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

In the paper

“Increasing evidence points to a central role for immune dysregulation in autism spectrum disorder (ASD).”

• Also stated in: § Abstract · hedged

  “Although accumulating evidence indicates that immune dysregulation increases the risk for, and contributes to the pathophysiology of, ASD”

In the paper

“Recent reports have also highlighted the strong contribution of copy number variants (CNVs) to ASD, accounting for 7–20% of cases of this disorder23–25.”

What the sources say

• Not checked yetcites [23] Marshall, C. R. et al. Structural variation of chromosomes in autism spectrum disorder. Am. J. Hum. Genet. 82, 477–488 (2008). source
• Not checked yetcites [24] O'Roak, B. J. & State, M. W. Autism genetics: strategies, challenges, and opportunities. Autism Res. 1, 4–17 (2008). source
• Not checked yetcites [25] Luo, R. et al. Genome-wide transcriptome profiling reveals the functional impact of rare de novo and recurrent CNVs in autism spectrum disorders. Am. J. Hum. Genet. 91, 38–55 (2012). source

In the paper

“recent reports have suggested that the environment may have a much larger role in causing ASD than had been initially proposed4,5.”

What the sources say

• 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 [5] Rosenberg, R. E. et al. Characteristics and concordance of autism spectrum disorders among 277 twin pairs. Arch. Pediatr. Adolesc. Med. 163, 907–914 (2009). source

In the paper

“Instead, ASD seems to be associated with a large number of genetic mutations, including possibly hundreds of rare causal variants and over one hundred common variants of small effect18,19.”

What the sources say

• Not checked yetcites [18] Gaugler, T. et al. Most genetic risk for autism resides with common variation. Nat. Genet. 46, 881–885 (2014). source
• Not checked yetcites [19] Berg, J. M. & Geschwind, D. H. Autism genetics: searching for specificity and convergence. Genome Biol. 13, 247 (2012). source

In the paper

“in 1992, it was estimated that 1 in 500 children in the USA had ASD, but by 2007 this figure had been adjusted to 1 in 110, and current estimates have reached the alarming level of 1 in 68 US children and 1 in 42 boys2.”

What the sources say

• Not checked yetcites [2] Developmental Disabilities Monitoring Network Surveillance Year 2010 Principal Investigators & Centers for Disease Control and Prevention (CDC). Prevalence of autism spectrum disorder among children aged 8 years — autism and developmental disabilities monitoring network, 11 Sites, United States, 2010. MMWR Surveill. Summ. 63, 1–21 (2014).

In the paper

“there is evidence of ongoing immune dysregulation in individuals with ASD and animal models of this disorder”

In the paper

“Like ASD, childhood disorders of the immune system such as asthma, life-threatening food allergies and autoimmune disorders have reached epidemic levels over the past two decades9,10.”

What the sources say

• Not checked yetcites [9] Jackson, K. D., Howie, L. D. & Akinbami, L. J. Trends in allergic conditions among children: United States, 1997–2011. NCHS Data Brief 121, 1–8 (2013).
• Not checked yetcites [10] Akinbami, L. J. et al. Trends in asthma prevalence, health care use, and mortality in the United States, 2001–2010. NCHS Data Brief 94, 1–8 (2012).

In the paper

“A MET variant that includes a common G-to-C single nucleotide polymorphism (SNP) in its promoter (the rs1858830 ‘C’ allele) is associated with decreased MET signalling in the temporal lobe and ASD27–29.”

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 [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
• Not checked yetcites [29] Jackson, P. B. et al. Further evidence that the rs1858830 C variant in the promoter region of the MET gene is associated with autistic disorder. Autism Res. 2, 232–236 (2009). source

In the paper

“variants in all three classes of MHC genes have been reported to enhance ASD risk, namely the MHC class I HLA-A2 haplotype, the MHC class II DRβ1 alleles and the complement C4B null allele in the MHC class III region47.”

What the sources say

• 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

“These syndromes are caused by mutations in single genes (fragile X mental retardation protein 1 (FMR1), methyl-CpG-binding protein 2 (MECP2), TSC1 or TSC2, neurofibromin 1 (NF1) and PTEN, respectively) and account for 5–7% of ASD cases20–22.”

