Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by social communication deficits and repetitive behaviors.
Research increasingly points to dysregulation of the innate immune system and neuroinflammation as contributing factors in ASD.
Key facts:
- Inflammatory cytokines and chemokines are consistently elevated in the blood of individuals with ASD. These suggest activation of the innate immune system.
- Immune cells like monocytes and microglia exhibit altered activation and inflammation in ASD.
- Postmortem brains show signs of chronic neuroinflammation and microglia activation.
- Maternal immune activation during pregnancy increases ASD risk and leads to immune changes in animal models.
Source: Brain Behav Immun. 2022
Aberrant Innate Immune Activation in ASD
The innate immune system provides rapid defense against pathogens through immune cells like monocytes, macrophages, and microglia.
When activated, these cells release proinflammatory signaling proteins called cytokines and chemokines.
Numerous studies have found heightened levels of innate inflammatory cytokines like interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α in the blood of children with ASD compared to controls.
Chemokines that attract immune cells are also often increased.
These widespread increases suggest chronic activation of the innate immune system in ASD.
The heightened inflammatory state likely involves monocytes and macrophages, which produce these cytokines when activated.
Monocyte numbers are frequently elevated in ASD. Isolated ASD monocytes exhibit exaggerated cytokine responses when stimulated with compounds that activate innate immunity.
This hyper-responsiveness correlates with more severe ASD behaviors.
Dysfunctional regulation of innate immunity is further evidenced by deficient levels of anti-inflammatory cytokines like IL-10 and transforming growth factor (TGF)-β in ASD.
These molecules normally restrain inflammation. Without proper control, inflammation persists.
Chronic Neuroinflammation in ASD Brains
While innate activation in ASD blood indicates peripheral inflammation, there is also evidence that neuroinflammation occurs in the ASD brain.
Examination of postmortem brain tissue has repeatedly found increased activation of microglia, the brain’s innate immune cells.
Microglia exhibit an inflammatory phenotype and release cytokines like IL-6 and TNF-α.
Multiple studies report greater microglia density and enlarged cell bodies in ASD brains, indicative of chronic activation.
Microglia are in closer contact with neurons in ASD cortex, with processes wrapped around neuronal cell bodies.
This is concerning since activated microglia can damage neurons.
The neuroinflammation appears non-acute, suggesting an ongoing issue.
Supporting these findings, ASD brains show heightened expression of innate immune response genes.
Transcriptomic analyses identify enriched gene networks related to microglia, NF-κB inflammation, and interferon responses.
While microglia are essential for normal brain development and function, chronic activation alters their homeostasis and likely contributes to pathological outcomes.
Aberrant microglia-neuron interactions during critical developmental windows could underlie the neuronal connectivity issues characteristic of ASD.
Maternal Immune Activation Increases ASD Risk
Clinically, maternal infections and inflammation during pregnancy increase the risk for ASD and other neurodevelopmental conditions in offspring.
This demonstrates how early life immune system dysregulation can disrupt neurodevelopment.
Mouse models mimic this maternal immune activation (MIA) by stimulating the maternal immune system during gestation.
The offspring exhibit ASD-relevant behaviors as well as aberrant innate immunity.
MIA mice show exaggerated cytokine responses in macrophage cultures. Their microglia also appear overactive.
Notably, blocking entry of inflammatory monocytes into the brains of MIA mice prevents neuroinflammation and improves behaviors.
This demonstrates that prenatal inflammation has consequences extending after birth, altering developmental trajectories.
Mechanisms of Immune-Brain Interactions in ASD
Exactly how innate immune disturbances contribute to ASD requires further research.
There are several working hypotheses:
- Cytokines and chemokines access the brain: These molecules cross the blood-brain barrier or are produced within the brain. Inflammatory factors directly affect neurons and neurodevelopment.
- Microglia pruning and maturation: Chronic microglia activation could disturb their roles in synaptic pruning and neuronal maturation during development.
- Microglia-neuron interactions: Activated microglia damage neurons through inflammatory factor release and physical engulfment.
- Pre-priming by maternal inflammation: Maternal inflammation may epigenetically or developmentally alter fetal monocytes and microglia, pre-disposing them to hyperactivity postnatally.
- Gut-immune interactions: ASD is associated with gastrointestinal issues. Changes to gut microbiota may dysregulate immunity.
Moving Forward in ASD Innate Immune Research
The consistent evidence for innate immune involvement in ASD makes this a promising area for continued research and potential therapeutic development.
However, ASD is heterogeneous, and immune dysregulation likely only represents one pathological mechanism among subsets of individuals.
Studies often identify ASD subgroups with shared immune abnormalities like increased inflammatory cytokine production.
Defining these endophenotypes based on innate markers could improve personalized medicine approaches.
Technologies like transcriptomics and epigenetic profiling of immune cells may uncover novel mechanisms underlying chronic inflammation in ASD.
Advancing our understanding of innate immunity and neuroinflammation in ASD will provide clues into the origins of this multifaceted condition, opening new avenues for diagnosis and treatment.
The parallels between many neurodevelopmental disorders further suggest that insights gained from ASD immune research could elucidate pathological mechanisms shared across neurological conditions.
References
- Study: Innate immune dysfunction & neuroinflammation in autism spectrum disorder (ASD)
- Authors: H K Hughes et al. (2022)
