jimmunol.1502149
http://www.jimmunol.org/content/196/8/3217

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Brief Reviews
Environmental Immunology: Lessons Learned from
Exposure to a Select Panel of Immunotoxicants
Joanna M. Kreitinger,* Celine A. Beamer,† and David M. Shepherd†
Exposure to environmental contaminants can produce
profound effects on the immune system. Many classes
of xenobiotics can significantly suppress or enhance im-
mune responsiveness depending on the levels (i.e., dose)
and context (i.e., timing, route) of exposure. Although
defining the effects that toxicants can have on the im-
mune system is a valuable component to improving
public health, environmental immunology has greatly
enhanced our understanding of how the immune system
functions and has provided innovative avenues to ex-
plore new immunotherapies. This Brief Review focuses
on three examples of how immunotoxicology has
benefitted the field of immunology, presenting informa-
tion on the aryl hydrocarbon receptor signaling path-
way, the immunomodulatory effects of nanomaterials,
and the impact of xenobiotic exposure on the develop-
ing immune system. Collectively, contributions from
immunotoxicology have significantly enhanced public
health and spurred seminal advances in both basic
and applied immunology. The Journal of Immunol-
ogy, 2016, 196: 3217–3225.
I
t 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. Although our genetic
make-up is essentially set at birth, the environment that 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 (gas-
trointestinal tract), dermal contact (skin), and parenteral
(circulation/muscles) as a result of intentional or accidental
exposure (Fig. 1). Therefore, the study of how xenobiotics
influence the immune system, also known as immunotox-
icology or environmental immunology, is a critical compo-
nent of immunology. Understanding how environmental
*Cellular, Molecular, and Microbial Biology Graduate Program, Division of Biological
Sciences, University of Montana, Missoula, MT 59812; and †Department of Biomedical
and Pharmaceutical Sciences, University of Montana, Missoula, MT 59812
ORCIDs: 0000-0003-0341-7429 (J.M.K.); 0000-0003-4995-6145 (C.A.B.).
Received for publication October 2, 2015. Accepted for publication February 16, 2016.
This work was supported by National Institute of Environmental Health Sciences/
National Institute of General Medical Sciences Grant ES013784 and National Institute
of Environmental Health Sciences Grant ES025386 (both to D.M.S.) and by National
Institute of General Medical Sciences Grant GM103546 (to C.A.B.).
www.jimmunol.org/cgi/doi/10.4049/jimmunol.1502149
The Journal of
Immunology
contaminants impact immune responsiveness not only helps
in the effective regulation of pollutants and improving public
health, it 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 environ-
mental toxicants as it pertains to human health (because this
information is much too extensive for a Brief Review) but
instead to emphasize recent contributions that environmental
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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 environ-
mental compounds on immune function, and the develop-
ment of potentially novel immunotherapies.
Discovering the aryl hydrocarbon receptor. Although multiple sci-
entific advances coalesced into the discovery of the aryl hydro-
carbon receptor (AhR), a common theme existed among them:
the necessity to understand mechanisms of xenobiotic toxicity.
Specifically, the observation in the 1970s that polycyclic aro-
matic hydrocarbons 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 AhR and, in fact, could
do so in mammalian hepatocytes with 30,000 times the affinity
of other environmental compounds, including polycyclic aromatic
hydrocarbons (4). With this discovery, AhR research and its
impacts across multiple physiological systems, including
immunology, were just beginning.