What the sources say

• Not checked yetcites [20] Santini, E. & Klann, E. Reciprocal signaling between translational control pathways and synaptic proteins in autism spectrum disorders. Sci. Signal. 7, re10 (2014). source
• Not checked yetcites [21] Franz, D. N. & Weiss, B. D. Molecular therapies for tuberous sclerosis and neurofibromatosis. Curr. Neurol. Neurosci. Rep. 12, 294–301 (2012). source
• Not checked yetcites [22] Schaaf, C. P. & Zoghbi, H. Y. Solving the autism puzzle a few pieces at a time. Neuron 70, 806–808 (2011). source

In the paper

“As this time frame is too short for genetic changes at a population level to have had an appreciable impact on the prevalence of these conditions, these increases must have an environmental catalyst.”

In the paper

“the HLA associations are not specific to ASD; they are also associated with other neurodevelopmental disorders and autoimmune disorders, including rheumatoid arthritis and SLE, which occur at higher rates in the relatives of individuals 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

“paternal immune disorders and a general familial history of immune disorders in the absence of maternal immune conditions also appear to contribute, suggesting a heritable component for this autoimmune association48,64.”

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 [64] McDougle, C. J. et al. Toward an immune-mediated subtype of autism spectrum disorder. Brain Res. 1617, 72–92 (2014). source

In the paper

“Some antibodies have potent co-agonist properties, leading to increased calcium influx through NMDARs and eventually neuronal death71, whereas other clones with slightly different epitopes are not pathogenic and yet others cross-react with C1q, a component of the complement cascade72.”

What the sources say

• Not checked yetcites [71] Lee, J. Y. et al. Neurotoxic autoantibodies mediate congenital cortical impairment of offspring in maternal lupus. Nat. Med. 15, 91–96 (2009). source
• Not checked yetcites [72] Zhang, J., Jacobi, A. M., Wang, T. & Diamond, B. Pathogenic autoantibodies in systemic lupus erythematosus are derived from both self-reactive and non-self-reactive B cells. Mol. Med. 14, 675–681 (2008). source

In the paper

“Injecting NMDA receptor (NMDAR)-specific autoantibodies derived from the blood of patients with SLE into a pregnant mouse alters brain development and impairs cognitive behaviour in the offspring70.”

What the sources say

• Not checked yetcites [70] Brimberg, L., Sadiq, A., Gregersen, P. K. & Diamond, B. Brain-reactive IgG correlates with autoimmunity in mothers of a child with an autism spectrum disorder. Mol. Psychiatry 18, 1171–1177 (2013). source

In the paper

“recent estimates suggest that between 50 and 60% of the risk for ASD is unaccounted for, which implies that environmental factors or gene–environment interactions contribute substantially to the risk for this disorder4,16.”

What the sources say

• 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

“although 30–60% of individuals with SLE possess NMDAR-specific autoantibodies, each antibody clone has unique physiological effects.”

In the paper

“these offspring have larger brains especially in the frontal lobes, which may be consistent with the aberrant white matter tracts found in a subset of young children with ASD78–81.”

What the sources say

• 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
• Not checked yetcites [79] Bauman, M. D. et al. Maternal antibodies from mothers of children with autism alter brain growth and social behavior development in the rhesus monkey. Transl Psychiatry 3, e278 (2013). source
• Not checked yetcites [80] Ben Bashat, D. et al. Accelerated maturation of white matter in young children with autism: a high b value DWI study. Neuroimage 37, 40–47 (2007). source
• Not checked yetcites [81] Billeci, L., Calderoni, S., Tosetti, M., Catani, M. & Muratori, F. White matter connectivity in children with autism spectrum disorders: a tract-based spatial statistics study. BMC Neurol. 12, 148 (2012). source

In the paper

“These antibodies recognize fetal brain proteins of 37, 39 and 73kD and may confer specific pathophysiology (such as abnormal brain enlargement, self-injurious behavior and greater language deficits) depending on the antibody clone75.”

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

“These proteins are immuexpressed in the developing brain, where they have roles in growth cone motility, dendritic morphology, cellular stress and metabolism, and/or transcription regulation76.”

What the sources say

• Not checked yetcites [76] Braunschweig, D. & Van de Water, J. Maternal autoantibodies in autism. Arch. Neurol. 69, 693–699 (2012). source

In the paper

“such disorders also increase the risk of intellectual disability and several other neurodevelopmental disorders, suggesting that immune disorders generally increase the vulnerability of the developing brain to developmental defects66.”

What the sources say

• Not checked yetcites [66] Kohane, I. S. et al. The co-morbidity burden of children and young adults with autism spectrum disorders. PLoS ONE 7, e33224 (2012). source

In the paper

“This prediction may fit with the recurrent observation that a subset of girls with ASD show more social communication impairments and lower cognitive abilities than boys with matched low IQs74.”

