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

In the paper

“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”

What the sources say

• Not checked yetcites [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). source

In the paper

“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)”

In the paper

“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”

In the paper

“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.”

What the sources say

• Not checked yetcites [3] Hertz-Picciotto, I. & Delwiche, L. The rise in autism and the role of age at diagnosis. Epidemiology 20, 84–90 (2009). source

In the paper

“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).”

What the sources say

• Not checked yetcites [6] Pessah, I. N. et al. Immunologic and neurodevelopmental susceptibilities of autism. Neurotoxicology 29, 532–545 (2008). source

In the paper

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

In the paper

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

What the sources say

• Not checked yetcites BOX 1

In the paper

“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.”

What the sources say

• Not checked yetcites [38] Okunishi, K. et al. Hepatocyte growth factor significantly suppresses collagen-induced arthritis in mice. J. Immunol. 179, 5504–5513 (2007). source
• Not checked yetcites [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). source
• Not checked yetcites [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). source
• Not checked yetcites [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). source
• Not checked yetcites [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). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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. source
• Not checked yetcites [8] Silverstein, A. M. The most elegant immunological experiment of the XIX century. Nat. Immunol. 1, 93–94 (2000). source

In the paper

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

What the sources say

• Not checked yetcites [27] Campbell, D. B. et al. Disruption of cerebral cortex MET signaling in autism spectrum disorder. Ann. Neurol. 62, 243–250 (2007). source
• Not checked yetcites [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. source
• Not checked yetcites [31] Rudie, J. D. et al. Autism-associated promoter variant in MET impacts functional and structural brain networks. Neuron 75, 904–915 (2012). source

In the paper

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

What the sources say

• Not checked yetcites [46] Hsiao, E. Y. Immune dysregulation in autism spectrum disorder. Int. Rev. Neurobiol. 113, 269–302 (2013). source
• Not checked yetcites [47] Needleman, L. A. & McAllister, A. K. The major histocompatibility complex and autism spectrum disorder. Dev. Neurobiol. 72, 1288–1301 (2012). source

In the paper

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

What the sources say

• Not checked yetcites [17] Devlin, B. & Scherer, S. W. Genetic architecture in autism spectrum disorder. Curr. Opin. Genet. Dev. 22, 229–237 (2012). source

In the paper

“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.”

What the sources say

• Not checked yetcites [31] Rudie, J. D. et al. Autism-associated promoter variant in MET impacts functional and structural brain networks. Neuron 75, 904–915 (2012). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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). source

In the paper

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

In the paper

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

In the paper

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

In the paper

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

What the sources say

• Not checked yetcites [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. source

In the paper

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

What the sources say

• Not checked yetcites [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). source

In the paper

“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.”

What the sources say

• Not checked yetcites [14] Bailey, A. et al. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol. Med. 25, 63–77 (1995). source
• Not checked yetcites [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). source
• Not checked yetcites [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. source
• Not checked yetcites [16] Sandin, S. et al. The familial risk of autism. JAMA 311, 1770–1777 (2014). source

In the paper

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

In the paper

“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.”

What the sources say

• Not checked yetcites [48] Gough, S. C. & Simmonds, M. J. The HLA region and autoimmune disease: associations and mechanisms of action. Curr. Genom. 8, 453–465 (2007). source
• Not checked yetcites [63] Piton, A. et al. Mutations in the calcium-related gene IL1RAPL1 are associated with autism. Hum. Mol. Genet. 17, 3965–3974 (2008). source

In the paper

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

What the sources say

• Not checked yetcites [65] Atladottir, H. O. et al. Association of family history of autoimmune diseases and autism spectrum disorders. Pediatrics 124, 687–694 (2009). source

In the paper

“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.”

In the paper

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

In the paper

“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.”

What the sources say

• Not checked yetcites [49] Keil, A. et al. Parental autoimmune diseases associated with autism spectrum disorders in offspring. Epidemiology 21, 805–808 (2010). source

In the paper

“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.”