In the years following identification of AhR, characterizing
its expression in nonhepatic tissues became a key focus. In
1984, thymic expression of AhR in Sprague-Dawley rats was
determined to occur at high levels for twice as long (42 d versus
21 d) after parturition compared with nonimmune 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 AhR were
Address correspondence and reprint requests to Dr. David M. Shepherd, Department of
Biomedical and Pharmaceutical Sciences, University of Montana, SB 284, 32 Campus
Drive, Missoula, MT 59812. E-mail address: david.shepherd@umontana.edu
Abbreviations used in this article: AhR, aryl hydrocarbon receptor; AhR/NP, AhR
agonist–loaded NP; AuNP, gold NP; BPA, bisphenol A; DC, dendritic cell; EAE,
experimental autoimmune encephalomyelitis; HSC, hematopoietic stem cell; ILC, in-
nate lymphoid cell; ITE, 2-(19H-indole-39-carbonyl)-thiazole-4-carboxylic acid methyl
ester; MWCNT, multi-walled carbon nanotube; NM, nanomaterial; NP, nanoparticle;
PEG, polyethylene glycol; TCDD, 2,3,7,8 tetrachlorodibenzo-p-dioxin.
Copyright Ó 2016 by The American Association of Immunologists, Inc. 0022-1767/16/$30.00
3218 BRIEF REVIEWS: ENVIRONMENTAL TOXICANTS AND IMMUNITY

FIGURE 1. Exposure to and effects of environmental

toxicants. Toxicants may access the human body through
four points of entry (skin, blood, respiratory, and digestive
tracts), as shown in blue, and affect numerous organs,
including the immune system. Toxicants interact with the
immune system as a result of deliberate or unintentional
exposure, causing either immune activation or immune
suppression. Depending on the disease context, this may
be either beneficial or detrimental because undesirable
immune activation or immune suppression may result in
adverse health effects.

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found to cause severe thymic atrophy and humoral immune play a significant role in AhR-mediated immune suppression.
suppression (6). The succession of rapid discoveries through- AhR activation in DCs increases the expression of regulatory
out the 1980s broadened the expanse of AhR-mediated sup- genes, including IDO-1 and IDO-2 (Ido1 and Ido2), reti-
pression within the immune system to include thymic atrophy, naldehyde dehydrogenase 1 (aldh1a1), and TGF-b3. Conse-
reduced cell-mediated immunity, diminished humoral Ab re- quently, AhR-activated regulatory DCs can be potent inducers
sponses, and an overall reduction in the ability to respond to of Foxp3+ regulatory T cells (16–20). In contrast, AhR func-
and resist infectious diseases (5–9). tions as a regulator of innate/inflammatory responses in mac-
With a potential link made between AhR and observed sup- rophages, as illustrated by the negative regulation of LPS-
pression of the immune system, immunologists entered into induced inflammation and subsequent enhanced sensitivity
the field, which to this point had predominantly been pio- to lethal shock (21). Also, AhR activation in monocytes/
neered by toxicologists and biochemists. The interweaving of macrophages results in dysregulated cytokine and chemokine
discoveries from these disciplines expanded our understanding production, a consistent effect observed in murine and human
of the AhR signaling pathway and its role in innate and cells (22, 23). Lastly, the differentiation and/or maturation of
adaptive immune responses, as recently reviewed by Stockinger monocytes/macrophages and DCs is affected by AhR, an effect
et al. (10). Because several recent reviews focused on AhR acti- that contributes to immune dysregulation (24–26).
vation in T cells, our focus is on what we consider three key Human NK cells, which express AhR in stage 3 immature
areas of ongoing investigation: the role of AhR in the innate NK cells and “NK-22” cells, play an important role in innate
immune system, the crusade to identify endogenous ligands, immune responses to mucosal infections that may be altered
and the development of novel AhR-mediated immunotherapies.
Innate immune cells vary widely in their expression of AhR
(Fig. 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 (dioxin response elements or xenobiotic
response elements) within their promoter/enhancer regions (12,
13), and it was shown that cross-talk between AhR and NF-kB
can significantly impact multiple proinflammatory signals (14).
Neutrophils, as well as most granulocytes, do not express AhR at
significant levels and appear to be predominantly influenced by
AhR activation through indirect mechanisms (15).
Professional APCs (e.g., macrophages and dendritic cells FIGURE 2. AhR expression in immune cells. AhR expression (x-axis) and
[DCs]) constitutively express AhR at relatively high levels and outcomes of AhR activation (y-axis) by immune cell type.
