The Role of the Immune System in Autism Spectrum Disorder
Open accessAbstract
Autism is a neurodevelopmental disorder characterized by deficits in communication and social skills as well as repetitive and stereotypical behaviors. While much effort has focused on the identification of genes associated with autism, research emerging within the past two decades suggests that immune dysfunction is a viable risk factor contributing to the neurodevelopmental deficits observed in autism spectrum disorders (ASD). Further, it is the heterogeneity within this disorder that has brought to light much of the current thinking regarding the subphenotypes within ASD and how the immune system is associated with these distinctions. This review will focus on the two main axes of immune involvement in ASD, namely dysfunction in the prenatal and postnatal periods. During gestation, prenatal insults including maternal infection and subsequent immunological activation may increase the risk of autism in the child. Similarly, the presence of maternally derived anti-brain autoantibodies found in ~20% of mothers whose children are at risk for developing autism has defined an additional subphenotype of ASD. The postnatal environment, on the other hand, is characterized by related but distinct profiles of immune dysregulation, inflammation, and endogenous autoantibodies that all persist within the affected individual. Further definition of the role of immune dysregulation in ASD thus necessitates a deeper understanding of the interaction between both maternal and child immune systems, and the role they have in diagnosis and treatment.
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Claims the paper makes
0 of 212 cited sources checked · 0 supported · 0 flagged
- Premisenone given
In ASD, the postnatal environment shows related but distinct profiles of immune dysregulation, inflammation, and endogenous autoantibodies that persist in the affected person.
“The postnatal environment, on the other hand, is characterized by related but distinct profiles of immune dysregulation, inflammation, and endogenous autoantibodies that all persist within the affected individual.”
Quote in the paperNot a substantial claim - Premisecitation
Genes identified by large genome-wide studies explain only a fraction of ASD diagnoses.
“genes implicated by large genome-wide studies have been shown to account for only a fraction of ASD diagnoses”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisenone given
Many infections other than rubella have been linked to the incidence of ASD.
“in the intervening years numerous other infections have been connected to the incidence of ASD”
Quote in the paperNot a substantial claim - Premisenone given
Prenatal insults such as maternal infection and the resulting immunological activation may raise the risk of autism in the child.
“During gestation, prenatal insults including maternal infection and subsequent immunological activation may increase the risk of autism in the child.”
Quote in the paperNot a substantial claim - Interpretationreasoning
Immune dysfunction is a viable risk factor that contributes to the neurodevelopmental deficits seen in autism spectrum disorder.
“research emerging within the past two decades suggests that immune dysfunction is a viable risk factor contributing to the neurodevelopmental deficits observed in autism spectrum disorders (ASD).”
Quote in the paperSubstantial claim- Rests on an assumption: Findings from animal models of maternal immune activation and maternal autoantibody transfer are informative about the pathogenesis of human ASD.
- Rests on an assumption: ASD can be divided into immune-related subphenotypes that are meaningful for diagnosis and treatment.
- Premisereasoning
Abnormal immune function, including inflammation, cytokine dysregulation, and anti-brain autoantibodies, can significantly influence ASD.
“mounting evidence for the ability of the immune system and abnormal immune function, including inflammation, cytokine dysregulation, and anti-brain autoantibodies, to act as a significant influence on ASD”
Quote in the paperSubstantial claim - Premisecitation
Croen and Braunschweig found that maternal autoantibodies reactive to proteins near 37 and 73 kDa were only found in women whose children later received an ASD diagnosis, using banked mid-pregnancy blood samples.
“In a study utilizing banked mid-pregnancy (prospective) blood samples, the authors noted that maternal autoantibodies reactive to proteins near 37 and 73 kDa were only found in women whose children later received a diagnosis of ASD”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Croen and Braunschweig, 2008a
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- Premisecitation
Disruption of normal cytokine levels is a significant risk factor for neurodevelopmental defects including schizophrenia and autism.
“There is strong evidence that disruption of normal cytokine levels has a significant role as a risk factor for several neurodevelopmental defects, including schizophrenia and autism”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
The link between congenital rubella syndrome and autism has been supported by other studies.
“thus establishing a link between CRS and autism that has been supported by others”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Deykin and MacMahon, 1979 source
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- Premisenone given
In IL-6 knockout mice, the poly(I:C) MIA model produced no statistically significant differences in prepulse inhibition or social behavior compared with untreated IL-6 knockouts.
“attempting the poly(I:C) MIA model in IL-6 knockout mice showed no statistically significant differences in PPI or social behavior via the three-chamber test from untreated IL-6 knockouts”
Quote in the paperSubstantial claim- Rests on an assumption: Findings from animal models of maternal immune activation and maternal autoantibody transfer are informative about the pathogenesis of human ASD.
- Premisecitation
In the common MIA model, challenging pregnant rodents with infection or poly(I:C) causes significant immunological, neurodevelopmental, and behavioral changes in the offspring.
“The MIA model in its most common design involves challenging pregnant rodents via direct infection (eg, influenza, Escherichia coli) or the dsRNA mimic poly (I:C); significant immunological, neurodevelopmental, and behavioral changes are then observed in the offspring”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Gilmore et al, 2005 source
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- cites Meyer et al, 2005 source
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- cites Urakubo et al, 2001 source
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- Rests on an assumption: Findings from animal models of maternal immune activation and maternal autoantibody transfer are informative about the pathogenesis of human ASD.
- Premisecitation
Warren et al. found that six of 11 mothers of young children had circulating antibodies targeting lymphocyte antigens of their children.
“a study that examined serum from 11 mothers of young children and found six with circulating antibodies that targeted lymphocyte antigens of the children”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Warren et al, 1990 source
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- Premisecitation
Congenital measles, mumps, cytomegalovirus, polyomaviruses, and influenza have been implicated in ASD incidence.
“Varying reports have also implicated measles and mumps (Deykin and MacMahon, 1979), cytomegalovirus (Libbey et al, 2005), polyomaviruses (Lintas et al, 2010), and influenza”
Quote in the paperNot a substantial claim0 of 3 sources checked - Interpretationreasoning
The maternal response to infection, rather than specific pathogens, can lead to ASD in the offspring.
“The implication is that the response to the infection, not just a few select pathogens, can lead to ASD in the offspring.”
Quote in the paperSubstantial claim- Rests on an assumption: Findings from animal models of maternal immune activation and maternal autoantibody transfer are informative about the pathogenesis of human ASD.
- Interpretationnone given
Autoantibodies against proteins important for healthy neurodevelopment are a plausible pathogenic mechanism in a subset of ASD cases.
“autoantibodies to proteins that are a key to healthy neurodevelopment are also thought to be a viable pathogenic mechanism in a subset of cases”
Quote in the paperNot a substantial claim- Rests on an assumption: Findings from animal models of maternal immune activation and maternal autoantibody transfer are informative about the pathogenesis of human ASD.
- Interpretationreasoning
The evidence strongly suggests a connection between maternal infection and altered neurodevelopment.
“the evidence presented thus far strongly suggests a connection between maternal infection and altered neurodevelopment”
Quote in the paperSubstantial claim- Rests on an assumption: Findings from animal models of maternal immune activation and maternal autoantibody transfer are informative about the pathogenesis of human ASD.
- Premisecitation
Brimberg et al. found that mothers of children with ASD were four times as likely to have circulating anti-brain antibodies compared with general population women.
“Brimberg et al (2013) examined plasma from 2431 mothers of ASD children and compared it with plasma from 654 GP women, finding that mothers of children with ASD were four times as likely to have circulating anti-brain antibodies.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Brimberg et al, 2013 source
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- Premisecitation
Jones et al. found that elevated mid-gestational inflammatory cytokines and chemokines were more associated with ASD with intellectual disability than with ASD without ID, developmental delay without ASD, and typically developing controls, including higher GM-CSF, TNF-α, IFNγ, IL-1α, IL-1β, IL-4, and IL-6.
