Researchers believe that autism may be closely linked with immune system abnormalities. Many believe that there are environmental factors that can trigger changes in certain immune system molecules. One set of molecules in particular are being investigated: MHCI (major histocompatibility complex I) molecules, which mediate the adaptive immune response in humans. They are present in neurons and it is possible that developing brain neurons may contribute to autism by changing the manner in which synapses develop. The hypothesis is that changes in MHCI are triggered by specific environmental factors and that these factors cause changes in synaptic connectivity. Researchers suggest that environmental factors affect MHCI through cytokines, which are proteins that regulate communication between cells within the immune system.
Indeed, many of those diagnosed with autism tend to have up-regulated, or hyper-active, cytokines in their brain. It is possible that these cytokines alter synaptic connectivity by changing MHCI levels, and these changes in turn contribute to the onset of autism. This hypothesis, however, has yet to be tested. If it is true, however, it may be possible to determine how cytokines and MHCI interact in such a way that affects the brain negatively. This could in turn prove helpful in developing ways of preventing autism.
Furthermore, there is an antibody subtype responsible for most of the immune response to invading pathogens called immunoglobulin G, or IgG. Neurotypical children tend to have much lower amounts of this than children with autism. It is therefore possible that there are problems in proper signaling of cells to produce specific factors or proteins. This leads such children to be more susceptible to infections, which may contribute to the onset of autis. This means that there would be something awry in the communication among the cells of a developing immune system within such children, resulting in abnormal levels of IgG.
Numerous other studies have suggested links between neuro-inflammation and autism spectrum disorders as well:
“Perhaps one of the most substantive studies in the last decade was conducted at the John Hopkins Institute, and involved an analysis of autopsy specimens and cerebrospinal fluid (CSF) samples from affected individuals and controls (2). The results indicated a neuroinflammatory response, regardless of age (in patients between 5 and 46 years of age), involving excess microglial activation and increased pro-inflammatory cytokine profiles. The study carries high statistical significance [for review of study, see Ref. (27)] and indicates an inflammatory state probably exists in the brains of these patients. Similar findings were found in a more recent autopsy study of microglia densities in fronto-insular and visual cortices of patients with ASD versus controls, and found a statistically significant (p ≤ 0.0002) increase in microglial density in both regions (4). Other immune abnormalities have also been found indicating an inflammatory state. Transforming growth factor beta 1 (TGF-β1) is reduced in ASD cohorts versus controls and individuals with other developmental disorders and was found to be inversely proportional to behavior outcomes (irritability, lethargy, stereotypy, and hyperactivity) as well as with levels of social adaptability (28).
Natural killer cells (NK cells) are abnormal in sub-groups of ASD. NK cells respond to macrophage-derived cytokines and are essential in tumor prevention and host anti-viral activity. Enstrom et al. (29) found a significant reduction in NK cell cytotoxicity and a 2.5-fold increase in KSP-37, an NK gene normally induced during active viral infection. They concluded that ASD patients have activated but resting NK cells with increased levels of cytolytic proteins and an altered response to stimulation with changes in gene expression (29). Supporting these findings, cancer mortality rates are higher in ASD (20), and the only identified risk factor for mortality associated with the recent H1N1 outbreak was developmental delay (30). Both of these findings suggest immune dysfunction in ASD, and either or both of these findings could be linked with the NK cell abnormalities identified by Enstrom et al. (29).”
Abnormal gut micro flora has also been associated with autism spectrum disorders:
“Abnormal clostridia species have been found repeatedly in ASD (63–67). The theory of clostridia involvement was postulated by Bolte in 1998 who suggested that clostridia toxin adversely affected neurotransmitter function that could result in neurobehavioral changes presenting as autism (68). Supporting this hypothesis, Parracho et al. outlined robust measures of microflora abnormalities in ASD cases suffering from bowel problems using PCR analysis and found a clear and consistent abnormality in the clostridia species present in ASD sufferers versus controls. Clostridium histolytica were found in higher levels in the ASD group versus healthy unrelated controls (p < 0.01) and healthy related controls (p < 0.05) (65).
A clinical trial was carried out to assess the bowel and behavioral impact of anti-microbial therapy directed against these abnormal clostridia species (69). Oral vancomycin was used for 6 weeks. Behavioral measurements were carried out before and after, as well as clinical assessment of bowel symptoms. The numbers were low but the response to intervention was reported as statistically significant. 8 of the 10 patients studied improved in terms of behavior and bowel symptoms with some scoring within the neurotypical range. Discontinuation of vancomycin after the 6-week trial period led to a gradual regression in bowel and behavioral symptoms in all participants (69) suggesting that gut environment gives preference to these abnormal species. As yet, there has been no investigation of the combined approach of anti-microbial therapy and other interventions targeted at altering microbiota composition.
