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Neurotoxicology and Teratology

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Cytokine dysregulation in autism spectrum disorders (ASD): Possible role ofthe environment

Paula E. Goines a, Paul Ashwood b,⁎a University of California, Davis, School of Veterinary Medicine, Department of Molecular Biosciences, Sacramento, CA, USAb University of California, Davis, School of Medicine, Department of Medical Microbiology and Immunology, Sacramento, CA, USA

⁎ Corresponding author at: University of California, Da2805 Wet Lab Building, Sacramento, CA 95817, USA. Tel.:

E-mail address: [email protected] (P. Ashwoo

0892-0362/$ – see front matter © 2012 Elsevier Inc. Allhttp://dx.doi.org/10.1016/j.ntt.2012.07.006

Please cite this article as: Goines PE, Ashwoment, Neurotoxicol Teratol (2012), http://d

a b s t r a c t
a r t i c l e i n f o
Article history:Received 4 April 2012Received in revised form 3 July 2012Accepted 31 July 2012Available online xxxx

Keywords:Autism spectrum disorderCytokineToxicantImmunologyEnvironmentNeurodevelopment

Autism spectrum disorders (ASD) are neurodevelopmental diseases that affect an alarming number of indi-viduals. The etiological basis of ASD is unclear, and evidence suggests it involves both genetic and environ-mental factors. There are many reports of cytokine imbalances in ASD. These imbalances could have apathogenic role, or they may be markers of underlying genetic and environmental influences. Cytokines actprimarily as mediators of immunological activity but they also have significant interactions with the nervoussystem. They participate in normal neural development and function, and inappropriate activity can have avariety of neurological implications. It is therefore possible that cytokine dysregulation contributes directlyto neural dysfunction in ASD. Further, cytokine profiles change dramatically in the face of infection, disease,and toxic exposures. Imbalances in cytokines may represent an immune response to environmental contrib-utors to ASD. The following review is presented in two main parts. First, we discuss select cytokines implicat-ed in ASD, including IL-1Β, IL-6, IL-4, IFN-γ, and TGF-Β, and focus on their role in the nervous system. Second,we explore several neurotoxic environmental factors that may be involved in the disorders, and focus ontheir immunological impacts. This review represents an emerging model that recognizes the importance ofboth genetic and environmental factors in ASD etiology. We propose that the immune system provides crit-ical clues regarding the nature of the gene by environment interactions that underlie ASD pathophysiology.

© 2012 Elsevier Inc. All rights reserved.

1. Introduction

Autism spectrum disorders (ASD) are clinically variable neurodevel-opmental disorders that arise in early childhood. ASD is diagnosed in 1out of every 88 children in the United States, and is characterized bystereotypic behaviors and impaired language and communication(American Psychiatric Association, 1994; Lord et al., 1994; Prevention,2009; CDC, 2012). The biological basis of ASD remains largely elusive.Postmortem investigations have demonstrated abnormal brain growth,including neuronal overgrowth in some regions (Courchesne et al.,2011), and undergrowth in others (Schumann and Amaral, 2006). Al-tered ratios of excitatory to inhibitory signaling in the brain may alsocontribute to ASD (Fatemi et al., 2002b; Rubenstein and Merzenich,2003; Fatemi et al., 2010; Yizhar et al., 2011). Inheritance analyseshave demonstrated a large genetic component, although a recent twinstudy suggests that non-genetic environmental factors alsomake a sub-stantial contribution (Hallmayer et al., 2011; Ronald and Hoekstra,2011). A multitude of genes have been implicated in autism, but onlya few cases can be traced to specific rare genetic variants, and many ofthe implicated genes are also found in typically developing populations

vis, UC Davis M.I.N.D. Institute,+1 916 703 0405.d).

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od P, Cytokine dysregulationx.doi.org/10.1016/j.ntt.2012

(State and Levitt, 2011). Collectively, these findings suggest that autismresults from complex interactions between multiple susceptibilitygenes and environmental factors.

A growing body of evidence implicates immunological disturbancesin ASD. Several of the genes linked to ASD have critical roles in immunesignaling, activation, and regulation (Torres et al., 2002; Campbell et al.,2006; Lee et al., 2006; Torres et al., 2006; Varga et al., 2009; Orlova andCrino, 2010). Individuals with autism and their family members (pri-marily mothers) demonstrate increased autoimmunity, altered cellularimmunity, and skewed expression of soluble mediators such as cyto-kines (Vargas et al., 2005; Braunschweig et al., 2008; Li et al., 2009;Morgan et al., 2010; Goines et al., 2011a; Onore et al., 2011). Cytokineabnormalities in ASD are an important clue for researchers as theymight result from genetic and environmental factors, and may contrib-ute directly to neurological dysfunction. The following considers theneurological significance of cytokine dysregulation in ASD, and how en-vironmental factors can modulate the cytokine response.

1.1. Cytokines: the common language between the immune and nervoussystem

The immune system and the nervous system interact extensively. Itis therefore not surprising that immune dysfunction is often noted inneurological disorders. Immune mediators known as cytokines are

in autism spectrum disorders (ASD): Possible role of the environ-.07.006

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2 PE Goines, P. Ashwood / Neurotoxicology and Teratology xxx (2012) xxx–xxx

key facilitators of cross-systemic communication. Cytokines are pro-teins that control the nature, duration, and intensity of an immune re-sponse. They are highly pleiotropic, and can act in an autocrine,paracrine, and/or endocrine fashions. Immune cells, including dendriticcells, macrophages, neutrophils, T cells, and B cells, are the primarysource of cytokines; though many additional cell types, including neu-rons, produce and respond to them. Cytokines share structural similar-ities and signaling pathways with neurotrophins and neurologicallyrelevant growth factors. In many ways, cytokines represent a commonlanguage between the immune system and the nervous system.

Cytokines influence both the development and function of the ner-vous system. Their significance varies based on the timing, duration,and intensity of the neuro-immune interaction. For example, cytokinesimpact the developing brain differently than the adult brain; and maybe beneficial at one concentration while harmful at another. Cytokinesare involved in normal aspects of neurodevelopment, including pro-genitor cell differentiation, cellular localization/migration within thenervous system, and synaptic network formation (Deverman andPatterson, 2009). During infection and illness, cytokinesmediate neuro-logical changes associatedwith fever and sickness behavior by signalingdirectly to the hypothalamus (Dantzer, 2001; Skurlova et al., 2006).Emerging evidence also implicates cytokines in higher order neurolog-ical functions, including cognition and memory (McAfoose and Baune,2009; Derecki et al., 2010). Imbalanced cytokine production, signaling,and/or regulation can therefore have a wide range of neurologicalconsequences.

2. Cytokines in ASD

Aberrant expression of cytokines and their signaling intermediariesis often noted in ASD (Table 1). This is observed in the brain (Vargaset al., 2005; Grigorenko et al., 2008; Voineagu et al., 2011; Ziats and

Table 1Cytokines in autism spectrum disorders. A variety of independent clinical studies have linkOften multiple cytokines were associated with ASD in a single study, which is noted in par

Cytokine Findings in autism

IL-1Β Elevated plasma levels in children with ASD, correlated with regressive onset.

Elevated plasma levels in high functioning children with ASD. (IL-1RA, IL-5, ILElevated plasma levels in adults with severe ASD. (IL-6 and endotoxin levels aPeripheral blood cells from ASD subjects produce higher baseline levels. (SimiPeripheral blood cells from ASD subjects produce higher levels with TLR2 or T(Similar trends for IL-6 and TNFα)

IL-6 Elevated plasma levels in children with ASD, correlated with regressive onset.