“Most recently, studies have demonstrated that elevated mid-gestational levels of inflammatory cytokines and chemokines are more highly associated with the ASD subphentoype that presents with intellectual disability (ID), compared with ASD without ID, developmental delay (DD) without ASD, and typically developing controls (Jones et al, 2016).These included higher levels of GM-CSF, TNF-α, IFNγ, IL-1”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Jones et al, 2016
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- Premisecitation
Congenital rubella syndrome is associated with a markedly increased incidence of autism, reported as 741 per 10,000 in Chess's preschool sample and later 905 per 10,000.
“The study reported 18 children with some degree of autism, implying an incidence of 741 cases per 10 000 among the population of CRS children”
- Also stated in: § Congenital Infection · plain
“Chess followed-up as the children aged and found even higher rates of autism (905 per 10 000)”
Quote in the paperNot a substantial claim0 of 3 sources checked - Also stated in: § Congenital Infection · plain
- Premisecitation
Maternal infection diagnosed at hospital admission, especially bacterial infection, correlates with increased ASD risk.
“A more expansive study by Zerbo et al (2015) found that maternal infection diagnosed at a hospital admission, especially bacterial ones, correlated with increased risk of ASD.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Zerbo et al, 2015 source
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- Premisecitation
In animal models, an activated maternal immune response alone, without infection, is sufficient to produce changes in the offspring.
“it has now been demonstrated through animal models that merely an activated immune response in the mother, absent any infection, is sufficient to lead to changes in the offspring”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Shi et al, 2003 source
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- Rests on an assumption: Findings from animal models of maternal immune activation and maternal autoantibody transfer are informative about the pathogenesis of human ASD.
- Premisecitation
Children with autism were more likely than their non-autistic siblings or controls to have serum that tested positive by western blot against fresh human brain samples from caudate, putamen, and prefrontal cortex.
“Singer et al (2006) found that children with autism were more likely than their non-autistic siblings or controls to have serum that tested positive via western blot to fresh human brain samples (caudate, putamen, and prefrontal cortex).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Singer et al (2006) source
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- Premisecitation
Among positive samples, those with ASD immunostained more strongly than controls.
“and among positive samples, those with ASD immunostained more strongly than controls (Mazur-Kolecka et al, 2014).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Mazur-Kolecka et al, 2014 source
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- Premisecitation
Numerous studies have shown a connection between HLA alleles and the incidence of autism, particularly class II DRB1.
“Numerous studies have shown a connection between the members of the expansive family of HLA alleles and incidence of autism (Torres et al, 2012), in particular the class II DRB1.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Torres et al, 2012
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Braunschweig et al. found that reactivity to LDH, STIP1, and CRMP1 correlated with increased stereotypic behaviors in the child.
“when behavioral outcomes were characterized in the children of the 7% of mothers with a combined reactivity to LDH, STIP1, and CRMP1 (corresponding to the original 37/73 kDa band pattern) this pattern of reactivity correlated with an increase in stereotypic behaviors in the child”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Braunschweig et al, 2013 source
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- Premisecitation
45 and 62 kDa antibodies in children correlated with autism severity, IQ, and impaired motor function and social interaction as scored on the Vineland Adaptive Behavior Scales.
“The authors showed that 45 and 62 kDa antibodies in the children correlated with severity of autism, IQ, and impaired motor function and social interaction, as scored on the Vineland Adaptive Behavior Scales.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Piras et al, 2014 source
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- Premisecitation
In a 2011 study of 277 children with ASD and 189 typical developing controls, ASD children were more likely to test positive for anti-brain autoantibodies by western blotting against human and macaque cerebellar protein medleys.
“A larger 2011 study expanded on these findings, testing plasma from a cohort of 277 children with ASD and 189 TD controls for reactivity to human and macaque cerebellar protein medleys, with ASD children more likely to test positive for anti-brain autoantibodies via western blotting (Goines et al, 2011a).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Goines et al, 2011a
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- Premisecitation
The hypervariable region 3 of DRB1*0401 is associated with increased relative risk for autism in children from Utah.
“The hypervariable region 3 of DRB1*0401 has been associated with an increased relative risk for autism in children from Utah (Warren et al, 1996).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Warren et al, 1996 source
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- Premisecitation
Braunschweig et al. identified seven developmentally regulated fetal brain proteins recognized by maternal autoantibodies: LDH-A, LDH-B, STIP1, CRMP1, CRMP2, cypin, and YBX1.
“Studies by Braunschweig et al (2013) utilized two-dimensional gel electrophoresis followed by tandem mass spectrometry peptide sequencing to identify seven developmentally regulated proteins in the fetal brain that are recognized by maternal autoantibodies.These are lactate dehydrogenase A and B (LDH-A and LDH-B), stress-induced phosphoprotein 1 (STIP1), collapsin response mediator proteins 1 and”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Braunschweig et al, 2013 source
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- Premisecitation
The presence of anti-neuronal antibodies was higher in severe diagnoses (87.5%) than in mild or moderate diagnoses (25%).
“the presence of such antibodies was higher in severe diagnoses (87.5%) than mild/ moderate diagnoses (25%)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Mostafa and Al-Ayadhi (2012) source
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- Premisecitation
In a subset examined by immunohistochemistry, 21% of samples from children with ASD showed intense immunoreactivity, while none of the typical developing controls did.
“When a subset of subject samples was examined via immunohistochemistry (IHC), 21% of those from children with ASD had 'intense immunoreactivity' while none of the TD controls exhibited such reactivity.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Wills et al, 2009 source
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- Premisecitation
Children with autism showed positive serum anti-brain reactivity against prenatal rat proteins by western blot, with banding patterns different from those of non-autistic siblings and other controls.
“A similar result found that children with autism showed positive serum anti-brain reactivity against prenatal rat proteins by western blot, with a different set of banding patterns relative to their non-autistic siblings and other controls (Zimmerman et al, 2007).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Zimmerman et al, 2007 source
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- Interpretationcitation
After birth and throughout childhood, an individual with ASD may have endogenous anti-brain autoantibodies, separate from maternal IgG, that correlate with aberrant behaviors and impaired development.
“After birth and at least throughout childhood, an individual with ASD may have endogenous anti-brain autoantibodies, separate from any maternal IgG, which correlate with aberrant behaviors and impaired development.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Piras et al, 2014 source
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- Premisecitation
Numerous studies have reported circulating anti-brain immunoglobulins in patients with ASD and in related conditions such as multiple sclerosis, schizophrenia, and systemic lupus erythematosus.
“numerous studies have reported the presence of circulating anti-brain immunoglobulins in patients with ASD, as well as related conditions such as multiple sclerosis (Ryberg, 1982), schizophrenia (Henneberg et al, 1994), and systemic lupus erythematosus (SLE) (Libbey and Fujinami, 2010;Mackay et al, 2015;Suurmond and Diamond, 2015).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Maternal and child-borne autoantibodies each retain distinct and defining characteristics despite correlations between the two populations.
“showing that while correlations between the two discrete autoantibody populations do exist, maternal-and child-borne autoantibodies each retain their own distinct and defining characteristics.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Piras et al, 2014 source
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- Premisecitation
Braunschweig et al. found atypical anxiety and sociality alongside impaired motor and sensory abilities after a single intravenous injection in mice.
“Braunschweig et al (2012b) performed a similar study to demonstrate atypical anxiety and sociality alongside impaired motor and sensory abilities following a single intravenous injection.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Braunschweig et al, 2012b
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- Rests on an assumption: Findings from animal models of maternal immune activation and maternal autoantibody transfer are informative about the pathogenesis of human ASD.
- Premisecitation
Nordahl et al. found that children born to mothers with this autoantibody binding pattern had higher total cerebral volume than ASD children born to autoantibody-negative mothers and typically developing controls.
“children born to mothers with this pattern of autoantibody binding also exhibited higher total cerebral volume when compared both to children with ASD born to autoantibody-negative mothers as well as typically developing control children”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Nordahl et al, 2013 source
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- Premisecitation
In a cohort of 355 Italian children with autism and their mothers and unaffected siblings, autoantibodies in autistic individuals correlated with increased severity, stereotypies, and cognitive impairment.