The Journal of Immunology
by environmental AhR ligands (27, 28). Indeed, 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 func-
tion is potentiated following AhR activation (29). Conversely,
other reports demonstrate that AhR activation can suppress
NK cell function, suggesting that 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 im-
munity, were shown to have compromised bacterial clearance
and reduced IL-22 expression when they lack AhR (30).
Although investigations into the role of AhR in ILCs are
relatively recent, existing studies indicate AhR activation in
ILC subsets effectively regulates transcriptional activation and,
consequently, the clearance of mucosal infections, immune
tissue development, and regulation of chronic inflammatory
diseases, such as inflammatory bowel disease (31). Collectively,
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 im-
pacts of AhR activation within the immune system often have
had dual roles: to identify the immunomodulatory effects of
AhR signaling in immune cells and to assess the breadth of
immunotoxicity following exposure to large classes of xeno-
biotics. Early discoveries by toxicologists and biochemists
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, the recent discovery of putative
endogenous AhR ligands yielded several compounds that can
bind and activate AhR with relatively high affinity (32). For
example, 2-(19H-indole-39-carbonyl)-thiazole-4-carboxylic acid
methyl ester (ITE) from porcine lung tissue (33) and the
tryptophan derivatives 6-formylindolo[3,2-b]carbazole and
L-kynurenine are “natural” AhR-activating compounds that can
significantly impact the generation of immunity (18, 34–37).
However, although these chemicals activate AhR and can induce
similar transcriptional responses to TCDD, such as the induc-
tion of signature cytochrome P450s (CYP1A1, CYP1A2,
CYP1B1), they are highly susceptible to metabolism by these
xenobiotic-metabolizing enzymes, thereby limiting their effec-
tive half-life and associated toxicities (37). At present, at least
one of these compounds (ITE) is being evaluated for potential
therapeutic use in humans (discussed below). Notably, we have
a limited understanding of the specific biomolecular interactions
that occur between ligands and AhR as the result of the lack of a
defined crystal structure for this receptor. Therefore, it is diffi-
cult to accurately predict what the clinical outcomes will be if/
when AhR-binding compounds are eventually tested in hu-
mans, who are generally considered to express a 10-fold lower-
affinity AhR compared with (most) rodents. This relationship
remains to be confirmed in significantly larger human cohorts,
thereby representing a prominent gap in our understanding of
AhR biology.
With AhR now recognized as a potent immune regulator, it
has become an attractive target for immunotherapy. However,
3219
there are many factors that must be fully considered when
intentionally targeting AhR to achieve specific immune regu-
lation. It is well documented that the effects of AhR activa-
tion during an immune response vary based on the target cell
(10, 11, 32, 37). AhR activation can increase inflammatory
responses or, alternatively, promote immune regulation or tol-
erance (38). Recently, nanoparticles (NPs) containing ITE,
an AhR agonist, were used successfully to treat experimental
autoimmune encephalomyelitis (EAE), a mouse model of
multiple sclerosis. In these studies, gold NPs (AuNPs) were
used for parenteral delivery of ITE and an antigenic self-
peptide, myelin oligodendrocyte glycoprotein 35–55 (39).
Within 6 h of administration, splenic DCs, which inter-
nalized ITE-loaded NPs, significantly upregulated AhR-
responsive genes, including aldh1a1 and cytochrome P450
1a1, the prototypical AhR target gene. Ultimately, a marked
reduction in EAE disease scores was observed following ad-
ministration of ITE-loaded and ITE/myelin oligodendrocyte
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glycoprotein 35–55-loaded NPs, an outcome that was at-
tributed to a significant induction of disease-specific regula-
tory T cells (39).
Although parenteral administration of AhR agonist–loaded
NPs (AhR/NPs) showed significant amelioration of EAE in
mice, AuNP uptake was not isolated to DCs in these animals;
it was observed in several immune and nonimmune cells (39).
Because unguided NPs can often yield off-target adverse ef-
fects, we hypothesize that using 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
nonspecific uptake of AhR/NPs by bystander cells. Ulti-
mately, intentional modulation of AhR holds great promise
for the development of novel immunotherapeutics to treat
patients suffering from multiple sclerosis and potentially other
devastating immune-mediated diseases.