What the sources say

• Not checked yetcites [74] Wang, L. et al. Female mouse fetal loss mediated by maternal autoantibody. J. Exp. Med. 209, 1083–1089 (2012). The first study to demonstrate a molecular mechanism whereby maternally derived autoantibodies exert sex-specific effects. source

In the paper

“the effects of these anti-NMDAR antibodies are sex-specific in mice: they cause death through apoptosis of NR2A-expressing neurons, which are enriched in the brainstem of female, but not male, fetuses73.”

What the sources say

• Not checked yetcites [73] Franchin, G. et al. Anti-DNA antibodies cross-react with C1q. J. Autoimmun. 44, 34–39 (2013). source

In the paper

“Elevations in IL-1β, IL-6, IL-8, IL-12p40 are specifically associated with a regressive form of ASD and more impaired stereotypical behaviours, and elevations in the chemokines C-C motif chemokine 2 (CCL2), CCL5 and eotaxin are associated with higher aberrant behaviour scores and more impaired development120.”

What the sources say

• Not checked yetcites [120] Ashwood, P. et al. Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome. Brain Behav. Immun. 25, 40–45 (2011). source

In the paper

“These changes include increases in IL-1β, IL-6, IL-8, IL-12p40 and granulocyte-macrophage colony-stimulating factor (GM-CSF), which are generally considered to be ‘pro-inflammatory’, and decreases in IL-10 and transforming growth factor-β (TGF-β), which are generally considered to be ‘anti-inflammatory’115–120.”

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 [116] Vargas, D. L., Nascimbene, C., Krishnan, C., Zimmerman, A. W. & Pardo, C. A. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann. Neurol. 57, 67–81 (2005). source
• Not checked yetcites [117] Molloy, C. A. et al. Elevated cytokine levels in children with autism spectrum disorder. J. Neuroimmunol. 172, 198–205 (2006). source
• 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
• Not checked yetcites [119] Ashwood, P. et al. Decreased transforming growth factor β1 in autism: a potential link between immune dysregulation and impairment in clinical behavioral outcomes. J. Neuroimmunol. 204, 149–153 (2008). source
• Not checked yetcites [120] Ashwood, P. et al. Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome. Brain Behav. Immun. 25, 40–45 (2011). source

In the paper

“These data point to a specific temporal window of immune activation during the first trimester of fetal development and the association with a specific duration of fever suggests that an immune activation threshold must be surpassed to confer risk of developing ASD.”

In the paper

“Both mouse and non-human primate MIA offspring also exhibit deficiencies in sensorimotor gating and increased anxiety, co-morbidities observed in a subset of individuals with ASD.”

In the paper

“Thus, the presence of maternally derived brain-directed autoantibodies in early development is associated with a higher incidence of ASD and specific pathophysiology.”

In the paper

“a single low dose intraventricular injection at mid-gestation of IgG-ASD in mice causes increases in repetitive behaviours and alterations in social approach behaviour83.”

What the sources say

• Not checked yetcites [83] Singer, H. S. et al. Prenatal exposure to antibodies from mothers of children with autism produces neurobehavioral alterations: a pregnant dam mouse model. J. Neuroimmunol. 211, 39–48 (2009). source

In the paper

“individuals with ASD have an increased incidence of autoimmune disorders, allergy and asthma65,103.”

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
• Not checked yetcites [103] Onore, C., Careaga, M. & Ashwood, P. The role of immune dysfunction in the pathophysiology of autism. Brain Behav. Immun. 26, 383–392 (2012). source

In the paper

“Because unaffected siblings of people with ASD harbor similar autoantibody profiles107,113, brain-directed autoantibodies may not be generally predictive of ASD and may instead represent secondary autoimmune processes or evidence of a previous CNS injury.”

What the sources say

• 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 [113] Wills, S. et al. Detection of autoantibodies to neural cells of the cerebellum in the plasma of subjects with autism spectrum disorders. Brain Behav. Immun. 23, 64–74 (2009). source

In the paper

“Data from more than a million children born between the years of 1980 and 2005 revealed an almost 3-fold increase in the rate of ASD in children born to mothers who were hospitalized for viral infection in the first trimester and in children of women who experienced an episode of fever lasting a week or more before gestational week 3290,91.”

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
• Not checked yetcites [91] Atladottir, H. O. et al. Maternal infection requiring hospitalization during pregnancy and autism spectrum disorders. J. Autism Dev. Disord. 40, 1423–1430 (2010). source

In the paper

“maternal infection during pregnancy has been associated with other developmental disorders as well, including schizophrenia and mood disorders93.”