“An examination of anti-brain autoantibodies in a cohort of 355 Italian children with autism and their mothers and unaffected siblings found that autoantibodies in autistic individuals correlated with increased severity, stereotypies, and cognitive impairment (Piras et al, 2014).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Piras et al, 2014 source
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- Premisecitation
In a 2009 study of plasma from 63 young children with ASD, 21% had antibodies positive against both human and macaque cerebellum samples by western blot, while only 1 of 63 typical developing controls (2%) tested positive.
“A 2009 study of plasma from 63 young children with ASD found that 21% of them had antibodies positive against both human and macaque cerebellum samples via western blot, while only one out of the 63 typical developing (TD) controls (2%) tested positive (Wills et al, 2009).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Wills et al, 2009 source
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- Interpretationnone given
Children with ASD may have their own endogenous anti-brain autoantibodies, distinct from maternal autoantibodies, that are connected with atypical development.
“children may have their own, endogenous antibrain autoantibodies that are connected with atypical development, distinct from the previously described maternal autoantibodies.”
Quote in the paperNot a substantial claim - Premisecitation
The presence of anti-neuronal antibodies was higher in females (90%) than in males (53.3%).
“as well as in females (90%) compared with males (53.3%).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Mostafa and Al-Ayadhi (2012) source
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- Premisecitation
In a cohort of 80 Saudi children with ASD versus 80 GP controls, anti-neuronal antibodies tested by immunofluorescence against monkey cerebellum were higher in the ASD group (62.5% vs 5%).
“Mostafa and Al-Ayadhi (2012), who found a higher rate of anti-neuronal antibodies in a cohort of 80 Saudi children with ASD vs 80 -GP controls, as tested via immunofluorescence against monkey cerebellum (62.5 vs 5%)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Mostafa and Al-Ayadhi (2012) source
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- Premisecitation
DRB1 is associated with autism in Han Chinese, Egyptian, and Saudi populations.
“DRB1 was also associated with autism in Han Chinese (Chien et al, 2012), Egyptian (Mostafa et al, 2013), and Saudi populations (Al-Hakbany et al, 2014).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation
Autoimmunoreactivity to neuronal progenitor cells was far more common in children with autism than in controls.
“A later study found autoimmunoreactivity to neuronal progenitor cells (NPCs) to be far more common in children with autism than controls”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Mazur-Kolecka et al, 2014 source
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- Interpretationreasoning
Maternal autoantibodies appear to influence, or even define, a specific subset of autism spectrum disorder.
“it seems evident that maternal autoantibodies appear to influence, if not define, a specific subset of ASD.”
Quote in the paperNot a substantial claim - Premisecitation
Unstimulated NK cells, specifically the CD56dim subset, stained positive for perforin, granzyme B, and IFN-γ at higher frequencies in ASD patients compared with GP controls.
“The authors then showed that unstimulated NK cells-specifically the CD56 dim subset-stained positive for perforin, granzyme B, and IFN-γ at higher frequencies in ASD patients as compared with general population (GP) controls.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Enstrom et al, 2009b
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- Premisecitation
A 2008 study identified 11 genes differentially expressed in children with autism and in early onset and developmental regression subsets compared with the general population, with overexpression confirmed for 7 of 11 by qPCR.
“Another 2008 study identified 11 genes that were differentially expressed in children with autism, as well as within the subsets of early onset and developmental regression, as compared with the general population (overexpression in autism samples were confirmed for seven of 11 via qPCR) (Gregg et al, 2008).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Gregg et al, 2008 source
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- Premisecitation
A more recent report noted a decrease in CD4+CD25high regulatory T cells in children with autism.
“A more recent report noted a decrease in CD4 + CD25 high regulatory T cells in children with autism (Mostafa et al, 2010).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Mostafa et al, 2010 source
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- Premisecitation
An examination of neuroinflammation in brains from individuals with autism implicated T cell skewing.
“as did an examination of neuroinflammation in brains from individuals with autism (Vargas et al, 2005).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Vargas et al, 2005 source
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- Premisecitation
In a review of genome-wide expression studies, of 464 genes identified, six of the top 10 KEGG ontology pathways were immune system functions.
“When Lintas et al (2012) reviewed several genome-wide expression studies in 2012 (including the two just mentioned), they found a strong connection to the immune system; of the 464 genes identified, six out of the top 10 KEGG ontology pathways were functions of the immune systems.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Lintas et al (2012) source
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- Premisecitation
A 1990 study suggested that CD4+ cell levels were decreased in autism.
“while a supporting 1990 study suggested CD4 + cell levels were decreased in autism (Yonk et al, 1990).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Yonk et al, 1990 source
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- Premisecitation
A 2014 RNA-seq gene ontology analysis showed that the autism transcriptome was heavily enriched for immune response genes.
“A 2014 RNA-seq study built upon this concept with a gene ontology analysis showing that the autism transcriptome was heavily enriched for immune response genes (Gupta et al, 2014).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Gupta et al, 2014 source
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- Premisecitation
A model describes a significantly altered neuroimmune milieu that persists in constant dysregulation in ASD.
“They describe a model whereby a significantly altered neuroimmune milieu persists in constant dysregulation.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Voineagu et al, 2011 source
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- Premisecitation
A module of genes upregulated in ASD was enriched for astrocytes and activated microglia.
“The authors also defined a module of genes upregulated in ASD that was enriched for astrocytes and activated microglia.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Voineagu et al, 2011 source
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- Interpretationreasoning
The larger picture is a cascading network of genetic interactions leading to ongoing, persistent immune imbalance.
“the larger picture is one of a cascading network of genetic interactions that leads to ongoing, persistent immune imbalance.”
Quote in the paperSubstantial claim - Premisecitation
A 14-basepair insertion in HLA-G was found more often in individuals with ASD and in their mothers.
“Interestingly, Guerini et al (2015) discovered a 14-basepair insertion in HLA-G that was found more often in individuals with ASD and their mothers.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Guerini et al (2015) source
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- Premisecitation
In ASD and control brains, hundreds of genes were differentially expressed.
“Voineagu, et al, examined gene expression in ASD and control brains, and as expected found hundreds of genes that were differentially expressed (Voineagu et al, 2011).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Voineagu et al, 2011 source
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- Premisecitation
Immune-relevant gene sets fell into six classes: antigen-specific immune response, inflammation, cell death, autoimmune diseases, migration, and the natural killer T cell pathway.
“These immune-relevant gene sets fell into six classes: antigenspecific immune response, inflammation, cell death, autoimmune diseases, migration, and the natural killer T cell pathway.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Garbett et al, 2008 source
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- Premisecitation
NK cells in children with autism had higher expression of NK cytotoxicity genes.
“A more recent study of NK cells recapitulates the genetic changes previously alluded to, showing that NK cells in children with autism had higher expression of NK cytotoxicity genes (Enstrom et al, 2009b).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Enstrom et al, 2009b
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- Premisecitation
Of 31 differentially expressed gene sets, 19 were connected to the immune system.
“the authors found 31 sets of genes that were differentially expressed between autistic and control samples; of these, 19 were connected to the immune system.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Garbett et al, 2008 source
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- Premisecitation
Linkage studies found an association between ASD and a single SNP, rs1858830, in the promoter of MET.
“Linkage studies by Campbell et al (2006), have found an association between ASD and a single SNP (rs1858830) in the promoter of MET.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Campbell et al (2006) source
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Cultured monocytes from ASD patients responded differently to TLR stimulation.
“Enstrom et al (2010) showed that cultured monocytes from ASD patients responded differently to TLR stimulation”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Enstrom et al (2010) source
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Upon stimulation, NK cells showed much lower staining to these same targets compared with GP controls.
“Interestingly, upon stimulation, NK cells showed much lower staining to these same targets as compared with GP.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Enstrom et al, 2009b
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- Premisecitation
A 2008 study found 152 transcripts with varied expression in the temporal cortex of children and adults with autism, 130 of which were upregulated.
