nihms281022.pdf

MATERNAL INFECTION AND IMMUNE INVOLVEMENT IN

AUTISM

Paul H. Patterson

Biology Division, California Institute of Technology Pasadena, CA 91125 USA

Abstract

Recent studies have highlighted a connection between infection during pregnancy and increased

risk for autism in the offspring. Parallel studies of cerebral spinal fluid, blood, and postmortem

brains reveal an ongoing, hyper-responsive inflammatory-like state in many young as well as adult

autism subjects. There are also indications of gastrointestinal problems in at least a subset of

autistic children. Work with animal models of the maternal infection risk factor indicate that

aspects of brain and peripheral immune dysregulation can be begin during fetal development and

be maintained through adulthood. The offspring of infected, or immune-activated dams also

display cardinal behavioral features of autism, as well as neuropathology consistent with that seen

in human autism. These rodent models are proving useful for the study of pathogenesis and gene-

environment interaction, as well as for the exploration of potential therapeutic strategies.

Maternal infection and autism

There is little public awareness that infection during pregnancy significantly increases the

probability of the offspring becoming schizophrenic. In fact, it has been estimated that if

viral (influenza, Herpes simplex virus, rubella), bacterial (urinary tract) and parasitic

(toxoplasma) infections could be prevented in pregnant women, >30% of schizophrenia

cases could be eliminated (1). The public health implications are enormous, but not widely

recognized (2). Similarly, there is little public or scientific awareness that maternal infection

also increases the risk for development of autism in the offspring. An extraordinary recent

study of over 10,000 autism cases in the Danish Medical Register found a strong association

with maternal viral infection in the first trimester and a less robust, but significant

association with maternal bacterial infection in the second trimester (3). These new results

greatly extend prior work on the connection between maternal infection and autism (4).

Supporting the epidemiology, recent results with rodent models of the maternal infection

risk factor reveal that the offspring display features of autism, as well as immune-related

disruptions in the brain and periphery. Moreover, new work on human autism spectrum

disorders (ASD) reinforces this immune connection.

Corresponding author: php@caltech.edu.

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Author Manuscript

Trends Mol Med

. Author manuscript; available in PMC 2012 July 1.

Published in final edited form as:

Trends Mol Med

. 2011 July ; 17(7): 389–394. doi:10.1016/j.molmed.2011.03.001.

NIH-PA Author Manuscript

Immune-related abnormalities in autism

A variety of organ systems exhibit inflammatory-like changes in autism. The evidence

comes from quantifying immune-related proteins and RNAs, as well as

immunohistochemistry. Findings from epidemiology are also relevant.

Brain and CSF

A groundbreaking paper by Carlos Pardo and colleagues (5) revealed an inflammatory-like

state in post-mortem autism brains as indicated by elevated cytokines and activated

microglia and astrocytes. Importantly, these changes were found in subjects ranging in age

from 5 to 44 years old, indicating that this immune-activated state is established early and

appears to be permanent. Moreover, cytokine elevation was also found in the cerebral spinal

fluid (CSF) of living autistic children ages 3 to 10 years old. Recent results from studies of

some of the same postmortem brains and new autism brain samples, as well as CSF, have

supported these conclusions (6, 7). Consistent with these findings are results from a variety

of microarray studies that show dysregulation of immune-related genes (e.g. cytokines and

chemokines) in autistic brains (8). It is also clear that there is considerable heterogeneity

among the autism samples, as might be expected from the extreme disparities in behavioral

symptoms among ASD subjects.

Peripheral immune system and GI tract

Possibly related to the inflammatory-like state in the central nervous system are

abnormalities in the peripheral immune system (9). Although there have been many papers

on this topic over the years, recent reports from Judy Van de Water and Paul Ashwood have

utilized blood samples from a well characterized, large cohort of ASD children. These

authors report that, compared to controls and non-ASD children with developmental

disabilities, several cytokines and chemokines, including interleukin-1

(IL-1

), IL-6, IL-8

and IL-12p40, are elevated in the ASD plasma of very young children (ages 2–5 years old),

and that these increases are associated with more impaired communication and aberrant

behaviors (8, 10, 11). In addition, peripheral blood mononuclear cells display altered

cytokine responses to stimulation

in vitro

(12, 13).