What the sources say

• Not checked yetcites [59] Parmley, J. L. & Hurst, L. D. How do synonymous mutations affect fitness? Bioessays 29, 515–519 (2007). source
• Not checked yetcites [60] Takahashi, H. & Craig, A. M. Protein tyrosine phosphatases PTPδ, PTPσ, and LAR: presynaptic hubs for synapse organization. Trends Neurosci. 36, 522–534 (2013). source

In the paper

“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”

What the sources say

• Not checked yetcites [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). source
• Not checked yetcites [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). source
• Not checked yetcites [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). source

In the paper

“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.”

In the paper

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

In the paper

“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.”

In the paper

“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.”

In the paper

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

In the paper

“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.”

What the sources say

• Not checked yetcites [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. source

In the paper

“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.”

In the paper

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

What the sources say

• Not checked yetcites [53] Deng, Y. & Tsao, B. P. Genetic susceptibility to systemic lupus erythematosus in the genomic era. Nat. Rev. Rheumatol. 6, 683–692 (2010). source

In the paper

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

What the sources say

• Not checked yetcites [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). source

In the paper

“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”

What the sources say

• Not checked yetcites [48] Gough, S. C. & Simmonds, M. J. The HLA region and autoimmune disease: associations and mechanisms of action. Curr. Genom. 8, 453–465 (2007). source

In the paper

“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.”

What the sources say

• Not checked yetcites [55] Careaga, M. & Ashwood, P. Autism spectrum disorders: from immunity to behavior. Methods Mol. Biol. 934, 219–240 (2012). source
• Not checked yetcites [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). source

In the paper

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

In the paper

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

What the sources say

• Not checked yetcites [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). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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. source
• Not checked yetcites [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. source

In the paper

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

What the sources say

• Not checked yetcites [57] Sanders, S. J. et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485, 237–241 (2012). source
• Not checked yetcites [58] Sauna, Z. E. & Kimchi-Sarfaty, C. Understanding the contribution of synonymous mutations to human disease. Nat. Rev. Genet. 12, 683–691 (2011). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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. source

In the paper

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

What the sources say

• Not checked yetcites [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. source

In the paper

“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.”

What the sources say

• Not checked yetcites [68] Iaccarino, L. et al. Polarization of TH2 response is decreased during pregnancy in systemic lupus erythematosus. Reumatismo 64, 314–320 (2012). source

In the paper

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

In the paper

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

What the sources say

• Not checked yetcites [48] Gough, S. C. & Simmonds, M. J. The HLA region and autoimmune disease: associations and mechanisms of action. Curr. Genom. 8, 453–465 (2007). source

In the paper

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

What the sources say

• Not checked yetcites [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). source

In the paper

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

In the paper

“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.”

In the paper

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

What the sources say

• Not checked yetcites [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). source

In the paper

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

In the paper

“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.”

In the paper

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

What the sources say

• Not checked yetcites [85] Patterson, P. H. Maternal infection and immune involvement in autism. Trends Mol. Med. 17, 389–394 (2011). source
• Not checked yetcites [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. source
• Not checked yetcites [87] Chess, S. Follow-up report on autism in congenital rubella. J. Autism Child. Schizophr. 7, 69–81 (1977). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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. source

In the paper

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

What the sources say

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

In the paper

“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.”

What the sources say

• Not checked yetcites [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). source
• Not checked yetcites [99] Shi, L. et al. Activation of the maternal immune system alters cerebellar development in the offspring. Brain Behav. Immun. 23, 116–123 (2009). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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). source

In the paper

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

What the sources say

• Not checked yetcites [123] Napolioni, V. et al. Plasma cytokine profiling in sibling pairs discordant for autism spectrum disorder. J. Neuroinflammation 10, 38 (2013). source
• Not checked yetcites [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). source

In the paper

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

In the paper

“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.”

What the sources say

• Not checked yetcites [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). source

In the paper

“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.”

What the sources say

• Not checked yetcites [121] Ashwood, P. et al. Associations of impaired behaviors with elevated plasma chemokines in autism spectrum disorders. J. Neuroimmunol. 232, 196–199 (2011). source

In the paper

“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.”

