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Could Autism Be An Autoimmune Disorder

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Autism May Be An Autoimmune Disorder

Autism Jargon: Autoimmune Disorder

  • 20/10/2019

Watch: Jess Falconer is one of a number of Kiwi adults being diagnosed with autism after their child’s diagnosis. Credits: Video – Newshub; Image – Getty

American research has found that autism spectrum disorder could be an autoimmune disease.

Physician scientist Matthew P. Anderson and his colleagues from the Beth Israel Deaconess Medical Centre , a teaching hospital of Harvard Medical School, have discovered cellular features – indicating an immune response targeting specific brain cells – in more than two-thirds of autistic brains analysed postmortem.

These cellular features are believed to provide new insight into the causes of autism, potentially paving the way to improved diagnosis and treatment. 

“Investigators typically aim potential treatments at specific pathologies in brain diseases… such as the Lewy bodies seen in Parkinson’s,” Anderson said in a BIDMC press release. “Until now, we have not had a promising target like that in autism.” 

The research, published in the Annals of Neurology journal, discovered an accumulation of immune cells surrounding blood vessels in the brain known as perivascular lymphocyte cuffs. Anderson noticed the cuffed blood vessels when examining brains donated to Autism BrainNet, a non-profit tissue bank.

The lymphocyte cuffs Anderson observed were unlike those found in any other documented infection or autoimmune disorder of the brain.


What Is Niehs Doing

Unraveling the genetic and environmental underpinnings of autoimmune disease is a focus at NIEHS and the National Toxicology Program . Progress happens through multiple research efforts, such as:

Fact Sheets

  • Strickland FM, Hewagama A, Wu A, Sawalha AH, Delaney C, Hoeltzel MF, Yung R, Johnson K, Mickelson B, Richardson BC. 2013. Arthritis Rheum. 65:18721881. Diet influences expression of autoimmune associated genes and disease severity by epigenetic mechanisms in a transgenic lupus model.
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    Autism And Bipolar Disorder

    People with bipolar disorder tend to alternate between a frenzied state known as mania and episodes of depression.

    It is important to understand the symptoms of true bipolar disorder from those of autism by looking at when the symptoms appeared and how long they lasted. For example, a child with autism may be consistently high-energy and socially intrusive through childhood. As such, her tendency to talk to strangers and make inappropriate comments are likely part of her autism, and not a symptom of a manic mood swing.

    Treatments: Some of the medications used to treat bipolar disorder can be problematic for some with autism who has difficulty recognizing and expressing feelings. A psychiatrist can provide additional medications that may be safer.

    Uc Davis Health Study Finds That Male Offspring Are At Higher Risk To Maternal Immunity Activation

    Children with autism born to mothers who had immune conditions during their pregnancy are more likely to have behavioral and emotional problems, a UC Davis Health study has found. The study examined maternal immune history as a predictor of symptoms in children with autism.

    Paul Ashwood

    We tested the ability of maternal immune history to predict ASD symptoms and the possible role that the sex of the offspring plays, said Paul Ashwood, professor of microbiology and immunology and faculty member at the UC Davis MIND Institute.

    Autoantibodies In Individuals With Asd

    In addition to antibodies targeting the GI epithelium, autoantibodies specific to self-proteins in the brain, CNS and cellular components have been frequently reported in individuals with ASD . Autoantibodies are a common feature in autoimmunity, and their presence may be predictive of the development of certain autoimmune disorders . Presence of autoantibodies that react to components of the brain and CNS in individuals with ASD have been identified since as early as 1988, when antibodies to neuron-axon filament proteins were found in 10 out of 15 children with ASD . A year later, researchers identified IgG and IgM antibodies that target cerebellar neurofilaments . Anti-myelin basic protein antibodies were identified in individuals with ASD in 1993 and later supported by additional studies . The anti-MBP results have been replicated in additional studies, including a 2013 investigation that linked these autoantibodies to both severity of ASD as well as allergic manifestations . However, other studies have refuted these findings which underscores the wide variations of immune phenotypes seen in ASD .

    Table 4. Studies identifying presence of autoantibodies in individuals with ASD.

    Could The Gut Microbiome Be Linked To Autism

    A child with autism spectrum disorder communicates using symbols during lunch.Credit: BSIP/UIG via Getty

    Before Ethan Loyola reached his first birthday, it was clear that something was wrong with his gut. As a baby, he had been given several courses of antibiotics to treat severe ear infections, after which he experienced foul-smelling, acidic diarrhoea that left him convulsed with pain. Around the age of one, Ethan lost the words hed started to say and stopped making eye contact. Soon after that, he received a diagnosis: autism spectrum disorder .