Although an early report from Wakefield and colleagues muddied the waters considerably,

there have been several subsequent papers providing evidence of inflammation in the

gastrointestinal (GI) tract of at least a subset of ASD children (14, 15). These findings

include immune cell infiltrates present in the colon, ileum and duodenum, as well as

increased T cell activation in the intestinal mucosa. These inflammatory changes are

associated with autoimmune responses that could contribute to the observations of decreased

mucosal integrity, or “leaky gut” (16). Disruption of the mucosal barrier can also occur in

the apparent absence of inflammation, however, as in irritable bowel syndrome. Thus, leaky

gut symptoms do not necessarily connote inflammation. This issue needs to be clarified in

ASD, as does the question of the frequency of GI symptoms in ASD compared to controls.

These are difficult questions to answer because of the problems in obtaining GI samples

from ASD and control children without overt GI symptoms. Perhaps related to GI symptoms

is the finding of an abnormal gut microbiota composition in ASD (17). It is thus of particular

interest that a small study of antibiotic treatment aimed at the gut found temporary

improvement in some behavioral symptoms (9). This is potentially important, as it

represents a possibly safe intervention and thus could be followed up with a large, blinded

study. In addition, dietary modification is reported to provide behavioral improvements for

some ASD children (14). There is considerable interest among parents of autistic children

regarding the possibility of adverse reactions to certain dietary components. This could then

lead to GI problems such as a leaky gut, which may or may not have an inflammatory basis.

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The possibility of a connection between peripheral immune abnormalities and altered

behavior in ASD is fascinating, but unsubstantiated, at this point. On the one hand, it could

be that genetic susceptibility or an environmental insult biases the subject toward both brain

and immune dysregulation simultaneously and that these symptoms occur independently.

For example, several ASD candidate genes are known to regulate both brain and immune

system development and/or function (9). On the other hand, it is possible that immune

irregularities, such as in peripheral immune cells or the GI tract, interact with an abnormal

brain to exacerbate behavioral symptoms. For instance, it is well known from animal and

human studies that elevated peripheral cytokines can cause striking changes in behavior (4).

Autoimmune connections

Further support for immune system dysregulation comes from epidemiologic studies of

ASD. The largest of these found that some autoimmune diseases (rheumatoid arthritis, celiac

disease and type 1 diabetes) are more common in mothers of ASD children than in mothers

of typically developing children (18). These results and those from prior studies (9) could

mean that an abnormal immune system is genetically passed on to the offspring. It is also

possible that maternal autoimmune reactions could have deleterious effects on fetal brain

development. The latter hypothesis receives support from the finding that ~12% of mothers

with children with ASD offspring have anti-fetal brain antibodies in their serum, a figure

significantly higher than in mothers of typical children (9). Animal studies support the idea

that such antibodies could be relevant for pathophysiology; when IgG from human mothers

of children with ASD is injected into rhesus macaques or mice at midgestation, some of the

offspring display abnormal behaviors that are not seen in offspring of animals injected with

IgG from mothers of typically developing children (19, 20).

Animal models of the maternal infection risk factor

The maternal infection risk factor is currently being studied in mice, rats and monkeys. The

experiments involve infecting the mother or simply activating her immune system in the

absence of pathogens.

Rodent models

The epidemiologic evidence highlighting maternal infection as a risk factor for autism and

schizophrenia has stimulated the development of several rodent models. These involve

infection of pregnant mice or rats (nasal application of influenza virus) or mimicking such

infections by activating the maternal immune system in the absence of pathogen. The latter

approach has proven particularly popular, and involves maternal injection of the synthetic

double stranded RNA, poly(I:C), to evoke an anti-viral inflammatory response, or maternal

injection of lipopolysaccharide (LPS), to evoke an anti-bacterial inflammatory response.

Although these three approaches undoubtedly yield somewhat different cascades of gene

activation, analysis of the offspring has thus far revealed considerable overlap in behavioral

abnormalities and neuropathology (4,21). Moreover, similar results have been obtained in

both the mouse and rat models of maternal immune activation (MIA). Several cardinal

symptoms of autism are observed in the offspring of immune-activated dams, including

deficits in communication (assayed by ultrasonic vocalizations; 22) and social interaction

(assayed in the 3 chamber paradigm; 23). Other behaviors in the offspring that are consistent

with autism symptoms include elevated anxiety and a prepulse inhibition deficit (4, 21).

