Immune mediators in the brain and peripheral tissues in autism spectrum disorder

Immune responses to vaccines do not cause ASD.

“recent studies have debunked the myth of a link between ASD and early childhood vaccines13.”

• Also stated in: § Abstract · boosted

  “Despite the unequivocal and compelling research behind the conclusion that vaccines do not cause ASD”

• cites [13] Taylor, L. E., Swerdfeger, A. L. & Eslick, G. D. Vaccines are not associated with autism: an evidence-based meta-analysis of case-control and cohort studies. Vaccine 32, 3623–3629 (2014). sourceNot checked yet

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Several ASD risk genes encode components of the immune system.

“Several ASD risk genes encode components of the immune system”

• Also stated in: § Genetic studies · plain

  “several ASD-associated genes encode components of the immune system (TABLE 1)”

Several molecular signalling pathways link immune activation to ASD phenotypes, including pathways downstream of cytokines, MET, MHCI molecules, microglia and complement factors.

“several molecular signalling pathways have been identified that link immune activation to ASD phenotypes, including pathways downstream of cytokines, hepatocyte growth factor receptor (MET), MHCI molecules, microglia and complement factors”

Wider diagnostic criteria and enhanced public awareness cannot account for all, and in some estimates most, of the rise in ASD prevalence.

“Although the wider diagnostic criteria for, and enhanced public awareness of, ASD have surely contributed to this increase, these factors cannot account for all, and in some estimates most, of this rise in prevalence3.”

• cites [3] Hertz-Picciotto, I. & Delwiche, L. The rise in autism and the role of age at diagnosis. Epidemiology 20, 84–90 (2009). sourceNot checked yet

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Most diverse environmental factors contributing to ASD converge on alterations in immune responses during prenatal or early postnatal development.

“Although there is a long list of diverse environmental factors that contribute to ASD6, most of these converge on alterations in immune responses during prenatal or early postnatal development (FIG. 1).”

• cites [6] Pessah, I. N. et al. Immunologic and neurodevelopmental susceptibilities of autism. Neurotoxicology 29, 532–545 (2008). sourceNot checked yet

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One or more environmental factors have increased the likelihood of children developing ASD.

“This implies that one or more factors in our environment have increased the likelihood of children to develop ASD.”

Immune status can have profound effects on brain development and cognition.

“immune status can have profound effects on brain development and cognition (BOX 1)”

• cites BOX 1Not checked yet

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Increased MET signalling ameliorates disease pathogenesis in several models of classic systemic inflammatory diseases, including multiple sclerosis and systemic lupus erythematosus.

“Increased MET signalling ameliorates disease pathogenesis in several models of classic systemic inflammatory diseases, including multiple sclerosis and systemic lupus erythematosis (SLE) among others38–42.”

• cites [38] Okunishi, K. et al. Hepatocyte growth factor significantly suppresses collagen-induced arthritis in mice. J. Immunol. 179, 5504–5513 (2007). sourceNot checked yet

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• cites [39] Futamatsu, H. et al. Hepatocyte growth factor ameliorates the progression of experimental autoimmune myocarditis: a potential role for induction of T helper 2 cytokines. Circ. Res. 96, 823–830 (2005). sourceNot checked yet

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• cites [40] Kuroiwa, T. et al. Hepatocyte growth factor prevents lupus nephritis in a murine lupus model of chronic graft-versus-host disease. Arthritis Res. Ther. 8, R123 (2006). sourceNot checked yet

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• cites [41] Oh, K. et al. Ameliorating effect of hepatocyte growth factor on inflammatory bowel disease in a murine model. Am. J. Physiol. Gastrointest. Liver Physiol. 288, G729–G735 (2005). sourceNot checked yet

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• cites [42] Mizuno, S., Matsumoto, K., Li, M. Y. & Nakamura, T. HGF reduces advancing lung fibrosis in mice: a potential role for MMP-dependent myofibroblast apoptosis. FASEB J. 19, 580–582 (2005). sourceNot checked yet

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The genetic composition and initial programming of the immune system in utero and shortly after birth determines how much environmental insult the immune system can buffer during the lifetime of each individual.

“The genetic composition and initial programming of the immune system in utero and shortly after birth7,8 determines how much environmental insult the immune system can buffer during the lifetime of each individual.”

• cites [7] Bilbo, S. D. & Schwarz, J. M. Early-life programming of later-life brain and behavior: a critical role for the immune system. Front. Behav. Neurosci. 3, 14 (2009). An extensive review of the lifelong consequences of in utero and early postnatal environmental insults on brain and immune function. sourceNot checked yet

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• cites [8] Silverstein, A. M. The most elegant immunological experiment of the XIX century. Nat. Immunol. 1, 93–94 (2000). sourceNot checked yet

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Reduced MET levels may cause ASD phenotypes.

“suggesting that reduced MET levels may indeed cause ASD phenotypes27,30,31.”

• cites [27] Campbell, D. B. et al. Disruption of cerebral cortex MET signaling in autism spectrum disorder. Ann. Neurol. 62, 243–250 (2007). sourceNot checked yet

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• cites [30] Voineagu, I. et al. Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature 474, 380–384 (2011). A landmark study identifying the enrichment of synaptic and immune gene modules in the transcriptomes of individuals with ASD. sourceNot checked yet

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• cites [31] Rudie, J. D. et al. Autism-associated promoter variant in MET impacts functional and structural brain networks. Neuron 75, 904–915 (2012). sourceNot checked yet

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Variants in the HLA locus confer risk for neurodevelopmental disorders.

“variants in the human leukocyte antigen (HLA) locus also confer risk for neurodevelopmental disorders46,47.”

• cites [46] Hsiao, E. Y. Immune dysregulation in autism spectrum disorder. Int. Rev. Neurobiol. 113, 269–302 (2013). sourceNot checked yet

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• cites [47] Needleman, L. A. & McAllister, A. K. The major histocompatibility complex and autism spectrum disorder. Dev. Neurobiol. 72, 1288–1301 (2012). sourceNot checked yet

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No single gene has been identified that substantially increases the risk of developing ASD.

“However, no single gene has been identified to date that substantially increases the risk of developing ASD17.”

• cites [17] Devlin, B. & Scherer, S. W. Genetic architecture in autism spectrum disorder. Curr. Opin. Genet. Dev. 22, 229–237 (2012). sourceNot checked yet

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ASD individuals with the MET 'C' allele exhibit reduced structural and functional connectivity in temporoparietal lobes compared with ASD individuals without the variant and control individuals.

“individuals with ASD and the MET ‘C’ allele exhibit reduced structural and functional connectivity in temporoparietal lobes in comparison with both ASD individuals without the MET variant and control individuals31.”

• cites [31] Rudie, J. D. et al. Autism-associated promoter variant in MET impacts functional and structural brain networks. Neuron 75, 904–915 (2012). sourceNot checked yet

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Structural MRI in ASD individuals with the MET 'C' allele shows decreased cortical thickness in several brain regions associated with socio-communicative function.

“structural MRI in ASD individuals with the MET ‘C’ allele shows decreased cortical thickness in several brain regions that are associated with socio-communicative function32.”

• cites [32] Hedrick, A. et al. Autism risk gene MET variation and cortical thickness in typically developing children and adolescents. Autism Res. 5, 434–439 (2012). sourceNot checked yet

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Maternal immune system-related risk factors, including autoimmunity, infection and fetal reactive antibodies, are associated with ASD.

“many maternal immune system-related risk factors — including autoimmunity, infection and fetal reactive antibodies — are associated with ASD”

The immune system is a point of convergence for various ASD-related genetic and environmental risk factors.

“These findings indicate that the immune system is a point of convergence for various ASD-related genetic and environmental risk factors.”

Reduced MET expression may contribute to ASD-related pathophysiology in Rett syndrome.

“suggesting that reduced MET expression may contribute to the ASD-related pathophysiology in this syndrome.”

The MET 'C' allele and exposure to high levels of air pollution during prenatal development act synergistically to increase risk of ASD.

“the MET ‘C’ allele and exposure to high levels of air pollution during prenatal development act synergistically to increase risk of this disorder45.”

• cites [45] Volk, H. E. et al. Autism spectrum disorder: interaction of air pollution with the MET receptor tyrosine kinase gene. Epidemiology 25, 44–47 (2014). A proof-of-concept study showing how gene–environment synergies may contribute to an increase in the incidence of ASD. sourceNot checked yet

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The MET 'C' allele leads to disrupted expression of multiple downstream targets of the MET signalling cascade.

“This variant leads to disrupted expression of multiple downstream targets of the MET signalling cascade28.”

• cites [28] Campbell, D. B., Li, C., Sutcliffe, J. S., Persico, A. M. & Levitt, P. Genetic evidence implicating multiple genes in the MET receptor tyrosine kinase pathway in autism spectrum disorder. Autism Res. 1, 159–168 (2008). sourceNot checked yet

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Genetic mutations are a major cause of ASD.

“Early estimates of the heritability of ASD of around 90%14,15, and even recently revised estimates of between 38 and 54%, strongly suggest that genetic mutations are a major cause of ASD4,16.”

• cites [14] Bailey, A. et al. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol. Med. 25, 63–77 (1995). sourceNot checked yet

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• cites [15] Steffenburg, S. et al. A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden. J. Child Psychol. Psychiatry 30, 405–416 (1989). sourceNot checked yet

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• cites [4] Hallmayer, J. et al. Genetic heritability and shared environmental factors among twin pairs with autism. Arch. Gen. Psychiatry 68, 1095–1102 (2011). A critical reappraisal of heritability in ASD showing a large role for non-genetic factors. sourceNot checked yet

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• cites [16] Sandin, S. et al. The familial risk of autism. JAMA 311, 1770–1777 (2014). sourceNot checked yet

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Mutations in genes for several members of the IL-1 cytokine receptor family are associated with ASD.

“mutations in genes for several members of the IL-1 cytokine receptor family are also associated with ASD.”

There is up to a 50% increase in the odds of an ASD diagnosis among children who have a parent who has had an autoimmune disorder.

“Estimates indicate that there is up to a 50% increase in the odds of an ASD diagnosis among children who have a parent who has had an autoimmune disorder48,63.”