What the sources say

• Not checked yetcites [94] Patterson, P. H. Maternal infection: window on neuroimmune interactions in fetal brain development and mental illness. Curr. Opin. Neurobiol. 12, 115–118 (2002). source

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [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). source
• Not checked yetcites [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). source
• Not checked yetcites [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). source
• Not checked yetcites [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). source
• Not checked yetcites [108] Singer, H. S. et al. Antibrain antibodies in children with autism and their unaffected siblings. J. Neuroimmunol. 178, 149–155 (2006). source
• Not checked yetcites [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). source
• Not checked yetcites [110] Singh, V. K. & Rivas, W. H. Prevalence of serum antibodies to caudate nucleus in autistic children. Neurosci. Lett. 355, 53–56 (2004). source
• Not checked yetcites [111] Silva, S. C. et al. Autoantibody repertoires to brain tissue in autism nuclear families. J. Neuroimmunol. 152, 176–182 (2004). source
• Not checked yetcites [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). source

In the paper

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

What the sources say

• Not checked yetcites [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). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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. source
• Not checked yetcites [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). source

In the paper

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

In the paper

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

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [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. source

In the paper

“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.”

What the sources say

• Not checked yetcites [152] Finegold, S. M. Desulfovibrio species are potentially important in regressive autism. Med. Hypotheses 77, 270–274 (2011). source
• Not checked yetcites [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). source

In the paper

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

In the paper

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

In the paper

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

What the sources say

• Not checked yetcites [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). source
• Not checked yetcites [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. source

In the paper

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

What the sources say

• Not checked yetcites [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). source

In the paper

“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.”

In the paper

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

In the paper

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

In the paper

“ameliorates stereotypic and anxiety-like behaviour”

What the sources say

• Not checked yetcites [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). source

In the paper

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

In the paper

“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.”

What the sources say

• Not checked yetcites [139] Tetreault, N. A. et al. Microglia in the cerebral cortex in autism. J. Autism Dev. Disord. 42, 2569–2584 (2012). source
• Not checked yetcites [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). source
• Not checked yetcites [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). source

In the paper

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

In the paper

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

What the sources say

• Not checked yetcites [149] Salzman, N. H. Microbiota–immune system interaction: an uneasy alliance. Curr. Opin. Microbiol. 14, 99–105 (2011). source
• Not checked yetcites [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). source
• Not checked yetcites [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). source

In the paper

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

In the paper

“improves sensorimotor gating”

What the sources say

• Not checked yetcites [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). source

In the paper

“rectifies microbiota imbalances”

What the sources say

• Not checked yetcites [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). source

In the paper

“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.”

In the paper

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

What the sources say

• Not checked yetcites [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). source

In the paper

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

In the paper

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

What the sources say

• Not checked yetcites [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). source
• Not checked yetcites [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). source

In the paper

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

What the sources say

• Not checked yetcites [172] Goshen, I. & Yirmiya, R. Interleukin-1 (IL-1): a central regulator of stress responses. Front. Neuroendocrinol. 30, 30–45 (2009). source
• Not checked yetcites [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). source

In the paper

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

What the sources say

• Not checked yetcites [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). source

In the paper

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

What the sources say

• Not checked yetcites [174] Pribiag, H. & Stellwagen, D. Neuroimmune regulation of homeostatic synaptic plasticity. Neuropharmacology 78, 13–22 (2014). source

In the paper

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

What the sources say

• Not checked yetcites [168] Yoshida, T. et al. Interleukin-1 receptor accessory protein organizes neuronal synaptogenesis as a cell adhesion molecule. J. Neurosci. 32, 2588–2600 (2012). source
• Not checked yetcites [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). source

In the paper

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

What the sources say

• Not checked yetcites [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). source

In the paper

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

What the sources say

• Not checked yetcites [168] Yoshida, T. et al. Interleukin-1 receptor accessory protein organizes neuronal synaptogenesis as a cell adhesion molecule. J. Neurosci. 32, 2588–2600 (2012). source
• Not checked yetcites [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). source

In the paper

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

What the sources say

• Not checked yetcites [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). source
• Not checked yetcites [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). source

In the paper

“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.”