There is also a Theory of Mind deficit in autism, in which the subject has difficulty intuiting

the thoughts of another person, which can lead to social difficulties. Approaching this type

of deficit in rodents is just beginning, using assays for empathy (24), for instance. Regarding

neuropathology, the offspring of infected mothers, or mothers given poly(I:C), also exhibit

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several abnormalities commonly found in autism including a spatially-restricted deficit in

Purkinje cells in the cerebellum (25).

Because maternal infection is a risk factor for both autism and schizophrenia, it is not

surprising that some of the features of the latter disorder have also been found in the

offspring of immune-activated mothers. These include enlarged ventricles, changes in the

serotonergic and dopaminergic pathways, as well as enhanced responses to a hallucinogen

(4, 21, 27). At least some of these symptoms can be differentially expressed as a function of

the timing of the maternal infection (28). It is also possible that the severity of MIA is a

factor in which symptoms are expressed in the offspring. Genetic background also likely

influences the outcome of maternal infection in terms of ASD versus schizophrenia. It

should also be pointed out that, in addition to the obvious phenotypic differences, there are a

number of striking similarities between schizophrenia and ASD phenotypes in humans.

These include some shared behavioral abnormalities as well as neuropathological features

(29). These overlaps in phenotypes make it difficult to firmly identify features that can be

used to distinguish ASD and schizophrenia phenotypes in animal models. The response to

hallucinogenic drugs, or even the presence of spontaneous hallucinogen-like activity in the

brain, is a potentially fruitful area that can be explored in this context. Regarding features

specific to autism, deficits in male neonate and adult communication are found in the MIA

mouse model (22), and this can be further examined by analyzing the qualitative nature of

these ultrasonic vocalizations (USVs), and as a function of the social settings in which they

occur (24). That is, experiments can evaluate the types of syllables, their grouping and order,

the consistency of usage in various social situations, how they change with development,

and whether there is indeed “mouse song” that has the characteristics of bird song.

How does activation of the maternal immune response alter fetal brain development? The

manipulation of cytokines has revealed that the elevation of the pro-inflammatory cytokine

IL-6 (which is induced by MIA) is essential for development of the abnormal behaviors and

changes in brain gene expression in the offspring (23). That is, injection of IL-6 alone is

sufficient to yield the abnormal behaviors in the offspring seen with MIA. Conversely,

blocking IL-6 during MIA prevents the development of these behaviors. Moreover,

elevation of the anti-inflammatory cytokine IL-10 also protects against MIA (30). These

results support the theory that the balance between pro-and anti-inflammatory influences is

important in fetal brain development.

Where do these cytokines act? Several groups have found that MIA induces pro-

inflammatory cytokines in the fetal brain itself. For example, IL-6 mRNA and protein are

elevated in the fetal brain following maternal poly(I:C) administration. This finding is

consistent with a feed-forward, self-reinforcing inflammatory cycle. This possibility needs

to be further tested with assays in postnatal offspring to determine if parallels to the findings

in autism brains can be found. It must also be determined if maternal IL-6 (or other signals)

is directly responsible for evoking the cytokine responses observed in the fetal brain.

Other work has highlighted the placental response to MIA as an indirect pathway towards

altering fetal brain development (31,32). Maternal injection of poly(I:C) increases IL-6

mRNA as well as maternally-derived IL-6 protein in the placenta. This activates the

endogenous immune cells in the decidua, and maternally-derived IL-6 activates the Janus

kinase (JAK)- signal transducer and activator of transcription 3 (STAT3) pathway

specifically in the spongiotrophoblast layer, which results in expression of acute phase

genes. Importantly, this parallels an IL-6-dependent disruption of the growth hormone-

insulin-like growth factor axis in the placenta. Together, these IL-6-mediated effects of MIA

represent an indirect mechanism by which MIA can alter fetal development (Fig. 1). There

is also severe placental inflammation when pregnant rats are given a high dose of LPS, and

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this reaction can be blocked by administration of an IL-1 receptor antagonist (33).

