Latest findings confirm pathological role of the immune system and inflammation in autism

Jul 5, 2018 | Autism Science and Research News

Immunological phenomena, including altered reactivity of the immune system, could be a hallmark of autism

Association between immune dysfunction and pathogenesis of autism suspected in a subset of individuals

Accumulating evidence suggests an association between immune dysfunction and pathogenesis of Autism Spectrum Disorders (ASD) in a large number of affected individuals. Furthermore, findings from various diverse fields of science such as neuroimaging and neuroimmunology, as well as numerous experimental animal studies, point to the immune and the nervous system being intricately interconnected.

Immunological phenomena, including skewed cytokine production and altered reactivity of various types of immune cells, have been observed in individuals with autism by many research teams. In recent months, several new investigations have added to and expanded the existing body of knowledge.

A recent investigation of neonatal blood spots by researchers Krakowiak and colleagues found altered profiles of inflammatory markers in samples of babies who later developed autism, as well as a correlation between the severity of autism and altered levels of inflammatory markers in neonates.

A postmortem study by Lee and colleagues confirmed previous findings of brain inflammation in autism. Their results provided evidence of a shift in the type of microglia, brain immune cells, that “may indicate impaired synaptic plasticity and a chronic vulnerability to exaggerated immune responses”.

Two separate investigations into levels of S100B protein, a marker of neuronal damage and altered immune function, both found significant elevated levels in patients with autism, again implying a potential role of the immune system in the pathophysiology of this disorder.

“Sickness behavior, a term used to describe changes in the subjective experience and behavior occurring in a physically ill person, provides an example of how, through multiple mechanisms, the immune system can influence brain function and subsequent behavior. Nonspecific symptoms of sickness behavior include fever, nausea, reduced appetite, fatigue, irritability, and withdrawal from physical and social environments.” (Masi et al. 2017)

Peripheral markers may not reflect the immune state in CNS in autism

A longitudinal study by Pardo and colleagues observed high cerebrospinal levels of selected chemokines involved in microglia function. The authors found no systemic inflammation markers in serum samples of individuals with autism, suggesting that peripheral markers may not optimally reflect the immune status of the central nervous system.

The second study in recent months to look at serum samples observed significantly different levels of two selected cytokines, but only after subjects with Asperger’s syndrome, a milder form of autism, were excluded from the analysis, indicating different pathophysiological mechanisms in different autism subgroups. Based on their findings the authors suggest that “Future research into the pathophysiological mechanisms of ASD should pay more attention to the different subdiagnoses of ASD.”

In addition to investigations of serum samples, several groups looked at immune profiles in selected cell types. An imbalance between the anti- and pro-inflammatory milieu in blood leukocytes of autistic children was noted by Ahmad and colleagues.

A group of scientists at UC Davis, California exposed peripheral blood mononuclear cells from children with autism to external stressors. After stimulation the cells of children who were more developmentally impaired showed stronger proinflammatory response and/or more skewed activation of immune T-cells, again suggesting the existence of several possible immune subphenotypes, or subgroups, within autism population.

Further support for the notion that altered immune functions may play a role in the specific cognitive and behavioural problems in autism came from a Chinese study, which found the same pattern of distinct inflammatory and immune profiles in Chinese children and adolescents with autism compared to controls, in line with previous findings of such differences in Western populations.

Various different immunological measures, such as levels of chemoattractant molecules, was correlated with more severely impaired cognitive function, as well as inattention and hyperactivity symptoms.

Maternal immune activation (MIA) and infection during pregnancy, and the presence of autoimmune diseases or metabolic disorders in the mother, are well known risk factors for autism, schizophrenia and bi-polar disorder in the offspring.