In the paper

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

What the sources say

• Not checked yetcites [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). source

In the paper

“deficits in associative memory168,169”

What the sources say

• Not checked yetcites [168] Yoshida, T. et al. Interleukin-1 receptor accessory protein organizes neuronal synaptogenesis as a cell adhesion molecule. J. Neurosci. 32, 2588–2600 (2012). source
• Not checked yetcites [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). source

In the paper

“modulates hippocampal synaptic function185,187”

What the sources say

• Not checked yetcites [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). source
• Not checked yetcites [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). source

In the paper

“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”

In the paper

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

What the sources say

• Not checked yetcites [159] Finegold, S. M., Downes, J. & Summanen, P. H. Microbiology of regressive autism. Anaerobe 18, 260–262 (2012). source
• Not checked yetcites [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. source

In the paper

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

What the sources say

• Not checked yetcites [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). source

In the paper

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

In the paper

“enhances hippocampal long-term potentiation188”

What the sources say

• Not checked yetcites [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). source

In the paper

“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.”

What the sources say

• Not checked yetcites [162] Goines, P. E. & Ashwood, P. Cytokine dysregulation in autism spectrum disorders (ASD): possible role of the environment. Neurotoxicol. Teratol. 36, 67–81 (2013). source
• Not checked yetcites [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). source
• Not checked yetcites [164] Gambino, F. et al. IL1RAPL1 controls inhibitory networks during cerebellar development in mice. Eur. J. Neurosci. 30, 1476–1486 (2009). source
• Not checked yetcites [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). source
• Not checked yetcites [166] Yoshida, T. & Mishina, M. Zebrafish orthologue of mental retardation protein IL1RAPL1 regulates presynaptic differentiation. Mol. Cell. Neurosci. 39, 218–228 (2008). source
• Not checked yetcites [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). source
• Not checked yetcites [168] Yoshida, T. et al. Interleukin-1 receptor accessory protein organizes neuronal synaptogenesis as a cell adhesion molecule. J. Neurosci. 32, 2588–2600 (2012). source

In the paper

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

What the sources say

• Not checked yetcites [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). source
• Not checked yetcites [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). source

In the paper

“increases the number of dendritic spines186”

What the sources say

• Not checked yetcites [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). source

In the paper

“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”

What the sources say

• Not checked yetcites [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). source
• Not checked yetcites [216] Paolicelli, R. C. et al. Synaptic pruning by microglia is necessary for normal brain development. Science 333, 1456–1458 (2011). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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). source

In the paper

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

In the paper

“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”

What the sources say

• Not checked yetcites [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). source

In the paper

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

In the paper

“MEF2 negatively regulates the establishment of hippocampal connections201”

What the sources say

• Not checked yetcites [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). source

In the paper

“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.”

What the sources say

• Not checked yetcites [115] Goines, P. et al. Autoantibodies to cerebellum in children with autism associate with behavior. Brain Behav. Immun. 25, 514–523 (2011). source
• Not checked yetcites [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). source
• Not checked yetcites [209] Ebert, D. H. & Greenberg, M. E. Activity-dependent neuronal signalling and autism spectrum disorder. Nature 493, 327–337 (2013). source
• Not checked yetcites [210] Morgan, J. T. et al. Abnormal microglial-neuronal spatial organization in the dorsolateral prefrontal cortex in autism. Brain Res. 1456, 72–81 (2012). source

In the paper

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

What the sources say

• Not checked yetcites [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). source
• Not checked yetcites [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. source

In the paper

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

What the sources say

• Not checked yetcites [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. source
• Not checked yetcites [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). source
• Not checked yetcites [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). source

In the paper

“are also associated with ASD risk through genetic mutations”

In the paper

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

What the sources say

• Not checked yetcites [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. source
• Not checked yetcites [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). source
• Not checked yetcites [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). source

In the paper

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

In the paper

“negatively regulates the initial establishment of cortical connections”

