nihms-668862.pdf

Neuroimmunology in Brain Development and Disease

A. Kimberley McAllister [Professor]

and

Center for Neuroscience, UC Davis, Davis, CA USA

Paul H. Patterson [Professor]

Biological Sciences, California Institute of Technology, Pasadena, CA USA

Although neural-immune cross-talk during disease and/or trauma has been studied for many

years, the dogma has been that there is little interaction between the immune and nervous

systems in healthy individuals. This belief was historically based on indications that the

blood-brain barrier (BBB) blocks immune cell infiltration into the central nervous system

(CNS), leading to limited immune responses in the CNS, and by a lack of classical immune

proteins in the brain (

Murphy and Sturm 1923

;

Joly et al. 1991

). However, recent

observations from both clinical and basic science research have caused a paradigm shift in

our understanding of neural-immune interactions, indicating clearly that there is extensive

communication between these systems (

McAllister and van de Water 2009

). There is now

clear evidence that environmental insults that alter the immune response can affect brain

development as well as behavior (

Meyer et al. 2011

;

Patterson 2009

). Moreover, mouse

models of neurodevelopmental disorders have provided strong support for immune

involvement in CNS development and disease (

Patterson 2009

;

Patterson 2011

). Finally,

several different kinds of immune molecules, including cytokines, major histocompatibility

complex (MHC) proteins, and complement, are expressed in the developing and adult brain

and have critical functions in brain development and plasticity (

Stephan et al. 2012

; Garay

and McAllister 2009;

Shatz 2009

;

Elmer and McAllister 2012

). In this Special Issue, we

include reviews covering a range of topics from epidemiology, indicating a role for immune

dysregulation in neurodevelopmental disorders, to basic mechanisms underlying the effects

of immune molecules in brain development and disease.

Interest in neural-immune crosstalk has gained momentum as evidence accumulates

regarding the potential involvement of immune dysregulation in many neurological and

psychiatric disorders, as well as in healthy brain function. In addition to its well-documented

role in trauma, neural inflammation is clearly present in several degenerative diseases,

including Alzheimer’s and Parkinson’s disease (

Lucin and Wyss-Coray, 2009

). CNS

resident immune cells, called microglia, may lose activity with age, leading to inefficient

clearance of toxic protein aggregates that characterize neurodegenerative diseases.

Moreover, the BBB becomes more permeable with healthy aging, which is accompanied by

increased immune activation, expression of stress-induced and inflammatory genes, and

CNS immune cell infiltration (

Lucin and Wyss-Coray, 2009

). Finally, neural-immune

crosstalk may even occur in the non-diseased brain since BBB permeability is altered by

Neither author has a conflict of interest.

HHS Public Access

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Dev Neurobiol

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Published in final edited form as:

Dev Neurobiol

. 2012 October ; 72(10): 1269–1271. doi:10.1002/dneu.22054.

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many factors, including addictive drugs, toxins, subclinical infection, stress, and some

medications (

van den Pol, 2009

In addition to a clear role for neural-immune crosstalk in degenerative disorders, there is

rapidly increasing evidence for immune involvement in neurodevelopmental disorders.

Although several neurodevelopmental disorders are caused by mutations in single genes,

two of the most common disorders of neural development—autism spectrum disorders

(ASD) and schizophrenia (SZ)—appear to be caused by a combination of mutations and

environmental exposures. Interestingly, many of the diverse range of environmental factors

that confer elevated risk for these disorders converge on an altered immune response. Each

of the reviews included in this Special Issue discuss this issue from distinct perspectives.

Alan Brown describes the increasingly compelling epidemiological evidence that several

types of maternal infection increase the risk for offspring to develop ASD or SZ. This

review also summarizes recent studies that report correlations between maternal cytokines,

which are immune signaling molecules, and risk for these disorders. In addition to maternal

infection, there is also ample evidence for changes in expression of immune genes in ASD

and SZ patients. Michel and Mirnics summarize evidence that immune genes contribute to

increased risk for ASD and SZ and expression of these genes is altered in postmortem ASD

and SZ brains. Needleman and McAllister focus specifically on the evidence for a role for

the diverse array of genes within the major histocompatibility complex (MHC) in conferring

increased risk for ASD. Finally, in addition to ASD and SZ, immune dysregulation is also

centrally involved in fetal alcohol spectrum disorder (FASD); Kane, Phelan, and Drew

comprehensively describe this disorder and the role of immune cells in mediating it.

Together, data from several of the approaches covered in these reviews converges on the

conclusion that environmental and genetic changes in immune responses contribute

significantly to ASD, SZ, and FASD.