“As innate immunity pathways are imperative in orchestrating the first line-of-defense mechanism against infection-causing pathogens and environmental triggers, their involvement in ASD and its co-morbidities can be thought of as the missing genetic link for environmental factors in the pathophysiology of ASD.” (Nazeen 2016)

Animal studies confirm causative links between the immune system and neurological development and behaviours

In addition to human epidemiological studies, research into maternal immune activation in animal models, including nonhuman primates, confirms that the maternal immune response is the critical link between exposure to infection during pregnancy and subsequent changes in the brain and behavioural development of offspring. For example, in the context of 4:1 male to female ratio of autism in humans, animal studies show that the function of microglia – brain immune and neuron-supporting cells – is disturbed in the brain of offspring from immune challenged mothers, and these effects in the brain are gender-specific, affecting only male animals.

Data from the recent primate study by Rose and colleagues suggests long-term behavioural and immune activation was present in primate offspring following MIA; at one and four years of age the offspring who had been exposed to infection prenatally continued to display skewed immune reactivity, as well as autism-related symptoms including increased stereotyped behaviours.

The recent experimental study by Allard et al. is one of many that shows how fetal exposure to infections agents such as Streptococcus B bacteria later lead to neurodevelopmental abnormalities in the offspring that are strongly reminiscent of autism in humans: abnormal social interaction and communication and impaired processing of sensory information.

In a groundbreaking new study researchers from the University of Virginia School of Medicine were able to manipulate social behaviours and personalities of various species of animals by changing the way their immune system responds to pathogens. They showed that interferon gamma was essential to normal social interaction – blocking the molecule caused the animals’ brains to become overly connected, making the mice less willing to interact with others.

This study, which was published in Nature, concludes that the immune molecule plays a “profound role in maintaining proper social function”.

It is also of particular interest that large doses of another pro-inflammatory cytokine, interferon-alpha given to humans in cancer treatment cause symptoms that mimic idiopathic autism: withdrawing, loss of interest in the surroundings and non-communication. Previously mentally-health adults often display symptoms of anxiety, irritability, decline in cognition and executive functioning, motor coordination problems, and loss of verbal ability – difficulty speaking: “Patients had slowed thinking, and they ceased to speak. One patient complained of difficulties in finding words, which inhibited his talking. Writing became unreadable, and patients could not fill in their self-assessment questionnaires. They had intermittent perseveration of speech and inability to stop ongoing behavior in daily activities.”

Similarly, another group of scientists observed that manipulating levels of Il-6, another molecule involved in pro-inflammatory signaling, changes social behaviours of study animals – by lowering its levels in the brain researchers were able to increase animals’ sociability and reduce autism-like behaviors.

“Animal studies illuminate the mechanisms through which perinatal infection and maternal immune activation negatively effect brain development and offspring social behaviours. These effects are replicated amongst many different studies and animal models of inflammation and infection, and suggest that inhibiting inflammatory pathways is a promising way of improving cognitive function and lack of sociability in human autism.”

“Whether we like it or not, there is a piling up of evidence that the immune system has a major impact on brain function: The brain is not isolated from the rest of the body.”

Translating research into practice – attenuating the risk of autism in babies exposed to maternal immune activation

Parallel to investigating the mechanisms by which early immune stressors influence brain development and function in later life, several research teams are looking into ways of preventing or attenuating the damaging effects. In a mouse study by Vuillermot and colleagues, animal offspring of mothers that were exposed to infections during pregnancy displayed abnormal social behaviours later on in life, but those mice that were given extra vitamin D before the infection developed normally, indicating that supplementing vitamin D during pregnancy may help prevent autism in babies whose mothers are exposed to infections.

“This work raises the possibility that early dietary supplementation with vitamin D may open new avenues for a successful attenuation or even prevention of neurodevelopmental disorders following maternal inflammation during pregnancy.” (Vuillermotet al. 2017)

“Animal studies illuminate the mechanisms through which perinatal infection and maternal immune activation negatively effect brain development and offspring social behaviours. These effects are replicated amongst many different studies and animal models of inflammation and infection, and suggest that inhibiting inflammatory pathways is a promising way of improving cognitive function and lack of sociability in human autism.”

