The Role of Inflammation in Autism
Inflammation is one of the characteristics of autism. However, it is not just a comorbid condition, but rather a factor that may contribute to genetic and brain alterations in children. Inflammation can alter the expression of genes responsible for brain development and function, and it may also cause direct damage to the central nervous system.
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Immune System Activation
Many studies connect autism with inflammatory and aberrant immune-system findings.
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Neuroinflammation
Microglial activation, cytokine changes, and inflammatory markers suggest involvement of the brain immune system.
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Genetic Expression Changes
Inflammation and oxidative stress may affect DNA repair, gene expression, and neurological development.
AN BIOLOGICAL MODEL
Inflammation as a central mechanism
Brain
Inflammation may affect microglia, astroglia, cytokines, brain volume, and neuronal survival.
Genes
Inflammatory cytokines and oxidative stress may alter gene expression and interfere with DNA repair.
Trigger
AN emphasizes that inflammation often has triggers, and one of the most common biological triggers is infection.
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Inflammatory immune system
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Microglial activation
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Astroglial activation
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Cytokine abnormalities
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Oxidative stress
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DNA damage and altered repair
SCIENTIFIC RATIONALE
Evidence of Inflammation in Children with Autism
The publications on the etiology of autism with an assessment of the reliability of the data were analyzed in a large meta-analysis article. The largest number of publications showed an association between ASD and the inflammatory/aberrant immune system, out of them, 95% of studies showed a positive relationship). Moreover, according to the authors, the strength of evidence was the highest in these articles.
A 2016 study fully confirms the role of inflammation in ASD, showing that at least 69% of children with ASD had neuroinflammation and microglial activation.
Another study showed that fetal inflammation due to viral or bacterial infections in some cases can lead to damage to the CNS, which can lead to various neurological disorders such as schizophrenia, cerebral palsy and ASD.
As well, it was discussed that perinatal neuroinflammation can lead to further autistic symptoms in a child.
Analysis of samples of cerebrospinal fluid and serum in children with autism and in healthy children led to the conclusion that children with autism had abnormal levels of neopterin, biopterin, cytokine, and cytokine receptors; once again pointing to the role of neuroinflammation in the development of ASD.
Evidence of Inflammation in Children with Autism
It is known that some children with autism may have brain volume 30% larger than neurotypical children.
Such an increase in the brain is called proliferation or hyperplasia. A study of the brain tissue of a child with autism and its comparison with the control showed that a child with autism has a significantly higher cell proliferation in the brain than the control.
In one of the review articles, where various molecular mechanisms of such proliferation in autism are considered, it is mentioned that children with autism have been found to have impaired genetic expression, leading to proliferation, which causes an increase in brain size. That is, the increase in many areas of the brain, characteristic of some children with autism, is not overgrowth, but rather the swelling of the brain as a result of constant neuroinflammation.
This increase in the early period of development is explained by proliferative and hypertrophic astrocytes, while a decrease in brain volume by the time the first autistic symptoms appear can be explained by the death of neurons as a result of prolonged proliferative inflammation.
Brain findings connected with inflammation
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Activation of microglia and astroglia in the middle frontal gyrus, anterior cingulate gyrus, and cerebellum
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Elevated levels of tumor growth factor anti-inflammatory cytokines-1 and protein-1 chemoattractant pro-inflammatory macrophages
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Increased levels of IFN-gamma, MCP-1, TGF-beta2, and IL-8 in cerebrospinal fluid
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Reduction in quinolinic acid and neopterin and increase in biopterin level in CSF
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Increased levels of TNF-alpha in CSF
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Elevated expression of some immunogenic genes in the superior temporal gyrus
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Reactive gliosis in BA22, BA44, and BA39
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Elevated pro-inflammatory cytokines in the frontal cortex
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Increased expression of NF-KappaB in the orbitofrontal cortex
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Increase in the concentration of 3-chlorotyrosine in the cerebellum and temporal cortex
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Elevated levels of cytokines IL-1b, IL-6, and IL-17
All of these findings directly indicate the state of neuroinflammation in children with autism.
Effect of Inflammation on Genetic Changes
In many cases, it has been shown that oxidative stress, which causes DNA damage, is a consequence of inflammation. In vitro, inflammatory cytokines have been found to induce the production of nitric oxide and nitric oxide synthase, which inhibits DNA repair.
Moreover, in another study, it was shown that at sites of inflammation, macrophages and neutrophils that are the molecules of inflammation produce active forms of oxygen and nitrogen, which leads to oxidative stress.
It is well-known that in other diseases such as cancer, inflammation leads to certain types of genetic changes.
But what causes inflammation?
Inflammation is a response of our immune system to any kind of danger from outside, but the most common danger that we face every day is infection.