• cites [48] Gough, S. C. & Simmonds, M. J. The HLA region and autoimmune disease: associations and mechanisms of action. Curr. Genom. 8, 453–465 (2007). sourceNot checked yet

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• cites [63] Piton, A. et al. Mutations in the calcium-related gene IL1RAPL1 are associated with autism. Hum. Mol. Genet. 17, 3965–3974 (2008). sourceNot checked yet

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Autoimmune disorders are over-represented in the ASD population.

“autoimmune disorders are over-represented in the ASD population65.”

• cites [65] Atladottir, H. O. et al. Association of family history of autoimmune diseases and autism spectrum disorders. Pediatrics 124, 687–694 (2009). sourceNot checked yet

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Seven proteins - LDH A and B, YBX1, cypin, STIP1, CRMP1 and CRMP2 - have been reported to be targeted by these antibodies.

“Seven proteins — lactate dehydrogenase A and B (LDH), Y-Box-binding protein 1 (YBX1), guanine deaminase (cypin), stress-induced phosphoprotein 1 (STIP1), collapsin response mediator protein 1 (CRMP1) and CRMP2 — have recently been reported to be targeted by these antibodies.”

Antibody clones recognizing the NR2A and NR2B NMDAR subunits appear to be a major cause of the behavioural changes.

“Antibody clones recognizing the NR2A and NR2B NMDAR subunits appear to be a major cause of the behavioural changes.”

The combination of a specific DRβ1*11 allele with a family history of autoimmune disorders increases the odds ratio for the association of this allele with ASD.

“The combination of a specific DRβ1*11 allele with a family history of autoimmune disorders increases the odds ratio for the association of this allele with ASD49.”

• cites [49] Keil, A. et al. Parental autoimmune diseases associated with autism spectrum disorders in offspring. Epidemiology 21, 805–808 (2010). sourceNot checked yet

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A rare ASD-associated mutation has been identified in IL1RAPL1.

“A rare ASD-associated mutation has also been identified in a gene encoding another IL-1 family receptor, IL1RAPL1 (interleukin-1 receptor accessory protein-like 1)59,60.”

• cites [59] Parmley, J. L. & Hurst, L. D. How do synonymous mutations affect fitness? Bioessays 29, 515–519 (2007). sourceNot checked yet

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• cites [60] Takahashi, H. & Craig, A. M. Protein tyrosine phosphatases PTPδ, PTPσ, and LAR: presynaptic hubs for synapse organization. Trends Neurosci. 36, 522–534 (2013). sourceNot checked yet

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ASD-associated deficiencies in the complement gene C4 within the MHC class III region are among the strongest genetic risk factors for SLE.

“ASD-associated deficiencies in a complement gene — C4 — within the MHC class III region50,51 are also among the strongest genetic risk factors for SLE52”

• cites [50] Mostafa, G. A., Shehab, A. A. & Al-Ayadhi, L. Y. The link between some alleles on human leukocyte antigen system and autism in children. J. Neuroimmunol. 255, 70–74 (2013). sourceNot checked yet

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• cites [51] Warren, R. P., Burger, R. A., Odell, D., Torres, A. R. & Warren, W. L. Decreased plasma concentrations of the C4B complement protein in autism. Arch. Pediatr. Adolesc. Med. 148, 180–183 (1994). sourceNot checked yet

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• cites [52] Warren, R. P. et al. Increased frequency of the null allele at the complement C4b locus in autism. Clin. Exp. Immunol. 83, 438–440 (1991). sourceNot checked yet

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A female-specific vulnerability to these antibodies could result in increased rates of resorption of female fetuses leading to an increase in the proportion of male offspring, similar to the male skewing seen in ASD.

“A female-specific vulnerability to these antibodies could result in increased rates of resorption of female fetuses leading to an increase in the proportion of male offspring, similar to the male skewing seen in ASD.”

Female fetuses with these antibodies that are carried to term would be expected to show more profound deficits.

“Additionally, female fetuses with these antibodies that are carried to term would be expected to show more profound deficits.”

Fetal-brain-reactive antibodies have been found in approximately 11% of mothers of children with ASD in the absence of any evidence of autoimmunity.

“Fetal-brain-reactive antibodies have also been found in approximately 11% of mothers of children with ASD in the absence of any evidence of autoimmunity.”

Autoimmunity in pregnant women, even at a clinically undetected level, may be associated with production of maternal antibodies that can reach the fetal brain and potentially perturb fetal brain development.

“Thus, autoimmunity in pregnant women, even at a clinically undetected level, may be associated with the production of maternal antibodies that can reach the fetal brain and potentially perturb fetal brain development.”

Disrupting the function of any of these proteins could alter brain development, thereby contributing to ASD pathogenesis.

“Disrupting the function of any of these proteins could alter brain development, thereby contributing to ASD pathogenesis.”

53% of mothers of a child with ASD who test positive for anti-brain antibodies also have anti-nuclear antibodies, versus 13.4% of mothers of an ASD child without anti-brain antibodies.

“53% of mothers of a child with ASD who test positive for anti-brain antibodies also have anti-nuclear antibodies — an indicator of latent autoimmunity— versus 13.4% of mothers of an ASD child without anti-brain antibodies69.”

• cites [69] Diamond, B., Huerta, P. T., Mina-Osorio, P., Kowal, C. & Volpe, B. T. Losing your nerves? Maybe it's the antibodies. Nat. Rev. Immunol. 9, 449–456 (2009). An excellent review of the mechanisms by which autoantibodies modulate brain function and behaviour. sourceNot checked yet

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The association of maternal autoimmune disorders with ASD in offspring may be mediated by passive transfer to the fetus of maternal IgG antibodies reactive to self-proteins in the mother or child.

“The association of maternal autoimmune disorders with ASD in offspring may be mediated by the passive transfer to the fetus of maternal IgG antibodies (mAbs) that exhibit reactivity to self-proteins in the mother or child.”

Individuals with idiopathic ASD exhibit a 34% decrease in plasma levels of C4b.

“individuals with idiopathic ASD exhibit a 34% decrease in plasma levels of C4b53.”

• cites [53] Deng, Y. & Tsao, B. P. Genetic susceptibility to systemic lupus erythematosus in the genomic era. Nat. Rev. Rheumatol. 6, 683–692 (2010). sourceNot checked yet

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ASD-associated mutations, copy number variants and somatic mosaics in IL1RAPL1 mostly result in loss of function.

“ASD-associated mutations, CNVs and somatic mosaics have subsequently been discovered in this gene, most of which result in a loss of function62.”

• cites [62] Bahi, N. et al. IL1 receptor accessory protein like, a protein involved in X-linked mental retardation, interacts with neuronal calcium sensor-1 and regulates exocytosis. Hum. Mol. Genet. 12, 1415–1425 (2003). sourceNot checked yet

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Maternal immune disorders such as rheumatoid arthritis, SLE and type-1 diabetes account for the largest portion of the increased ASD risk in offspring.

“maternal immune disorders such as rheumatoid arthritis, SLE and type-1 diabetes account for the largest portion of this increased risk for ASD in offspring”

• cites [48] Gough, S. C. & Simmonds, M. J. The HLA region and autoimmune disease: associations and mechanisms of action. Curr. Genom. 8, 453–465 (2007). sourceNot checked yet

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Two recent exome sequencing studies of individuals with ASD found synonymous SNPs in the gene encoding IL-1R2.

“Two recent exome sequencing studies of individuals with ASD found synonymous SNPs in the gene encoding the IL-1β decoy receptor IL-1R2 (IL-1 receptor type 2)55,56.”

• cites [55] Careaga, M. & Ashwood, P. Autism spectrum disorders: from immunity to behavior. Methods Mol. Biol. 934, 219–240 (2012). sourceNot checked yet

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• cites [56] O'Roak, B. J. et al. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat. Genet. 43, 585–589 (2011). sourceNot checked yet

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Mutations in a wide array of immune genes contribute to ASD.

“Together, these findings indicate that mutations in a wide array of immune genes contribute to ASD.”

Similar species-specific aberrant social behaviours in offspring are caused by injecting pregnant mice with human IgG-ASD.

“Similar species-specific aberrant social behaviours in offspring are caused by injecting pregnant mice with human IgG-ASD82.”

• cites [82] Wolff, J. J. et al. Differences in white matter fiber tract development present from 6 to 24 months in infants with autism. Am. J. Psychiatry 169, 589–600 (2012). sourceNot checked yet

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Injecting pregnant non-human primates with maternal antibodies from mothers of ASD children induces ASD-like behavioural changes in offspring, including reduced reciprocal interactions and inappropriate approach behaviours.

“injecting pregnant non-human primates with mAbs from mothers of ASD children (mAbs-ASD) induces ASD-like behavioural changes in offspring, including reduced reciprocal interactions and inappropriate approach behaviours77,78.”

• cites [77] Braunschweig, D. et al. Autism-specific maternal autoantibodies recognize critical proteins in developing brain. Transl Psychiatry 3, e277 (2013). A seminal study identifying fetal protein targets of ASD-specific maternal antibodies. sourceNot checked yet

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• cites [78] Martin, L. A. et al. Stereotypies and hyperactivity in rhesus monkeys exposed to IgG from mothers of children with autism. Brain Behav. Immun. 22, 806–816 (2008). The first study to show a causal relationship between antibodies from mothers of ASD children and ASD-like behaviours in a non-human primate model. sourceNot checked yet

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Synonymous SNPs can affect protein folding and messenger RNA splicing, stability and structure.

“synonymous SNPs can affect protein folding and messenger RNA splicing, stability and structure57,58.”

• cites [57] Sanders, S. J. et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485, 237–241 (2012). sourceNot checked yet

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• cites [58] Sauna, Z. E. & Kimchi-Sarfaty, C. Understanding the contribution of synonymous mutations to human disease. Nat. Rev. Genet. 12, 683–691 (2011). sourceNot checked yet

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Women with rheumatoid arthritis or SLE are more than four times as likely as women without these disorders (10.5% versus 2.6%) to harbor peripheral antibodies reactive to neurons from fetal and adult mice brains.