What the sources say

• Not checked yetcites [93] Missault, S. et al. The risk for behavioural deficits is determined by the maternal immune response to prenatal immune challenge in a neurodevelopmental model. Brain Behav. Immun. 42, 138–46 (2014). source

In the paper

“peripheral cytokine profiles in individuals with ASD and their unaffected siblings are similar122, suggesting that these changes alone may not be sufficient to cause ASD.”

What the sources say

• Not checked yetcites [122] Abdallah, M. W. et al. Neonatal levels of cytokines and risk of autism spectrum disorders: an exploratory register-based historic birth cohort study utilizing the Danish Newborn Screening Biobank. J. Neuroimmunol. 252, 75–82 (2012). source

In the paper

“most maternal infections that fall within this time-window and are above this threshold do not lead to ASD in offspring, suggesting that the immune status of the mother and the immuno-genetic background of the developing child may both be critical factors in determining outcome.”

In the paper

“a recent study associated specific autoantibodies recognizing cerebellar targets of 45 and 65 kDa with ASD diagnosis, impaired behavioural scores, and lower cognitive and adaptive function in comparison to children without the antibodies114.”

What the sources say

• Not checked yetcites [114] Morris, C. M., Zimmerman, A. W. & Singer, H. S. Childhood serum anti-fetal brain antibodies do not predict autism. Pediatr. Neurol. 41, 288–290 (2009). source

In the paper

“Poly(I:C) injection at mid-gestation in mice and non-human primates generates offspring that display all (in mice) or some (in non-human primates) of the three core behavioural symptoms of ASD95–97.”

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 [96] Smith, S. E., Li, J., Garbett, K., Mirnics, K. & Patterson, P. H. Maternal immune activation alters fetal brain development through interleukin-6. J. Neurosci. 27, 10695–10702 (2007). source
• Not checked yetcites [97] Malkova, N. V., Yu, C. Z., Hsiao, E. Y., Moore, M. J. & Patterson, P. H. Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism. Brain Behav. Immun. 26, 607–616 (2012). The first report to demonstrate face and construct validity of the poly(I:C) rodent model of MIA for the three core symptoms of ASD. source

In the paper

“This discrepancy may represent a critical difference in the timing of exposure, with insults during gestation having greater pathogenic impact than the limited potential for exposure after the BBB is formed and brain architecture is more developed.”

In the paper

“Thus, these results do not fit the classic definition of neural inflammation and suggest caution in interpreting changes in cytokines at one time-point as indicative of an inflammatory process (BOX 3)145.”

What the sources say

• Not checked yetcites [145] Garay, P. A., Hsiao, E. Y., Patterson, P. H. & McAllister, A. K. Maternal immune activation causes age- and region-specific changes in brain cytokines in offspring throughout development. Brain Behav. Immun. 31, 54–68 (2013). The first study to show age- and region-specific immune changes in the brains of offspring from MIA rodents. source

In the paper

“These changes do not correlate with changes in serum cytokine levels and are not accompanied by changes in BBB permeability or immune cell infiltration into the brain parenchyma.”

In the paper

“One of the networks of genes is associated with synaptic function and is down-regulated, whereas the other module contains immune-related genes and is up-regulated in ASD.”

In the paper

“microglia in the dorsolateral prefrontal cortex exhibit increased MHCII expression (a marker of activation), activated morphology (amoeboid shape), and increased density137,138.”

What the sources say

• 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 [138] Morgan, J. T. et al. Microglial activation and increased microglial density observed in the dorsolateral prefrontal cortex in autism. Biol. Psychiatry 68, 368–376 (2010). source

In the paper

“A broad spectrum of cytokines are elevated in the fetal brain hours after poly(I:C) injection in pregnant mice142,143 and many of these cytokines remain chronically altered in the brains of offspring throughout postnatal development and into adulthood144.”

What the sources say

• Not checked yetcites [142] Zimmerman, A. W. et al. Cerebrospinal fluid and serum markers of inflammation in autism. Pediatr. Neurol. 33, 195–201 (2005). source
• Not checked yetcites [143] Arrode-Bruses, G. & Bruses, J. L. Maternal immune activation by poly I:C induces expression of cytokines IL-1β and IL-13, chemokine MCP-1 and colony stimulating factor VEGF in fetal mouse brain. J. Neuroinflammation 9, 83 (2012). source
• Not checked yetcites [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). source

In the paper

“Taken together, these results indicate ongoing dysregulation of the immune system and altered expression of immune molecules in the CNS in ASD and in mouse models of MIA.”