Nanomaterials and the immune system. Nanotechnology repre-
sents 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, although enabling novel
applications and technological advances, also give rise to safety
concerns that cannot be ignored. Several of those same char-
acteristics that make nanomaterials (NMs) so promising from
a technological standpoint, also make their interactions with
biological systems difficult to anticipate and critically impor-
tant to investigate methodically.
Over the last decade, researchers from industry, academia,
and federal agencies have been collaborating to establish spe-
cific assays and NMs criteria that will assess the impact of
NMs on immune function. Currently, no comprehensive
guidelines exist. Because NMs 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 NMs research.
For example, many NMs absorb in the UV–visible range and
may even catalyze enzyme reactions or quench fluorescent
dyes commonly used in end-point and kinetic assays. Simi-
larly, although exposure to a particular NM may result in no
3220 BRIEF REVIEWS: ENVIRONMENTAL TOXICANTS AND IMMUNITY
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, NMs produced in lower quantities that have
potent and selective effects on the immune system (e.g.,
nickel, gold, and cobalt NM) may exhibit greater immuno-
toxicity. Thus, we must assemble a comprehensive under-
standing of the relationship between diverse NMs and specific
components of the immune response resulting from different
testing scenarios.
As a result of NM size and unique properties, the immune
system efficiently recognizes engineered NMs as foreign bod-
ies, resulting in multilevel responses that can range from acute
to chronic, and from immunostimulatory to immunosup-
pressive (40). Although NMs-induced immune activation
may increase the incidence of allergic reactions, inflammatory
responses, or autoimmunity, NMs-induced suppression may
reduce maturation and proliferation of immune cells, result-
ing in increased susceptibility to infectious diseases or tumor
growth. Although a desirable interaction between NMs 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 inflamma-
tion, or lowered response to infection and cancerous cells.
Moreover, inadvertent recognition of NMs as foreign by im-
mune cells may result in host toxicity and/or reduced thera-
peutic efficacy of conventional pharmaceuticals.
Carbon nanotubes are a family of NMs made up entirely of
carbon. Within this family, multi-walled carbon nanotubes
(MWCNTs) are of special interest to the industry because of
their broad applications 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, as well as 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 (41–43).
Numerous studies clearly demonstrate that MWCNTs induce
lung injury through acute and chronic inflammation, granu-
loma formation, and substantial interstitial lung fibrosis, as
well as exacerbate asthma-like conditions in mice (44–46).
This section surveys recent efforts to define the effects of
MWCNTs on the innate immune system. Once NMs deposit
in the lungs, alveolar macrophages are responsible for their
uptake and processing through phagocytosis, macro-
pinocytosis, and clathrin/caveolin-dependent and -indepen-
dent endocytosis (47–49). A number of studies similarly
linked MWCNT-induced oxidant stress, phagolysosomal
permeabilization, cathepsin B release, NLRP3 inflammasome
assembly, and caspase-1 activation with secretion of important
regulatory cytokines (e.g., IL-1b and IL-18) (50–55). Acti-
vation of the NLRP3 inflammasome by MWCNTs is con-
sistent with reports showing that other inhaled particles
(e.g., silica and asbestos) cause lung injury through
NLRP3 inflammasome activation (56). Upon internalization,
MWCNTs induce lysosomal dysfunction and autophagosome
accumulation, which may disrupt autophagy (57, 58). In
turn, disruption of autophagy may enhance NLRP3 inflam-
masome accumulation, resulting in exaggerated IL-1b pro-
duction and lung fibrosis (59). Interestingly, variation in
the dimensions and surface properties of NMs affects the
autophagic responses of cells (60, 61). Similarly, variation
in MWCNT surface structure activates alternate autophagy
signaling pathways (mTOR dependent to mTOR indepen-
dent) (62). Agents that can selectively induce autophagic cell
death in tumor cells are promising tools to treat or supple-
ment current cancer therapies. Thus, modulation of auto-
phagy by NMs may be a potential therapeutic strategy. Taken
together, these studies provide novel insights on how NMs,
such as MWCNTs, contribute to inflammasome activation,
autophagic cell death, and induction of the stress response, as
well as the role of NM surface chemistry in the modulation of
these signaling processes for therapeutic benefit. These find-
ings are particularly relevant given that dysfunction or dys-
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regulation of inflammasome activation and autophagy is
associated with several immune-mediated diseases.