“women with rheumatoid arthritis or SLE are more than four times as likely as women without these disorders (10.5% versus 2.6%) to harbor peripheral antibodies with reactivity to neurons from the brains of fetal and adult mice69.”

• cites [69] Diamond, B., Huerta, P. T., Mina-Osorio, P., Kowal, C. & Volpe, B. T. Losing your nerves? Maybe it's the antibodies. Nat. Rev. Immunol. 9, 449–456 (2009). An excellent review of the mechanisms by which autoantibodies modulate brain function and behaviour. sourceNot checked yet

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Mothers with autoimmune disorders fail to develop an anti-inflammatory immune system profile that typically occurs during pregnancy.

“mothers with autoimmune disorders fail to develop an anti-inflammatory immune system profile that typically occurs during pregnancy67”

• cites [67] Patterson, P. H. Immune involvement in schizophrenia and autism: etiology, pathology and animal models. Behav. Brain Res. 204, 313–321 (2009). An authoritative review of immune contributions to neurodevelopmental disorders. sourceNot checked yet

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Fetal maternal antibodies could enter the fetal brain during early gestation because the blood-brain barrier is not mature until the postnatal period.

“These fetal mAbs could theoretically enter the fetal brain during early gestation because the blood–brain barrier (BBB) is not mature until the postnatal period68.”

• cites [68] Iaccarino, L. et al. Polarization of TH2 response is decreased during pregnancy in systemic lupus erythematosus. Reumatismo 64, 314–320 (2012). sourceNot checked yet

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Maternal autoimmunity can impair brain development in offspring in a sex-specific way.

“Collectively, these results suggest mechanisms whereby maternal autoimmuntity can impair brain development in offspring in a sex-specific way.”

Autoimmune disorders, allergies and asthma strongly associate with the families of children with ASD.

“autoimmune disorders, allergies and asthma strongly associate with the families of children with ASD48.”

• cites [48] Gough, S. C. & Simmonds, M. J. The HLA region and autoimmune disease: associations and mechanisms of action. Curr. Genom. 8, 453–465 (2007). sourceNot checked yet

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Several studies suggest that these maternal antibodies are ASD-specific, since these antibodies did not detect proteins of these sizes in mothers of unaffected children.

“Several studies suggest that these mAbs are ASD-specific, since these antibodies did not detect proteins of these sizes in mothers of unaffected children75.”

• cites [75] Frazier, T. W., Georgiades, S., Bishop, S. L. & Hardan, A. Y. Behavioral and cognitive characteristics of females and males with autism in the Simons Simplex Collection. J. Am. Acad. Child Adolesc. Psychiatry 53, 329–340 (2014). sourceNot checked yet

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Animal models show a causal link between activation of the maternal immune system and altered neurodevelopment.

“animal models show a causal link between activation of the maternal immune system and altered neurodevelopment”

Maternally derived anti-brain autoantibodies have a much higher degree of association with ASD diagnosis and specific pathophysiology than patients' own autoantibodies.

“the maternally derived anti-brain autoantibodies discussed above have a much higher degree of association with ASD diagnosis and specific pathophysiology than patients’ own autoantibodies.”

Lower levels of TGF-β in these children with ASD are associated with less adaptive behaviours and worse behavioural symptoms.

“The lower levels of TGF-β in these children with ASD are associated with less adaptive behaviours and worse behavioural symptoms118.”

• cites [118] Okada, K. et al. Decreased serum levels of transforming growth factor-β1 in patients with autism. Prog. Neuropsychopharmacol. Biol. Psychiatry 31, 187–190 (2007). sourceNot checked yet

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Many reports have identified changes in cytokine levels in the blood of individuals with ASD who are over 2 years of age.

“many reports have identified changes in cytokine levels in the blood of individuals with ASD who are over 2 years of age.”

MIA-induced ASD-like behaviours and neuropathologies in offspring appear to be caused by altered levels of maternal cytokines, including IL-2, IL-6 and IL-10.

“These MIA-induced ASD-like behaviours and neuropathologies in offspring appear to be caused by altered levels of maternal cytokines, including IL-2, IL-6 and IL-10.”

ASD incidence increased from 0.05% to 8-13% in children of mothers exposed to the 1964 rubella pandemic during pregnancy.

“ASD incidence increased from 0.05% to 8–13% in children of mothers that were exposed to the 1964 rubella pandemic during pregnancy85–87.”

• cites [85] Patterson, P. H. Maternal infection and immune involvement in autism. Trends Mol. Med. 17, 389–394 (2011). sourceNot checked yet

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• cites [86] Chess, S. Autism in children with congenital rubella. J. Autism Child. Schizophr. 1, 33–47 (1971). The first report of increased incidence of ASD using specific behavioural criteria in a large cohort of children with congenital rubella. sourceNot checked yet

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• cites [87] Chess, S. Follow-up report on autism in congenital rubella. J. Autism Child. Schizophr. 7, 69–81 (1977). sourceNot checked yet

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A recent study using a mouse model of MIA found that the degree of maternal immune response (as measured by weight loss and TNF serum levels) to prenatal immune challenge with poly(I:C) is positively associated with the severity of sensorimotor gating deficits in the offspring.

“a recent study using a mouse model of MIA found that the degree of maternal immune response (as measured by weight loss and tumor necrosis factor (TNF) serum levels) to prenatal immune challenge with poly(I:C), a viral mimic, is positively associated with the severity of sensorimotor gating deficits in the offspring92.”

• cites [92] Atladottir, H. O., Henriksen, T. B., Schendel, D. E. & Parner, E. T. Autism after infection, febrile episodes, and antibiotic use during pregnancy: an exploratory study. Pediatrics 130, e1447–e1454 (2012). The largest epidemiological study so far on ASD incidence following maternal infection. sourceNot checked yet

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Several recent reports have described elevated levels of pro-inflammatory cytokines in the amniotic fluid of mothers of children with ASD.

“several recent reports have described elevated levels of pro-inflammatory cytokines in the amniotic fluid of mothers of children with ASD88,89.”

• cites [88] Swisher, C. N. & Swisher, L. Letter: congenital rubella and autistic behavior. N. Engl. J. Med. 293, 198 (1975).Not checked yet

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• cites [89] Abdallah, M. W. et al. Amniotic fluid inflammatory cytokines: potential markers of immunologic dysfunction in autism spectrum disorders. World J. Biol. Psychiatry 14, 528–538 (2013). sourceNot checked yet

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Mouse MIA offspring show localized aberrations in Purkinje cells, similar to the localized deficits in cerebellar Purkinje cells that have been reported in many postmortem ASD cases.

“mouse MIA offspring show localized aberrations in Purkinje cells98, similar to the localized deficits in cerebellar Purkinje cells that have been reported in many postmortem ASD cases99.”

• cites [98] Bauman, M. D. et al. Activation of the maternal immune system during pregnancy alters behavioral development of rhesus monkey offspring. Biol. Psychiatry 75, 332–341 (2014). sourceNot checked yet

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• cites [99] Shi, L. et al. Activation of the maternal immune system alters cerebellar development in the offspring. Brain Behav. Immun. 23, 116–123 (2009). sourceNot checked yet

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Definitive evidence that maternal infection during pregnancy is a risk factor for ASD in offspring was obtained through studies of the Danish health registry.

“Definitive evidence that maternal infection during pregnancy is a risk factor for ASD in offspring was obtained through more recent studies of the Danish health registry90.”

• cites [90] Goines, P. E. et al. Increased midgestational IFN-γ, IL-4 and IL-5 in women bearing a child with autism: a case-control study. Mol. Autism 2, 13 (2011). sourceNot checked yet

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Natural killer cells from individuals with ASD are defective in their normal function of lysing infected cells when challenged.

“Natural killer (NK) cells from individuals with ASD are defective in their normal function of lysing infected cells when challenged123,124.”

• cites [123] Napolioni, V. et al. Plasma cytokine profiling in sibling pairs discordant for autism spectrum disorder. J. Neuroinflammation 10, 38 (2013). sourceNot checked yet

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• cites [124] Warren, R. P., Foster, A. & Margaretten, N. C. Reduced natural killer cell activity in autism. J. Am. Acad. Child Adolesc. Psychiatry 26, 333–335 (1987). sourceNot checked yet

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Evidence exists for impaired immune cell function and responsiveness to immune challenge in ASD.

“evidence exists for impaired immune cell function and responsiveness to immune challenge in ASD.”

Numerous single-case studies have associated ASD with a variety of parasitic, bacterial and viral prenatal infections including toxoplasmosis, syphilis, varicella, cytomegalovirus, mumps and herpes simplex virus infection.

“Numerous single-case studies have also associated ASD with a variety of parasitic, bacterial and viral prenatal infections including toxoplasmosis, syphilis, varicella, cytomegalovirus, mumps and herpes simplex virus infection84.”

• cites [84] Camacho, J. et al. Embryonic intraventricular exposure to autism-specific maternal autoantibodies produces alterations in autistic-like stereotypical behaviors in offspring mice. Behav. Brain Res. 266, 46–51 (2014). sourceNot checked yet

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Several cytokines were decreased (GM-CSF, IFN-γ, IL-2, IL-4 and IL-6) in neonatal blood samples from individuals who were later diagnosed with ASD in a large recent longitudinal study using the Danish Newborn Screening Biobank.

“several cytokines were decreased (GM-CSF, interferon-γ (IFN-γ), IL-2, IL-4 and IL-6) in neonatal blood samples from individuals who were later diagnosed with ASD in a large recent longitudinal study using the Danish Newborn Screening Biobank121.”

• cites [121] Ashwood, P. et al. Associations of impaired behaviors with elevated plasma chemokines in autism spectrum disorders. J. Neuroimmunol. 232, 196–199 (2011). sourceNot checked yet

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The timing of MIA and the type of antigen used for immune challenge can lead to overlapping yet distinct phenotypes, including behavioural outcomes and transcriptome signatures in the developing brains of offspring.

“These studies support the idea that the timing of MIA and the type of antigen that is used for immune challenge can lead to overlapping yet distinct phenotypes, including behavioural outcomes and transcriptome signatures in the developing brains of offspring94.”