Elevated plasma levels in adults with severe autism. (IL-Β and endotoxin levelPeripheral blood cells from ASD subjects produce higher baseline levels. (SimiPeripheral blood cells from children with ASD produce higher levels with TLR2lation. (Similar trends for IL-6 and TNFαLymphoblasts from ASD subjects produce more IL-6. (Also TNF-α)Increased IL-6 staining in postmortem cerebellar sections from ASD subjectsIncreased IL-6 in postmortem brain specimens (various regions) from ASD subchemokines).Increased IL-6 in postmortem brain tissue from ASD subjects. (Also increased

IL-4 Increased IL-4 in mid-gestational serum samples from mothers giving birth toIncreased IL-4 in amniotic fluid samples from mothers giving birth to a child w(Also IL-10, TNF-α and TNF-Β)Peripheral blood cells from ASD subjects stimulated with PMA-ionomycin wer

IFN-γ Increased IFN-γ in mid-gestational serum samples from mothers giving birthIncreased plasma levels in individuals with ASD. (Also IL-12)Peripheral blood cells stimulated with PMA-ionomycin are less likely to be IFN(And more likely to be IL-4+)Unstimulated whole blood from ASD subjects produced significantly more IFNand TNF-α)NK cells from children with ASD produced higher IFN-γ under resting conditioperforin and granzyme B)Increased IFN-γ in post mortem brain specimens from ASD subjects. (Also inc

TGF-Β Decreased plasma TGF-Β in children with ASD. Lower levels correlated with mDecreased serum TGF-Β in adults with ASD.Increased TGF-Β levels in postmortem brain specimens (various regions) from

Please cite this article as: Goines PE, Ashwood P, Cytokine dysregulatioment, Neurotoxicol Teratol (2012), http://dx.doi.org/10.1016/j.ntt.2012

Rennert, 2011) peripheral blood (Molloy et al., 2006; Ashwood et al.,2011a, 2011b) and the gastrointestinal tract (DeFelice et al., 2003;Ashwood et al., 2004). Cytokine imbalances during development and/or throughout life could impact neural activity and mediate behavioralaspects of the disorder. The following considers the significance of sev-eral cytokines linked to ASD.

2.1. Interleukin (IL)-1B

IL-1Β is an inflammatory cytokine expressed very early in immuneresponses (Jiang et al., 1997). In tissue, IL-1Β propagates inflamma-tion by activating local immune cells and the vascular endothelium.Systemically, IL-1Β stimulates IL-6 production and eventually anacute phase response in the liver. Systemic IL-1Β can cross the bloodbrain barrier (Banks et al., 1991) and stimulate its own expressionin the hypothalamus, which leads to neuroendocrine changes associ-ated with fever and sickness behavior (Dantzer, 2001; Skurlova et al.,2006). IL-1Β receptors are structurally related to toll-like receptors(TLRs), and signaling is achieved through NF-κB and MAP kinase(MAPK) signaling cascades (O'Neill, 2000). IL-1Β belongs to an evolu-tionarily conserved family of proteins that function beyond immunity(Barksby et al., 2007). It shares structural homology with fibroblastgrowth factors (Zhang et al., 1991), which are critical in embryonicneurodevelopment, and are implicated in autism and schizophrenia(Tabares-Seisdedos and Rubenstein, 2009; Stevens et al., 2010).

Genes for IL-1Β, its receptor, and its receptor-associated proteins areassociatedwith intellectual disability, schizophrenia, and autism (Katilaet al., 1999; Piton et al., 2008; Handley et al., 2010). Children and adultswith autism have increased plasma IL-1Β and skewed cellular IL-1Β re-sponses following stimulation (Ashwood et al., 2011a, 2011b; Suzuki etal., 2011). Compared to controls, monocytes from children with ASDproduce excessive IL-1Β following LPS exposure (Jyonouchi et al.,

ed cytokines to ASD. This table presents detailed findings for each individual cytokine.entheses.

Reference

(IL-6, IL-8 and IL-12p40 also elevated) (Ashwood et al., 2011a,2011b)

-8, IL-12p70, IL-13, IL-17 and GRO-α also elevated) (Suzuki et al., 2011)lso elevated) (Emanuele et al., 2010)lar trends for IL-6 and TNF-α) (Jyonouchi et al., 2001)LR4 stimulation, and lower levels with TLR-9 stimulation. (Enstrom et al., 2010)

(IL-1Β, IL-8, and IL-12p40 also elevated) (Ashwood et al., 2011a,2011b)

s also elevated) (Emanuele et al., 2010)lar trends for IL-1Β and TNF-α) (Jyonouchi et al., 2001)or TLR4 stimulation, and lower levels with TLR-9 stimu- (Enstrom et al., 2010)

(Malik et al., 2011)(Wei et al., 2011)

jects. (Also increased TGF-Β and inflammatory (Vargas et al., 2005)

TNF-α, IFN-γ, GM-CSF, and IL-8) (Li et al., 2009)a child with ASD. (Also IL-5 and IFN-γ) (Goines et al., 2011b)ith ASD (Abdallah et al., 2011)

e more likely to be IL-4+ (And less likely to be IFN-γ+) (Gupta et al., 1998)to a child with ASD. (Also IL-4 and IL-5) (Goines et al., 2011b)

(Singh, 1996)-γ+ (Gupta et al., 1998)

-γ compared to controls. (Also increased IL-1RA, IL-6, (Croonenberghs et al.,2002)

ns, and lower levels after stimulation. (Also observed with (Enstrom et al., 2009a)

reased TNF-α, IL-6, GM-CSF, and IL-8) (Li et al., 2009)ore severe behavioral scores. (Ashwood et al., 2008)

(Okada et al., 2007)ASD subjects. (Also IL-6 and inflammatory chemokines) (Vargas et al., 2005)

n in autism spectrum disorders (ASD): Possible role of the environ-.07.006


3PE Goines, P. Ashwood / Neurotoxicology and Teratology xxx (2012) xxx–xxx

2001; Enstrom et al., 2010), and lower levels following exposure to TLR9 agonists (Enstrom et al., 2010). The IL-1 antagonist, IL-1ra, is also in-creased amongASD subjects (Suzuki et al., 2011). IL-1ra reduces inflam-mation by competing for the IL-1Β receptor, and increased levels mayrepresent an attempt to counteract inflammation in ASD. Postmortembrains from ASD subjects had normal IL-1Β levels (Li et al., 2009), butgiven that peripheral IL-1Β can enter the brain (Banks et al., 1991), in-creased systemic levels could directly impact neurological processes.

IL-1Β disruption can have a variety of neurological consequences rel-evant to ASD. The cytokine and its receptors are found throughout thenervous system during critical developmental periods (Giulian et al.,1988). IL-1Β induces neural progenitor cell proliferation in someCNS re-gions, while inhibiting it in others (de la Mano et al., 2007). This couldcontribute to the region-specific overgrowth and undergrowth ob-served in the ASD brain. Excitatory synapse formation is partially medi-ated by the IL-1 receptor and receptor-associated proteins (Yoshidaet al., 2011). Altering these proteins can tip the balance between excit-atory and inhibitory signaling, which might underlie neurological fea-tures of ASD (Rubenstein and Merzenich, 2003). Increased IL-1ra inASD suggests an attempt to counterbalance IL-1Β and may or may notbe beneficial. Following brain injury, IL-1ra upregulation serves aneuroprotective role by dampening excessive inflammation (Loddickand Rothwell, 1996). However, if administered during critical windowsof neurodevelopment, IL-1ra can negatively impact neurogenesis, brainmorphology, memory consolidation, and behavior (Spulber et al., 2008,2010, 2011). This shows that some level of IL-1B signaling is essentialduring development. In adulthood, IL-1Β is implicated in CNS disorderslike Alzheimer's disease and the advancement of amyloid-containingplaques (Griffin et al., 1995). While excessive IL-1B contributes to pa-thology in some cases, it may have a protective role in others. For exam-ple, IL-1Β limits neuronal damage following excitotoxic exposures(Strijbos and Rothwell, 1995), and mice lacking IL-1Β fail to undergoremyelination following experimental autoimmune encephalitis (EAE)induction (Mason et al., 2001). IL-1Β is involved in higher order brainprocesses and is induced in the hippocampus during learning processes,and is critical for maintenance of long-term potentiation (LTP) (Rosset al., 2003). Both over expression (Barrientos et al., 2009) and under ex-pression of IL-1 beta (Goshen et al., 2007; Labrousse et al., 2009) are as-sociated with impairments in memory and learning.