Given the rapid growth of nanotechnology and the myriad
potential physicochemical properties, NMs will influence and
advance emerging medical technologies in both therapeutics
and diagnostic applications. Scientists are engineering NM-
based approaches to 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 de-
velopment. NMs-based delivery systems offer the following
potential advantages: site-specific delivery of drugs, peptides,
and genes; improved in vitro and in vivo stability; and reduced
side effects. Although in recent years our understanding of
NMs 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 par-
ticle coating can dictate NM compatibility with the immune
system. For example, NMs can be designed by attaching to
polyethylene glycol (PEG) of other types of polymers to create
a hydrophobic environment, thus shielding them from im-
mune recognition (63). Although these polymers may shield
NMs from most immune surveillance, some data suggest
the formation of PEG-specific Abs (64, 65) and accelerated
clearance of PEG liposomes from the blood, thus changing
the pharmacokinetic profiles (66–68). Therefore, generation
of NM-specific Abs may affect the efficacy and safety of NM-
based therapeutics. In contrast, NMs can be designed to elicit
an immune response by either direct activation of APCs or
delivering Ag to specific cellular compartments (69). One of
the most heavily researched areas in nanomedicine is NP-
based drug delivery (70, 71). Although this research is pro-
ducing effective reagents and making poorly soluble drugs
useful through encapsulation, controlled release, and target-
ing, the NPs themselves are usually not therapeutic.
In this final section, we briefly review the effects of AuNPs
on immune function. As a result of their fairly simple prep-
aration and functionalization with drugs or other ligands,
The Journal of Immunology
unique optical properties, and tuneability with regard to a
desired size or shape (72–74), AuNP-based immunotherapies
have been a promising carrier for immune therapies in can-
cer Ag and immune adjuvant delivery (75–77), as well as
in photothermal ablation and light-triggered drug delivery
(78–80). However, because AuNPs can accumulate in the
immune system and exhibit many toxic side effects, they
should be used cautiously as a delivery system.
As with other NMs, the size, shape, and electrical charge
alter the recognition and uptake of AuNPs in both phagocytic
and nonphagocytic cells. Interestingly, in nonphagocytic cells,
positively charged AuNPs appear to be taken up to a much
greater extent than negatively charged ones, whereas in
phagocytic cells, particle charge has little effect on uptake.
Furthermore, in nonphagocytic cells, AuNPs were taken up via
clathrin-mediated endocytosis and localized to secondary ly-
sosomes, whereas in phagocytic cells, AuNPs were taken up
through phagocytosis and located in phagosomes (81). Later
studies showed that phagocytosis of 30- versus 150-nm-
diameter AuNPs occurred via different mechanisms (e.g.,
clathrin-mediated pinocytosis and scavenger receptor–medi-
ated phagocytosis, respectively) (82). In vitro AuNPs induce
proinflammatory cytokine expression in macrophages in a
size-dependent manner (83). In contrast, other laboratories
showed that AuNPs can inhibit IL-1b–mediated inflamma-
tory responses and TLR9 responses, also in a size-dependent
manner (84, 85). Although these studies also suggested that
particles , 5 nm had the greatest impact on immune re-
sponse, others determined that more hydrophobic ∼2-nm
AuNPs exhibited the greatest expression of inflammatory
cytokines by mouse splenocytes (86). Oligonucleotide-
conjugated 13-nm AuNPs increased the expression of in-
flammatory and defense response genes as categorized by gene
ontology analysis in human PBMCs, yet similar responses
were not observed in the 293 T cell line (87), suggesting that
assessing the 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 depen-
dent. Finally, because AuNPs inevitably accumulate in high
concentrations in the liver and spleen for extended periods of
time (88, 89), it is important to better understand how
AuNPs interact with the immune system before develop-
ing them as a therapeutic delivery platform. It appears that
therapeutic AuNPs may be similar to chemotherapeutics’
double-edged sword because they can be therapeutic, yet they
can also be toxic. Additionally, the differing results regard-
ing the inflammatory or anti-inflammatory effects of AuNPs
merit further consideration. Although the distribution and
immune-modulatory activity of AuNPs in vivo may cause
inflammatory or anti-inflammatory side effects, these prop-
erties might also be manipulated for therapeutic applications,
such as vaccine and immune adjuvant delivery. These studies
highlight the need to design NMs that do not adversely affect
the biological systems where they will be used and demon-
strate that it is crucial to simultaneously ascertain the thera-
peutic and toxic properties of any metal-containing NP.