• cites [94] Patterson, P. H. Maternal infection: window on neuroimmune interactions in fetal brain development and mental illness. Curr. Opin. Neurobiol. 12, 115–118 (2002). sourceNot checked yet

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The diversity of infectious agents suggests that general immune activation during gestation, rather than a specific immune disorder or virus, underlies the link with ASD.

“This diversity of infectious agents suggests that general immune activation during gestation, rather than a specific immune disorder or virus, underlies the link with ASD.”

A subset of individuals with ASD have autoantibodies reactive to CNS self-proteins, including serotonin receptors, glial fibrillary acidic protein, myelin basic protein, and unidentified targets in the basal ganglia, prefrontal cortex, cingulate gyrus and cerebellum.

“A subset of individuals with ASD also have autoantibodies that are reactive to CNS self-proteins, including serotonin receptors104, glial fibrillary acidic protein104, myelin basic protein105–107, and unidentified targets in the basal ganglia, prefrontal cortex, cingulate gyrus and cerebellum104,105,107–112.”

• cites [104] Mostafa, G. A. & Al-Ayadhi, L. Y. The possible relationship between allergic manifestations and elevated serum levels of brain specific auto-antibodies in autistic children. J. Neuroimmunol. 261, 77–81 (2013). sourceNot checked yet

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• cites [105] Singh, V. K., Warren, R., Averett, R. & Ghaziuddin, M. Circulating autoantibodies to neuronal and glial filament proteins in autism. Pediatr. Neurol. 17, 88–90 (1997). sourceNot checked yet

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• cites [106] Singh, V. K., Warren, R. P., Odell, J. D., Warren, W. L. & Cole, P. Antibodies to myelin basic protein in children with autistic behavior. Brain Behav. Immun. 7, 97–103 (1993). sourceNot checked yet

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• cites [107] Vojdani, A. et al. Antibodies to neuron-specific antigens in children with autism: possible cross-reaction with encephalitogenic proteins from milk, Chlamydia pneumoniae and Streptococcus group A. J. Neuroimmunol. 129, 168–177 (2002). sourceNot checked yet

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• cites [108] Singer, H. S. et al. Antibrain antibodies in children with autism and their unaffected siblings. J. Neuroimmunol. 178, 149–155 (2006). sourceNot checked yet

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• cites [109] Singh, V. K., Singh, E. A. & Warren, R. P. Hyperserotoninemia and serotonin receptor antibodies in children with autism but not mental retardation. Biol. Psychiatry 41, 753–755 (1997). sourceNot checked yet

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• cites [110] Singh, V. K. & Rivas, W. H. Prevalence of serum antibodies to caudate nucleus in autistic children. Neurosci. Lett. 355, 53–56 (2004). sourceNot checked yet

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• cites [111] Silva, S. C. et al. Autoantibody repertoires to brain tissue in autism nuclear families. J. Neuroimmunol. 152, 176–182 (2004). sourceNot checked yet

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• cites [112] Cabanlit, M., Wills, S., Goines, P., Ashwood, P. & Van de Water, J. Brain-specific autoantibodies in the plasma of subjects with autistic spectrum disorder. Ann. NY Acad. Sci. 1107, 92–103 (2007). sourceNot checked yet

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Acute immune activation caused by maternal infection during specific periods of gestation contributes to ASD risk in offspring.

“acute immune activation that is caused by maternal infection during specific periods of gestation also contributes to ASD risk in offspring84.”

• cites [84] Camacho, J. et al. Embryonic intraventricular exposure to autism-specific maternal autoantibodies produces alterations in autistic-like stereotypical behaviors in offspring mice. Behav. Brain Res. 266, 46–51 (2014). sourceNot checked yet

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Maternal cytokines appear to be necessary for the ASD-like phenotypes in offspring because poly(I:C) injections in mid-gestation on an IL-6 knockout background, co-administration of an IL-6 function-blocking antibody and poly(I:C), or overexpression of IL-10 by macrophages prevent the MIA-induced changes in gene expression and behaviour.

“Maternal cytokines also appear to be necessary for the ASD-like phenotypes in offspring because poly(I:C) injections in mid-gestation on an IL-6 knockout background, co-administration of an IL-6 function-blocking antibody and poly(I:C), or overexpression of the anti-inflammatory cytokine IL-10 by macrophages, prevent the MIA-induced changes in gene expression and behaviour95,101.”

• cites [95] Knuesel, I. et al. Maternal immune activation and abnormal brain development across CNS disorders. Nat. Rev. Neurol. 10, 643–660 (2014). A comprehensive review of empirical evidence linking MIA to numerous CNS disorders. sourceNot checked yet

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• cites [101] Ponzio, N. M., Servatius, R., Beck, K., Marzouk, A. & Kreider, T. Cytokine levels during pregnancy influence immunological profiles and neurobehavioral patterns of the offspring. Ann. NY Acad. Sci. 1107, 118–128 (2007). sourceNot checked yet

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Studies using several animal models of maternal infection during pregnancy support the association of MIA with ASD phenotypes.

“Studies using several animal models of maternal infection during pregnancy support the association of MIA with ASD phenotypes.”

These results provide strong support for the involvement of MIA with ASD in offspring.

“these results provide strong support for the involvement of MIA with ASD in offspring.”

Changes in peripheral cytokine levels may be developmentally regulated since measurements at earlier ages differ in both the cytokines altered and the direction of their change in ASD.

“These changes in peripheral cytokine levels may be developmentally regulated since measurements at earlier ages differ in both the cytokines altered and the direction of their change in ASD.”

A weighted gene co-expression network analysis comparing the expression of more than 30,000 genes in post-mortem autistic and control brains revealed two distinct networks - each comprising more than 400 genes - that are disrupted in the brains of individuals with ASD.

“A weighted gene co-expression network analysis comparing the expression of more than 30,000 genes in post-mortem autistic and control brains revealed two distinct networks — each comprising more than 400 genes — that are disrupted in the brains of individuals with ASD30.”

• cites [30] Voineagu, I. et al. Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature 474, 380–384 (2011). A landmark study identifying the enrichment of synaptic and immune gene modules in the transcriptomes of individuals with ASD. sourceNot checked yet

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The T-cell repertoire is highly influenced by the composition of gut microbiota.

“The T-cell repertoire (defined as the various sub-types — each with their own effector properties — and myriad T-cell receptor clones within these sub-types) in particular, is highly influenced by the composition of gut microbiota152,153.”

• cites [152] Finegold, S. M. Desulfovibrio species are potentially important in regressive autism. Med. Hypotheses 77, 270–274 (2011). sourceNot checked yet

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• cites [153] Gaboriau-Routhiau, V. et al. The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses. Immunity 31, 677–689 (2009). sourceNot checked yet

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The brains of individuals with ASD show changes in the expression of genes encoding proteins that were initially discovered in the immune system.

“the brains of individuals with ASD also show changes in the expression of genes encoding proteins that were initially discovered in the immune system.”

The offspring of MIA mice exhibit peripheral immune abnormalities.

“The offspring of MIA mice exhibit peripheral immune abnormalities.”

MIA offspring show altered gut bacterial profiles, especially higher Clostridia spp, similar to human ASD observations.

“These MIA offspring also have abnormal microbiota signatures, most significantly in elevated levels of Clostridia spp, paralleling findings in humans with ASD150,158.”

• cites [150] Song, Y., Liu, C. & Finegold, S. M. Real-time PCR quantitation of clostridia in feces of autistic children. Appl. Environ. Microbiol. 70, 6459–6465 (2004). sourceNot checked yet

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• cites [158] Hsiao, E. Y. et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 155, 1451–1463 (2013). A proof-of-concept study showing that ASD-like behaviours can be ameliorated by modulation of the microbiota. sourceNot checked yet

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Increases in soluble TNF receptors that blunt the inflammatory response occur in the CSF and serum from individuals with ASD.

“increases in soluble TNF receptors that blunt the inflammatory response in the CSF and serum from individuals with ASD141.”

• cites [141] Komori, H. et al. Cerebrospinal fluid biopterin and biogenic amine metabolites during oral R-THBP therapy for infantile autism. J. Autism Dev. Disord. 25, 183–193 (1995). sourceNot checked yet

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These studies clearly show that an environmental risk factor for ASD causes long-lasting immune dysregulation that is associated with ASD-like phenotypes in rodents.

“these studies do clearly show that an environmental risk factor for ASD causes long-lasting immune dysregulation that is associated with ASD-like phenotypes in rodents.”

Sufficient evidence indicates that general abnormalities in peripheral immunity are a common feature in the ASD population.

“sufficient evidence indicates that general abnormalities in peripheral immunity are a common feature in the ASD population.”

This imbalance could influence peripheral immune responses, potentially contributing to the observed abnormalities in immune cell composition and function in these individuals.

“this imbalance could influence peripheral immune responses, potentially contributing to the observed abnormalities in immune cell composition and function in these individuals.”

Oral B. fragilis treatment ameliorates stereotypic and anxiety-like behaviour in MIA mice.

“ameliorates stereotypic and anxiety-like behaviour”

• cites [157] Coury, D. L. et al. Gastrointestinal conditions in children with autism spectrum disorder: developing a research agenda. Pediatrics 130 (Suppl. 2), S160–S168 (2012). sourceNot checked yet

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Gut microbiota may act as a 'tuning fork' for the immune system.

“recent studies suggest that gut microbiota may act as a ‘tuning fork’ for the immune system.”

Other results contradict these findings: some studies have shown decreases or no change in sensitive markers of CNS immune activation - including quinolinic acid, neopterin and biopterin - in the cerebrospinal fluid of individuals with ASD.

“some studies have shown decreases or no change in sensitive markers of CNS immune activation — including quinolinic acid, neopterin and biopterin — in the cerebrospinal fluid (CSF) of individuals with ASD139–141.”

• cites [139] Tetreault, N. A. et al. Microglia in the cerebral cortex in autism. J. Autism Dev. Disord. 42, 2569–2584 (2012). sourceNot checked yet

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• cites [140] Tani, Y., Fernell, E., Watanabe, Y., Kanai, T. & Langstrom, B. Decrease in 6R-5,6,7,8-tetrahydrobiopterin content in cerebrospinal fluid of autistic patients. Neurosci. Lett. 181, 169–172 (1994). sourceNot checked yet

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• cites [141] Komori, H. et al. Cerebrospinal fluid biopterin and biogenic amine metabolites during oral R-THBP therapy for infantile autism. J. Autism Dev. Disord. 25, 183–193 (1995). sourceNot checked yet

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In mouse models of MIA, offspring with ASD-like behaviours and neuropathology also exhibit long-lasting changes in cytokine levels in the brain.