In the paper

“Offspring from the poly (I:C) mouse model of MIA exhibit gastrointestinal changes that are also found in some humans with ASD155,156, including increased intestinal permeability and abnormal intestinal cytokine profiles157.”

What the sources say

• Not checked yetcites [155] Mazmanian, S. K., Liu, C. H., Tzianabos, A. O. & Kasper, D. L. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 122, 107–118 (2005). source
• Not checked yetcites [156] de Magistris, L. et al. Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. J. Pediatr. Gastroenterol. Nutr. 51, 418–424 (2010). source
• 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

“Monocytes isolated from individuals with ASD also exhibit impaired responses to challenge: they secrete excess pro-inflammatory cytokines following challenge with ligands for Toll-like receptor 4 (TLR-4; a receptor that is responsive to bacterial pathogens) but show reduced production of these same cytokines when challenged with ligands for TLR-9 (a receptor that is responsive to viral pathogens)”

What the sources say

• 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
• Not checked yetcites [125] Enstrom, A. M., Onore, C. E., Van de Water, J. A. & Ashwood, P. Differential monocyte responses to TLR ligands in children with autism spectrum disorders. Brain Behav. Immun. 24, 64–71 (2010). source

In the paper

“T-cells from adult MIA offspring secrete excess pro-inflammatory cytokines when challenged and show a bias toward TH1 and TH17 phenotypes100,132,133.”

What the sources say

• Not checked yetcites [100] Amaral, D. G., Schumann, C. M. & Nordahl, C. W. Neuroanatomy of autism. Trends Neurosci. 31, 137–145 (2008). 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
• Not checked yetcites [133] Hsiao, E. Y., McBride, S. W., Chow, J., Mazmanian, S. K. & Patterson, P. H. Modeling an autism risk factor in mice leads to permanent immune dysregulation. Proc. Natl Acad. Sci. USA 109, 12776–12781 (2012). source

In the paper

“Although cytokines are generally increased at birth and in the adult brain, levels of many cytokines are decreased in frontal cortical regions during peak periods of synaptogenesis and plasticity144.”

What the sources say

• Not checked yetcites [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). source

In the paper

“Collectively, these findings suggest that MIA induces an irregular immune phenotype that persists into adulthood in rodents, as in ASD, but is distinct in nature from the T-cell response profile in ASD.”

In the paper

“Since the immune system is primarily tasked with tissue repair and homeostatic processes, these alterations could represent compensatory responses to dysfunctional network activity and cellular stress.”

In the paper

“The idea that therapies directed at altering the gut microbiota may regulate immune function and rescue ASD-related phenotypes has received support from animal models of ASD.”

In the paper

“Certain microbiota signatures in the gut inhibit the differentiation of brain-supportive T cell populations, whereas administration of Bacteriodes fragilis (B. fragilis) restores the proper balance of T cell populations in mice154.”

What the sources say

• Not checked yetcites [154] Ishikawa, H. et al. Effect of intestinal microbiota on the induction of regulatory CD25+ CD4+ T cells. Clin. Exp. Immunol. 153, 127–135 (2008). source

In the paper

“T-cell skewing to a TH2 phenotype (which is considered ‘anti-inflammatory’ and found in a subset of the ASD population) has been associated with better cognitive and adaptive behaviour126,131, but in another study, elevated levels of the classic TH2 cytokine IL-4 have been associated with greater impairments in non-verbal communication119.”

What the sources say

• Not checked yetcites [126] Warren, R. P., Margaretten, N. C., Pace, N. C. & Foster, A. Immune abnormalities in patients with autism. J. Autism Dev. Disord. 16, 189–197 (1986). source
• 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 [119] Ashwood, P. et al. Decreased transforming growth factor β1 in autism: a potential link between immune dysregulation and impairment in clinical behavioral outcomes. J. Neuroimmunol. 204, 149–153 (2008). source

In the paper

“reporting elevations in GM-CSF, IL-6, IL-8, TNF-α and IFN-γ levels in the frontal cortex and in IL-6, TGF-β and MCP-1 levels in the anterior cingulate gyrus and cerebellum115,135,136.”

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 [135] Onore, C. E., Schwartzer, J. J., Careaga, M., Berman, R. F. & Ashwood, P. Maternal immune activation leads to activated inflammatory macrophages in offspring. Brain Behav. Immun. 38, 220–226 (2014). source
• Not checked yetcites [136] Li, X. et al. Elevated immune response in the brain of autistic patients. J. Neuroimmunol. 207, 111–116 (2009). source

In the paper

“myeloid cell populations from these animals are elevated and produce increased levels of IL-12p40 and CCL3, which is consistent with a pro-inflammatory immune profile132,134.”