References:

Ahmad S.F., Nadeem A., Ansari M.A., et al. (2017) Imbalance between the anti-and pro-inflammatory milieu in blood leukocytes of autistic children. Mol Immunol. Feb;82:57-65. doi: 10.1016/j.molimm.2016.12.019.

Ahmad SF, Zoheir KM, Ansari MA, et al. (2016) Dysregulation of Th1, Th2, Th17, and Tregulatory cell-related transcription factor signaling in children with autism. Mol Neurobiol. Jun 25. doi: 10.1007/s12035-016-9977-0.

Akcakaya N.H., Tekturk P., Cagatay A., et al. (2016) Atypical enterovirus encephalitis causing behavioral changes and autism-like clinical manifestations: case report. Acta Neurol Belg. Dec;116(4):679-681. doi: 10.1007/s13760-016-0614-5.

Allard MJ, Bergeron JD, Baharnoori M, et al. (2016) A sexually dichotomous, autistic-like phenotype is induced by Group B Streptococcus maternofetal immune activation. Autism Res. May 25. doi: 10.1002/aur.1647.

Careaga M., Murai T. & Bauman M.D. (2017) Maternal Immune Activation and Autism Spectrum Disorder: From Rodents to Nonhuman and Human Primates. Biol Psychiatry. Mar 1;81(5):391-401. doi: 10.1016/j.biopsych.2016.10.020.

Careaga M., Rogers S., Hansen R.L., et al. (2017) Immune Endophenotypes in Children With Autism Spectrum Disorder. Biol Psychiatry. Mar 1;81(5):434-441. doi: 10.1016/j.biopsych.2015.08.036.

Doenni VM, Gray JM, Song CM, et al. (2016) Deficient adolescent social behavior following early-life inflammation is ameliorated by augmentation of anandamide signaling. Brain Behav Immun. Nov;58:237-247. doi: 10.1016/j.bbi.2016.07.152.

Filiano AJ, Xu Y, Tustison NJ, et al. (2016) Unexpected role of interferon-γ in regulating neuronal connectivity and social behaviour. Nature. 2016 Jul 21;535(7612):425-9. doi: 10.1038/nature18626.

López-Cacho JM, Gallardo S, Posada M, et al. (2016) Characterization of immune cell phenotypes in adults with autism spectrum disorders. J Investig Med. Oct;64(7):1179-85. doi: 10.1136/jim-2016-000070.

Gentile I., Zappulo E., Riccio M.P., et al. (2017) Prevalence of Congenital Cytomegalovirus Infection Assessed Through Viral Genome Detection in Dried Blood Spots in Children with Autism Spectrum Disorders. In Vivo. May-Jun;31(3):467-473. doi: 10.21873/invivo.11085.

Guloksuz, S.A., Abali, O., Aktas Cetin E., et al. (2017) Elevated plasma concentrations of S100 calcium-binding protein B and tumor necrosis factor alpha in children with autism spectrum disorders. Rev Bras Psiquiatr. Jan 12:0. doi: 10.1590/1516-4446-2015-1843.

Han Y.M., Cheung W.K., Wong C.K., (2017) Distinct Cytokine and Chemokine Profiles in Autism Spectrum Disorders. Front Immunol. Jan 23;8:11. doi: 10.3389/fimmu.2017.00011.

Krakowiak P., Goines P.E., Tancredi D.J., et al. (2017) Neonatal Cytokine Profiles Associated With Autism Spectrum Disorder. Biol Psychiatry. Mar 1;81(5):442-451. doi: 10.1016/j.biopsych.2015.08.007.

Lee A.S., Azmitia E.C. & Whitaker-Azmitia P.M. (2017) Developmental microglial priming in postmortem autism spectrum disorder temporal cortex. Brain Behav Immun. May;62:193-202. doi: 10.1016/j.bbi.2017.01.0190.

Masi A., Glozier N., Dale R., et al. (2017) The Immune System, Cytokines, and Biomarkers in Autism Spectrum Disorder. Neurosci Bull. Apr;33(2):194-204. doi: 10.1007/s12264-017-0103-8.