    As Ethan grew older, his digestive issues continued, and he struggled around other people and in unusual situations. He had his hands over his ears, didnt want to be in crowds, says his mother, Dana Woods. It was just too overwhelming. Then Ethans dad saw a flyer tacked up at an autism therapy clinic. Scientists at Arizona State University in Tempe, near the familys Phoenix home, were looking for children with autism to try an experimental treatment called microbiota transfer therapy, which would be used to recolonize the childrens guts with bacteria from donors who were not on the autistic spectrum. Ethans parents enrolled him in the study.

    Although far from conclusive, these findings are driving researchers to probe the links between gut microbes and autism symptoms and to begin testing ASD treatments that repopulate the gut microbiome from scratch.

    An Accumulation Of T Cells And Astrocytes In Postmortem Brain Tissue Hints At Possible Autoimmune Origins For Many Cases Of Autism

    Jan 13, 2020

    About four years ago, pathologist Matthew Anderson was examining slices of postmortem brain tissue from an individual with autism under a microscope when he noticed something extremely odd: T cells swarming around a narrow space between blood vessels and neural tissue. The cells were somehow getting through the blood-brain barrier, a wall of cells that separates circulating blood from extracellular fluid, neurons, and other cell types in the central nervous system, explains Anderson, who works at Beth Israel Deaconess Medical Center in Boston. I just have seen so many brains that I know that this is not normal. 

    He soon identified more T-cell swarms, called lymphocytic cuffs, in a few other postmortem brains of people who had been diagnosed with autism. Not long after that, he started to detect another oddity in the brain tissuetiny bubbles, or blebs. Id never seen them in any other brain tissue that Ive looked at for many, many different diseases, he says. Anderson began to wonder whether the neurological features he was observing were specific to autism. 


    General Immunological Findings In Autism Spectrum Disorders

    Long exposure to toxic, environmental or occupational chemicals, have been shown to stimulate the production of autoantibodies to nervous system antigens. Titers of antibodies against neurofilaments and myelin basic protein correlated significantly with urinary mercury and blood lead levels, the standard indicators of toxic exposure. In addition, levels of these antibodies proved to correlate with sensorimotor deficits. Gut-associated lymphoid tissues can interact with toxins, chemicals and pollutants. If covalent reactions are formed between the drugs or other chemical compounds and the GALT, this can lead to immune responses and chemically-induced Type I- Type IV allergic reactions . Many infectious agents including measles, Rubella virus and Cytomegalovirus vaccines have long been suggested as etiologic factors in autism .

    Leaky Gut And Fetal Immune Health

    Could Autism Be Caused by Gut Microbes? | Dr. Emeran Mayer | Big Think

    Another risk factor that can pass to the fetus is intestinal permeability, commonly referred to as leaky gut. Excess sugars and starches in the diet along with chronic stress can inflame the gut and cause the intestinal lining to become porous, or leaky. Because some 80 percent of the bodys immune system resides in the gut, a leaky gut triggers a cascade of inflammation that extends beyond the gut and into the brain and body, including the placenta of a pregnant woman.

    Damaged gut walls will allow undigested foods, bacteria, and other pathogens to escape from the intestines into the bloodstream. These circulating pathogens affect the fetus by stimulating an immune response that may affect the development of the fetal brain.

    Maternal Immunity Conditions And Autism

    Maternal immune conditions are caused by a dysfunction of the mothers immune system. They include allergies, asthma, autoimmune diseases, autoinflammatory syndromes and immunological deficiency syndromes. Previous studies have shown that maternal immune conditions are more prevalent in mothers of children with autism spectrum disorder .

    The researchers enrolled 363 mothers and their children from the Autism Phenome Project and Girls with Autism Imaging of Neurodevelopment study at the UC Davis MIND Institute. The median age of the children was three years.

    The researchers measured the childrens autism severity and assessed a set of behavioral and emotional problems such as aggression and anxiety. They also measured the childrens development and cognitive functioning.

    The study found that around 27% of the mothers had immune conditions during their pregnancy. Of these mothers, 64% reported a history of asthma, the most common immune condition. Other frequent conditions included Hashimotos thyroiditis , Raynauds disease , alopecia , psoriasis and rheumatoid arthritis .

    The study also found that maternal immune conditions are associated with increased behavioral and emotional problems but not reduced cognitive functioning in children with autism.