In summary, IL-1Β participates in neurological processes, and ap-pears to have a role in both CNS pathology and healing. Normal, ho-meostatic levels of IL-1Β and its antagonist IL-1ra are necessary forproper brain development and function. This “Goldilocks” state is typ-ical of many cytokines, where too much or too little is not desirable.Alterations in IL-1Β systems due to genetic mechanisms or environ-mental exposures may contribute to autism.

2.2. Interleukin (IL)-6

IL-6 is an inflammatory cytokine that shares functional propertieswith IL-1Β. Like IL-1Β, IL-6 is produced early in immune reactions, al-though it appears later and persists longer (Jiang et al., 1997). IL-6 isbest known for stimulating the acute phase response in the liver, gener-ating fever, and activating lymphocytes. Despite the functional similar-ities with IL-1Β, IL-6 differs drastically in terms of structure andsignaling properties. It is a member of the neuropoietic cytokine family,which includes leukemia inhibitory factor (LIF), ciliary neurotrophicfactor (CNTF), and IL-11. These cytokines signal through a gp130 recep-tor complex (Ward et al., 1994), and activate JAK-STAT (specificallySTAT 3) and MAPK signaling pathways (Heinrich et al., 2003). In addi-tion to their inflammatory properties, neuropoietic cytokines have anumber ofwell-described roles in the nervous system, and are intricate-ly involved in neurodevelopment and function (Bauer et al., 2007;McAfoose and Baune, 2009). IL-6 and its receptors are expressed atlow levels in the healthy brain (Gadient and Otten, 1994a, 1994b) andat higher levels in a variety of disease states (Huell et al., 1995; Hang

Please cite this article as: Goines PE, Ashwood P, Cytokine dysregulationment, Neurotoxicol Teratol (2012), http://dx.doi.org/10.1016/j.ntt.2012

et al., 2004). Peripheral IL-6 can cross the blood brain barrier and influ-ence a variety of processes in the adult brain (Banks et al., 1994).

Prenatal cytokine imbalancesmay contribute to neurodevelopmentaldisorders like autism and schizophrenia through “fetal programming”.Fetal programming is the concept that maternal factors like inflamma-tion and chronic stress can alter the gestational environment, skewdevelopment, and lead to long termphysiological and behavioral conse-quences (Patterson, 2009; Bilbo, 2010). IL-6 readily crosses the placentaand enters fetal tissues, which is unique among cytokines, and can in-duce changes in placental physiology and gene expression (Zaretskyet al., 2004; Aaltonen et al., 2005; Dahlgren et al., 2006; Hsiao andPatterson, 2011). Animal models show that IL-6 is necessary and suffi-cient to alter neurodevelopmental outcomes, leading to changes in be-havior, cognition, neuropathology, GABA dysregulation, and skewedimmune function among offspring (Samuelsson et al., 2006; Smith etal., 2007). Similar effects are seen with prenatal exposure to infectionor the infectious mimic poly I:C (Smith et al., 2007; Malkova et al.,2012). IL-6 can impact a variety of processes in the developing brain.IL-6 and its familymembers regulate self-renewal among neuronal pre-cursors (Escary et al., 1993; Yoshimatsu et al., 2006), direct neuronalmigration (Wei et al., 2011), promote cell survival (Kushima et al.,1992), and regulate neurite outgrowth (Ihara et al., 1997). IL-6 expo-sure during critical windows can also alter synaptic networks. ChronicIL-6 overexpression reduces expression of glutamate receptors andL-type calcium channels in culture and in vivo (Vereyken et al., 2007),and increases the ratio of excitatory to inhibitory synapses in culturesof cerebellar granular cell cultures (Wei et al., 2011). This is of particularinterest in autism, given that skewed excitatory and inhibitory ratiosmay be an underlying factor in its pathogenesis.

Despite intriguing evidence from animal models, two recent humanstudies question whether gestational IL-6 alone contributes to autism. Aretrospective examination of IL-6 in archived mid-pregnancy maternalserum and amniotic fluid showed that increased levels associated withdevelopmental disorders, but not autism (Abdallah et al., 2011; Goineset al., 2011b). This suggests that gestational IL-6 might be a marker forneurodevelopmental diseases, but is insufficient on its own to causeASD. IL-6 can affect many sequential phases of neurodevelopment, sothe timing of the exposurewill largely dictate the neurological outcome.Therefore, excessive IL-6 during one phase of neurodevelopment couldhave one set of consequences, while similar expression during anotherphase has an entirely different effect. A longitudinal examination ofIL-6 throughout gestation is therefore needed to obtain amore completepicture of its relevance in neurodevelopmental disorders.

IL-6 can also impact processes in the adult brain, and physiologicallevels are critical for homeostasis, cognition, learning, and memory.Physiological levels of IL-6 are critical for normal CNS function, andboth over and under expression leads to neurological problems. Miceoverexpressing IL-6 in the CNS have overt symptoms including tremor,ataxia, and seizure (Campbell et al., 1993), and more subtle alterationsin cognition and avoidance behaviors (Heyser et al., 1997). IL-6 is tran-scribed in the hippocampus during LTP (Balschun et al., 2004).Overexpression of IL-6 reduces LTP (Bellinger et al., 1995; Li et al.,1997), while under expression increases it and improves learning andmemory (Balschun et al., 2004; Braida et al., 2004).With regard to socialbehaviors, mice overexpressing IL-6 are more social than mice that lackthe cytokine, while mice lacking IL-6 demonstrate higher aggressionand emotionality (Alleva et al., 1998; Armario et al., 1998).

Many independent studies show IL-6 dysregulation in individualswith autism. Children and adults with the disorder have higher circulat-ing IL-6 levels compared to typically developing controls (Emanuele etal., 2010; Ashwood et al., 2011a, 2011b). Further, cellular IL-6 produc-tion is increased with and without stimulation (Jyonouchi et al., 2001;Enstrom et al., 2010; Malik et al., 2011). Increased IL-6 is also found inpostmortem brain specimens from ASD subjects. Specifically, immuno-histochemical analysis of cerebellar sections showed significantly moreIL-6 staining in autism postmortem brain specimens (Wei et al., 2011).




Two additional analyses of homogenates of the frontal cortex and ante-rior cingulate gyrus also showed higher IL-6 levels (Vargas et al., 2005;Li et al., 2009). Given the ability of IL-6 to impact processes in the adultbrain, it is conceivable that increased IL-6 in autism could contribute toongoing aspects of the disorder. Alternatively, it might be an epiphe-nomenon, and represent a biomarker of infectious or toxic environmen-tal exposures and altered biological homeostasis.

In summary, there is extensive evidence that IL-6 can alterneurodevelopment and function. While it is unclear whether gesta-tional IL-6 in humans is related to autism, a dysregulation of IL-6 isobserved later in life in individuals with autism. The significance ofthese findings is unclear, and may be the result of other genetic andenvironmental factors in autism. These possibilities warrant furtherinvestigation.

2.3. Interleukin (IL)-4

IL-4 is a class I cytokine that activates Jak/Stat (STAT 6), MAPK, andPI3 kinase signaling cascades (Nelms et al., 1999). Immunologically,IL-4 has a variety of interesting roles, and can 1) induce “alternativelyactivated” macrophages that promote tissue repair over inflammation,2) activate basophils andmast cells, 3) promote B-cell isotype switchingtowards IgG1 and IgE, 4) participate in immune responses againsthelminthes by inducing epithelial cell turnover in the gut, and 5) partic-ipate in allergy and asthma-related immune responses (Kuperman andSchleimer, 2008; Byers and Holtzman, 2011; Oliphant et al., 2011).