Williams et al. recently reported consistently abnormal Firmicutes to Bacteriodetes ratios from biopsy specimens in children with ASD versus inflammatory bowel disease (IBD) controls. This was linked to reduced disaccharidases (starch digesting enzymes), which in the same study were also found to be low in the ASD group. Williams et al. postulated a link between high carbohydrate transit to the large intestine in ASD leading to alteration in the proportion of Firmicutes to Bacteriodetes. The appearance of this “compositional dysbiosis” was highly correlated in the ASD group with Firmicutes to Bacteriodetes ratio of 31:69 (versus controls 27:73) in the ileal biopsies (p < 0.0006) and 32:68 (versus controls 25:75) in the cecal biopsies (p < 0.022) (66).
Although microflora are known to alter host immune function, including cytokine production [for review see Ref. (70–73)], to our knowledge there has, to date, been no investigation of the relationship between abnormal microflora and cytokine production in ASD, although a few studies have examined cytokines in ASD patients with bowel symptoms and found positive correlations (72–74).”
Indeed, gastrointestinal disorders are more common among those with autism spectrum disorder:
“Gastrointestinal (GI) symptoms, including abdominal pain, bloating, diarrhea and constipation have been reported in a subset of subjects with ASD. Those with GI symptoms have been found to have inflammatory cytokine profiles in mucosal immune cells and peripheral blood compared to controls. The exact relationship between GI symptoms and ASD is unclear. The GI tract is the site of extensive and specific immune activity, and it has been proposed that immune mediated GI pathology may lead to systemic immune activation and inflammation in the brain. However, there is yet to be concrete data to support this claim.”
In another study, conducted with mouse models of autism, researchers suggested that levels of an APP fragment in the blood could explain abnormalities of immune cell function and populations. Both of these are observed, as noted before, in autism patients. Researchers at USF argued that the relevant protein fragment may be an effective biomarker for autism and that this may constitute a new research target for understanding the disorder’s underlying biological pathways.
This is the amyloid precursor protein. It has usually been the focus of research surrounding the genesis of Alzheimer’s disease, but some scientific reports have suggested there are elevated levels of the protein fragment sAPP-alpha in the blood of those with autism. This fragment is an important growth factor for nerves and the studies imply that it possibly plays a role in the immune responses of T-cells.
“To study the autism-related effects of this protein fragment on postnatal neurodevelopment and behavior, Dr. Tan and his team inserted the human DNA sequence coding for the sAPP-α fragment into the genome of a mouse model for autism. While the studies are ongoing, the researchers documented the protein fragment’s effects on the immune system of the test mice.
“We used molecular biology and immunohistochemistry techniques to characterize T-cell development in the thymus and also function in the spleen of the test animals,” Dr. Tan said. “Then we compared transgenic mice to their wild-type littermates.””
They found that higher levels of this substance in transgenic mice produced higher numbers of cytotoxic T-cell numbers. These researchers found impairment int he recall function of memory T-cells, implying that there may be an adaptive immune response that is negatively affected by high levels of the protein fragment.
In general, research frequently centers around cytokines and autoimmunity. Cytokines are proteins whose purpose is to regulate the nature, length and intensity of an immune response. They are generated by the immune system itself. While they were an essential component of the development and health of the central nervous system, it is possible that abnormal production of this substance during critical points of brain development could have long-term affects on the brain related to the symptoms of autism. Higher levels of pro-inflammatory cytokines such as TNF-alpha and decreased levels of anti-inflammatory cytokines, such as IL-10, have been found in children with autism. Such imbalances may increase inflammation and damage tissues.
Cytokines secreted by T cells can be distinguished into TH1 (associated with inflammation and cell response) and TH2 (associated with asthma and allergies). Higher levels of TH2-producing lymphocytes have been found in subjects with autism relative to controls. Another study links abnormal TH1 cytokine profile, and yet another found unusually high levels of both cytokines without a compensatory increase of the regulatory cytokine IL-10 in children with autism. A 2005 study found that those with autism exhibited inflammation in which there was an over-activation of these brain cells. Abnormal cytokine patterns were also found in brains and cerebrospinal fluid of these subjects compared with controls.
As noted before, autoimmunity remains a likely candidate for symptoms of autism. This results when an immune system cannot differentiate self from non-self and the immune system attacks its own body. Lupus and rheumatoid arthritis are examples of these. It is possible that at least some of those with autism may have autoimmune abnormalities which results in the cells attacking the child’s brain. This harms brain tissue and causes it to develop abnormally. Indeed, numerous studies suggest the presence of auto-antibodies specific to the relevant brain tissue in both human and animal models, such as neuronal and glial filament and myelin basic protein, as well as other unidentified brain antigens. Autoimmune activity thus can be associated with autism in some cases, although it is hard to tell if these abnormalities are the result of cause or effect.