“A 2008 study explored transcriptomic changes in the temporal cortex of children and adults with autism, finding 152 transcripts with varied expression, 130 of which were upregulated (Garbett et al, 2008).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Garbett et al, 2008 source
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- Interpretationcitation
Immune dysregulation was a common trend in genomic studies, particularly in NK cell and cytokine pathways.
“Immune dysregulation was a common trend in genomic studies, particularly in the NK cell and cytokine pathways.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Lintas et al (2012) source
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- Premisecitation
PHA-stimulated PBMCs from ASD showed a differential response, including reduced numbers of CD134- and CD25-activated CD3+, CD4+, and CD8+ T cells.
“Ashwood et al (2011b) demonstrated a differential response by PHA-stimulated peripheral blood mononuclear cells (PBMCs), including reduced numbers of CD134-and CD25-activated CD3 + , CD4 + , and CD8 + T cells.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Ashwood et al (2011b)
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Significantly more CD56+ NK cells were observed in children with ASD compared with controls.
“The authors also found considerable levels of immune dysregulation, observing significantly more CD56 + NK cells in children with ASD compared with controls.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Enstrom et al, 2009b
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- Premisecitation
A mouse model implicated T cell skewing in ASD-relevant behavioral deficits.
“A previously mentioned mouse model also implicated T cell skewing in ASD-relevant behavioral deficits (Ponzio et al, 2007)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Ponzio et al, 2007 source
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- Premisecitation
A reduction in NK cell activity was shown in teenage and adult autism patients, with 12 of 31 patients showing lower activity in PBMCs by K562 chromium-release assays.
“A reduction in NK cell activity was shown in teenage and adult autism patients, with 12 out of 31 patients showing lower activity in PBMCs via K562 chromium-release assays (Warren et al, 1987).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Warren et al, 1987 source
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- Premisecitation
Genes significantly upregulated in ASD were heavily enriched for immune and inflammatory response functions, immunoglobulin domains, and other immune-regulatory ontologies.
“The genes significantly upregulated in ASD were heavily enriched for immune and inflammatory response functions, immunoglobulin domains, and other immune-regulatory ontologies.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Voineagu et al, 2011 source
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- Premisecitation
The authors suggest that immune system genes may function as a fundamental convergence for autistic disorders.
“The authors suggest that immune system genes may function as a fundamental convergence for autistic disorders.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Ziats and Rennert (2011) source
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- Interpretationnone given
Taken together, the genetic forces noted in children and adults with autism are myriad but insufficiently explanatory.
“Taken together, the genetic forces noted in both children and adults with autism are myriad, but insufficiently explanatory.”
Quote in the paperNot a substantial claim - Interpretationcitation
The apparent shift in subclass to IgG4 means that children with autism likely have a higher percentage of circulating IgG with inherently lower affinity for antibody receptors on leukocytes.
“the apparent shift in subclass to IgG4 means that children with autism are likely to have a higher percentage of circulating IgG with an inherently lower affinity for the antibody receptors on leukocytes (Enstrom et al, 2009a;Zaman et al, 2016).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Enstrom et al, 2009a
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- cites Zaman et al, 2016 source
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- Premisecitation
A 2006 study showed increases in the anti-inflammatory Th2 cytokines IL-4, IL-5, and IL-13 from PHA-stimulated PBMCs.
“A 2006 study showed increases in the anti-inflammatory Th2 cytokines IL-4, IL-5, and IL-13 from PHA-stimulated PBMCs (Molloy et al, 2006)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Molloy et al, 2006 source
Not checked in the free run.
- Premisecitation
A 2012 follow-up study ruled out abnormal B-cell function as the source of aberrant IgG levels.
“A 2012 follow-up study ruled out abnormal B-cell function as the source of aberrant IgG levels (Heuer et al, 2012).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Heuer et al, 2012 source
Not checked in the free run.
- Premisecitation
Vargas et al showed higher levels of MCP-1, TGF-β, and IL-6 in the brains of autistic patients.
“Vargas et al (2005) likewise showed the presence of an active neuroinflammatory environment, finding higher levels of MCP-1, TGF-β, and IL-6 in the brains of autistic patients.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Vargas et al (2005) source
Not checked in the free run.
- Premisecitation
A mouse model showed Th1-skewed T-cell development in amniotic fluid alongside stereotypies in offspring after pregnant dams were treated with IL-2.
“while a mouse model in 2007 showed Th1-skewed T-cell development in amniotic fluid alongside stereotypies in the offspring following treatment of pregnant dams with IL-2 (Ponzio et al, 2007).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Ponzio et al, 2007 source
Not checked in the free run.
- Interpretationcitation
An increased pro-inflammatory environment in ASD seems well supported.
“Although an increased pro-inflammatory environment seems well supported (Haroon et al, 2012)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Haroon et al, 2012 source
Not checked in the free run.
- Premisecitation
Increased levels of the chemokines MCP-1, RANTES, and eotaxin were found in children from the same cohort.
“Examining children from the same cohort, the authors also published on increased levels of the chemokines MCP-1, RANTES, and eotaxin (Ashwood et al, 2011c).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Ashwood et al, 2011c
Not checked in the free run.
- Premisecitation
A 2002 study demonstrated an increase in the blood cytokines IL-1RA and IFN-γ, suggesting a more Th1-like proinflammatory response.
“a 2002 study demonstrated an increase in the blood cytokines IL-1RA and IFN-γ, suggesting a more Th1-like, proinflammatory response (Croonenberghs et al, 2002a)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Croonenberghs et al, 2002a
Not checked in the free run.
- Premisecitation
Increased cytokine or chemokine levels were correlated with increased aberrant behavior and impaired development.
“In both studies, increased cytokine or chemokine levels were correlated with increased aberrant behavior and impaired development (Ashwood et al, 2011a(Ashwood et al, , 2011c)).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Ashwood et al, 2011a
Not checked in the free run.
- cites Ashwood et al, 2011c
Not checked in the free run.
- Premisecitation
In 104 children with ASD, significantly lower atypical levels of CD57+ NK cells were found compared with both age-matched and adult controls.
“Siniscalco et al (2016) examined 104 children with ASD, and found significantly lower, atypical levels of CD57 + NK cells as compared with both age-matched and adult controls.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Siniscalco et al, 2016
Not checked in the free run.
- Premisecitation
A 2012 report using dried blood samples suggested that children with ASD had lower levels of both Th1-like and Th2-like cytokines.
“In contrast to most of the above studies, a 2012 report using dried blood samples suggested that children with ASD had lower levels of both Th1-like and Th2-like cytokines (Abdallah et al, 2012b).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Abdallah et al, 2012b
Not checked in the free run.
- Premisecitation
Many studies found no increase in the Th2 cytokine IL-10.
“Of particular note is that many of the above studies found no increase in the Th2 cytokine IL-10 (Croonenberghs et al, 2002a;Krakowiak et al, 2015;Li et al, 2009;Molloy et al, 2006).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Croonenberghs et al, 2002a
Not checked in the free run.
- cites Krakowiak et al, 2015
Not checked in the free run.
- cites Li et al, 2009
Not checked in the free run.
- Premisecitation
Offending antibodies of either origin appear to persist systemically for extended periods.
“Offending antibodies of either origin appear to persist systemically for extended periods of time (Mostafa and Al-Ayadhi, 2012;Piras et al, 2014;Singer et al, 2006;Zimmerman et al, 2007)”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation
A large 2011 study found an increase in plasma levels of a broad range of cytokines, including IL-12p40, IL-1β, IL-6, IL-8, and GM-CSF, in children with ASD.
“A large 2011 study of children with ASD found an increase in plasma levels of a broad range of cytokines, including the Th1-like IL-12p40 and pro-inflammatory cytokines IL-1β, IL-6, IL-8, and GM-CSF (Ashwood et al, 2011a).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Ashwood et al, 2011a
Not checked in the free run.
- Premisecitation
Increased plasma levels of the weakly active IgG4 subclass were found among ASD patients.
“A later study with children from the same cohort found increased plasma levels of the weakly active IgG4 subclass among ASD patients (Enstrom et al, 2009a), as did an earlier study comparing ASD children to their siblings (Trajkovski et al, 2004).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Enstrom et al, 2009a
Not checked in the free run.