What the sources say

• Not checked yetcites [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). source
• Not checked yetcites [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. source

In the paper

“MEF2 interacts with FMRP to regulate glutamatergic synaptic function206”

What the sources say

• Not checked yetcites [206] Parikshak, N. N. et al. Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism. Cell 155, 1008–1021 (2013). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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. source
• Not checked yetcites [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). source
• Not checked yetcites [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). source

In the paper

“regulate neurogenesis through phagocytosis of neural precursor cells”

What the sources say

• Not checked yetcites [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. source
• Not checked yetcites [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). source
• Not checked yetcites [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). source

In the paper

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

What the sources say

• Not checked yetcites [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). source
• Not checked yetcites [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. source

In the paper

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

In the paper

“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 paper

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

What the sources say

• Not checked yetcites [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). source
• Not checked yetcites [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. source

In the paper

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

In the paper

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

What the sources say

• Not checked yetcites [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). source

In the paper

“deficits in functional connectivity across brain regions”

What the sources say

• Not checked yetcites [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). source
• Not checked yetcites [216] Paolicelli, R. C. et al. Synaptic pruning by microglia is necessary for normal brain development. Science 333, 1456–1458 (2011). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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). source
• Not checked yetcites [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). source

In the paper

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

What the sources say

• Not checked yetcites [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). source
• Not checked yetcites [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). source

In the paper

“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”

What the sources say

• Not checked yetcites [131] Plioplys, A. V., Greaves, A., Kazemi, K. & Silverman, E. Lymphocyte function in autism and Rett syndrome. Neuropsychobiology 29, 12–16 (1994). source
• Not checked yetcites [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). source

In the paper

“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.”

In the paper

“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.”

In the paper

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

In the paper

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

In the paper

“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).”

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [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). source

In the paper

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

In the paper

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

What the sources say

• Not checked yetcites [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). source
• Not checked yetcites [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). source

In the paper

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

In the paper

“and ASD-like behaviours215,216”

What the sources say

• Not checked yetcites [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). source
• Not checked yetcites [216] Paolicelli, R. C. et al. Synaptic pruning by microglia is necessary for normal brain development. Science 333, 1456–1458 (2011). source

In the paper

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

What the sources say

• Not checked yetcites [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). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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). source

In the paper

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

What the sources say

• Not checked yetcites [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. source
• Not checked yetcites [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). source

In the paper

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

What the sources say

• Not checked yetcites [226] Streit, W. J. & Xue, Q. S. Life and death of microglia. J. Neuroimmune Pharmacol. 4, 371–379 (2009). source

In the paper

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

In the paper

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

What the sources say

• Not checked yetcites [222] Schafer, D. P. et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74, 691–705 (2012). source

In the paper

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

What the sources say

• Not checked yetcites [223] Bialas, A. R. & Stevens, B. TGF-β signaling regulates neuronal C1q expression and developmental synaptic refinement. Nat. Neurosci. 16, 1773–1782 (2013). source

In the paper

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

What the sources say

• Not checked yetcites [239] Posey, D. J. et al. A pilot study of D-cycloserine in subjects with autistic disorder. Am. J. Psychiatry 161, 2115–2117 (2004). source
• Not checked yetcites [240] Sandler, R. H. et al. Short-term benefit from oral vancomycin treatment of regressive-onset autism. J. Child Neurol. 15, 429–435 (2000). source
• Not checked yetcites [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).

In the paper

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

What the sources say

• Not checked yetcites [219] Truedsson, L., Bengtsson, A. A. & Sturfelt, G. Complement deficiencies and systemic lupus erythematosus. Autoimmunity 40, 560–566 (2007). source

In the paper

“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.”

What the sources say

• Not checked yetcites [227] Costa-Mattioli, M. & Monteggia, L. M. mTOR complexes in neurodevelopmental and neuropsychiatric disorders. Nat. Neurosci. 16, 1537–1543 (2013). source
• Not checked yetcites [228] Takei, N. & Nawa, H. mTOR signaling and its roles in normal and abnormal brain development. Front. Mol. Neurosci. 7, 28 (2014). source