What the sources say

• 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
• Not checked yetcites [134] Mandal, M. et al. Maternal immune stimulation during pregnancy shapes the immunological phenotype of offspring. Brain Behav. Immun. 33, 33–45 (2013). source

In the paper

“circulating levels of CD4+ T cell populations are low, biased towards an anti-inflammatory (TH2) profile and exhibit a dysfunctional response to stimulation in individuals with ASD126–130.”

What the sources say

• Not checked yetcites [126] Warren, R. P., Margaretten, N. C., Pace, N. C. & Foster, A. Immune abnormalities in patients with autism. J. Autism Dev. Disord. 16, 189–197 (1986). source
• Not checked yetcites [127] Ashwood, P. et al. Altered T cell responses in children with autism. Brain Behav. Immun. 25, 840–849 (2011). source
• Not checked yetcites [128] Gupta, S., Aggarwal, S., Rashanravan, B. & Lee, T. Th1- and Th2-like cytokines in CD4+ and CD8+ T cells in autism. J. Neuroimmunol. 85, 106–109 (1998). source
• Not checked yetcites [129] Warren, R. P., Yonk, J., Burger, R. W., Odell, D. & Warren, W. L. DR-positive T cells in autism: association with decreased plasma levels of the complement C4B protein. Neuropsychobiology 31, 53–57 (1995). source
• Not checked yetcites [130] Stubbs, E. G. & Crawford, M. L. Depressed lymphocyte responsiveness in autistic children. J. Autism Child. Schizophr. 7, 49–55 (1977). The first report to identify immune cell abnormalities in individuals with ASD. source

In the paper

“oral treatment with B. fragilis restores intestinal permeability and serum cytokine levels”

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

“Cytokines and their receptors are expressed by neurons and glia throughout development and regulate a diverse array of physiological processes in brain development, plasticity and function159.”

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

In the paper

“STAT1 is also implicated in spatial learning177”

What the sources say

• Not checked yetcites [177] Tropea, D. et al. Gene expression changes and molecular pathways mediating activity-dependent plasticity in visual cortex. Nat. Neurosci. 9, 660–668 (2006). source

In the paper

“In the periphery, numerous cytokines signal through the janus kinase–signal transducer and activation of transcription (JAK–STAT) pathway, which comprises three mammalian JAK and seven STAT proteins175.”

What the sources say

• Not checked yetcites [175] Nagakura, I., Van Wart, A., Petravicz, J., Tropea, D. & Sur, M. STAT1 regulates the homeostatic component of visual cortical plasticity via an AMPA receptor-mediated mechanism. J. Neurosci. 34, 10256–10263 (2014). source

In the paper

“STAT1 is upregulated in the visual cortex following long-term mononuclear deprivation, where it regulates AMPA receptor surface expression and synaptic function174,176.”

What the sources say

• Not checked yetcites [174] Pribiag, H. & Stellwagen, D. Neuroimmune regulation of homeostatic synaptic plasticity. Neuropharmacology 78, 13–22 (2014). source
• Not checked yetcites [176] Murray, P. J. The JAK–STAT signaling pathway: input and output integration. J. Immunol. 178, 2623–2629 (2007). source

In the paper

“Findings from both epidemiological studies and animal models indicate that cytokine imbalances can disturb fetal development and/or chronically impair brain function161.”

What the sources say

• Not checked yetcites [161] Garay, P. A. & McAllister, A. K. Novel roles for immune molecules in neural development: implications for neurodevelopmental disorders. Front. Synaptic Neurosci. 2, 136 (2010). source

In the paper

“MHCI molecules have been implicated in ASD through genetic associations (described above) and as a downstream effector of MIA190.”

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

“Receptor binding activates the kinase function of JAK, which recruits and phosphorylates STAT. Upon STAT dimerization, the complex translocates to the nucleus, where it regulates the transcription of genes involved in cell growth, differentiation and function, and immune genes including those encoding MHCI molecules.”

What the sources say

• Not checked yetcites [175] Nagakura, I., Van Wart, A., Petravicz, J., Tropea, D. & Sur, M. STAT1 regulates the homeostatic component of visual cortical plasticity via an AMPA receptor-mediated mechanism. J. Neurosci. 34, 10256–10263 (2014). source

In the paper

“MET is expressed throughout the neocortex, hippocampus180, cerebellum181 and brainstem182, where it is enriched in excitatory pre- and post-synaptic compartments183.”

