Thimerosal 277IL‐1β, IL‐6, tumor necrosis factor (TNF), monocyte chemotactic protein
(MCP)‐1 and CCL8 (IL‐8) [87–90]. Plasma levels of IL‐1β, IL‐6 and IL‐8 were
increased in children with ASD and correlated with regressive autism, as well
as impaired communication and aberrant behavior [90,91]. Abnormal immune
responses in individuals with ASD have been reported for nearly 40 years
including the presence of self‐reactive antibodies to neuroantigens that we
have described in Chapter 8. The evidence of increased neuroinflammation in
brain specimens obtained from subjects with ASD has shown increased infil-
tration of lymphocytes and macrophages, validating a leaky BBB. For example,
Vargas et al. analyzed autopsied brain tissues from cerebellum, midfrontal, and
cingulate gyrus from 11 patients with autism and fresh‐frozen tissues from
seven patients and CSF from six living autistic patients for cytokine protein
profiling [92,93]. They showed an active neuroinflammatory process in the
cerebral cortex, white matter, and in the cerebellum of autistic patients.
Immunocytochemical studies showed marked activation of microglia and
astroglia, and cytokine profiling of the CSF indicated that MCP‐1 and TNF‐β1,
derived from neuroglia, were the most prevalent cytokines in brain tissues.
CSF showed a unique proinflammatory profile of cytokines, including a
marked increase in MCP‐1. Their findings, which have been verified by a large
group of other investigators, indicate that innate neuroimmune reactions play
a pathogenic role in an undefined proportion of autistic patients, suggesting
that future therapies might involve modifying neuroglial responses in the brain
[88,94]. Several studies have shown immune abnormalities in patients with
ASD, specifically in their blood circulation including abnormal or skewed T
helper cell cytokine profiles [95–99], decreased lymphocyte numbers [98],
abnormal T lymphocyte responses [97–102], and disparity of serum immuno-
globulin levels [100]. In summary, these findings support modifications in the
immune responses in a significant proportion of children with ASD.
Masi et al. (103) have reported that serum concentrations of IL‐1β, IL‐6,
IL‐8, interferon‐gamma (IFN‐γ), and MCP‐1 were significantly higher in indi-
viduals with ASD than in controls. Xu et al. (104) carried out a series of studies
that strongly suggested that IL‐6, TNF‐α, and IFN‐γ are significantly elevated
in different tissues in ASD patients. Importantly, these aforementioned bio-
markers can be manifestations of neurointoxication or neuroinflammation,
and mercury‐containing vaccines in particular induce neuroinflammation
[103–106]. For example, oxidative stress is commonly known as one of the
main effects of mercury present in thimerosal‐containing vaccines that induces
neuroinflammation. In humans, exposure to metallic mercury is known to
cause elevated levels of IL‐1β, IL‐2, IL‐6, IL‐8, IFN‐γ, and TNF‐α [106].
Mercury‐containing vaccines can also cause autoimmune dysfunction. Studies
completed on human workers exposed to metallic mercury vapors show auto‐
antibodies to S‐100 proteins, myelin basic protein (MBP), and myelin‐associated
glycoprotein (MAG) [106].