The receptors for IL-4 are expressed in the brain under normal con-ditions throughout life (Nolan et al., 2005). During development, IL-4promotes oligodendrogenesis among neuronal progenitor cells,(Butovsky et al., 2006), and improves survival in embryonic hippocam-pal cultures (Araujo and Cotman, 1993). IL-4 influences retinal circuitryby regulating progenitor cell proliferation and differentiation (da Silvaet al., 2008). During later phases of neurodevelopment, IL-4 can altersynapse formation; increasing the proportion of GABAergic synapsesin cell culture models (Sholl-Franco et al., 2002).

Two recent studies have linked developmental IL-4 exposures to au-tism, though its role in pathogenicity versus protection is unclear.Mothers giving birth to a child with autism show higher levels of IL-4in mid-pregnancy serum samples (Goines et al., 2011b) and amnioticfluid (Abdallah et al., 2011) compared to controls. IL-4 is not thoughtto cross the placenta, and maternal serum and amniotic fluid IL-4 mayor may not relate to IL-4 in fetal tissues. Other cytokines were alsoupregulated in these archived samples, including IFN-γ, TNF-α, andthe anti-inflammatory cytokine IL-10. This raises thequestion ofwheth-er IL-4 acts alone, or in concert with other cytokines. Increased IL-4mayrepresent a regulatory reflex to inflammation along with IL-10. IL-4'srole in pregnancy and fetal health is unclear. Increased levels duringpregnancy have been associated with poor outcomes such as pretermlabor (Dudley et al., 1996) but also healthy outcomes such as protectionfrom preeclampsia (Kronborg et al., 2011; Rajakumar et al., 2011).More subtle neurodevelopmental outcomes have not thoroughly beenexplored with respect to gestational IL-4.

In the adult brain, IL-4 largely serves a neuroprotective role, and isassociated with higher order cognitive processes. It is upregulatedduring CNS inflammation, inducing alternative activation of glialcells and protecting from apoptosis (Garg et al., 2009; Sholl-Francoet al., 2009; You et al., 2011). In a mouse model for Alzheimer's dis-ease, IL-4 can attenuate disease progression (Kiyota et al., 2010). Fol-lowing LPS exposure, IL-4 reduces inflammation and improvesmemory and LTP in the aged hippocampus (Nolan et al., 2005). An el-egant study by Derecki et al. showed that IL-4-producing T cells accu-mulate in the meningeal spaces during cognitive tasks. Depletion ofIL-4 led to an inflammatory phenotype among meningeal myeloidcells, and a dramatic decline in cognitive capacity. Remarkably, cogni-tive deficits in IL-4 deficient mice could be reversed by reintroducingthe cytokine in adulthood (Derecki et al., 2010).


Among individuals diagnosed with autism, plasma and CNS IL-4levels appear to be normal (Vargas et al., 2005; Li et al., 2009;Ashwood et al., 2011a, 2011b). However, IL-4 producing T cells areproportionately higher in children with autism compared to controls(Gupta et al., 1998). Given the evidence that meningeal IL-4 produc-ing T cells are critical for normal cognitive function in adulthood, itis possible that dysregulation in this cell population could contributeto altered behavior throughout life (Derecki et al., 2010).

Collectively, IL-4 serves a variety of neurological roles, and is in-creased in autism. Its role during gestation is unclear due to a dearthof in-vivo studies of pregnancy and neurobehavioral outcomes fol-lowing developmental IL-4 exposures. The significance of increasedIL-4 producing T cells in subjects with autism is also unclear. Exten-sive evidence suggests that IL-4 is neurologically beneficial, so itmay be that increased IL-4 in autism represents an immunological at-tempt to regulate other detrimental processes, and does not contrib-ute to the disease itself. Future studies should explore this possibility.

2.4. Interferon-gamma (IFN-γ)

Interferon gamma (IFN-γ) is the sole type II interferon. It sharessome functional similarities with type I interferons like IFN-α andIFN-Β but has unique structural features, receptors, and signaling path-ways. IFN-γ is producedprimarily by T cells andNatural Killer (NK) cellsduring cell-mediated immune responses, and functions largely to acti-vate macrophages and combat viral infections (Boehm et al., 1997;Schroder et al., 2004). It signals mainly through the JAK/STAT (STAT1),and MAPK cascades (Hu et al., 2001; Platanias, 2005). IFN-γ and IL-4counterbalance one another's activity via TH1/TH2 interactions, sodysregulation in one cytokine often impacts the other. It is thereforenot surprising that both cytokines are implicated in ASD.

Developmental exposure to IFN-γ has been linked to autism.Mothers of children with autism have higher serum IFN-γ duringthe second trimester compared to controls (Goines et al., 2011b).Like IL-4, IFN-γ does not cross the placenta, and the relationship be-tween maternal serum levels and fetal exposure to the cytokine isunclear. If the cytokine is present in fetal tissues, it could interferewith normal neural development and synapse formation. IFN-γ pro-motes neuronal differentiation among neural progenitor cells(Barish et al., 1991; Jonakait et al., 1994; Wong et al., 2004;Butovsky et al., 2006; Zahir et al., 2009; Leipzig et al., 2010; Li etal., 2010), however, these cells appear to be abnormal and exhibitcompromised function and strange patterns of neuronal marker ex-pression (Walter et al., 2011). IFN-γ also impacts dendritic morphol-ogy and synapse formation, leading to long-term changes in cellularconnectivity and communication. Depending on cell culture condi-tions, IFN-γ either promotes or inhibits dendrite outgrowth throughSTAT 1 and MAPK signaling pathways (Barish et al., 1991; Kim et al.,2002a; Wong et al., 2004; Song et al., 2005; Andres et al., 2008). Inculture, excessive IFN-γ alters patterns of excitatory signaling andreceptor expression (Vikman et al., 2001), and animals lacking thecytokine have fewer pre-synaptic terminals (Victorio et al., 2010).Interestingly, mice overexpressing IFN-γ show increased MHC I inthe brain (Corbin et al., 1996). MHC I is critical for T cell and NK cellrecognition of self and foreign entities, and was historically thought tobe absent in the CNS. However, recent studies have demonstrated thatit is expressed in the CNS, and has an essential role in synapse formationand plasticity (Shatz, 2009). IFN-γ may therefore induce abnormalitiesin synaptic organization by altering MHC I expression. Collectively,these studies show that direct exposure to IFN-γ can cause abnormalneurodevelopment, which may explain features of autism.

If excess IFN-γ is not present in fetal tissues, excessive maternallevels could have an indirect impact on fetal development. Interest-ingly, IFN-γ has a variety of critical roles in pregnancy, and directs as-pects of placental development, health, and maintenance (Murphyet al., 2009). Increased gestational IFN-γ is associated with adverse




pregnancy outcomes including recurrent miscarriage (Jenkins et al.,2000). Therefore, IFN-γ might be an indicator of compromised healthin pregnancy, which could lead to neurodevelopmental abnormalities.

Peripheral IFN-γ is up-regulated in a number of neurological disor-ders including multiple sclerosis (Martins et al., 2011) and Down's syn-drome (Torre et al., 1995). Individuals with autism have increasedplasma levels of IFN-γ (Singh, 1996), which correlates with other pe-ripheral inflammatory mediators such as nitric oxide (Sweeten et al.,2004a, 2004b). Peripheral immune cells from ASD subjects producehigher basal levels of IFN-γ but fail to respond further following immu-nological stimulation (Gupta et al., 1998; Croonenberghs et al., 2002;Enstrom et al., 2009a). In addition to peripheral IFN-γ dysregulation,postmortem brain specimens showed increased levels of IFN-γ (Liet al., 2009), suggesting IFN-γmay directly impact CNS processes in au-tism. In the developed nervous system, IFN-γ is historically associatedwith neurodegeneration, although some evidence suggests it mayhave a beneficial role. IFN-γ can cross the blood brain barrier at lowlevels (Pan et al., 1997), but is barely detectable in the healthy nervoussystem (Traugott and Lebon, 1988; De Simone et al., 1998). In the CNS,IFN-γ is up-regulated following infectious exposures (De Simone et al.,1998), and in diseases including cerebral palsy (Folkerth et al., 2004),multiple sclerosis (Traugott and Lebon, 1988), HIV dementia (Noltinget al., 2009), and Parkinson's (Barcia et al., 2011; Mangano et al.,2011). High levels are harmful in cell culture, and cause enhanced glu-tamate induced neurotoxicity (Mizuno et al., 2008). However, in cellculture and in vivo, low IFN-γ levels reduce oxidative-stress induced ap-optosis through activation of astrocytes (Garg et al., 2009; Victorio et al.,2010) and may be neuroprotective in some cases. In a mouse model ofAlzheimer's disease, overexpressing IFN-γ actually attenuated plaqueformation (Chakrabarty et al., 2010), while protective roles for IFN-γhave been suggested during some phases of demyelinating autoim-mune disorders (Kumar and Sercarz, 1998). It is therefore difficult todetermine whether IFN-γ has a pathogenic role in ASD, or if it repre-sents a potentially beneficial immune response to damage associatedwith genetic and/or environmental influences.