What the sources say

• Not checked yetcites [180] Nicolas, C. S. et al. The Jak/STAT pathway is involved in synaptic plasticity. Neuron 73, 374–390 (2012). source
• Not checked yetcites [181] Judson, M. C., Bergman, M. Y., Campbell, D. B., Eagleson, K. L. & Levitt, P. Dynamic gene and protein expression patterns of the autism-associated met receptor tyrosine kinase in the developing mouse forebrain. J. Comp. Neurol. 513, 511–531 (2009). source
• Not checked yetcites [182] Ieraci, A., Forni, P. E. & Ponzetto, C. Viable hypomorphic signaling mutant of the Met receptor reveals a role for hepatocyte growth factor in postnatal cerebellar development. Proc. Natl Acad. Sci. USA 99, 15200–15205 (2002). source

In the paper

“recent reports suggest that JAK–STAT signalling is important for normal brain functions and that cytokines regulate this signalling in neurons.”

In the paper

“IFN-γ enhances STAT1 expression, which reduces visual cortical plasticity174.”

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

“reduced MET expression, as seen in ASD, alters key neurodevelopmental processes and is associated with structural and functional alterations in ASD26.”

What the sources say

• Not checked yetcites [26] Peng, Y., Huentelman, M., Smith, C. & Qiu, S. MET receptor tyrosine kinase as an autism genetic risk factor. Int. Rev. Neurobiol. 113, 135–165 (2013). source

In the paper

“During development, microglia phagocytize debris from naturally-occurring cell death”

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

“MHCI molecules are found on all nucleated cells in the body, where they mediate the adaptive and innate immune responses.”

In the paper

“mediates the effects of MHCI on cortical connectivity in normal brain development and the MIA-induced deficit in synapse formation in newborn neurons190.”

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

“MEF2C haploinsufficiency syndrome is a recently discovered neurodevelopmental disorder that is characterized by autism-like behaviours, intellectual disability, high rates of epilepsy and abnormal movements202.”

What the sources say

• Not checked yetcites [202] Flavell, S. W. et al. Activity-dependent regulation of MEF2 transcription factors suppresses excitatory synapse number. Science 311, 1008–1012 (2006). source

In the paper

“this interaction controls the expression of protocadherin 10 (Pcdh10), which is another ASD-linked gene and is necessary for MEF2-mediated activity-dependent synapse elimination207.”

What the sources say

• Not checked yetcites [207] Zang, T. et al. Postsynaptic FMRP bidirectionally regulates excitatory synapses as a function of developmental age and MEF2 activity. Mol. Cell. Neurosci. 56, 39–49 (2013). source

In the paper

“they have recently been shown to have important roles in the normal brain211.”

What the sources say

• Not checked yetcites [211] Suzuki, K. et al. Microglial activation in young adults with autism spectrum disorder. JAMA Psychiatry 70, 49–58 (2013). source

In the paper

“In cortical pyramidal neurons, MHCI is present both pre- and post-synaptically at glutamatergic synapses, where its surface expression is tightly modulated by activity, therefore allowing it to regulate synaptic plasticity191,193–199.”

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 [193] Elmer, B. M. & McAllister, A. K. Major histocompatibility complex class I proteins in brain development and plasticity. Trends Neurosci. 35, 660–670 (2012). source
• Not checked yetcites [194] Lee, H. et al. Synapse elimination and learning rules co-regulated by MHC class I H2-Db. Nature 509, 195–200 (2014). source
• Not checked yetcites [195] Goddard, C. A., Butts, D. A. & Shatz, C. J. Regulation of CNS synapses by neuronal MHC class I. Proc. Natl Acad. Sci. USA 104, 6828–6833 (2007). source
• Not checked yetcites [196] Needleman, L. A., Liu, X. B., El-Sabeawy, F., Jones, E. G. & McAllister, A. K. MHC class I molecules are present both pre- and postsynaptically in the visual cortex during postnatal development and in adulthood. Proc. Natl Acad. Sci. USA 107, 16999–17004 (2010). source
• Not checked yetcites [197] Glynn, M. W. et al. MHCI negatively regulates synapse density during the establishment of cortical connections. Nat. Neurosci. 14, 442–451 (2011). source
• Not checked yetcites [198] Fourgeaud, L. et al. MHC class I modulates NMDA receptor function and AMPA receptor trafficking. Proc. Natl Acad. Sci. USA 107, 22278–22283 (2010). source
• Not checked yetcites [199] Huh, G. S. et al. Functional requirement for class I MHC in CNS development and plasticity. Science 290, 2155–2159 (2000). source

In the paper

“MEF2 transcription factors regulate gene expression in an activity-dependent manner, affecting the expression of many proteins that regulate synaptic plasticity and function during neural development200,201.”