Nanotechnology has generated, and will continue to gen-
erate, a wide spectrum of novel NMs that will revolutionize
many fields. Existing studies demonstrated that nanotech-
nology offers advantages over traditional medicines, such as
3221
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 NMs pose in
occupational, medicinal, consumer, or environmental expo-
sure settings because of their unpredictable chemical and bi-
ological nature. Immune reactions are a key concern for
potential adverse effects of NMs. Although certain predictions
can be made regarding the immunotoxicity of NMs, the
unique nature of these structures make it difficult, if not
impossible, to predict how some NMs will interact with in-
tracellular structures, such as DNA, cell membranes, and
cytoskeletal proteins. NMs exposure has not yet been linked to
human disease because of the relatively recent emergence of
nanotechnology and the lack of epidemiologic data. Thus,
future research into NMs is highly relevant from a public
health perspective, as well as for the novel insights that it will
yield on the basic functions of the immune system.
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Effects of xenobiotics on the developing immune system. To develop
novel and safe therapies that provide efficient protection
against infectious diseases or immune-mediated diseases in
children or those 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 the 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: the developing immune system
may be more sensitive to environmental chemical exposures
than the adult immune system, and the environment
significantly impacts the 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,
it potentially extends to additional generations through
epigenetic changes. Therefore, uncovering the effects of
environmental insults on the developing immune system is
expected to benefit public health and provide novel insights
into immune system ontogeny. The increased risk for 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
for adverse immune outcomes persisting into later life (90).
These differential immune effects can take many forms, which
are briefly described below for a select few toxicants.
Perhaps one of the more comprehensive datasets for de-
velopmental 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 (91).
3222 BRIEF REVIEWS: ENVIRONMENTAL TOXICANTS AND IMMUNITY
These effects can contribute to increased incidence of auto-
immunity and decreased responsiveness to infectious patho-
gens, such as influenza A (92, 93). 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 (94).