2.5. Transforming growth factor-beta (TGF-Β)

TGF-Β is a highly pleiotropic cytokine thatmaintains immune homeo-stasis, directs lymphocyte differentiation, and orchestrates aspects of em-bryonic development. TGF-Β is largely immunosuppressive; limitingexcessive T cell activity and inflammation (Mantel and Schmidt-Weber,2011). It exists in three isoforms, each with distinct and overlappingroles. TGF-Β1 is best characterized, and is the founding member of theTGF-Β superfamily of proteins, which includes growth differentiation fac-tors, bonemorphogenic proteins (BMPs), activins, and inhibins (Kingsley,1994). TGF-Β superfamily signaling occurs largely via SMAD pathways,though MAPK cascades are also triggered (Yu et al., 2002; Shi andMassague, 2003).

TGF-Β superfamily proteins are critical for proper neurodevelopment.For example, BMPs have an important role in early neural induction anddifferentiation (Reissmann et al., 1996; Bachiller et al., 2000; Tropepeet al., 2001). TGF-Β1 is involved in neuronal migration, survival, andsynapse formation. Mice lacking the cytokine demonstrate improperCNS development, including a disorganized extracellular matrix, wide-spread neuronal degeneration, microgliosis, reduced expression ofsynaptophysin, and deficits in both glutamatergic and GABAergic synap-ses (Brionne et al., 2003; Heupel et al., 2008; Vashlishan et al., 2008).Overexpressing TGF-Β in vivo also disrupts the extracellular matrix, andleads to seizures, motor incoordination, hydrocephalus, and behavioralabnormalities (Wyss-Coray et al., 1995; Depino et al., 2011). Changes inCNS expression levels of IL-6, Neuroligin 3 and reelin are also observedwith TGF-Β overexpression (Depino et al., 2011), which is intriguingbecause many of these proteins are altered in autism (Persico et al.,2001; Laumonnier et al., 2004; Fatemi et al., 2005). Interestingly, CNSoverexpression of TGF-Β during development vs. adulthood leads to


opposite behavioral consequences (Depino et al., 2011). Early in life,overexpression led to decreased social behavior and heightened anxi-ety/depression behaviors, while overexpression later in life had theexact opposite effect. This highlights the importance of timingwhen con-sidering the neurological consequences of cytokine imbalances.

There is no evidence for TGF-Β dysregulation during gestational de-velopment in autism. This does not negate the possibility that it is in-volved, as these endpoints are extremely difficult to measure in vivo.However, there is evidence for TGF-Β dysregulation in individuals diag-nosed with the disorder themselves. Plasma TGF-Β is decreased in chil-dren and adults with ASD (Okada et al., 2007; Ashwood et al., 2008),and lower levels of the cytokine correlate with more severe autism be-haviors (Ashwood et al., 2008). The connection between low TGF-Βand behavioral phenotype is unclear, although thisfinding lends promiseto the goal of developing a simple ASD testing regime based on biologicalmarkers in addition to behavioral symptoms. In contrast to peripheralTGF-Β in ASD, postmortem brain specimens show increased levels com-pared to controls (Vargas et al., 2005). The reason for this periphery/brain disparity is unclear. Although, TGF-Β does not cross the bloodbrain barrier (Kastin et al., 2003), the cytokine and its receptors areexpressed normally throughout the nervous system (Gomes et al.,2005) and it is conceivable that peripheral and brain levels are indepen-dent. In the adult brain, TGF-Β is generally thought to be neuroprotective.CNS levels spike following injury and infection, and increase with age,HIV dementia, andAlzheimer's disease,which leads to protection againstdisease-related neural degeneration and apoptosis (Henrich-Noack et al.,1994; Krupinski et al., 1996; Ruocco et al., 1999; Buckwalter andWyss-Coray, 2004; Doyle et al., 2010). However, TGF-Β can also contrib-ute to pathogenicity. For example, high levels of the cytokine cause glialscarring and fibrosis (Moon and Fawcett, 2001), and increase diseasesusceptibility and severity in a murine model of multiple sclerosis(Wyss-Coray et al., 1997).

Overall, the role of TGF-Β in the nervous system is complex, andvaries based on the timing and context of the interaction. IncreasedTGF-Β in the brain of ASD subjects might represent a protective reflexto a disease state, or perhaps contribute to the pathology of the diseaseitself. In the periphery, ASD subjects have decreased TGF-Β aswell as in-creased inflammatory markers (Jyonouchi et al., 2001; Croonenberghset al., 2002; Emanuele et al., 2010; Ashwood et al., 2011a, 2011b). Thissuggests a global immune dysregulation in ASD, with an improper bal-ance between regulation and activation, which could have widereaching consequences for many systems in the body.

3. Environmental factors in autism and immune dysfunction

There is now general consensus that autism has an environmentalcomponent (Pessah, 2008; Hallmayer et al., 2011). For our purposes,the “environment” is a broad term used to define non-genetic, toxic,infectious, and/or immune factors that may contribute to the disor-der. The hypothesis follows that an ill-timed exposure could cause au-tism in genetically susceptible individuals (Fig. 1). For example, somegenes associated with autism may cause inappropriate immune re-sponses (Heuer et al., 2011; Onore et al., 2011), while others reducethe capacity to deal appropriately with toxins (D'Amelio et al.,2005). These individuals are more susceptible to environmental influ-ences, which could lead to ASD.

Environmental toxicants can cause both neural and immune dys-function. This is likely mediated through disrupted cell signaling andhomeostasis. Many toxicants alter calcium homeostasis, which canhave a variety of consequences for immune development and function(Limke et al., 2003; Toscano and Guilarte, 2005; Savignac et al., 2007;Vig and Kinet, 2009; Pessah et al., 2010; Bhatti et al., 2011). Toxicantscan also disrupt endocrine function, which can have a variety of immu-nological consequences (Rivest, 2010; De Vito et al., 2011; Schug et al.,2011). The following section considers environmental factors that




may be related to autism, and focuses on their role in the immunesystem.

3.1. Heavy metals

Heavy metals like lead and mercury are widespread environmentaltoxins. Developmental exposure to these compounds is associated withlower IQ, endocrine disruptions, and behavioral disturbances (Bellingerand Dietrich, 1994; Steuerwald et al., 2000; Cordier et al., 2002;Selevan et al., 2003; Winneke, 2011). Heavy metals also haveimmunotoxic properties, leading in some instances to autoantibody pro-duction (Waterman et al., 1994; Bagenstose et al., 1999; Rowley andMonestier, 2005) and skewed cytokine profiles (discussed below). Bothof these immunological phenomena are observed in ASD (Enstromet al., 2009b; Onore et al., 2011). These features have made them possi-ble, though controversial, candidates in autism.

