The Role of the Immune System in Autism Spectrum Disorder

Abstract

Autism is a neurodevelopmental disorder characterized by deficits in communication and social skills as well as repetitive and stereotypical behaviors. While much effort has focused on the identification of genes associated with autism, research emerging within the past two decades suggests that immune dysfunction is a viable risk factor contributing to the neurodevelopmental deficits observed in autism spectrum disorders (ASD). Further, it is the heterogeneity within this disorder that has brought to light much of the current thinking regarding the subphenotypes within ASD and how the immune system is associated with these distinctions. This review will focus on the two main axes of immune involvement in ASD, namely dysfunction in the prenatal and postnatal periods. During gestation, prenatal insults including maternal infection and subsequent immunological activation may increase the risk of autism in the child. Similarly, the presence of maternally derived anti-brain autoantibodies found in ~20% of mothers whose children are at risk for developing autism has defined an additional subphenotype of ASD. The postnatal environment, on the other hand, is characterized by related but distinct profiles of immune dysregulation, inflammation, and endogenous autoantibodies that all persist within the affected individual. Further definition of the role of immune dysregulation in ASD thus necessitates a deeper understanding of the interaction between both maternal and child immune systems, and the role they have in diagnosis and treatment.

Figure 1

Overview of the immune system as a mediator of behavior. Understanding how immune dysfunction in ASD can lead to changes in behavior requires understanding a complex network of interactions between several cell types from both the innate and adaptive arms of the immune system. Several immune factors mediate effects of CNS function. T-cell and NK-cell subpopulations may have altered activity and an impaired reaction to stimulation. Some cytokines can inhibit neurogenesis and promote neuron death, while others can promote the growth and proliferation of neurons and oligodendrocytes. Complement proteins and microglia can participate in synaptic scaling and pruning, while brain-reactive autoantibodies can change the development or function of neurons. When the many components of the immune system are dysregulated, these networks can lead to changes in neurodevelopment and behavior.

Figure 2

Maternal immune dysregulation during gestation is a risk factor for autism and numerous interrelated factors may lead to dysregulation of the maternal immune system. Infection during the pregnancy, such as by rubella or influenza virus, can create an inflammatory immune environment and spur the production of maternal cytokines, which can not only directly affect the placenta but also to a limited degree may cross the placenta and enter the fetal compartment to have lasting effects on the development of the fetus. These effects can also be achieved in the absence of active infection, whether though a generalized inflammatory response or loss of immune regulation. Animal models of MIA have been particularly significant in underscoring the importance of maternal immune regulation. In addition, a subset of women may produce anti-brain autoantibodies that can likewise gain access to the developing fetal brain and bind to fetal proteins, thereby altering the course of neurodevelopment. Activation of the maternal immune system during fetal development is thus an important factor in the etiology of ASD, and may lead to changes in neurodevelopment.

Figure 3

Ongoing immune dysregulation persists in autism. After birth and at least throughout childhood, an individual with ASD may have endogenous anti-brain autoantibodies, separate from any maternal IgG, which correlate with aberrant behaviors and impaired development. There also exists a broad picture of ASD-related immune dysregulation, including an increased inflammatory cytokine milieu (eg, IL-6, IL-8, and MCP-1), thus leading to an increased, pro-inflammatory Th1/Th2 ratio. T-cell and NK-cell populations may also be skewed, displaying a shift in cell subpopulations. NK cells in particular show an increased baseline activity but a decreased response to activation, rendering the cells unable to properly respond to stimuli. NK cells interact with activating and inhibitory KIRs, many of which are genetically linked to ASD. Other genetic factors include the oncogene MET and members of the diverse family of HLA genes. The broader background of immunogenetic factors of ASD includes multiple networks of the immune system, such as pathways that regulate cytokines and NK cells, which together constitute a broad, endogenous environment of atypical immune regulation and response.