Conversely, early life exposure to TCDD was recently dem-
onstrated to enhance the CD4+ T cell response to viral in-
fection in the lung; however, this response ultimately resulted
in greater bronchopulmonary inflammation and, con-
sequently, reduced antiviral immunity (95, 96). Additionally,
the AhR signaling pathway plays a requisite role in the de-
velopment and function of HSCs and progenitor cells; con-
sequently, AhR-null mice possess abnormalities in these
cellular populations (97–100). Moreover, recent reports de-
scribed a critical usefulness for AhR antagonists (along with
Notch ligand agonists) in the regulation and generation of
HSCs from cord blood, providing significant advances for
allograft transplantation (97, 101). Taken together, AhR is
now recognized as a critical regulator of key cells in the de-
veloping immune system; consequently, a greater under-
standing of its effects will benefit the development of novel
immunotherapies and result in 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), organophos-
phates (i.e., diazinon), and carbamates (i.e., carbofuran), were
reported to induce developmental immunotoxicity in rodents
(102). Additionally, prenatal exposure of humans to DDE is
associated with reduced levels of IgG and recurrent respiratory
infections in infants (103, 104). These results are intriguing
because of reports that DDE can also enhance allergic re-
sponses in infants via induction of Th2 cytokines (105) but
not via modulation of IgE, IL-33, or TSLP (106). Exposure of
the developing immune system to heavy metals, such as lead,
a known developmental toxicant, can adversely affect the
generation of innate immune cells, such as macrophages and
DCs (107). Specifically, dysregulated macrophage and DC
effector functions, including reduced phagocytosis, lysosomal
activation, and excessive production of reactive oxygen species
and other inflammatory mediators (i.e., TNF-a, PGE2),
contribute to Th2-biased immune responses in lead-exposed
animals (108–110), ultimately contributing to imbalanced
and inappropriate immune responses that can be persistent
and increase the risk for inflammatory disorders and disease
later in life (107). Thus, these studies have advanced our
understanding of ontogeny of the innate immune system and
support the hypothesis that early life exposure to these envi-
ronmental 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 known whether these environmental chemicals ad-
versely affect the developing immune system, although, very
recently, this has been an area of intense investigation (111).
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
(112). Perinatal exposure to low doses of BPA rendered the
neonatal immune system more susceptible to food intolerance
(113), and prenatal, but not postnatal, BPA exposure can
enhance the postnatal development of experimental allergic
asthma (114). Because BPA was shown to induce epigenetic
regulation (i.e., DNA methylation, microRNA expression,
and histone acetylation) in reproductive tissues, it will be
interesting to determine whether similar effects exist in the
developing immune system that may consequently affect the
generation of inflammatory or immune-mediated disease
(115). At the least, it is expected that further research on the
potential immunotoxic effects of BPA and other endocrine
disruptors will help us to 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
Downloaded from http://www.jimmunol.org/ by guest on October 21, 2019
outcomes, including immune deficiency, deviation, or dys-
regulation. Although it is hypothesized that these effects
manifest themselves during the course of development or
maturation of an organism, it is also possible that immuno-
toxicity can be transgenerational, although additional studies
are necessary to firmly establish this potential outcome. If
confirmed, these long-term effects could have profound im-
plications on the immune system and its ability to respond
effectively to infectious pathogens and tumor cells or to reg-
ulate appropriately self-directed responses that underlie au-
toimmunity. However, it is expected 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, the U.S. Environmental Pro-
tection Agency is the only chemical regulatory agency to have
specific immunotoxicity testing requirements, and these are
primarily for assessing pesticides (116). In contrast, the phar-
maceutical industry uses a weight-of-evidence approach that
is only exercised for immunological evaluation if standard
toxicological assays show cause for concern. Regardless, nu-
merous examples exist demonstrating the potential adverse
effects that exposure to environmental chemicals can and do
have on the immune system. Although xenobiotic exposure
can come from environmental, occupational, or recreational
sources, this list of potential threats has expanded recently 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 AhR regulates immune development and
function, the use of chemicals, such as TCDD, has been in-
voked as environmental stressors, as well as biological probes.
The Journal of Immunology
These studies have resulted in a greater understanding of the
critical role of the AhR in HSCs, progenitor cells, and innate and
adaptive immune cells. In the study of NMs, immunotoxicol-
ogists have been on the cutting-edge of discovery, identifying
powerful biomedical uses and establishing necessary safety pa-
rameters for these xenobiotics. Experiments using NMs also
yielded novel, fundamental insights into inflammatory processes,
such as the generation and regulation of the inflammasome, as
well as 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 AhR signaling modulators (both agonists
and antagonists), environmental pollutants (i.e., TCDD, PCBs)
that induce epigenetic modifications, and endocrine disruption
by xenoestrogens (i.e., BPA), are expected to enhance public
health, as well as spur development of novel immunotherapeu-
tics designed to improve childhood health. In this manner, en-
vironmental immunology provides innovation at the intersection
of immunology and the environment in which we live.
Disclosures
The authors have no financial conflicts of interest.
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