- cites Trajkovski et al, 2004
Not checked in the free run.
- Premisecitation
The immune environment can affect behavior.
“Given the ability of the immune environment to affect behavior (Filiano et al, 2016)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Filiano et al, 2016 source
Not checked in the free run.
- Premisecitation
Reports indicate that the presence of these antibodies may correlate with adverse conditions in patients.
“Although reports indicate the presence of these antibodies may correlate with adverse conditions in the patients (Braunschweig et al, 2012a;Goines et al, 2011a;Mostafa and Al-Ayadhi, 2012;Piras et al, 2014)”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Braunschweig et al, 2012a
Not checked in the free run.
- cites Goines et al, 2011a
Not checked in the free run.
- cites Mostafa and Al-Ayadhi, 2012 source
Not checked in the free run.
- Premisenone given
Endogenous anti-brain autoantibodies in ASD are separate from maternal IgG.
“After birth and at least throughout childhood, an individual with ASD may have endogenous anti-brain autoantibodies, separate from any maternal IgG, which correlate with aberrant behaviors and impaired development.”
Quote in the paperNot a substantial claim - Premisenone given
ASD is associated with a broad immune dysregulation including increased inflammatory cytokines such as IL-6, IL-8, and MCP-1.
“There also exists a broad picture of ASD-related immune dysregulation, including an increased inflammatory cytokine milieu (eg, IL-6, IL-8, and MCP-1), thus leading to an increased, pro-inflammatory Th1/Th2 ratio.”
Quote in the paperSubstantial claim - Premisenone given
T-cell populations may be skewed in ASD, showing a shift in cell subpopulations.
“T-cell and NK-cell populations may also be skewed, displaying a shift in cell subpopulations.”
Quote in the paperNot a substantial claim - Interpretationreasoning
The increased inflammatory cytokine milieu in ASD leads to an increased pro-inflammatory Th1/Th2 ratio.
“There also exists a broad picture of ASD-related immune dysregulation, including an increased inflammatory cytokine milieu (eg, IL-6, IL-8, and MCP-1), thus leading to an increased, pro-inflammatory Th1/Th2 ratio.”
Quote in the paperNot a substantial claim - Premisenone given
Endogenous anti-brain autoantibodies in ASD correlate with aberrant behaviors and impaired development.
“After birth and at least throughout childhood, an individual with ASD may have endogenous anti-brain autoantibodies, separate from any maternal IgG, which correlate with aberrant behaviors and impaired development.”
Quote in the paperNot a substantial claim - Premisenone given
NK cells in ASD show a decreased response to activation.
“NK cells in particular show an increased baseline activity but a decreased response to activation, rendering the cells unable to properly respond to stimuli.”
Quote in the paperNot a substantial claim - Premisenone given
Individuals with ASD may have endogenous anti-brain autoantibodies after birth and at least throughout childhood.
“After birth and at least throughout childhood, an individual with ASD may have endogenous anti-brain autoantibodies, separate from any maternal IgG, which correlate with aberrant behaviors and impaired development.”
Quote in the paperSubstantial claim - Premisecitation
Direct genetic evidence links ASD and schizophrenia.
“alongside direct genetic evidence that links ASD and schizophrenia (Cantor and Geschwind, 2008;Ellis et al, 2016;Zhou et al, 2016).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Interpretationreasoning
The decreased response to activation renders NK cells in ASD unable to properly respond to stimuli.
“NK cells in particular show an increased baseline activity but a decreased response to activation, rendering the cells unable to properly respond to stimuli.”
Quote in the paperNot a substantial claim - Premisenone given
NK-cell populations may be skewed in ASD, showing a shift in cell subpopulations.
“T-cell and NK-cell populations may also be skewed, displaying a shift in cell subpopulations.”
Quote in the paperNot a substantial claim - Premisecitation
Autoantibodies such as those described have been found in patients with other autoimmune disorders, including multiple sclerosis, schizophrenia, and SLE.
“Autoantibodies, such as those described above, have been found in patients of other autoimmune disorders, including multiple sclerosis (Ryberg, 1982), schizophrenia (Henneberg et al, 1994), and SLE (Libbey and Fujinami, 2010).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisenone given
Other genetic factors in ASD include members of the HLA gene family.
“Other genetic factors include the oncogene MET and members of the diverse family of HLA genes.”
Quote in the paperNot a substantial claim - Premisecitation
Numerous studies show that a significant risk factor for autism is a family history of autoimmune disease.
“Further lending credence to this association are numerous studies showing that a significant risk factor for autism is a family history of autoimmune disease (Brimberg et al, 2013;Gesundheit et al, 2013;Gottfried et al, 2015;Wu et al, 2015)”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
A 2015 study found more than double the risk of ASD in children of mothers with SLE than in controls.
“including a 2015 study that found a more than double risk of ASD in children of mothers with SLE than those of controls (Vinet et al, 2015).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Vinet et al, 2015 source
Not checked in the free run.
- Interpretationreasoning
These networks collectively form a broad internal setting of atypical immune regulation and response in ASD.
“The broader background of immunogenetic factors of ASD includes multiple networks of the immune system, such as pathways that regulate cytokines and NK cells, which together constitute a broad, endogenous environment of atypical immune regulation and response.”
Quote in the paperNot a substantial claim - Interpretationcitation
Similarities between autism and schizophrenia are such that results from animal models like the MIA model may be overlapping and confounded.
“Despite the differences between these two disorders, the similarities between them are such that results from animal models like the MIA model may be overlapping and confounded (Bauman et al, 2014;Young et al, 2016).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Interpretationreasoning
The broader background of immunogenetic factors in ASD includes multiple immune system networks, such as pathways regulating cytokines and NK cells.
“The broader background of immunogenetic factors of ASD includes multiple networks of the immune system, such as pathways that regulate cytokines and NK cells, which together constitute a broad, endogenous environment of atypical immune regulation and response.”
Quote in the paperNot a substantial claim - Interpretationreasoning
Immune dysregulation in autism persists from birth through at least childhood.
“Ongoing immune dysregulation persists in autism.”
Quote in the paperSubstantial claim - Premisenone given
NK cells in ASD show increased baseline activity.
“NK cells in particular show an increased baseline activity but a decreased response to activation, rendering the cells unable to properly respond to stimuli.”
Quote in the paperNot a substantial claim - Interpretationreasoning
A strong line of evidence is developing in support of maternal immune dysregulation affecting neurodevelopment, based on studies of maternal infection, immune activation, and maternal autoantibodies directed toward the developing fetal brain.
“In the prenatal environment, a strong line of evidence is beginning to develop in support of maternal immune dysregulation as it affects neurodevelopment based on studies on maternal infection, immune activation, and maternal autoantibodies directed toward the developing fetal brain.”
Quote in the paperNot a substantial claim
- Classified as probably not a substantial claim. 18
- May combine two claims. 75
- The quote only partly states this claim. 5
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisenone givenCongenital rubella infection is associated with autism.
“Nearly 50 years ago, an association of autism with congenital rubella infection was noted”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationAutism is strongly influenced by the genome, with heritability estimates generally centering around 50% to 55%.
“It is known that autism is strongly influenced by the genome-in contrast to earlier speculation, ranges of heritability estimates generally center ~50 or 55%”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
Premisenone givenMaternally derived anti-brain autoantibodies are present in about 20% of mothers whose children are at risk for autism and define an additional ASD subphenotype.
“the presence of maternally derived anti-brain autoantibodies found in ~20% of mothers whose children are at risk for developing autism has defined an additional subphenotype of ASD.”
Quote in the paperSubstantial claim- Rests on an assumption: ASD can be divided into immune-related subphenotypes that are meaningful for diagnosis and treatment.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationBrown et al. found an association between autism and elevated early gestational maternal C-reactive protein in Finnish children.
“an earlier investigation of Finnish children that showed an association between autism and elevated early gestational maternal C-reactive protein”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Brown et al, 2014 source
Not checked in the free run.