Nazeen S., Palmer N.P., Berger B., et al. (2016) Integrative analysis of genetic data sets reveals a shared innate immune component in autism spectrum disorder and its co-morbidities. Genome Biol. Nov 14;17(1):228. doi:10.1186/s13059-016-1084-z.

Pang Y, Dai X, Roller A, et al. (2016) Postnatal Lipopolysaccharide Exposure Leads to Enhanced Neurogenesis and Impaired Communicative Functions in Rats. PLoS One. Oct 10;11(10):e0164403. doi: 10.1371/journal.pone.0164403.

Pendyala G., Chou S., Jung Y., et al. (2017) Maternal Immune Activation Causes Behavioral Impairments and Altered Cerebellar Cytokine and Synaptic Protein Expression. Neuropsychopharmacology. Jun;42(7):1435-1446. doi: 10.1038/npp.2017.7.

Richetto J, Massart R, Weber-Stadlbauer U, et al. (2016) Genome-wide DNA Methylation Changes in a Mouse Model of Infection-Mediated Neurodevelopmental Disorders. Biol Psychiatry. Aug 12. doi: 10.1016/j.biopsych.2016.08.010.

Rose D.R, Careaga M., Van de Water J., et al. (2016) Long-term altered immune responses following fetal priming in a non-human primate model of maternal immune activation. Brain Behav Immun. Nov 19. doi: 10.1016/j.bbi.2016.11.020.

Saresella M, Piancone F, Marventano I, et al. (2016) Multiple inflammasome complexes are activated in autistic spectrum disorders. Brain Behav Immun. Oct;57:125-33. doi: 10.1016/j.bbi.2016.03.009.

Shaker N.M., Taha G.R., Kholeif H., et al. (2016) Serum Levels of S100b, Interleukin-6 and Anti-Transglutaminase Ii IgA as Immune Markers in a Sample of Egyptian Children with Autistic Spectrum Disorders. Autism Open Access, 6:5. doi: 10.4172/2165-7890.1000191.

Shen Y, Ou J, Liu M, et al. (2016) Altered plasma levels of chemokines in autism and their association with social behaviors. Psychiatry Res. Oct 30;244:300-5. doi: 10.1016/j.psychres.2016.07.057.

Spencer S.J., & Meyer U. (2017) Perinatal programming by inflammation. Brain Behav Immun. Jul;63:1-7. doi: 10.1016/j.bbi.2017.02.007.

Vuillermot S., Luan W., Meyer U. & Eyles D. (2017) Vitamin D treatment during pregnancy prevents autism-related phenotypes in a mouse model of maternal immune activation. Mol Autism. Mar 7;8:9. doi: 10.1186/s13229-017-0125-0.

Wei H, Ma Y, Liu J, et al. (2016) Inhibition of IL-6 trans-signaling in the brain increases sociability in the BTBR mouse model of autism. Biochim Biophys Acta. 2016 Oct;1862(10):1918-25. doi: 10.1016/j.bbadis.2016.07.013.

Wu W.L., Hsiao, E.Y., Yan Z., et al. (2016) The placental interleukin-6 signaling controls fetal brain development and behavior. Brain Behav Immun. Nov 9. doi: 10.1016/j.bbi.2016.11.007.

Further reading:

Adams F, Quesada JR, Gutterman JU. (1984) Neuropsychiatric manifestations of human leukocyte interferon therapy in patients with cancer. JAMA. Aug 17;252(7):938-41. doi: 10.1001/jama.1984.03350070056026.

Meyers CA. (1899) Mood and cognitive disorders in cancer patients receiving cytokine therapy. Adv Exp Med Biol.;461:75-81. Review. doi: 10.1007/978-0-585-37970-8_5.

Niiranen A, Laaksonen R, Iivanainen M, et al. (1988) Behavioral assessment of patients treated with alpha-interferon. Acta Psychiatr Scand. Nov;78(5):622-6. doi: 10.1111/j.1600-0447.1988.tb06395.x.

 

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