“In mouse models of MIA, offspring with ASD-like behaviours and neuropathology also exhibit long-lasting changes in cytokine levels in the brain.”

Children with ASD have excessive levels of Clostridium spp and Desulfovibrio spp in their gut microbiome.

“Children with ASD have excessive levels of Clostridium spp and Desulfovibrio spp in their gut microbiome149–151”

• cites [149] Salzman, N. H. Microbiota–immune system interaction: an uneasy alliance. Curr. Opin. Microbiol. 14, 99–105 (2011). sourceNot checked yet

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• cites [150] Song, Y., Liu, C. & Finegold, S. M. Real-time PCR quantitation of clostridia in feces of autistic children. Appl. Environ. Microbiol. 70, 6459–6465 (2004). sourceNot checked yet

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• cites [151] Parracho, H. M., Bingham, M. O., Gibson, G. R. & McCartney, A. L. Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children. J. Med. Microbiol. 54, 987–991 (2005). sourceNot checked yet

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Comparing results from animal studies using a single model (MIA) with ASD in humans resulting from a wide range of aetiologies may be misleading.

“comparing results from animal studies using a single model (MIA) with ASD in humans resulting from a wide range of aetiologies may be misleading.”

Oral B. fragilis treatment improves sensorimotor gating in MIA mice.

“improves sensorimotor gating”

• cites [157] Coury, D. L. et al. Gastrointestinal conditions in children with autism spectrum disorder: developing a research agenda. Pediatrics 130 (Suppl. 2), S160–S168 (2012). sourceNot checked yet

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Oral B. fragilis treatment rectifies microbiota imbalances in MIA mice.

“rectifies microbiota imbalances”

• cites [157] Coury, D. L. et al. Gastrointestinal conditions in children with autism spectrum disorder: developing a research agenda. Pediatrics 130 (Suppl. 2), S160–S168 (2012). sourceNot checked yet

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Cross-species comparisons from the current literature are not informative because of the often limited number of cytokines assayed in human samples, the wide range of ages, co-morbidities, and therapies within the patient population, and the challenge in comparing postnatal ages between rodents and humans.

“cross-species comparisons from the current literature are not informative because of the often limited number of cytokines assayed in human samples, the wide range of ages, co-morbidities, and therapies within the patient population, and the challenge in comparing postnatal ages between rodents and humans.”

Decreases in MET expression confer local hyperconnectivity, a putative hallmark of ASD pathophysiology.

“decreases in MET expression confer local hyperconnectivity, which is a putative hallmark of ASD pathophysiology189.”

• cites [189] Akimoto, M. et al. Hepatocyte growth factor as an enhancer of NMDA currents and synaptic plasticity in the hippocampus. Neuroscience 128, 155–162 (2004). sourceNot checked yet

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Targeting JAK-STAT signaling in the brain might help counter harmful cytokine-driven changes in brain development and function in ASD.

“it may represent an important therapeutic target for pathogenic cytokine-mediated alterations in brain development and function, like those described above for ASD.”

STAT1 and STAT3 have roles in hippocampal plasticity.

“STAT1 and STAT3 have roles in hippocampal plasticity178,179.”

• cites [178] Tai, D. J., Hsu, W. L., Liu, Y. C., Ma, Y. L. & Lee, E. H. Novel role and mechanism of protein inhibitor of activated STAT1 in spatial learning. EMBO J. 30, 205–220 (2011). sourceNot checked yet

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• cites [179] Feng, J. et al. Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons. Nat. Neurosci. 13, 423–430 (2010). sourceNot checked yet

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Other pro-inflammatory cytokines, such as TNF, also act in early brain maturation and later synaptic plasticity.

“Several other pro-inflammatory cytokines, including TNF, have similar diverse roles in early brain development and postnatal synaptic plasticity172,173.”

• cites [172] Goshen, I. & Yirmiya, R. Interleukin-1 (IL-1): a central regulator of stress responses. Front. Neuroendocrinol. 30, 30–45 (2009). sourceNot checked yet

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• cites [173] Bernardino, L. et al. Tumor necrosis factor-α modulates survival, proliferation, and neuronal differentiation in neonatal subventricular zone cell cultures. Stem Cells 26, 2361–2371 (2008). sourceNot checked yet

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Oral B. fragilis treatment increases number and duration of ultrasonic vocalizations in MIA mice.

“increases the number and duration of ultrasonic vocalizations in these mice157”

• cites [157] Coury, D. L. et al. Gastrointestinal conditions in children with autism spectrum disorder: developing a research agenda. Pediatrics 130 (Suppl. 2), S160–S168 (2012). sourceNot checked yet

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IFN-γ suppresses homeostatic mechanisms during visual-system plasticity that depends on experience.

“IFN-γ also negatively regulates homeostatic processes during experience-dependent plasticity in the visual system174.”

• cites [174] Pribiag, H. & Stellwagen, D. Neuroimmune regulation of homeostatic synaptic plasticity. Neuropharmacology 78, 13–22 (2014). sourceNot checked yet

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The same IL1RAPL1 model exhibits enhanced ratio of excitation to inhibition in amygdala.

“an enhanced ratio of excitation to inhibition in the amygdala”

• cites [168] Yoshida, T. et al. Interleukin-1 receptor accessory protein organizes neuronal synaptogenesis as a cell adhesion molecule. J. Neurosci. 32, 2588–2600 (2012). sourceNot checked yet

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• cites [169] Pavlowsky, A. et al. A postsynaptic signaling pathway that may account for the cognitive defect due to IL1RAPL1 mutation. Curr. Biol. 20, 103–115 (2010). sourceNot checked yet

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Deviations of IL-1β above or below physiological levels impair long-term potentiation and synaptic plasticity.

“deviations above or below physiological levels lead to impairments in long-term potentiation and synaptic plasticity”

• cites [171] Moretti, P. et al. Learning and memory and synaptic plasticity are impaired in a mouse model of Rett syndrome. J. Neurosci. 26, 319–327 (2006). sourceNot checked yet

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A mouse model of ASD-associated IL1RAPL1 null mutation exhibits reduced cortical synapse density.

“a mouse model mimicking the ASD-associated null mutation in IL1RAPL1 exhibits reduced cortical synapse density”

• cites [168] Yoshida, T. et al. Interleukin-1 receptor accessory protein organizes neuronal synaptogenesis as a cell adhesion molecule. J. Neurosci. 32, 2588–2600 (2012). sourceNot checked yet

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• cites [169] Pavlowsky, A. et al. A postsynaptic signaling pathway that may account for the cognitive defect due to IL1RAPL1 mutation. Curr. Biol. 20, 103–115 (2010). sourceNot checked yet

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MET signalling induced by HGF increases levels and clustering of synaptic proteins.

“MET signalling induced by hepatocyte growth factor (HGF) increases the levels and clustering of synaptic proteins184,185”

• cites [184] Eagleson, K. L., Milner, T. A., Xie, Z. & Levitt, P. Synaptic and extrasynaptic location of the receptor tyrosine kinase Met during postnatal development in the mouse neocortex and hippocampus. J. Comp. Neurol. 521, 3241–3259 (2013). sourceNot checked yet

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• cites [185] Tyndall, S. J. & Walikonis, R. S. The receptor tyrosine kinase Met and its ligand hepatocyte growth factor are clustered at excitatory synapses and can enhance clustering of synaptic proteins. Cell Cycle 5, 1560–1568 (2006). sourceNot checked yet

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Alterations in brain immune molecule expression by genetic mutations or environmental risk factors can produce short-lived or permanent shifts in how the brain develops and works.

“Alterations in the expression of these immune molecules in the brain, by genetic mutations or as a result of environmental risk factors, can lead to transient and/or lasting changes in brain development and function.”

B. fragilis has no effect on sociability deficits in MIA offspring.

“B. fragilis has no effect on the deficits in sociability in these offspring.”

• cites [157] Coury, D. L. et al. Gastrointestinal conditions in children with autism spectrum disorder: developing a research agenda. Pediatrics 130 (Suppl. 2), S160–S168 (2012). sourceNot checked yet

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The same IL1RAPL1 model exhibits deficits in associative memory.

“deficits in associative memory168,169”

• cites [168] Yoshida, T. et al. Interleukin-1 receptor accessory protein organizes neuronal synaptogenesis as a cell adhesion molecule. J. Neurosci. 32, 2588–2600 (2012). sourceNot checked yet

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• cites [169] Pavlowsky, A. et al. A postsynaptic signaling pathway that may account for the cognitive defect due to IL1RAPL1 mutation. Curr. Biol. 20, 103–115 (2010). sourceNot checked yet

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MET signalling induced by HGF modulates hippocampal synaptic function.

“modulates hippocampal synaptic function185,187”

• cites [185] Tyndall, S. J. & Walikonis, R. S. The receptor tyrosine kinase Met and its ligand hepatocyte growth factor are clustered at excitatory synapses and can enhance clustering of synaptic proteins. Cell Cycle 5, 1560–1568 (2006). sourceNot checked yet

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• cites [187] Kawas, L. H., Benoist, C. C., Harding, J. W., Wayman, G. A. & Abu-Lail, N. I. Nanoscale mapping of the Met receptor on hippocampal neurons by AFM and confocal microscopy. Nanomed. Nanotechnol. Biol. Med. 9, 428–438 (2013). sourceNot checked yet

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Increases or decreases in cytokines due to genetic mutations or downstream of MIA could harm brain development and function independently of inflammation.

“Collectively, these findings suggest that increases or decreases in cytokines owing to genetic mutations or downstream of MIA could have deleterious effects on brain development and function independent of any role in inflammation”

Immune proteins on neurons and glia control all phases of brain development and function.