    Evidence Of Inflammatory Cytokine Responses In Asd

    Neuroimmune interactions begin early in development, and the health of one system is contingent on the health of the other. Both systems share common signaling molecules and receptors, such as cytokines and neuropeptides/neurotransmitters. Aberrant responses from immune cells present in the CNS, including microglial cells in the brain, have been implicated in neuronal cell death , which is partly mediated through the actions of inflammatory cytokines and neuropeptides. The inflammatory cytokines IL-1, IL-6 and TNFα can directly affect the CNS, can alter neurodevelopment and, subsequently, may have an impact on behavior . For example, neuropoietic cytokines, such as IL-6, can have direct effects on neurons and glia in vitro, including changes in proliferation, survival, death, neurite outgrowth and gene expression ; while in vivo, the peripheral administration of IL-6 to gestating mice has been demonstrated to affect behavior and neurodevelopment of offspring . In addition, cytokines such as TNFα have been linked to oligodendrocyte toxicity, as well as aberrant neurite growth . While a cytokine-mediated mechanism has yet to be conclusively established in neurodevelopmental disorders such as ASD or schizophrenia, evidence of adverse immunological functioning in these disorders suggests that neuroimmune interactions may be altered and may affect neurodevelopment and early brain development .

    First Large Scale Study Links Autism And Autoimmunity

    American Autoimmune Related Diseases Association
    A new study of more than 2,700 mothers of children with autism shows that about one in 10 mothers have antibodies in their bloodstream that react with proteins in the brain of their babies.

    A new, large-scale study of more than 2,700 mothers of children with autism shows that about one in 10 mothers have antibodies in their bloodstream that react with proteins in the brain of their babies.

    The research, published in Molecular Psychology indicates that while the blood-brain barrier in the adult women prevents them from being harmed by the antibodies, that same filter in the fetuses is not well-developed enough and so may allow the “anti-brain” antibodies to pass through to the babies’ brains, possibly causing autism.

    The study was led by Dr. Betty Diamond, head of the Center for Autoimmune and Musculoskeletal Disorders at The Feinstein Institute for Medical Research in Long Island, New York, who said the very large sample size “gives a clearer impression of the prevalence of these antibodies.”

    “We at AARDA applaud Dr. Diamond’s research into an area that concerns all parents,” said Virginia T. Ladd, President of American Autoimmune Related Diseases Association, Inc. .

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    How Could Foods Worsen Autism

    Its not completely clear that foods do worsen autism, although there are many theories about how this could occur. It’s been suggested that autism could result from a loss of regulation of the immune system, causing an increase in inflammatory-causing chemical signals from white blood cells. It is felt that these chemicals may be responsible for the neurological abnormalities seen in children with autism.

    Recent studies suggest that children with autism may respond to certain foods, particularly gluten- and casein-containing foods, by producing more of these inflammatory cytokines. Blood cells from autistic children were cultured with various foods in a lab, and various inflammatory cytokines were measured. The cytokines from the autistic children were much higher than those from non-autistic children after being exposed to gluten or casein. If these findings were validated, similar tests could potentially be used in the future to determine who may benefit from dietary restrictions. It is important to note that no currently available test has been validated for general use.

    Autism May Be Linked To An Immune Disorder

    Until now, diagnosis for autism spectrum disorder have relied on behavioral assessments looking for symptoms including poor social and communication skills, restricted interests and repetitive behaviors. This may soon change however, as scientists have discovered features in the immune system that may activate the disorder. 

    In a study published in Annals of Neurology, researchers have discovered the presence of cellular features that infer an immune response targeting certain brain cells in over two thirds of autistic brains analyzed postmortem. Previously unobserved in autism, may lead to new insights in autisms origins, and eventually lead to better ways to diagnose the disorder as well as treatments. 

    In a study published in Annals of Neurology, researchers examined brains from the Autism BrainNet, a non-profit tissue bank. Upon their analysis, they noticed the presence of perivascular lymphocyte cuffs- a build-up of immune cells clustered around blood vessels in the brain. Although they have no previous link to autism, perivascular lymphocytic cuffing is known as an indicator of chronic inflammation of the brain, and is thus a common sign of a viral infection or autoimmune disorder . 

    Anderson also said, With this new research, we haven’t proved causality, but this is one clue in support of the idea that autism might be an autoimmune disorder, just like multiple sclerosis is thought to be .

    Autism Spectrum Disorders And Gut Bacteria

    In recent years we have been learning that the bacteria we harbor in our intestines may affect everything from the diseases we develop to our moods. This science is still in its infancy, and it is uncertain what, if any, role gut bacteria play in autism, but researchers have found differences in the gut microbiome among children with autism spectrum disorders. Fortunately, many studies are in progress, and we will likely have more information available in the near future regarding whether dietary changes might lead to a change in the gut microbiome that could be advantageous to children with autism.