3.2. Heavy metals: lead

Lead has a variety of toxicmechanisms, and shares structural featureswith calcium which allows it to compete for binding sites (Toscano andGuilarte, 2005). In addition to its neurotoxic activity, lead is highlyimmunotoxic (Toscano andGuilarte, 2005;Mishra, 2009). At high levels,it is immunosuppressive, leading to increased production of regulatorycytokines and enhanced susceptibility to infection (Valentino et al.,2007). At lower levels, lead appears to be immunostimulatory (Floheet al., 2002). One study showed that lead can tip the balance between in-flammation and regulation by increasing expression of IFN-γ and reduc-ing TGF-Β (Goebel et al., 2000): a cytokine profile which has beenobserved in autism (Singh, 1996; Gupta et al., 1998; Croonenberghset al., 2002; Ashwood et al., 2008; Enstrom et al., 2009a; Li et al., 2009).Lead and pro-inflammatory cytokines can function in concert to alterthe nervous system. When co-administered to glial cells, lead and cyto-kines such as IL-1Β changed matrix metalloproteinase expression in amanner that was not observed when either was administered alone(Lahat et al., 2002) and suggests that immune and environmental factorscould act synergistically on tissue remodeling.

There are conflicting reports regarding lead in autism. Higher serumlead levels have been documented in a few studies (Cohen et al., 1976;Shannon and Graef, 1996; Filipek et al., 1999), although more recentstudies show no difference between autism and control populations(Tian et al., 2011; Albizzati et al., 2012). Polymorphisms in ALAD, agene associated with heavy metal toxicity, have been described inASD (Rose et al., 2008) leading, some authors to speculate that childrenwith ASD have higher lead levels due to a decreased capacity to elimi-nate lead from the body (Kern et al., 2007). Others suggest increasedfrequency of pica (hand-to-mouth behaviors) in ASDmay also alter ex-posures to lead (Cohen et al., 1976; Shannon and Graef, 1996). Despite

Fig. 1. Multifactorial model for ASD etiology involving genes, the environment, and immunspond inappropriately to environmental influences, like an infection or toxic exposure. An evous and immune system. This disruption could lead to ASD, as well as the neurological, be


lead's well-established neurotoxic and immunotoxic mechanisms, it iscurrently debatable whether it contributes to autism.

3.3. Heavy metals: mercury

Mercury exerts its toxicity broadly throughout the body. It binds awide range of molecular groups including thiols, hydroxyls, and car-boxyls (Bridges and Zalups, 2010), and can dramatically increase intra-cellular calcium levels (Sakamoto et al., 1996; Limke et al., 2003).In the immune system, mercury's effects depend heavily on geneticbackground. For example, certain strains of mice reliably developanti-nuclear antibodies after mercury exposure, while others do not(Bagenstose et al., 1999; Rowley andMonestier, 2005). Mercury also im-pacts cytokine profiles; and some strains of mice strongly up-regulatethe TH2 cytokine IL-4 in response to mercury, while other strainsup-regulate TH1 cytokines like IFN-γ (Wu et al., 2001; Hemdan et al.,2007). In two humanmast cell lines,mercury exposurewas shown to in-crease IL-6 production (Kempuraj et al., 2010). Further, mercury inter-feres with cytokine-related signaling cascades including NF-κB and p38MAPK (Dieguez-Acuna et al., 2001; Kim et al., 2002b). Altered cytokinerepertoires in response to mercury exposure may contribute to the de-velopment of autoimmunity. Interestingly, IL-4 deficient mice produceautoantibodies in response to mercury exposure (Bagenstose et al.,1998; Kono et al., 1998), while IFN-γ deficient mice do not (Kono et al.,1998), suggesting that autoantibody production is IFN-γ dependent.

The evidence implicatingmercury in autism is somewhat contradic-tory. Several recent studies have shown no link between mercury bodyburdens and autism (Ip et al., 2004; Hertz-Picciotto et al., 2010;Albizzati et al., 2012; Wright et al., 2012). However, a reanalysis ofdata generated by Ip et al. showed there was in fact an association be-tweenmercury levels and autism that had been overlooked due to a sta-tistical error (Desoto andHitlan, 2007). Ethylmercury is a component inthe vaccine preservative thimerosal, which has received attention in re-cent years. It has neurotoxic capacities, and can alter calcium signalingand cytokine production (specifically IL-6) (Goth et al., 2006). Whilein vitro studies suggest toxic potential for thimerosal, a large numberof independent epidemiological studies show no link to autism(DeStefano, 2007; Miller and Reynolds, 2009; Price et al., 2010).

Two recent studies examined the correlation between gene tran-scription profiles (35,000+ genes) and heavy metal body burdens inchildren with autism and controls (Stamova et al., 2011; Tian et al.,2011). Mercury loads correlated with the expression of several immu-nologically relevant genes across all study participants. Further, therewere some unique correlations in the autism group for genes involvedin antigen presentation and recognition of self. This suggests that indi-viduals with ASD may have a unique immunological susceptibility toheavymetals, but the significance of these findings is not clear. Althoughgenomic expression profiles may suggest correlative changes in autism,

ity. This model begins with a genetic background that predisposes an individual to re-nvironmental exposure during a critical period could disrupt development of the ner-havioral, and immune dysfunctions observed in the disorder.




analysis of common polymorphisms associated with mercury transportand excretion, namelyMT1a, DMT1, LAT1, andMTF1,were unable to de-tect any differences in autism (Owens et al., 2011). However, in contrast,a different study showed that polymorphisms in MTF1 and the heavymetal transport gene (SLC11A3) are associated with the ASD (Serajeeet al., 2004). Additional genetic analyses are needed to rectify these dis-parate findings.

3.4. Pesticides

Pesticides are fairly non-persistent toxic compounds that are delib-erately spread throughout the environment in mass quantities. Whileminimizing off-target toxicity is a primary goal in pesticide develop-ment, several products have been banned once their toxic potential inhumans was recognized. Developmental exposure to several types ofpesticides, including organophosphates (OPs), organochlorines (OCs),and pyrethroids, is associated with neurological dysfunction and an in-creased risk for ASD (Garry et al., 2002; Kamel and Hoppin, 2004;Eskenazi et al., 2007; Roberts et al., 2007; Eskenazi et al., 2010;Bouchard et al., 2011). Genetic analyses also suggest that individualswith ASDmay be less capable of excreting pesticides, due to expressionof a less-active variant of the OP-metabolizing enzyme paroxonase(D'Amelio et al., 2005; Pasca et al., 2006). In addition to their neurotox-icity, many pesticides impact the immune system and cytokine produc-tion, which may be relevant for ASD (Banerjee et al., 1996; Li, 2007).

3.5. Pesticides: organochlorines

Organochlorine (OC) pesticides are structurally and functionally var-iable toxic compounds that include members like hexachlorobenzene,dicofol, and DDT; many of which have been banned (Crinnion, 2009).OCs interfereswith calcium signaling, voltage sensitive sodium channels,and GABA receptors, leading to neuro- and immunotoxicity (Casida,2009; Crinnion, 2009; Heusinkveld and Westerink, 2012). Immunologi-cally, these compounds impact both humoral and cell-mediated process-es, and reduce the host response to infectious challenges (Banerjee et al.,1996; Reed et al., 2004; Nagayama et al., 2007). A handful of studies haveexplored the impact of OCs on cytokine profiles. DDT reduced IL-2 pro-duction in cell culture by interfering with the transcription factorNF-κB (Ndebele et al., 2004). Given the central role of NF-κB in cytokineproduction and function, this is likely to have a wide-ranging immuno-logical impact. In contrast, cases of DDT or lindane poisoning in humansis associated with increased serum levels of IL-2, IL-4, and TNF-alpha, aswell as decreased levels of IFN-γ (Daniel et al., 2002; Seth et al., 2005). Itis not clear why IL-2 production in response to OCs differs in cell cultureversus in vivo. However, the findings of increased IL-4 and decreasedIFN-γ in humans suggest a TH2 immune bias following OC exposure,which could have downstream consequences for allergic and asthmaticdisorders. Similar immune profiles have been reported in some studiesof autism (Gupta et al., 1998).