“immune molecules on neurons or glia in the brain have been demonstrated to regulate every stage of brain development and function159,160”

• cites [159] Finegold, S. M., Downes, J. & Summanen, P. H. Microbiology of regressive autism. Anaerobe 18, 260–262 (2012). sourceNot checked yet

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• cites [160] Deverman, B. E. & Patterson, P. H. Cytokines and CNS development. Neuron 64, 61–78 (2009). An excellent review of the diverse and non-classical roles of cytokines in the developing brain. sourceNot checked yet

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IL-1β functions within a tight homeostatic range.

“IL-1β functions within a tight homeostatic range”

• cites [171] Moretti, P. et al. Learning and memory and synaptic plasticity are impaired in a mouse model of Rett syndrome. J. Neurosci. 26, 319–327 (2006). sourceNot checked yet

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Besides its immune functions, MET is critical in the brain across development.

“In addition to regulating immunity, MET has essential roles in the brain throughout development.”

MET signalling induced by HGF enhances hippocampal long-term potentiation.

“enhances hippocampal long-term potentiation188”

• cites [188] Lim, C. S. & Walikonis, R. S. Hepatocyte growth factor and c-Met promote dendritic maturation during hippocampal neuron differentiation via the Akt pathway. Cell. Signal. 20, 825–835 (2008). sourceNot checked yet

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IL-1β and its receptor participate in neurogenesis, synapse formation and plasticity from early prenatal CNS stages through adulthood.

“IL-1β and its receptors have important roles in a wide range of processes, including neurogenesis and synapse formation and plasticity, from early prenatal CNS development to postnatal development and adulthood162–168.”

• cites [162] Goines, P. E. & Ashwood, P. Cytokine dysregulation in autism spectrum disorders (ASD): possible role of the environment. Neurotoxicol. Teratol. 36, 67–81 (2013). sourceNot checked yet

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• cites [163] de la Mano, A. et al. Role of interleukin-1β in the control of neuroepithelial proliferation and differentiation of the spinal cord during development. Cytokine 37, 128–137 (2007). sourceNot checked yet

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• cites [164] Gambino, F. et al. IL1RAPL1 controls inhibitory networks during cerebellar development in mice. Eur. J. Neurosci. 30, 1476–1486 (2009). sourceNot checked yet

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• cites [165] Valnegri, P. et al. The X-linked intellectual disability protein IL1RAPL1 regulates excitatory synapse formation by binding PTPδ and RhoGAP2. Hum. Mol. Genet. 20, 4797–4809 (2011). sourceNot checked yet

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• cites [166] Yoshida, T. & Mishina, M. Zebrafish orthologue of mental retardation protein IL1RAPL1 regulates presynaptic differentiation. Mol. Cell. Neurosci. 39, 218–228 (2008). sourceNot checked yet

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• cites [167] Yoshida, T. et al. IL-1 receptor accessory protein-like 1 associated with mental retardation and autism mediates synapse formation by trans-synaptic interaction with protein tyrosine phosphatase δ. J. Neurosci. 31, 13485–13499 (2011). sourceNot checked yet

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• cites [168] Yoshida, T. et al. Interleukin-1 receptor accessory protein organizes neuronal synaptogenesis as a cell adhesion molecule. J. Neurosci. 32, 2588–2600 (2012). sourceNot checked yet

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These IL1RAPL1 model findings resemble those in Mecp2-null mice, a Rett syndrome model.

“These findings are similar to those found in Mecp2-null mice, a model of Rett syndrome169,170.”

• cites [169] Pavlowsky, A. et al. A postsynaptic signaling pathway that may account for the cognitive defect due to IL1RAPL1 mutation. Curr. Biol. 20, 103–115 (2010). sourceNot checked yet

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• cites [170] Houbaert, X. et al. Target-specific vulnerability of excitatory synapses leads to deficits in associative memory in a model of intellectual disorder. J. Neurosci. 33, 13805–13819 (2013). sourceNot checked yet

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MET signalling induced by HGF increases number of dendritic spines.

“increases the number of dendritic spines186”

• cites [186] Nakano, M. et al. Hepatocyte growth factor promotes the number of PSD-95 clusters in young hippocampal neurons. Exp. Neurol. 207, 195–202 (2007). sourceNot checked yet

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Microglial deficits, as in Cx3cr1 knockout mice, raise the density of immature cortical synapses.

“Deficits in microglia, such as those seen in the CX3C chemokine receptor 1 (Cx3cr1) knockout mice, lead to increased densities of immature synapses in the cerebral cortex”

• cites [215] Schafer, D. P., Lehrman, E. K. & Stevens, B. The “quad-partite” synapse: microglia-synapse interactions in the developing and mature CNS. Glia 61, 24–36 (2013). sourceNot checked yet

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• cites [216] Paolicelli, R. C. et al. Synaptic pruning by microglia is necessary for normal brain development. Science 333, 1456–1458 (2011). sourceNot checked yet

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Gestational immune-related ASD, idiopathic ASD and syndromic ASD might all meet at a molecular pathway centered on MEF2.

“Together, these findings suggest that ASD that is associated with immune dysregulation during gestation, as well as idiopathic and syndromic forms of ASD, may converge on a molecular pathway with MEF2 as a hub208.”

• cites [208] Tsai, N. P. et al. Multiple autism-linked genes mediate synapse elimination via proteasomal degradation of a synaptic scaffold PSD-95. Cell 151, 1581–1594 (2012). sourceNot checked yet

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Microglia and complement might carry the impact of environmental and genetic ASD risk factors.

“Microglia and complement may — like cytokines, MHCI and MEF2 — also mediate the effects of both environmental and genetic ASD risk factors.”

In integrative functional genomic analysis of ASD-associated genes, two co-expressed networks upregulated during early fetal and late fetal-early postnatal development showed binding site enrichment for MEF2A and MEF2C.

“two co-expressed networks upregulated during early fetal development and during late fetal–early postnatal development showed binding site enrichment for two isoforms of MEF2 (MEF2A and MEF2C)205”

• cites [205] Babatz, T. D., Kumar, R. A., Sudi, J., Dobyns, W. B. & Christian, S. L. Copy number and sequence variants implicate APBA2 as an autism candidate gene. Autism Res. 2, 359–364 (2009). sourceNot checked yet

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MEF2 transcription factors seem to link immune dysregulation to synaptic connectivity.

“they appear to mediate the effects of immune dysregulation on synaptic connectivity”

MEF2 negatively regulates establishment of hippocampal connections.

“MEF2 negatively regulates the establishment of hippocampal connections201”

• cites [201] Flavell, S. W. et al. Genome-wide analysis of MEF2 transcriptional program reveals synaptic target genes and neuronal activity-dependent polyadenylation site selection. Neuron 60, 1022–1038 (2008). sourceNot checked yet

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In some ASD cases, postmortem brain tissue, particularly prefrontal cortex, shows more activated microglia with a changed distribution.

“Activated microglia are present in increased numbers and with an altered distribution in postmortem brain tissue, especially the prefrontal cortex, in a subset of ASD cases115,137,209,210.”

• cites [115] Goines, P. et al. Autoantibodies to cerebellum in children with autism associate with behavior. Brain Behav. Immun. 25, 514–523 (2011). sourceNot checked yet

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• cites [137] Wei, H. et al. IL-6 is increased in the cerebellum of autistic brain and alters neural cell adhesion, migration and synaptic formation. J. Neuroinflammation 8, 52 (2011). sourceNot checked yet

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• cites [209] Ebert, D. H. & Greenberg, M. E. Activity-dependent neuronal signalling and autism spectrum disorder. Nature 493, 327–337 (2013). sourceNot checked yet

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• cites [210] Morgan, J. T. et al. Abnormal microglial-neuronal spatial organization in the dorsolateral prefrontal cortex in autism. Brain Res. 1456, 72–81 (2012). sourceNot checked yet

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During CNS development, MHCI promotes synapse elimination during activity-dependent refinement in developing visual system.

“promotes synapse elimination during activity-dependent refinement of connections in the developing visual system190,192”

• cites [190] Qiu, S., Anderson, C. T., Levitt, P. & Shepherd, G. M. Circuit-specific intracortical hyperconnectivity in mice with deletion of the autism-associated Met receptor tyrosine kinase. J. Neurosci. 31, 5855–5864 (2011). sourceNot checked yet

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• cites [192] Corriveau, R. A., Huh, G. S. & Shatz, C. J. Regulation of class I MHC gene expression in the developing and mature CNS by neural activity. Neuron 21, 505–520 (1998). The first report of the activity-dependent expression of MHCI molecules in the developing brain. sourceNot checked yet

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During development, microglia secrete trophic factors like IGF-1 and TGFβ.

“secrete trophic factors like insulin-like growth factor I (IGF-1) and TGFβ”

• cites [212] Prinz, M. & Priller, J. Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nat. Rev. Neurosci. 15, 300–312 (2014). An authoritative review of microglial origins and contributions to normal brain function and disease. sourceNot checked yet

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• cites [213] Butovsky, O. et al. Microglia activated by IL-4 or IFN-γ differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol. Cell. Neurosci. 31, 149–160 (2006). sourceNot checked yet

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• cites [214] Cunningham, C. L., Martinez-Cerdeno, V. & Noctor, S. C. Microglia regulate the number of neural precursor cells in the developing cerebral cortex. J. Neurosci. 33, 4216–4233 (2013). sourceNot checked yet

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MEF2 transcription factors are associated with ASD risk through genetic mutations.

“are also associated with ASD risk through genetic mutations”

During development, microglia participate in activity-dependent elimination of synaptic connections.

“participate in activity-dependent elimination of synaptic connections212–214”

• cites [212] Prinz, M. & Priller, J. Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nat. Rev. Neurosci. 15, 300–312 (2014). An authoritative review of microglial origins and contributions to normal brain function and disease. sourceNot checked yet

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• cites [213] Butovsky, O. et al. Microglia activated by IL-4 or IFN-γ differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol. Cell. Neurosci. 31, 149–160 (2006). sourceNot checked yet

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• cites [214] Cunningham, C. L., Martinez-Cerdeno, V. & Noctor, S. C. Microglia regulate the number of neural precursor cells in the developing cerebral cortex. J. Neurosci. 33, 4216–4233 (2013). sourceNot checked yet

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MEF2 proteins serve as key molecular convergence points downstream of multiple other ASD risk factors.