    Cytokines And Chemokines In Brain Tissue And Cerebrospinal Fluid

    An elevation of NF-B in neurons and microglia was found to be significant in orbitofrontal cortex of ASD individuals . Chez et al. evaluated the concentration of TNF- simultaneously in both serum and CSF of 10 male patients aged 2.59.7 with regressive ASD. The studys results must be interpreted cautiously since 7 out of 10 patients were on medications, including valproic acid and risperidone, which are thought to have anti-inflammatory and potentially immunomodulatory properties . Four patients had received treatment for autoimmunity in the past, but no details concerning timeframe of treatment were provided. The ratio of TNF- in CSF and serum ranged between 1.7 and 275, with an average value of 41.6, and the concentration of TNF- in CSF and the CSF/serum ratio were higher in patients who did not undergo immunomodulatory therapy. The authors hypothesized they may have observed a unique CNS response, as no apparent correlation exists between CSF and serum and the CSF/serum ratio described in other diseases is close to 1:1. A similar hypothesis concerning lack of association between different protein concentration in CSF and serum was confirmed by Pardo et al. . The results of studies conducted on CSF and brain tissue are summarized in Table .

    Table 4. Concentration of cytokines, chemokines, and growth factors in brain tissue and cerebrospinal fluid of ASD patients

    Pivotal Role Of Immune System As A Potential Target For Novel Therapeutic Methods

    Hope Research – finding the cause of autoimmune disease

    Interestingly, corticosteroids which have been used to treat other disorders in ASD patients were found to lessen autistic features. A child with ASD who developed autoimmune lymphoproliferative disorder improved greatly in language development and behavior after oral prednisolone therapy . A retrospective analysis showed that children with regressive autism benefited from steroid therapy in language development and behavioral spheres . Two other cases of behavioral improvement after corticosteroid therapy were reported in ASD and PDD . Limitations of steroid therapy include well-known side effects and lack of expected significant improvement in core ASD domains. To date, there is only one registered clinical trial registered using pregnenolone in an attempt to lessen irritability, sensory impairment, and social sphere in autistic individuals .

    Minocycline, a tetracycline antibiotic that could potentially alter inflammation and microglia activity , failed to exert clinical effects despite detected changes of hepatocyte growth factor and IL-8 in serum and BDNF changes in both serum and CSF . However, in a double-blind placebo-controlled trial, minocycline as an adjunctive therapy to risperidone showed reduction of hyperactivity and irritability . One clinical trial with minocycline aimed at measuring microglia activity by PET imagining is currently open .

    Is There A Connection Between The Immune System And Autism

    The ideal immune system will:

    • Recognize all foreign organisms .
    • Efficiently and rapidly destroy invaders.
    • Prevent a second infection with the same microbe .
    • Never cause damage to self.

    Things that can go wrong:

    • Immune deficiency/dysfunction: defective or ineffective response.
    • Hypersensitivity: Over-reaction to innocuous foreign material, out of proportion  to potential damage .
    • Autoimmunity: Inappropriate reaction towards self, loss of self-recognition.
    • Inflammation: Too-vigorous attack against invaders with bystander damage to normal tissue.

    Dysregulation of immunity in people with autism can lead to any of these four problems.

    There is a tendency towards a positive family history of autoimmunity in families Rheumatoid Arthritis, Thyroiditis with an ASD child.  Many, many types of autoantibodies have been found in ASD children but the significance of the many types of anti-brain antibodies is not yet clear. Several studies find that some ASD children have low immunoglobulins , and/or low T cell numbers, altered cytokine profiles, and/or low-normal functioning and/or low NK cells; a subset of children have true immunodeficiency.  Some children have low serum IgA, predisposing them to respiratory and GI infections.

    Outstanding Questions And Conclusion

    The evidence that immune dysfunction likely plays a role in the etiology/pathophysiology of ASD is becoming substantial. Familial autoimmunity is a common risk factor, and maternal autoantibodies and inflammation during gestation significantly increase the risk of having a child with ASD. Furthermore, individuals with ASD have significant immune dysfunction and inflammation. They also suffer from immune-mediated co-morbidities much more often than the typically developing population, including GI dysfunction and dysbiosis. The presence of autoantibodies in individuals with ASD is increased, and evidence of neuroinflammation has been substantiated both in vivo and in post-mortem brain tissue. Although the plethora of evidence identifying a connection between autoimmunity, immune dysfunction, and ASD is tantalizing, it still leaves many mechanistic questions regarding the impact of immune system dysfunction on the development of ASD.