Interestingly, a greater occurrence of placental trophoblast inclusions is found in placental

tissue from births of children who go on to develop ASD compared to non-ASD controls

(34). Relevant in this context are findings that chorioamnionitis and other obstetric

complications are significantly associated with socialization and communication deficits in

autistic infants (35).

As noted above, a number of abnormalities have been found in peripheral immune cells in

autism. Thus, it is of interest that T cells in mouse MIA offspring are in a hyper-responsive

state for at least a year after birth [36]. The prolonged nature of this pathology lends further

support to the hypothesis of a feed-forward, self-reinforcing cycle that begins in during

gestation and continues through adulthood. This is also consistent with the findings of

immune-related abnormalities in the brains of adult autism cases.

Non-human primate model

Thus far, there is a single report of a non-human primate model of maternal infection using

nasal application of influenza virus in the 3

trimester of rhesus monkey pregnancy. The

choice of 3

trimester does not, however, fit with what is known about the windows of

vulnerability for development of schizophrenia or autism. In the offspring of the infected

monkeys, widespread reduction in gray matter volume in the cortex, and reduced white

matter volume in the parietal cortex is observed (26). The infants born to infected mothers

appear to show signs of early autonomy from the mother, yet also exhibit increased distress.

Given the striking similarities between human and non-human primate behaviors during

normal early postnatal development (unlike rodents), much could be done with this type of

model using infection, LPS or poly(I:C).

Gene-environment interactions

A variety of mental disorders have been attributed in part to genes that increase the

susceptibility to environmental risk factors. To date, however, there is very little evidence

for such gene-environment interactions. Therefore, it is of interest that mice heterozygous

for the tuberous sclerosis 2 (

Tsc2

) gene display a social interaction deficit only when they

are born to mothers treated with poly(I:C) (37). That is, this behavioral deficit is most severe

when the MIA environmental risk factor is combined with a genetic defect that, in humans,

also carries a high risk for ASD. In addition, there is an excess of TSC-ASD individuals

born during the peak influenza season, an association that is not seen for TSC individuals

not displaying ASD symptoms (37). Similar experiments have been done looking at the

effects of poly(I:C) MIA in lines of DISC1 mice.

DISC1

(disrupted in schizophrenia 1) is a

gene associated with schizophrenia, bipolar and major depressive disorders, as well as

autism (38). In an inducible transgenic mouse line expressing a human truncated DISC1

protein in the forebrain, the combination of MIA and prenatal transgene expression results in

increased anxiety and depression-like symptoms and decreased social interaction compared

to either insult alone (39). An unexpected finding is that the combined gene-environmental

risk factors cause a decrease in ventricular enlargement compared to either alone. This

combination of insults alters the levels of several cytokines; notably IL-1

and IL-6 are

increased. Much remains to be done in this important line of experiments that combine

environmental risk factors with ASD candidate genes, both in characterizing the phenotypes

and in exploring the cellular and molecular sites of action of each factor. Results from

combining these factors should illuminate the pathways for each of them.

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Therapeutic manipulations

The findings summarized in the prior sections demonstrate that the maternal infection and

MIA models display face (similar symptoms) as well as construct (similar cause) value for

both autism and schizophrenia. These models can have predictive value as well. For

example, the manipulation of cytokines during pregnancy can prevent the development of

abnormal behaviors in the offspring in the poly(I:C) and LPS models. In addition,

pretreatment of pregnant rats with N-acetyl-cysteine, which increases calcium influx when

binding to glutamate receptors in combination with the transmitter, and also suppresses fetal

inflammatory responses to LPS, prevents many of the effects of maternal LPS

administration (4). The ability of IL-10 to block the effects of MIA is an attractive

intervention because endogenous IL-10 is essential for resistance to LPS-induced preterm

labor and fetal loss. Thus, administration of this cytokine enhances a natural protective

mechanism. However, increased IL-10 in the absence of MIA in pregnant mice can lead to

behavioral abnormalities in the adult offspring (30), a finding consistent with the fact that

normal human pregnancy involves increased inflammation. Therefore, postnatal cytokine

perturbations would potentially be a safer therapeutic approach. It is also clear that postnatal

cytokine manipulations can induce behavioral changes in the absence of MIA (40). Such

manipulations in MIA models could be a fruitful area of research.