May combine two claims. The quote only partly states this claim.
PremisecitationZimmerman et al. found serum reactivity to prenatal, postnatal, and adult rat brain proteins in 11 mothers of autistic children and none in control mothers; the children's ages of 2 to 18 years indicated that maternal autoantibodies may persist for years.
“A subsequent study used samples taken from 11 mothers with autistic children to strengthen these results, finding serum reactivity in those mothers to prenatal, postnatal, and adult rat brain proteins while finding none in control mothers”
- Also stated in: § Transplacental Maternal Autoantibodies to the Fetal Brain · hedged
“the children in this study ranged in age from 2 to 18 years old, indicating that the presence of autoantibodies in maternal serum is not a transient phenomenon and may persist for many years”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Zimmerman et al, 2007 source
Not checked in the free run.
- Also stated in: § Transplacental Maternal Autoantibodies to the Fetal Brain · hedged
May combine two claims. The quote only partly states this claim.
PremisecitationBraunschweig et al. found that two bands at 37 and 73 kDa were significantly more common among mothers of autistic children, especially children with regression, and that 12% of ASD mothers had both bands while no TD or DD mothers did.
“The authors identified two bands, at 37 and 73 kDa, that were significantly more common among mothers with autistic children, in particular children with regression rather than early onset.”
- Also stated in: § Transplacental Maternal Autoantibodies to the Fetal Brain · plain
“the authors found that 12% of samples from mothers of children with ASD showed both 37 and 73 kDa bands, while none of the mothers of TD or DD children did”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Braunschweig et al, 2008
Not checked in the free run.
- Also stated in: § Transplacental Maternal Autoantibodies to the Fetal Brain · plain
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMeyer et al. suggested that maternal IL-10 may attenuate behavioral and pharmacological dysfunctions in a poly(I:C) MIA model.
“A poly(I:C) MIA model by Meyer et al (2008) suggested that maternal IL-10 may be able to attenuate behavioral and pharmacological dysfunctions.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Meyer et al, 2008 source
Not checked in the free run.
- Rests on an assumption: Findings from animal models of maternal immune activation and maternal autoantibody transfer are informative about the pathogenesis of human ASD.
May combine two claims.
PremisecitationHuman studies found increased IFN-γ, IL-4, and IL-5 in sera from mid-gestational mothers whose child later received an ASD diagnosis, and elevated MCP-1, IL-4, TNF-α, and TNF-β in amniotic fluid.
“More recent human studies found increased levels of IFN-γ, IL-4, and IL-5 in sera from mid-gestational mothers with a child that would later be diagnosed (Goines et al, 2011b) and elevated MCP-1 (Abdallah et al, 2012a), IL-4, TNF-α, and TNF-β levels in amniotic fluid (Abdallah et al, 2013).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Goines et al, 2011b
Not checked in the free run.
- cites Abdallah et al, 2012a
Not checked in the free run.
- cites Abdallah et al, 2013 source
Not checked in the free run.
The quote only partly states this claim.
PremisecitationMaternal autoantibodies to fetal brain proteins have been found in mothers of autistic children.
“The notion that maternal autoantibodies to elements in the fetal compartment could elicit changes in neurodevelopment began over 25 years ago”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Warren et al, 1990 source
Not checked in the free run.
- Rests on an assumption: Findings from animal models of maternal immune activation and maternal autoantibody transfer are informative about the pathogenesis of human ASD.
May combine two claims.
PremisecitationZerbo et al. found maternal blood C-reactive protein levels lower in weeks 15-19 of pregnancies of a child with ASD than in the general population, and the results appeared not to be genetic.
“A 2016 study found maternal blood C-reactive protein levels to be lower in weeks 15-19 of pregnancies of a child with ASD than the general population, and although the results appear not to be genetic”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Zerbo et al, 2016 source
Not checked in the free run.
May combine two claims.
PremisecitationSmith et al. found that a single injection of IL-6 into pregnant mice at E12.5 led to offspring deficits in prepulse inhibition and latent inhibition, which were not seen after IL-1α, TNF-α, or IFN-γ injection.
“Smith et al (2007) showed in 2007 that a single injection of the pro-inflammatory cytokine IL-6 to pregnant mice at embryonic day 12.5 lead to offspring deficits in prepulse inhibition (PPI) and latent inhibition (LI), both autism-relevant behaviors; these results were not seen following injection of the pro-inflammatory cytokines IL-1α, TNF-α, or IFN-γ.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Smith et al, 2007 source
Not checked in the free run.
- Rests on an assumption: Findings from animal models of maternal immune activation and maternal autoantibody transfer are informative about the pathogenesis of human ASD.
May combine two claims.
PremisecitationIn a Swedish study of over 24,000 ASD cases, offspring of mothers hospitalized the year before pregnancy had increased ASD rates under any inpatient diagnosis, viral or bacterial, with no connection to gestational timing.
“A yet-larger 2015 study of over 24 000 Swedish ASD cases observed increased ASD rates among offspring of mothers hospitalized the year before pregnancy; risk for ASD increased under any inpatient diagnosis, including both viral and bacterial”
- Also stated in: § Congenital Infection · plain
“The authors found no connection with the gestational timing of infection, however”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Lee et al, 2015 source
Not checked in the free run.
- Also stated in: § Congenital Infection · plain
May combine two claims.
PremisecitationIn Shi et al., poly(I:C) treatment alone produced similar aberrant phenotypes, suggesting that the maternal immune response rather than the infection caused the effects.
“the authors observed similar aberrant phenotypes in the same mice when using only poly(I:C) treatment rather than infection, suggesting that it was the maternal immune response rather than the infection itself that was responsible”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Shi et al, 2003 source
Not checked in the free run.
- Rests on an assumption: Findings from animal models of maternal immune activation and maternal autoantibody transfer are informative about the pathogenesis of human ASD.
Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Premisenone givenOther neurodevelopmental disorders, such as schizophrenia, also occur alongside a spectrum of immune function changes.
“other neurodevelopmental disorders, such as schizophrenia, also present alongside a spectrum of changes in immune function”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationLabouesse et al. found that a single poly(I:C) injection increased 5-methylcytosine and 5-hydroxymethylcytosine on the GAD1 promoter, and these changes correlated with social interaction and working memory impairments.
“A 2015 epigenetic study also using a single poly (I:C) injection found significantly increased rates of 5-methylcytosine and 5-hydroxymethylcytosine on the glutamic acid decarboxylase (GAD1) promoter”
- Also stated in: § Maternal Immune Activation · plain
“These changes correlated with social interaction and working memory impairments”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Labouesse et al, 2015 source
Not checked in the free run.
- Rests on an assumption: Findings from animal models of maternal immune activation and maternal autoantibody transfer are informative about the pathogenesis of human ASD.
- Also stated in: § Maternal Immune Activation · plain
May combine two claims.
PremisecitationMalkova et al. found that male MIA offspring had lower rates and total length of ultrasonic vocalizations, reduced sociability in the three-chamber test, and higher repetitive behaviors.
“The authors looked at ultrasonic vocalization (USV) responses among male offspring and found lower rates and total length of vocalizations.”
- Also stated in: § Maternal Immune Activation · plain
“The male MIA offspring also showed several autismrelevant changes, such as reduced sociability in the threechamber apparatus, spending more time in the nonsocial chamber and less time with the social object, as well as significantly higher rates of repetitive behaviors such as selfgrooming and marble burying.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Malkova et al, 2012 source
Not checked in the free run.
- Rests on an assumption: Findings from animal models of maternal immune activation and maternal autoantibody transfer are informative about the pathogenesis of human ASD.
- Also stated in: § Maternal Immune Activation · plain
May combine two claims.
PremisecitationHsiao et al. found that poly(I:C) MIA increased IL-6 levels, and treatment with Bacteroides fragilis corrected IL-6 levels, aberrant behavior, stereotypies, and anxiety-like symptoms.