3.6. Pesticides: organophosphates

Organophosphates (OP) are esters of phosphoric acid that were in-troduced as replacements for various banned OC pesticides. They actprimarily through acetylcholinesterase (AChE) inhibition, leading to al-tered cholinergic signaling, parasympathetic and sympathetic perturba-tions, seizures, and/or respiratory arrest. OPs can also be toxic in theabsence of AChE inhibition, and may induce higher order neural andcognitive dysfunction (Duysen et al., 2001; Costa, 2006; Pancetti et al.,2007). Some OP developmental effects are more severe in males thanfemales (Levin et al., 2001, 2010), which is intriguing given that autismalso has a heavy male bias (Baron-Cohen et al., 2005).

OPs induce a variety of immunological phenomena relevant to au-tism (Galloway andHandy, 2003; Li, 2007). In general, OPs appear to in-duce a prolonged inflammatory state that may evolve into an adaptive


response characterized by up-regulation of both TH1 and TH2 cytokines.Acute OP intoxication is related to system-wide production of inflam-matory mediators (Hamaguchi et al., 2006; Roeyen et al., 2008; Anandet al., 2009). Within the CNS, acute and chronic exposure to OPs resultsin increased inflammatory cytokines including IL-1Β and IL-6 in multi-ple brain regions (Svensson et al., 2001; Henderson et al., 2002;Williams et al., 2003; Dhote et al., 2007; Dillman et al., 2009; Johnsonand Kan, 2010); similar to findings in the autism brain (Vargas et al.,2005; Li et al., 2009). OP induced inflammation can be long term,re-emerging and persisting long after the initial exposure (Chapmanet al., 2006). In primary cultures of human peripheral blood cells or as-trocytes, the OP pesticide chlorpyrifos up-regulates IL-6 and IFN-γ pro-duction and the expression of related genes (Mense et al., 2006).Children born tomothers working in agriculture had higher productionof TH2 cells at 12 and 24months of age. (Duramad et al., 2006a, 2006b).An immunosuppressive response can also be induced following expo-sure to various OPs, perhaps as a reflex to the toxin's initial inflammato-ry properties (Williams et al., 2003;Damodaran et al., 2006; Dhote et al.,2007). Collectively, these data suggest that OPs impact cytokine profilesin the short and long term, increasing inflammatory cytokines, TH1 andTH2 profiles and compensatory regulatory activity.

3.7. Pesticides: pyrethroids

Pyrethroids are a group of insecticides and repellants derived fromnatural compounds in the Chrysanthemum genus of plants. Theymedi-ate their toxicity by disrupting calcium signaling, interfering with volt-age sensitive sodium channels, and inducing oxidative stress (Shaferet al., 2005; Soderlund, 2012). Exposure to these compounds is associat-ed with a wide range of neurodevelopmental problems in mammalianmodels (Shafer et al., 2005; Wolansky and Harrill, 2008). Immunologi-cal abnormalities are also linked to pyrethroids. In human peripheralblood mononuclear cells, exposure to several different pyrethroid com-pounds suppressed both IFN-γ and IL-4 expression in a time and con-centration dependent manner (Diel et al., 2003). In a monocytic cellline, various synthetic pyrethroids and their metabolites reduced ex-pression of immunoregulatory IL-10, and increased production ofmore inflammatory cytokines IL-12 and TNF-α (Zhang et al., 2010). InaXenopus laevismodel, application of environmentally relevant concen-trations of various pyrethroids increased IL-1Β expression (Martiniet al., 2010). In primary human fetal astrocytes, the pyrethroid pesticidecyfluthrin was found to have an activating effect, and increased the ex-pression of genes involved in IFN-γ and IL-6 production and signaling(Mense et al., 2006).

3.8. Halogenated aromatic hydrocarbons

Halogenated aromatic hydrocarbons are toxic compounds that arehighly resistant to degradation. Two examples are polychlorinated bi-phenyls (PCBs) and polybrominated diphenyl ethers (PBDEs). PCBsand PBDEs consist of two aromatic rings with various chlorine(PCBs) or bromine (PBDEs) substitutions. There are over two hundreddifferent congeners each of PCBs and PBDEs, which differ based onthe number and orientation of halogen substitutions. Toxicity in thisclass of molecules is congener-specific, and involves varying degreesof 1) interaction with the Aryl hydrocarbon receptor (Ahr) (Mitchelland Elferink, 2009; Gu et al., 2012), 2) disruption of endocrine sys-tems (Morse et al., 1993; Van Birgelen et al., 1995; Stoker et al.,2005; Kuriyama et al., 2007; Lema et al., 2008), and/or 3) interferencewith calcium homeostasis through interactions with the ryanodinereceptor (Coburn et al., 2008; Pessah et al., 2009, 2010; Kim et al.,2011; Langeveld et al., 2012). These toxic mechanisms have both neu-rological and immunological significance.

Children with ASDmay be uniquely susceptible to halogenated aro-matic hydrocarbons. Postmortem analysis showed altered ryanodinereceptor expression in the brain of autism subjects compared to




controls, which could alter their sensitivity to Ryr-reactive compounds(Voineagu et al., 2011). Further, in a mouse model of Rett syndrome, agenetic disorder that shares features with autism, developmental expo-sure to PBDE-47 caused epigenetic, cognitive, and social differences thatwere not observed in wild type mice (Amir et al., 1999; Woods et al.,2012). Finally, children with ASD have unique immune responses toPBDEs, which is discussed in detail below (Ashwood et al., 2009).

3.9. Halogenated aromatic hydrocarbons: polychlorinated biphenyls(PCBs)

Polychlorinated biphenyls (PCBs) are ubiquitous in the environmentand in animal and human tissues. Theywerewidely used as additives toindustrial oils and lubricants until the late 1970s when their adversehealth effects became apparent. PCB exposure is linked to adverse preg-nancy outcomes and neurobehavioral deficits (Kuratsune et al., 1971;Rogan et al., 1988; Chen and Hsu, 1994; Eriksson and Fredriksson,1998; Howard et al., 2003; Kenet et al., 2007; Lein et al., 2007;Tsukimori et al., 2008; Kim et al., 2009; Boix et al., 2010; Kim andPessah, 2011), as well as immune dysfunction. In studies involving ma-rine animals, murinemodels, and humans, PCBs lead to generalized im-mune suppression, characterized by diminished cellular immunity andatrophied lymphoid organs (Davis and Safe, 1990; Narayanan et al.,1998; Fournier et al., 2000; Shin et al., 2000; Tan et al., 2003; Beinekeet al., 2005; Leijs et al., 2009). Cytokine profiles are also impacted byPCBs. In a murine model, perinatal exposure to a PCB mixture inducedinflammatory cytokine expression (primarily IL-6) in the brain ofadult offspring (Hayley et al., 2011). In human blood cells, PCB 52 andPCB 133 induced transcriptional changes in several cytokine signalingand regulation pathways (Wens et al., 2011). This effect was only ob-served in cells from male donors, suggesting a male-bias for some PCBeffects. Another study showed that PCB 118 enhanced IL-4 producingT-cell development (Gaspar-Ramirez et al., 2012), which correlateswith findings in children with ASD and their mothers (Gupta et al.,1998; Abdallah et al., 2011; Goines et al., 2011b).

PCBs likely exert their immunotoxicity by interfering withimmunologically-relevant signaling pathways. For example, dioxin-likePCBs interfere with Ahr signaling, which is critical for maintaining ahealthy immune balance in the skin and gut (Li et al., 2011;Monteleone et al., 2011). PCBs also disrupt the key cytokine signalingpathways JAK/STAT and MAPK. Immune cells exposed to PCB 47 and153 have compromised function and altered STAT 5 and ERK phosphor-ylation (Canesi et al., 2003). STAT 5 activation is central for regulatory Tcell development (Burchill et al., 2003; Adamson et al., 2009), and acti-vation of this molecule by PCBs might mediate some of their immuno-suppressive effects. Finally, some PCB congeners interfere withryanodine receptors,which are expressedwidely in the immune system.These receptors are regulated by cytokines including TGF-Β (Hosoi et al.,2001; Pessah et al., 2010), and can induce IL-6 production after engage-ment (Treves et al., 2011). In summary, PCBs alter immune functionthrough a variety of mechanisms that may be relevant to immune pro-files observed in autism.