What the sources say

• Not checked yetcites [200] Nelson, P. A. et al. MHC class I immune proteins are critical for hippocampus-dependent memory and gate NMDAR-dependent hippocampal long-term depression. Learn. Mem. 20, 505–517 (2013). source
• 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

“This pathway integrates signals from growth factors and hormones, neurotransmitters, cytokines, and stress mediators and involves cross-talk between two intracellular signaling cascades — RAS–ERK and phosphoinositide 3-kinase–AKT— that are essential in immune and neuronal function.”

In the paper

“the complement C4 gene lies within the MHC region and deficiencies in C4 are associated with ASD50,128,217.”

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 [128] Gupta, S., Aggarwal, S., Rashanravan, B. & Lee, T. Th1- and Th2-like cytokines in CD4+ and CD8+ T cells in autism. J. Neuroimmunol. 85, 106–109 (1998). source
• Not checked yetcites [217] Zhan, Y. et al. Deficient neuron–microglia signaling results in impaired functional brain connectivity and social behavior. Nat. Neurosci. 17, 400–406 (2014). source

In the paper

“In the immune system, mTOR integrates signals from the immune microenvironment to direct immune cell metabolism, differentiation and function, and is important for mounting an adaptive immune response229.”

What the sources say

• Not checked yetcites [229] Kassai, H. et al. Selective activation of mTORC1 signaling recapitulates microcephaly, tuberous sclerosis, and neurodegenerative diseases. Cell Rep. 7, 1626–1639 (2014). source

In the paper

“IGF-1, which ameliorates some behavioural and neuropathologies of Rett and 22q13 deletion syndrome, and is secreted by microglia, activates mTOR230.”

What the sources say

• Not checked yetcites [230] Powell, J. D., Pollizzi, K. N., Heikamp, E. B. & Horton, M. R. Regulation of immune responses by mTOR. Annu. Rev. Immunol. 30, 39–68 (2012). source

In the paper

“C1q typically complexes with other C1 proteins to activate the C3 convertase, which cleaves C3 into opsonizing fragments in the periphery220.”

What the sources say

• Not checked yetcites [220] Stevens, B. et al. The classical complement cascade mediates CNS synapse elimination. Cell 131, 1164–1178 (2007). A pioneering report of the complement cascade playing an unexpected part in synaptic pruning. source

In the paper

“Because TGF-β is increased in the CSF and postmortem brain tissue from individuals with ASD115, it is possible that these increases of TGF- β in ASD brains could cause and/or reflect compensatory or pathology-inducing alterations in synaptic pruning.”

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

In the paper

“Complement deficiency is also strongly linked to autoimmune disorders, especially SLE218.”

What the sources say

• Not checked yetcites [218] Odell, D. et al. Confirmation of the association of the C4B null allelle in autism. Hum. Immunol. 66, 140–145 (2005). source

In the paper

“many cytokine receptors found at the synapse typically activate mTOR signaling in the periphery, potentially causing phenotypes similar to monogenic forms of ASD.”

In the paper

“the signalling components for mTOR are present in neurons and are activated by a growing list of growth factors, guidance molecules and neurotransmitters227.”

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

In the paper

“In the peripheral immune system, the complement pathway mediates clearance of cellular debris and increases the degree of antibody binding to circulating bacteria and infected cells, thereby enhancing their destruction.”

In the paper

“One of these fragments, C3b, is thought to tag weak synapses in the CNS. These tagged synapses are subsequently pruned through phagocytosis by microglia expressing the complement receptor 3 (CR3)221.”

What the sources say

• Not checked yetcites [221] Gasque, P. Complement: a unique innate immune sensor for danger signals. Mol. Immunol. 41, 1089–1098 (2004). source

In the paper

“Minocycline could relieve ASD-related phenotypes directly through altering neural function or indirectly through ameliorating ongoing immune dysfunction or through regulating the intestinal microbiota241.”

What the sources say

• 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

“it may exert its effects through a combination of suppressing cytokine signalling, enhancing neurotrophic factor secretion and suppressing mTOR signalling243.”

What the sources say

• Not checked yetcites [243] Jung, H. J. et al. Minocycline inhibits angiogenesis in vitro through the translational suppression of HIF-1α. Arch. Biochem. Biophys. 545, 74–82 (2014). source

In the paper

“If inflammation is indeed adaptive, as implied by these reports, then treating individuals with anti-inflammatory agents could have unintended detrimental consequences.”