    Fibromyalgia Likely The Result Of Autoimmune Problems

    King’s College London
    New research has shown that many of the symptoms in fibromyalgia syndrome are caused by antibodies that increase the activity of pain-sensing nerves throughout the body. The results show that fibromyalgia is a disease of the immune system, rather than the currently held view that it originates in the brain.

    New research from the Institute of Psychiatry, Psychology & Neuroscience at King’s College London, in collaboration with the University of Liverpool and the Karolinska Institute, has shown that many of the symptoms in fibromyalgia syndrome are caused by antibodies that increase the activity of pain-sensing nerves throughout the body.

    The results show that fibromyalgia is a disease of the immune system, rather than the currently held view that it originates in the brain.

    The study, published today in the Journal of Clinical Investigation, demonstrates that the increased pain sensitivity, muscle weakness, reduced movement, and reduced number of small nerve-fibres in the skin that are typical of FMS, are all a consequence of patient antibodies.

    Furthermore, the mice injected with fibromyalgia antibodies recovered after a few weeks, when antibodies had been cleared from their system. This finding strongly suggests that therapies which reduce antibody levels in patients are likely to be effective treatments. Such therapies are already available and are used to treat other disorders that are caused by autoantibodies.

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    Autism And The Gluten

    Parents have been using the gluten-free, casein-free diet as an autism treatment for at least two decades . The controversial theory behind the treatment is that children with autism spectrum disorder have a “leaky gut” that allows fragments of large proteins to leak from their digestive tracts. Gluten and casein are proteins.

    According to this theory, the proteins gluten and caseinwhen leaked from the digestive tracthave an effect somewhat like opioids on the child’s developing brain.

    In addition, many children on the autism spectrum have digestive symptoms such as diarrhea, constipation, abdominal pain, or reflux, which in parents’ minds bolsters the case for some sort of dietary intervention.

    However, the truth is there’s little evidence to back up this treatment: A review of major studies on the GFCF diet in autism found minimal to no effect on autistic symptoms. Still, some parents maintain that the GFCF diet has helped their children , and some alternative practitioners continue to recommend it. This has led some to speculate on a potential connection to celiac disease.

    Peripheral Blood Cytokines Chemokines And Growth Factors

    Frequently, ASD individuals were reported to have a higher concentration of proinflammatory or lower concentration of anti-inflammatory cytokines in comparison to healthy controls or other developmental delays, although some results are contradictory . Interestingly, Tsilioni et al. distinguished two autistic groupswith initially low or high IL-6 and TNF levels, whereas another study divided subjects according to response to LPS stimulation and found high levels of IL-1 and IL-6 in LPS responders . One recent study focused on several soluble factors that have not previously been studied in ASD. Investigators researched IL-21, IL-22, IL-27, and cytotoxic T-lymphocyte-associated molecule-4 as indicators of pro- and anti-inflammatory balance and revealed dysregulation of immune milieu . Other differences between ASD subjects and healthy individuals included high MCP-1, RANTES, eotaxin , TARC, MDC , BDNF, and platelet-derived growth factor concentrations , low epidermal growth factor , and altered IL-23 and IL-8 . Intriguingly, a few studies included normally developing siblings as one of the control groups and found that their biomarker profile was distinct from other normally developing children .

    Several published studies did not confirm differences between ASD and healthy individuals in baseline or stimulated levels of cytokines, chemokines, or growth factors .

    Cytokines Role In Autism Spectrum Disorders

    Cytokines are a family of small proteins secreted by immune cells. They have the ability to induce directed chemotaxis in nearby responsive cells. Some chemokines are considered pro-inflammatory and can be induced during an immune response to recruit cells of the immune system to a site of infection. These proteins exert their biological effects by interacting with G protein-linked transmembrane receptors called chemokine receptors found on the surfaces of their target cell. Several studies have demonstrated elevated plasma levels of IL-12 and IFN-in autistic children compared with controls, withno changes for IL-6, TNF- and IFN- plasma levels, suggestinga potential TH1 shift. On the other hand, another study demonstrated, higher plasma IFN-in 10 autistic children comparedwith adult control subjects . Moreover,an increased plasma IFN-levels were observed in 29 autisticchildren; with a positive correlation with the generation of the intercellular CNS messenger and marker of oxidative stress, nitric oxide . The same research group observed that the macrophage product neopterin, was higher in serum samples from individuals with ASD compared with controls, which may reflect increased cell-mediated immune activation and IFN- production . Higher IFN-and neopterin levels correlated significantly with elevated, circulating numbers of monocytes observed in autistic children with elevated urine levels of neopterin and biopterin .

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