3.10. Halogenated aromatic hydrocarbons: polybrominated diphenylethers (PBDEs)

PBDEs are a group of flame retardants that are the subject of grow-ing concern due to their structural and functional similarities to PCBs.They are widely dispersed in the environment and bioaccumulate upthe food chain (Johnson-Restrepo and Kannan, 2009). EnvironmentalPBDE levels have jumped dramatically in the last several decades, andare increasingly found in human tissues and breast milk (Noren andMeironyte, 2000; Darnerud et al., 2001). Of note, this heightenedprevalence is concurrent with the apparent rise in ASD diagnoses(Hertz-Picciotto and Delwiche, 2009; Messer, 2010). While not linkedspecifically to ASD, PBDE exposure is associated with improper


neurodevelopment, hormonal disruptions, and a variety of behavior-al, motor, and cognitive issues (Alm et al., 2008; He, He et al., 2008;Roze et al., 2009; Herbstman et al., 2010; Kodavanti et al., 2010;Schreiber et al., 2010; Dingemans et al., 2011).

Some evidence shows that PBDEs can impact immune activity.Studies involving marine and murine models link PBDEs to changesin the immune system, including thymic and splenic atrophy, in-creased production of IL-10, lymphocyte depletion, reduced antibodyrecall responses, and decreased responses to pathogens (Fowles et al.,1994; Thuvander, 1999; Beineke et al., 2005; Zhou et al., 2006;Beineke et al., 2007a, 2007b; Lundgren et al., 2009; Watanabe et al.,2010; Bondy et al., 2011; Fair et al., 2012). There is little data regard-ing the impact of PBDEs on cytokine production and signaling, and fu-ture studies should examine these endpoints in more detail. Onerecent study considered the effect of BDE-47 on cytokine responsesin children with autism and controls. Peripheral blood mononuclearcells obtained from ASD and typically developing controls werepretreated with PBDE-47 and stimulated with LPS. Analysis of super-natant cytokines showed that BDE-47 had a divergent impact on cellsfrom ASD versus typical controls. Among controls, BDE-47 caused asignificant decrease in inflammatory cytokines production (IL-6,IL-12, GM-CSF, TNF-α), indicating broad immune suppression. In con-trast, children with ASD only down-regulated IL-6 in the presence ofBDE-47, and had significantly higher IL-1Β responses (Ashwoodet al., 2009). This suggests that BDE-47 can enhance some aspects ofinflammation in ASD. This diagnosis-specific immunotoxic effect sug-gests that children with ASD respond differently to PBDEs than typicalchildren. Robust inflammation in response to such exposures duringcritical developmental windows could have long term neurologicaleffects, and may be a possible mechanism in ASD. Future studiesshould continue to examine a potential role for PBDEs in immunedysfunction and neurodevelopmental disorders like autism.

3.11. Pathogenic exposures in autism

Early-life infections can skew fetal development, leading to aber-rant neural and immune activity. This is a widely suggested etiologi-cal mechanism in schizophrenia, and is increasingly implicated inautism as well (Patterson, 2009). Several infections, including mea-sles, cytomegalovirus, and rubella during pre- and perinatal periodshave been associated with autism (Chess, 1977; Markowitz, 1983;Ivarsson et al., 1990; Sweeten et al., 2004a, 2004b; Libbey et al.,2005; Meyer et al., 2011). A recent large-scale epidemiologicalstudy showed that infection-related hospitalizations during pregnan-cy significantly increased the risk of ASD (Atladottir et al., 2010). In-terestingly, the risk was not associated with any specific type ofinfection, suggesting that the general immunemechanism controllingthe response to the pathogen rather than the pathogen itself were in-volved. This response is likely guaranteed to include cytokines. In-deed, there is clinical evidence for altered gestational cytokinemilieus in autism (Abdallah et al., 2011; Goines et al., 2011b), whichcould be related to infectious exposures, and may mediate aspectsof the disorder.

As discussed in previous sections, several studies have linked earlyimmune challenges to long-term changes in behavioral and immuneparameters. For example, mice prenatally exposed to influenza(Fatemi et al., 2002a; Shi et al., 2003), the viral mimic Poly I:C(Vuillermot et al., 2010), or the bacterial component LPS (Romeroet al., 2010) demonstrate long term neurological and behavioral ab-normalities. This effect is largely mediated by cytokines like IL-6 andIL-1Β (Samuelsson et al., 2006; Smith et al., 2007; Bilbo et al., 2008).Prenatal infectious exposures can also impact the developing immunesystem, and lead to long term immune dysregulation. This was dem-onstrated by increased levels of IL-6, IL-2, and TNF-α in adult animalsthat had been prenatally exposed to LPS (Romero et al., 2010). Anoth-er interesting set of studies showed that an early life infection led to




neurological deficits in adulthood that only became apparent after animmunological stimulation (Bilbo et al., 2005a, 2005b; Bilbo andSchwarz, 2009). This suggests that early life infection can change im-mune responses later in life, and that this has neurological conse-quences. The concept that prenatal infections can impact both brainand immune development is intriguing, and should be explored fur-ther in autism.

Overall, when considering environmental exposures, it is impor-tant to take time to consider that the prevalence rates for ASD haveincreased dramatically over the last 10–20 years. These rates continueto increase year-on-year. Arguably concentrations for some com-pounds such as lead and chlorinated pesticides have fallen in the pop-ulation since their removal or reduction from the environment in the1970s. In contrast, levels of PBDEs and OPs have increased. Althoughit may be tempting to link compounds as risk factors for ASD basedsolely on similar time trends there is a need for more extensive re-search to begin to understand whether such temporal relationshipsare associated with risk for ASD. Future research should focus onthe relationships between environmental exposures and risk forASD diagnosis and whether environmental exposures to such com-pounds as PBDE induce cytokine responses that could modulate neu-ronal function in the pediatric population. Moreover, future researchshould discern whether children who develop a ASD are more sensi-tive to specific environmental exposures using cytokine production asreadouts. More research focused on environmental exposures andASD is warranted.

4. Conclusions

Cytokine imbalances are well documented in autism and havemany interesting implications. Cytokines are intricately involved inneurodevelopment and neuronal function, and an ill-timed cytokinedisruption can have long term neurological consequences. Further,cytokine expression is largely dependent on genetic and environmentalinfluences. Therefore, they may represent a biomarker for genetic or en-vironmental factors at play in autism. To illustrate the connection be-tween immunity, genes, the environment, and neurodevelopmentaloutcome, consider two scenarios: First, an individual may be geneticallypoised to mount an inappropriate immune response to an infectious ortoxic exposure. This individual might respond either too robustly or tooweakly to resolve the threat without collateral damage to the brain andother body systems (including the immune system). Second, an individ-ual may lack appropriate genetic machinery to excrete toxins; leading totheir accumulation in tissue. This could lead to an amplification of thetoxin's effects on a variety of body systems, including the brain and im-mune system. For each child, an environmental challenge during a criti-cal window of development could have especially severe consequences,causing abnormal CNS function, altered immune phenotypes, and per-haps autism. These scenarios represent an emerging global view of au-tism that considers a broad contribution of several factors, includinggenes, the environment, and the immune system. Cross-disciplinary in-vestigations that consider diverse biological contributions will be essen-tial to untangle ASD.

Conflict of interest statement

The authors report no conflict of interest.

Acknowledgements and financial disclosures

This study was supported by the National Institute of NeurologicalDisorders and Stroke (R21HD065269), Autism Speaks Foundation(7567), the Jane Botsford Johnson Foundation, National Alliance forResearch on Schizophrenia and Depression, the Peter Emch Founda-tion, and the Hartwell Foundation. The authors report no conflicts ofinterest for this study.


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