Neuroimmunology research has also recently made dramatic advances in understanding how

maternal infection and prenatal exposures contribute to neurodevelopmental disorders. An

understudied, but clearly critical, component of this pathway is the placenta. Hsiao and

Patterson describe how the placenta regulates maternal-fetal interactions, focusing on

placental regulation of the effects of maternal immune activation (MIA) on the developing

fetus. This review also discusses the intriguing evidence for a role for the placenta in

prenatal programming of neurodevelopmental disorders. The placenta is generally thought to

limit the maternal immune response from negatively impacting fetal development. While

maternal antibodies are passed across the placenta to the fetus to confer passive immunity,

some mothers generate antibodies that cross into the fetus and target fetal tissues. Because

the BBB is not fully developed during this period of gestation, these maternal antibodies can

enter the brain. It is well-known that autoantibodies from mothers with autoimmune

disorders cross the BBB and may contribute to cognitive impairments in offspring (

Bhat and

Steinman, 2009

). van de Water, Fox, and Amaral describe recent findings showing that

specific maternal antibodies that cross the BBB in offspring and recognize fetal brain

proteins are associated with increased risk for ASD.

The neural-immune theory of many neurodevelopmental disorders is also supported by

extensive evidence from animal models. Mouse models of the MIA risk factor demonstrate

McAllister and Patterson

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that maternal infection leads to abnormal behaviors in offspring that are consistent with SZ

and include the three core symptoms of ASD. These models are being studied in many

laboratories and their ability to model the anatomical, pharmacological, and behavioral

changes in ASD and SZ are discussed in several reviews in this Special Issue. Michel and

Mirnics introduce the mouse MIA model and this model is further discussed in the context

of genes within the MHC by Needleman and McAllister. The role of the placenta in

regulating and facilitating the effects of MIA in the offspring is discussed by Hsiao and

Patterson. Harvey and Boksa compare and contrast the many pre- and postnatal MIA mouse

models. This review critically assesses the strengths and potential pitfalls of these models

and their relevance to neurodevelopmental disorders in general, and to ASD and SZ in

particular. Mouse models of FASD have also revealed underlying pathology and the role of

microglia in this disorder as reviewed by Kane, Phelan, and Drew. Finally, van de Water,

Fox, and Amaral discuss recent reports in both mouse and non-human primate models that

have revealed detrimental effects of maternal antibodies on brain development and lead to

ASD-like behaviors.

Although the epidemiological evidence suggesting that immune dysregulation predisposes

offspring to ASD and SZ is increasingly compelling, little is known about how immune

dysregulation during early development causes behaviors and neuropathology characteristic

of ASD, SZ, or FASD in offspring. The role of microglia in contributing to FASD is

reviewed by Kane, Phelan, and Drew. Several microglial proteins within the MHC may also

contribute to ASD, as summarized by Needleman and McAllister. Most of the evidence to

date, however, strongly suggests that immune signaling molecules called cytokines are

essential for a peripheral immune response to alter brain development. The central role for

both maternal and fetal cytokines in mediating the effects of MIA on brain development are

described by Michel and Mirnics, Needleman and McAllister, Hsiao and Patterson, and

Harvey and Boksa. Although the effects of many cytokines remain to be investigated, one in

particular, the chemokine CXCL12 (also known as SDF-1) has been extensively studied for

its role in brain development. Zhu and Murakami summarize that the influence that

CXCL12 has on many stages of neural development and illustrate the point that the timing

of changes in cytokine levels caused by genetic or environmental factors will strongly

influence the types of developmental processes affected.

Despite the rapid recent progress in the field of neuroimmunology in the past few years,

many questions remain to be addressed. First, how central is immune dysregulation to

neurodevelopmental disorders such as ASD, SZ, and FASD? Does immune dysregulation

generally predispose individuals to neurodevelopmental disorders or is it the primary cause

of subsets of these disorders (an important question debated by Harvey and Boksa)? What

role does the placenta play in this process and can transfer of detrimental maternal cytokines

or antibodies to the fetus be prevented at the level of the placenta? What is the molecular

pathway triggered by maternal cytokines resulting from MIA that leads to the

neuropathology and altered behaviors characteristic of ASD and SZ? Finally, which

cytokines are the most important in causing neurodevelopmental disorders and can they, or

their receptors and/or signaling cascades, be targeted to prevent the MIA phenotype?

Answering these questions is essential to determine if immune molecules present novel

therapeutic approaches in the near future for these complex neurodevelopmental disorders.

McAllister and Patterson

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References

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Elmer BM, McAllister AK. Major histocompatibility complex I proteins in brain development and

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Garay PA, McAllister AK. Novel roles for immune molecules in neural development: implications for

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