“Another team also used a poly(I:C) MIA model to show increased IL-6 levels, and found that treatment with Bacteroides fragilis, which can repair tight junction integrity in the gut, corrected and restored IL-6 levels, aberrant behavior, stereotypies, and anxiety-like symptoms”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Hsiao et al, 2013 source
Not checked in the free run.
- Rests on an assumption: Findings from animal models of maternal immune activation and maternal autoantibody transfer are informative about the pathogenesis of human ASD.
May combine two claims.
PremisecitationIn follow-up work, pregnant mice challenged with influenza at E9.5 or poly(I:C) at E12.5 both had offspring with altered cerebellar development similar to autism.
“both groups had offspring with altered cerebellar development, akin to that seen in autism”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Shi et al, 2009 source
Not checked in the free run.
- Rests on an assumption: Findings from animal models of maternal immune activation and maternal autoantibody transfer are informative about the pathogenesis of human ASD.
May combine two claims.
PremisecitationIn Smith et al., co-administering anti-IL-6 antibody rescued aberrant behaviors and transcriptional changes, while anti-IFN-γ or anti-IL-1β did not, suggesting a specific role for IL-6 in ASD etiology.
“When the authors coadministered a neutralizing anti-IL-6 antibody to pregnant dams, they observed an apparent rescue of the aberrant behaviors and reversal of transcriptional changes; these rescue effects were not seen in the context of co-administered anti-IFN-γ or anti-IL-1β antibody, suggesting a specific role for IL-6 in the etiology of ASD.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Smith et al, 2007 source
Not checked in the free run.
- Rests on an assumption: Findings from animal models of maternal immune activation and maternal autoantibody transfer are informative about the pathogenesis of human ASD.
May combine two claims.
PremisecitationThe maternal immune activation model has repeatedly produced consistent results and supports a subset of autism with autism-relevant atypical behaviors.
“Some of the strongest support for maternal infection as a contributor to autism has come from the maternal immune activation (MIA) model, which has repeatedly shown consistent results, helping to establish a subset of autism that is supported by observations of autism-relevant atypical behaviors.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Gilmore et al, 2005 source
Not checked in the free run.
- cites Meyer et al, 2005 source
Not checked in the free run.
- cites Urakubo et al, 2001 source
Not checked in the free run.
- Rests on an assumption: Findings from animal models of maternal immune activation and maternal autoantibody transfer are informative about the pathogenesis of human ASD.
May combine two claims.
PremisecitationChoi et al. found that anti-IL-17 antibody given 2 days after MIA rescued some phenotypes such as ultrasonic vocalization calls and marble burying but not interaction deficits.
“treatment of the anti-IL-17 antibody 2 days after MIA induction saw rescue of some phenotypes, such as USV calls and marble burying, but not others, including interaction deficits”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Choi et al, 2016 source
Not checked in the free run.
- Rests on an assumption: Findings from animal models of maternal immune activation and maternal autoantibody transfer are informative about the pathogenesis of human ASD.
May combine two claims.
InterpretationcitationThe Th17 cell/IL-17 pathway may be critical in MIA-induced autism, with upregulated IL-17 acting downstream of increased IL-6.
“Put together, this suggests that the Th17 cell/IL-17 pathway may be critical in MIA-induced autism, caused by upregulated IL-17 acting downstream of increased IL-6 levels.”
Quote in the paperSubstantial claim- Rests on an assumption: Findings from animal models of maternal immune activation and maternal autoantibody transfer are informative about the pathogenesis of human ASD.
May combine two claims.
PremisecitationShi et al. infected pregnant mice with human influenza virus and observed abnormal behavior, exploration, and social interaction in their offspring.
“Shi et al (2003) infected two strains of pregnant mice with human influenza virus and observed abnormal behavior, exploration, and social interaction in their offspring.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Shi et al, 2003 source
Not checked in the free run.
- Rests on an assumption: Findings from animal models of maternal immune activation and maternal autoantibody transfer are informative about the pathogenesis of human ASD.
May combine two claims. The quote only partly states this claim.
PremisecitationSinger et al. found higher rates of anti-fetal brain antibodies in 100 mothers of children with autism compared with 100 control mothers, with targets at 73 kDa and 36 kDa and other brain-region-specific targets.
“Another study published that year looked at serum from 100 mothers of children with autism, again finding higher rates of anti-fetal brain antibodies as compared with 100 control mothers”
- Also stated in: § Transplacental Maternal Autoantibodies to the Fetal Brain · plain
“These antibodies were positive to adult and fetal human and rat brain proteins, including targets at 73 kDa and 36 kDa”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Singer et al, 2008 source
Not checked in the free run.
- Also stated in: § Transplacental Maternal Autoantibodies to the Fetal Brain · plain
May combine two claims.
PremisecitationBauman et al. extended the poly(I:C) maternal activation model to rhesus macaques and found abnormal vocal communication, social interaction, and repetitive behaviors in the offspring.
“A 2014 study by Bauman et al (2014), broadened the poly (I:C) maternal activation model to rhesus macaques, showing many abnormal behaviors, including in vocal communication and social interaction, as well as repetitive behaviors in the offspring of treated females.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Bauman et al, 2014 source
Not checked in the free run.
- Rests on an assumption: Findings from animal models of maternal immune activation and maternal autoantibody transfer are informative about the pathogenesis of human ASD.
May combine two claims.
PremisecitationMaternal fever may correlate with ASD risk, and this risk may be reduced by anti-fever medications.
“Some studies suggest fever as a correlate (Atladottir et al, 2012), with this risk potentially tempered by anti-fever medications, such as Advil, Tylenol, or Nyquil”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationWeber-Stadlbauer et al. found that offspring of mice given a single poly(I:C) injection at E9 had reduced interaction and increased fear expression, and several autism-relevant traits persisted through the paternal line to F2 and F3 generations with gene expression differences.
“finding that offspring of pregnant mice given a single poly (I:C) injection at day E9 showed reduced interaction (via the three-chamber apparatus) and increased fear expression in a cued Pavlovian conditioning test”
- Also stated in: § Maternal Immune Activation · plain
“they showed that several autism-relevant traits only persisted through the paternal line, without any further intervention, through the F2 and even the F3 generations, resulting in significant differences in gene expression”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Weber-Stadlbauer et al, 2016
Not checked in the free run.
- Rests on an assumption: Findings from animal models of maternal immune activation and maternal autoantibody transfer are informative about the pathogenesis of human ASD.
- Also stated in: § Maternal Immune Activation · plain
May combine two claims.
PremisecitationClass I A*01, A*02, and B*07 are positively associated with autism, while DRB1*03 and some DQB1 alleles are negatively associated.
“Other positively associated alleles are the class I A*01, A*02, and B*07, while DRB1*03 and some DQB1 alleles have been negatively associated with rates of autism (Al-Hakbany et al, 2014;Mostafa et al, 2013;Torres et al, 2006).”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationSinger et al. exposed pregnant mice to IgG from mothers of children with autism daily between E13 and E18 and observed alterations in sociability and anxiety.
“Singer et al (2009) exposed pregnant mice to IgG from mothers of children with autism daily between E13 and E18, observing alterations in sociability and anxiety.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Singer et al, 2009 source
Not checked in the free run.
- Rests on an assumption: Findings from animal models of maternal immune activation and maternal autoantibody transfer are informative about the pathogenesis of human ASD.
May combine two claims.
PremisecitationStrong correlations were found between the presence of anti-brain autoantibodies and aberrant behaviors, as well as decreased cognitive and adaptive functioning.
“The authors also found strong correlations between the presence of those antibodies and aberrant behaviors, as well as decreased cognitive and adaptive functioning.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Goines et al, 2011a
Not checked in the free run.
May combine two claims.
PremisecitationThe DRB1*11 and DRB1*1104 alleles occur at a higher rate in individuals with ASD.
“The DRB1*11 (Mostafa et al, 2013) and DRB1*1104 (Al-Hakbany et al, 2014) alleles have specifically been noted to occur at a higher rate in individuals with ASD.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Mostafa et al, 2013 source
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- cites Al-Hakbany et al, 2014
Not checked in the free run.
May combine two claims.