In fact, MIA models have proven valuable for testing other types of postnatal therapies.

Whereas acute antipsychotic drug administration in adult influenza and poly(I:C) MIA

offspring can ameliorate some of the behavioral deficits (4,21), administration of such

medications in immature MIA offspring, before the onset of behavioral abnormalities and

ventricular enlargement, is effective in preventing the onset of such symptoms (41,42).

Treatment for a week during adolescence, many weeks before beginning behavioral testing,

prevents the onset of abnormalities and the ventricular enlargement. Therefore, despite the

fact that MIA has induced many changes in the brain during fetal development, postnatal

behaviors can be subsequently altered. Although the classic action of these antipsychotic

medications involves blockade of the D2 dopamine receptor in the brain, it is also worth

noting in the present context that many of them have also been shown to influence cytokine

expression in peripheral immune cells (4).

It is also important to note, in the context of potential postnatal treatments, that in mouse

models of a number of rare genetic disorders with autistic symptoms such as fragile X, Rett

syndrome and TSC, behavioral abnormalities can be at least partially reversed in adulthood.

These findings have led to several clinical trials in these disorders (43).

Concluding remarks

A variety of techniques have been used to demonstrate the presence of a sub-clinical,

inflammatory-like state in the brain, CSF and peripheral immune system in many ASD

samples. There is also evidence for abnormalities in the GI tract, although the prevalence

and the precise phenotype in that system remain to be determined. Mouse and rat models

that mimic the autism maternal infection risk factor display face, construct, and predictive

validity for ASD. Many of the symptoms in these rodent models are also similar to those

expected for a schizophrenia model, which is consistent with the fact that maternal infection

is a validated risk factor for the latter disorder as well. To aid in distinguishing ASD from

schizophrenia behavioral symptoms in this and many other animal models, it will be of great

interest to further develop assays for hallucination-like activity in the brain (27), and to

explore the qualitative features of USVs (24). The application of electrophysiological tools

to MIA models has only just begun (44, 45), and the same is true of combining MIA with

ASD candidate genes. Some of the genes near the top of the list for future testing include

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CNTNAP2

(contactin associated protein-like 2) and MET receptor kinase, the former

because of its connection with language (46), and the latter because of its roles in the

nervous, immune and GI systems (47). Another area of great promise is extending MIA to

non-human primates, where ASD-like behaviors can be assessed in much more human-like

context than in rodents. The first report on the young offspring of influenza-infected rhesus

mothers has recently appeared (26), and the development of non-human primate poly(I:C)

and LPS models should prove useful.

Acknowledgments

Work cited from the author’s laboratory was supported by the National Institute of Mental Health, the California

Institute of Regenerative Medicine, and the Autism Speaks and Binational Science foundations. Due to space

limitations, reviews are cited rather than primary research articles wherever possible.

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Figure 1. Summary of MIA-induced effects on the placenta

Maternal injection of poly(I:C) activates the maternal immune system, elevating IL-6, which

enters the spiral arteries that descend through the decidua and spongiotrophoblast layers,

filling the maternal bloodspaces of the labyrinth. Resident immune cells in the decidua are

activated to express CD69 and further propagate the inflammatory response. IL-6 produced

by decidual cells acts on target cells in the spongiotrophoblast layer. Ligation of the IL-6Ra

with gp130 causes JAK/STAT3 activation and increases in acute phase proteins, such as

SOCS3, and down-regulation of placental growth hormone (GH) production. This leads to

reduced insulin-like growth factor binding protein 3 (IGFBP3) and IGFI. Global changes in

STAT3 activation in the spongiotrophoblast layer alter the production of placenta-specific

pro-lactin protein (PLP) and other pro-lactin proteins. These various changes in endocrine

factors very likely to lead to acute placental pathophysiology and subsequent effects on fetal

development. (Reproduced from ref. 31, with permission.)

Patterson

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Trends Mol Med

. Author manuscript; available in PMC 2012 July 1.

NIH-PA Author Manuscript