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Immune mediators in the brain and peripheral tissues in autism spectrum disorder

Nature Reviews Neuroscience volume 16, pages 469–486 (2015)Cite this article

Subjects

Key Points

  • Genetic and environmental risk factors for autism spectrum disorder (ASD) suggest that dysfunction of the immune system may contribute to the development of this disorder.

  • Maternal immune dysfunction due to autoimmune disease, infection or immunogenetics may alter common molecular signalling pathways in the developing brain, increasing the likelihood of ASD.

  • Individuals with ASD exhibit chronic changes in immune system function that may represent disease-related pathophysiology, beneficial compensation or a combination of both.

  • ASD-related changes in the expression of immune molecules in the brain are not always indicative of neuroinflammation, even though these changes may be detrimental to brain development and function.

  • Many immune molecules are expressed in the brain at synapses, and their signalling may converge on several intracellular signalling hubs, such as myocyte-specific enhancer factor 2 (MEF2) and mammalian target of rapamycin (mTOR), that also mediate idiopathic and syndromic forms of ASD.

  • Immune molecules provide a new and important set of targets for the development of new therapeutics for ASD.

Abstract

Increasing evidence points to a central role for immune dysregulation in autism spectrum disorder (ASD). Several ASD risk genes encode components of the immune system and many maternal immune system-related risk factors — including autoimmunity, infection and fetal reactive antibodies — are associated with ASD. In addition, there is evidence of ongoing immune dysregulation in individuals with ASD and in animal models of this disorder. Recently, several molecular signalling pathways — including pathways downstream of cytokines, the receptor MET, major histocompatibility complex class I molecules, microglia and complement factors — have been identified that link immune activation to ASD phenotypes. Together, these findings indicate that the immune system is a point of convergence for multiple ASD-related genetic and environmental risk factors.

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Figure 1: ASD risk factors during pregnancy converge on maternal immune system activation.
Figure 2: Immune molecules at glutamatergic synapses.
Figure 3: Synaptic immune signalling converges on mTOR.

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Acknowledgements

The authors thank members of the McAllister laboratory for ongoing discussions about the topics covered in this Review, especially B. M. Elmer. M.L.E. has been supported by a Dennis Weatherstone Predoctoral Fellowship from Autism Speaks (#7825), the Letty and James Callinan and Cathy and Andrew Moley Fellowship from the ARCS (Achievement Rewards for College Scientists) Foundation, and a Dissertation Year Fellowship from the University of California Office of the President. A.K.M. is supported by grants from the National Institute of Neurological Disorders and Stroke (NINDS; R01-NS060125-05), the National Institute of Mental Health (NIMH; P50-MH106438-01), the Simons Foundation (SFARI #321998), and the University of California Davis Research Investments in Science and Engineering Program.

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  1. Center for Neuroscience, University of California, Davis, 1544 Newton Court, Davis, 95618, California, USA

    Myka L. Estes & A. Kimberley McAllister

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Correspondence to A. Kimberley McAllister.

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Glossary

Autoimmune disorders

Disorders wherein the immune system attacks normal substances and tissues of the body.

Maternal immune activation

(MIA). An animal model of prenatal immune challenge generated by stimulating the maternal immune system with viral or bacterial mimics, live antigens or inflammatory cytokines.

Copy number variants

Deletions or duplications of chromosomal segments that lead to phenotypic diversity among individuals.

Single-nucleotide polymorphism

(SNP). The most common form of genetic variation due to nucleotide substitutions.

Human leukocyte antigen

(HLA). The gene locus that encodes the human versions of three different classes of major histocompatibility complex proteins.

Complement

A system of plasma proteins that attack extracellular pathogens, assist in pathogen and cellular debris clearance by phagocytes and facilitate synaptic pruning in the brain.

Maternal immunoglobulin G (IgG) antibodies

IgG antibodies that pass through the placenta during the third trimester and enter fetal circulation, where they persist at high titre levels for several months after birth.

Blood–brain barrier

(BBB). A selectively permeable network of endothelial cells, pericytes and astrocytes separating the circulating blood from the brain extracellular fluid. The BBB begins to form in the first trimester and is fully formed by birth in humans. Infection, disease and certain drugs can increase the permeability of the BBB.

Fetal-brain-reactive antibodies

Maternally derived immunoglobulin G antibodies that can cross the placenta and bind to fetal brain proteins.

Polyinosinic–polycytidylic acid

(Poly(I:C)). Mismatched double-stranded RNA that acts as a viral mimic.

Gut microbiota

A diverse set of microorganisms that inhabit the gut and shape host immune function.

Phagocytosis

The engulfment of extracellular pathogens or cellular debris by certain immune cells, including microglia.

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Estes, M., McAllister, A. Immune mediators in the brain and peripheral tissues in autism spectrum disorder. Nat Rev Neurosci 16, 469–486 (2015). https://doi.org/10.1038/nrn3978

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