“act as central molecular hubs downstream of several other ASD risk factors.”

During CNS development, MHCI negatively regulates initial establishment of cortical connections.

“negatively regulates the initial establishment of cortical connections”

• cites [190] Qiu, S., Anderson, C. T., Levitt, P. & Shepherd, G. M. Circuit-specific intracortical hyperconnectivity in mice with deletion of the autism-associated Met receptor tyrosine kinase. J. Neurosci. 31, 5855–5864 (2011). sourceNot checked yet

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• cites [192] Corriveau, R. A., Huh, G. S. & Shatz, C. J. Regulation of class I MHC gene expression in the developing and mature CNS by neural activity. Neuron 21, 505–520 (1998). The first report of the activity-dependent expression of MHCI molecules in the developing brain. sourceNot checked yet

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MEF2 works with FMRP to control glutamatergic synaptic activity.

“MEF2 interacts with FMRP to regulate glutamatergic synaptic function206”

• cites [206] Parikshak, N. N. et al. Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism. Cell 155, 1008–1021 (2013). sourceNot checked yet

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A genome-wide ASD transcriptome study found the MEF2 splicing factor A2BP1/RBFOX1 as a hub in a downregulated synaptic-function gene network.

“the MEF2 splicing factor ataxin-2-binding protein 1 (A2BP1; also known as RBFOX1) — previously implicated in ASD203,204 — was identified as a central hub within the network of downregulated genes associated with synaptic function.”

• cites [30] Voineagu, I. et al. Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature 474, 380–384 (2011). A landmark study identifying the enrichment of synaptic and immune gene modules in the transcriptomes of individuals with ASD. sourceNot checked yet

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• cites [203] Paciorkowski, A. R. et al. MEF2C haploinsufficiency features consistent hyperkinesis, variable epilepsy, and has a role in dorsal and ventral neuronal developmental pathways. Neurogenetics 14, 99–111 (2013). sourceNot checked yet

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• cites [204] Martin, C. L. et al. Cytogenetic and molecular characterization of A2BP1/FOX1 as a candidate gene for autism. Am. J.Med. Genet. B Neuropsychiatr. Genet. 144B, 869–876 (2007). sourceNot checked yet

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In development, microglia influence neurogenesis by engulfing neural precursor cells.

“regulate neurogenesis through phagocytosis of neural precursor cells”

• cites [212] Prinz, M. & Priller, J. Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nat. Rev. Neurosci. 15, 300–312 (2014). An authoritative review of microglial origins and contributions to normal brain function and disease. sourceNot checked yet

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• cites [213] Butovsky, O. et al. Microglia activated by IL-4 or IFN-γ differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol. Cell. Neurosci. 31, 149–160 (2006). sourceNot checked yet

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• cites [214] Cunningham, C. L., Martinez-Cerdeno, V. & Noctor, S. C. Microglia regulate the number of neural precursor cells in the developing cerebral cortex. J. Neurosci. 33, 4216–4233 (2013). sourceNot checked yet

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MHCI proteins appear across the CNS in neurons and glia of many mammals.

“They are also present throughout the CNS of many mammalian species in neurons and glial cells191,192.”

• cites [191] Elmer, B. M., Estes, M. L., Barrow, S. L. & McAllister, A. K. MHCI requires MEF2 transcription factors to negatively regulate synapse density during development and in disease. J. Neurosci. 33, 13791–13804 (2013). sourceNot checked yet

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• cites [192] Corriveau, R. A., Huh, G. S. & Shatz, C. J. Regulation of class I MHC gene expression in the developing and mature CNS by neural activity. Neuron 21, 505–520 (1998). The first report of the activity-dependent expression of MHCI molecules in the developing brain. sourceNot checked yet

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Poly(I:C)-induced MIA in mice causes dramatic increase in MHCI expression on cortical neurons from newborn offspring.

“poly(I:C)-induced MIA in mice causes a dramatic increase in the expression of MHCI molecules on cortical neurons from newborn offspring.”

MHCI signaling might be a shared route by which MHC mutations and maternal infection change connectivity in the developing offspring brain.

“Thus, changes in MHCI signalling may be a common mechanism through which genetic mutations in MHC genes and exposure to maternal infection could alter the establishment of connectivity in the developing brains of offspring.”

In the developing CNS, MHCI governs axon and dendrite growth.

“During CNS development, MHCI controls axonal and dendritic outgrowth”

• cites [190] Qiu, S., Anderson, C. T., Levitt, P. & Shepherd, G. M. Circuit-specific intracortical hyperconnectivity in mice with deletion of the autism-associated Met receptor tyrosine kinase. J. Neurosci. 31, 5855–5864 (2011). sourceNot checked yet

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• cites [192] Corriveau, R. A., Huh, G. S. & Shatz, C. J. Regulation of class I MHC gene expression in the developing and mature CNS by neural activity. Neuron 21, 505–520 (1998). The first report of the activity-dependent expression of MHCI molecules in the developing brain. sourceNot checked yet

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Dissociated neurons from MIA offspring exhibit profound deficit in forming glutamatergic synapses.

“Dissociated neurons from MIA offspring also exhibit a profound deficit in their ability to form glutamatergic synapses.”

Normalizing MHCI levels in cultured MIA neurons prevents MIA-induced decrease in synapse density.

“normalizing MHCI levels in cultured MIA neurons prevents the MIA-induced decrease in synapse density190.”

• cites [190] Qiu, S., Anderson, C. T., Levitt, P. & Shepherd, G. M. Circuit-specific intracortical hyperconnectivity in mice with deletion of the autism-associated Met receptor tyrosine kinase. J. Neurosci. 31, 5855–5864 (2011). sourceNot checked yet

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Cx3cr1 knockout microglial deficits lead to deficits in functional connectivity across brain regions.

“deficits in functional connectivity across brain regions”

• cites [215] Schafer, D. P., Lehrman, E. K. & Stevens, B. The “quad-partite” synapse: microglia-synapse interactions in the developing and mature CNS. Glia 61, 24–36 (2013). sourceNot checked yet

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• cites [216] Paolicelli, R. C. et al. Synaptic pruning by microglia is necessary for normal brain development. Science 333, 1456–1458 (2011). sourceNot checked yet

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Replacing brain microglia with wild-type cells through transplantation reverses somatic, neuropathological and behavioral abnormalities in two ASD mouse models: the MeCP2−/y Rett model and the MIA model.

“transplantation to reconstitute the brain with wild-type microglia reverses somatic phenotypes, neuropathological changes, and behavioural abnormalities in two mouse models of ASD — MeCP2−/y model of Rett syndrome232 and the MIA model132.”

• cites [232] Qin, S. et al. Failure to ubiquitinate c-Met leads to hyperactivation of mTOR signaling in a mouse model of autosomal dominant polycystic kidney disease. J. Clin. Invest. 120, 3617–3628 (2010). sourceNot checked yet

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• cites [132] Derecki, N. C. et al. Regulation of learning and memory by meningeal immunity: a key role for IL-4. J. Exp. Med. 207, 1067–1080 (2010). sourceNot checked yet

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The developmental trigger determines whether changed priming weakens or strengthens later immune responses.

“Depending on the developmental trigger, altered priming can impair or enhance reactions to subsequent immune challenges224,225.”

• cites [224] Bilbo, S. D. & Frank, A. Beach award: programming of neuroendocrine function by early-life experience: a critical role for the immune system. Horm. Behav. 63, 684–691 (2013). sourceNot checked yet

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• cites [225] Perry, V. H., Newman, T. A. & Cunningham, C. The impact of systemic infection on the progression of neurodegenerative disease. Nat. Rev. Neurosci. 4, 103–112 (2003). sourceNot checked yet

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Reconstituting the whole immune system from control animals corrects peripheral immune defects in MIA offspring, such as low regulatory T cells and excess CD4+ memory T cells with an inflammatory profile.

“Full immune system reconstitution from control animals also rescues peripheral immune abnormalities in MIA offspring, including deficits in regulatory T-cells and a disproportionate increase in CD4+ memory T cells with an inflammatory profile previously implicated in learning and memory deficits131,132”

• cites [131] Plioplys, A. V., Greaves, A., Kazemi, K. & Silverman, E. Lymphocyte function in autism and Rett syndrome. Neuropsychobiology 29, 12–16 (1994). sourceNot checked yet

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• cites [132] Derecki, N. C. et al. Regulation of learning and memory by meningeal immunity: a key role for IL-4. J. Exp. Med. 207, 1067–1080 (2010). sourceNot checked yet

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Changed mTOR signaling appears to contribute to several frequent monogenic ASD conditions, such as FXS, TSC, Rett syndrome, PTEN macrocephaly, neurofibromatosis type 1, MEF2C haploinsufficiency and 9q34.3 deletion syndrome.

“Alterations in mTOR signalling seem to underlie several common monogenic forms of ASD, including FXS, TSC, Rett syndrome, PTEN macrocephaly and neurofibromatosis type 1, and syndromes with autistic-like features, such as MEF2C haploinsufficiency and 9q34.3 deletion syndrome.”

Various immune pathways implicated in ASD converge on control of synapse creation and removal, shaping synaptic function and plasticity in both developing and adult brain.

“The results reviewed here suggest that many of the diverse immune contributions to ASD — including dysregulated signalling through MET, cytokines, MHCI and microglia–complement — share the downstream effect of regulating synapse formation and elimination, thereby controlling synaptic function and plasticity in the developing and mature brain.”

Bone marrow transplantation is a powerful but drastic way to restore immune function.

“One of the most effective, albeit drastic, therapeutic approaches for restoring immune function is bone marrow transplantation.”

Parts of the complement cascade might carry out certain microglial roles.

“Components of the complement cascade may mediate some of these microglial functions.”

Many immune risk factors probably converge on mTOR, the main intracellular signaling node for ASD-risk genes.

“it is likely that many immune risk factors will converge on the most common intracellular signaling hub for ASD-risk genes — the mammalian target of rapamycin (mTOR).”

mTOR may serve as a central integrator for brain immune signaling, MIA-related cytokine shifts, postnatal environmental exposures, immune-gene mutations and lifelong immune dysregulation.

“mTOR is thus a focal point to integrate immune signalling in the brain, changes in cytokine levels due to MIA, postnatal environmental insults or genetic mutations in immune genes, and ongoing immune dysregulation throughout life.”

A placebo-controlled, double-blind randomized trial in young people with FXS reported that three months of minocycline improved anxiety and mood-related behaviors.

“In a randomized double-blind, placebo-controlled trial in children and adolescents with FXS, three months of minocycline treatment improved anxiety and mood-related behaviours238.”

• cites [238] Leigh, M. J. et al. A randomized double-blind, placebo-controlled trial of minocycline in children and adolescents with fragile X syndrome. J. Dev. Behav. Pediatr. 34, 147–155 (2013). sourceNot checked yet

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This MEF2 hub also carries the impact of MEF2 and FMR1 mutations on ASD-related traits.

“this hub also mediates the effects of mutations in MEF2 and FMR1 in contributing to ASD-related phenotypes.”

In Fmr1 knockout mice, minocycline reverses synaptic abnormalities, anxiety and social deficits.

“minocycline, a broad-spectrum antibiotic that has immunosuppressive properties, corrects synaptic abnormalities, heightened anxiety and social deficits in Fmr1 knockout mice236,237.”

• cites [236] Bilousova, T. V. et al. Minocycline promotes dendritic spine maturation and improves behavioural performance in the fragile X mouse model. J. Med. Genet. 46, 94–102 (2009). sourceNot checked yet

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• cites [237] Rotschafer, S. E., Trujillo, M. S., Dansie, L. E., Ethell, I. M. & Razak, K. A. Minocycline treatment reverses ultrasonic vocalization production deficit in a mouse model of fragile X syndrome. Brain Res. 1439, 7–14 (2012). sourceNot checked yet

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Early immune challenges could either reduce or increase synaptic pruning by microglia.

“Thus, early immune insults have the potential to diminish or enhance microglia-mediated synaptic pruning.”

Cx3cr1 knockout microglial deficits lead to ASD-like behaviours.

“and ASD-like behaviours215,216”

• cites [215] Schafer, D. P., Lehrman, E. K. & Stevens, B. The “quad-partite” synapse: microglia-synapse interactions in the developing and mature CNS. Glia 61, 24–36 (2013). sourceNot checked yet

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• cites [216] Paolicelli, R. C. et al. Synaptic pruning by microglia is necessary for normal brain development. Science 333, 1456–1458 (2011). sourceNot checked yet

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Because MET converts extracellular cues into mTOR activation, the ASD-linked MET C variant is expected to reduce mTOR signaling.

“MET translates extracellular signals into mTOR activation; thus, the ASD-related MET C variant is predicted to lead to hypoactive mTOR signalling231.”

• cites [231] Ricciardi, S. et al. Reduced AKT/mTOR signaling and protein synthesis dysregulation in a Rett syndrome animal model. Hum. Mol. Genet. 20, 1182–1196 (2011). sourceNot checked yet

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One recent study found no benefit from wild-type microglia in three rodent Rett models, including the original model.

“a recent study failed to find any benefit of wild-type microglia in three rodent models of Rett syndrome including the model used in the original study235.”

• cites [235] Lv, Y. T. et al. Transplantation of human cord blood mononuclear cells and umbilical cord-derived mesenchymal stem cells in autism. J. Translat. Med. 11, 196 (2013). sourceNot checked yet

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Based on animal work, trials that aim to rebuild immune cells in people with ASD have begun.

“clinical trials using strategies to reconstitute immune cells in individuals with ASD have been initiated233,234.”

• cites [233] Derecki, N. C. et al. Wild-type microglia arrest pathology in a mouse model of Rett syndrome. Nature 484, 105–109 (2012). A seminal study showing immune cell-specific rescue of Rett syndrome-like behaviours and pathophysiology postnatally in a mouse model. sourceNot checked yet

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• cites [234] Sharma, A. et al. Autologous bone marrow mononuclear cell therapy for autism: an open label proof of concept study. Stem Cells Int. 2013, 623875 (2013). sourceNot checked yet

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Studies of monogenic ASD have repeatedly pointed to mTOR as a shared pathway.

“mTOR has been implicated as a common pathway in ASD from numerous studies of monogenic forms of ASD226.”

• cites [226] Streit, W. J. & Xue, Q. S. Life and death of microglia. J. Neuroimmune Pharmacol. 4, 371–379 (2009). sourceNot checked yet

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Agents targeting immune function could alleviate some symptoms associated with ASD.

“the possibility that agents targeting immune function could alleviate some of the symptoms associated with this spectrum of disorders.”

TGF-β released by astrocytes controls C1q expression and its deposition in the lateral geniculate nucleus.

“Astrocyte-dependent secretion of TGF-β regulates C1q expression and deposition in the lateral geniculate nucleus222.”

• cites [222] Schafer, D. P. et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74, 691–705 (2012). sourceNot checked yet

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Microglia can be primed early in development, like peripheral macrophages.

“microglia, like their macrophage relatives in the periphery, can be primed early in development223.”

• cites [223] Bialas, A. R. & Stevens, B. TGF-β signaling regulates neuronal C1q expression and developmental synaptic refinement. Nat. Neurosci. 16, 1773–1782 (2013). sourceNot checked yet

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Antibiotic treatment may improve symptoms in idiopathic ASD.

“antibiotic treatment may also improve symptoms in idiopathic forms of ASD239–241”

• cites [239] Posey, D. J. et al. A pilot study of D-cycloserine in subjects with autistic disorder. Am. J. Psychiatry 161, 2115–2117 (2004). sourceNot checked yet

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• cites [240] Sandler, R. H. et al. Short-term benefit from oral vancomycin treatment of regressive-onset autism. J. Child Neurol. 15, 429–435 (2000). sourceNot checked yet

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• cites [241] Ramirez, P. L., Barnhill, K., Gutierrez, A., Schutte, C. & Hewitson, L. Improvements in behavioral symptoms following antibiotic therapy in a 14-year-old male with autism. Case Rep. Psychiatry 2013, 239034 (2013).Not checked yet

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In brain, complement protein C1q is secreted by neurons.

“In the brain, the complement protein C1q is secreted by neurons219.”

• cites [219] Truedsson, L., Bengtsson, A. A. & Sturfelt, G. Complement deficiencies and systemic lupus erythematosus. Autoimmunity 40, 560–566 (2007). sourceNot checked yet

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mTOR, a serine/threonine kinase, governs numerous features of neural development and of mature brain function and plasticity.

“mTOR is a serine/threonine protein kinase that controls many aspects of neural development as well as the function and plasticity of the mature brain227,228.”

• cites [227] Costa-Mattioli, M. & Monteggia, L. M. mTOR complexes in neurodevelopmental and neuropsychiatric disorders. Nat. Neurosci. 16, 1537–1543 (2013). sourceNot checked yet

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• cites [228] Takei, N. & Nawa, H. mTOR signaling and its roles in normal and abnormal brain development. Front. Mol. Neurosci. 7, 28 (2014). sourceNot checked yet

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Some findings so far support the idea that immune dysregulation might converge on mTOR.

“there is some evidence to date that is consistent with the hypothesis that immune dysregulation may converge on this central signalling pathway.”

A shared signaling hub, MEF2, has already emerged from work on immune ASD risk factors.

“one common signaling hub — MEF2 —has already been identified (FIG. 3).”

Minocycline therapy might not work in ASD with regressive features.

“ASD with regressive features may be resistant to minocycline therapy242.”

• cites [242] Pardo, C. A. et al. A pilot open-label trial of minocycline in patients with autism and regressive features. J. Neurodev. Disord. 5, 9 (2013). sourceNot checked yet

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In ASD, changed levels of these immune molecules might affect brain development by disrupting their normal roles, not only or even mainly by causing inflammation.

“altered levels of these immune molecules in ASD may alter brain development through defects in their normal function in addition to, or even rather than, causing inflammation.”

The immune changes seen in ASD are not necessarily always inflammatory.

“the immune dysregulation associated with ASD may not always be pro-inflammatory.”

Numerous ASD-linked immune molecules have key roles in brain development, function and plasticity.

“many of the immune molecules associated with ASD play important parts in brain development, function and plasticity.”

Human studies suggest fever can lessen many ASD symptoms, particularly communication problems and repetitive behaviors.

“Studies in humans indicate that fever improves many ASD symptoms, especially deficits in communication and increases in repetitive behaviours244–246.”

• cites [244] Sullivan, R. C. Why do autistic children...? J. Autism Dev. Disord. 10, 231–241 (1980). sourceNot checked yet

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• cites [245] Cotterill, R. M. Fever in autistics. Nature 313, 426 (1985). sourceNot checked yet

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• cites [246] Curran, L. K. et al. Behaviors associated with fever in children with autism spectrum disorders. Pediatrics 120, e1386–e1392 (2007). sourceNot checked yet

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Several studies suggest fever temporarily corrects chronic mitochondrial dysfunction, a frequent ASD co-morbidity, through alterations in purinergic signalling.

“several studies suggest that fever temporarily corrects chronic mitochondrial dysfunction — a frequently observed co-morbidity seen in ASD — through alterations in purinergic signalling247,248.”

• cites [247] Naviaux, J. C. et al. Reversal of autism-like behaviors and metabolism in adult mice with single-dose antipurinergic therapy. Transl Psychiatry 4, e400 (2014). sourceNot checked yet

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• cites [248] Naviaux, J. C. et al. Antipurinergic therapy corrects the autism-like features in the fragile X (Fmr1 knockout) mouse model. Mol. Autism 6, 1 (2015). sourceNot checked yet

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In MIA mouse offspring, many brain immune molecules are lower in level and function during postnatal development, contrary to the commonly assumed inflammatory state in ASD.

“mouse models of MIA exhibit decreased levels and function of many types of immune molecules in the brains of offspring during postnatal development, which is the opposite of the widely assumed inflammatory processes present in ASD144.”

• cites [144] Meyer, U. et al. The time of prenatal immune challenge determines the specificity of inflammation-mediated brain and behavioral pathology. J. Neurosci. 26, 4752–4762 (2006). sourceNot checked yet

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