PremisecitationDalton et al. injected maternal serum containing anti-brain antibodies into pregnant mice daily between E10 and E17 and observed reduced exploration and motor control in the offspring compared with untreated dams.
“investigators injected maternal serum containing anti-brain antibodies into pregnant mice daily between E10 and E17, and observed reduced exploration and motor control in their offspring as compared with the offspring of untreated dams”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Dalton et al, 2003 source
Not checked in the free run.
- Rests on an assumption: Findings from animal models of maternal immune activation and maternal autoantibody transfer are informative about the pathogenesis of human ASD.
May combine two claims.
PremisecitationHLA-DR4 appears at increased rates in children with autism and in their mothers.
“Multiple studies have suggested HLA-DR4 as another risk factor, appearing at increased rates in children with autism as well as their mothers (Johnson et al, 2009;Lee et al, 2006).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationMartinez-Cerdeno et al. found structural changes in offspring of pregnant mice injected with autoreactive IgG, including higher radial glial cell proliferation and increased brain and neuron size.
“A follow on study using the same technique showed structural changes in the offspring of pregnant mice injected with autoreactive IgG, including higher proliferation of radial glial cells and increased brain and neuron size”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Martinez-Cerdeno et al, 2016 source
Not checked in the free run.
- Rests on an assumption: Findings from animal models of maternal immune activation and maternal autoantibody transfer are informative about the pathogenesis of human ASD.
May combine two claims.
PremisecitationBraunschweig et al. found that 23% of mothers of children with ASD had reactivity to highly specific antigen patterns compared with 1% of TD mothers, suggesting 98% specificity and 23% sensitivity.
“Confirmatory analysis of the identified targets confirmed that 23% of mothers whose children had ASD had reactivity to the highly specific antigen patterns compared with 1% of TD mothers.This preliminary analysis suggests a specificity of 98% with a sensitivity of 23%.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Braunschweig et al, 2013 source
Not checked in the free run.
May combine two claims. The quote only partly states this claim.
PremisecitationBauman et al. treated eight pregnant macaques with purified IgG from mothers positive for 37/73 kDa antibodies and found offspring deviations including rebuffed and unreciprocated friendship approaches and inappropriate vocalization, plus increased total cerebral volume.
“The authors then treated eight pregnant macaques with that IgG six times over the course of the second and third trimesters, and assessed macaque offspring for 2 years using a battery of developmental and social tests.They observed a number of deviations from typical behavior as compared with animals treated with IgG from mothers of TD children as well as untreated controls, including rebuffed and”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Bauman et al, 2013 source
Not checked in the free run.
- Rests on an assumption: Findings from animal models of maternal immune activation and maternal autoantibody transfer are informative about the pathogenesis of human ASD.
Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.
Interpretationnone givenThere is a broad picture of ASD-related immune dysregulation, including an increased inflammatory cytokine milieu such as IL-6, IL-8, and MCP-1, leading to an increased pro-inflammatory Th1/Th2 ratio.
“There also exists a broad picture of ASD-related immune dysregulation, including an increased inflammatory cytokine milieu (eg, IL-6, IL-8, and MCP-1), thus leading to an increased, pro-inflammatory Th1/Th2 ratio.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationCamacho et al. injected pregnant mice once intraventricularly at E14 with IgG from mothers with the 37 and 73 kDa autoantibodies or control mothers and observed atypical behaviors including stereotypical self-grooming and increased marble burying.
“A 2014 study injected pregnant mice only once, intraventricularly, on E14, with IgG from either mothers with the 37 and 73 kDa autoantibodies or control mothers; the authors observed atypical behaviors in the murine offspring, including stereotypical self-grooming and increased marble burying”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Camacho et al, 2014 source
Not checked in the free run.
- Rests on an assumption: Findings from animal models of maternal immune activation and maternal autoantibody transfer are informative about the pathogenesis of human ASD.
May combine two claims.
PremisecitationMartin et al. exposed pregnant macaques to IgG reactive or nonreactive to monkey brain protein and found higher motor activity and stereotypies among patient-treated offspring.
“A related study collected sera from both mothers of autistic and TD children, and exposed pregnant macaques to IgG either reactive or nonreactive to monkey brain protein, verified via western blot.The authors found higher levels of motor activity and stereotypies among patient-treated macaque offspring”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Martin et al, 2008 source
Not checked in the free run.
- Rests on an assumption: Findings from animal models of maternal immune activation and maternal autoantibody transfer are informative about the pathogenesis of human ASD.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAutoantibodies are associated with other neurological disorders, including schizophrenia and multiple sclerosis.
“Given the existence of autoantibodies associated with other neurological disorders such as schizophrenia (Henneberg et al, 1994) and multiple sclerosis (Ryberg, 1982)”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
InterpretationcitationAutoantibodies to these proteins in specific combinations were predictive for autism risk, suggesting a distinct maternal autoantibody-driven subset of ASD.
“In specific combinations, autoantibodies to these proteins were predictive for autism risk, which, although still at the level of laboratory research, suggests the presence of a distinct, maternal autoantibodydriven subset of ASD.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Braunschweig et al, 2013 source
Not checked in the free run.
- Rests on an assumption: Findings from animal models of maternal immune activation and maternal autoantibody transfer are informative about the pathogenesis of human ASD.
May combine two claims.
PremisecitationBraunschweig et al. found that paired reactivity to the 37 and 73 kDa bands correlated with lower expressive language, and reactivity to a 39 kDa band and paired 39/73 kDa reactivity correlated with broader ASD diagnosis and increased irritability on the Aberrant Behavior Checklist.
“finding that paired brain reactivity (ie, to the 37 and 73 kDa bands) correlated with lower expressive language”
- Also stated in: § Transplacental Maternal Autoantibodies to the Fetal Brain · plain
“reactivity to a protein band near 39 kDa was discovered, and paired reactivity to proteins at 39 and 73 kDa correlated with broader diagnosis of ASD as well as increased irritability on the Aberrant Behavior Checklist (ABC) scale”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Braunschweig et al, 2012a
Not checked in the free run.
- cites Piras et al, 2014 source
Not checked in the free run.
- Also stated in: § Transplacental Maternal Autoantibodies to the Fetal Brain · plain
May combine two claims.
InterpretationcitationThe western blot and immunohistochemistry results were strongly correlative, reinforcing the finding of an ASD subset with persistent circulating anti-brain antibodies.
“The western blot and IHC results were strongly correlative, reinforcing the findings of an ASD subset with persistent circulating anti-brain antibodies.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Wills et al, 2009 source
Not checked in the free run.
May combine two claims.
InterpretationcitationAutistic patients showed no decrease in overall NK count, similar to schizophrenia, suggesting that the cells themselves are dysfunctional.
“Autistic patients showed no decrease in overall NK count, a similar result to schizophrenia (DeLisi et al, 1983), suggesting that it is the cells themselves that are dysfunctional.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites DeLisi et al, 1983 source
Not checked in the free run.
May combine two claims.
InterpretationreasoningNK cells from individuals with ASD show higher resting but reduced stimulated cytolytic activity compared with typical developing controls.
“In essence, NK cells from individuals with ASD show higher resting but reduced stimulated cytolytic activity as compared with TD controls.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Enstrom et al, 2009b
Not checked in the free run.
May combine two claims.
PremisecitationThe authors suggest that these expression differences are unlikely to be directly pathological and that broad immunomodulation may be symptomatic of a larger cellular dysregulation.
“the authors suggest that these differences are unlikely to be directly pathological in their own right; rather, the evidence suggests broad immunomodulation as symptomatic of a larger cellular dysregulation”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Voineagu et al, 2011 source
Not checked in the free run.
May combine two claims.
PremisecitationIn control brains, dozens of genes showed different expression between temporal and frontal lobes, and these differences were not mirrored in ASD samples.
“In the control brains, dozens of genes exhibited different expression levels between the temporal and frontal lobes of the brain; these differences were not mirrored in the ASD samples.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Voineagu et al, 2011 source
Not checked in the free run.
Classified as probably not a substantial claim.
InterpretationreasoningAltered efficacy and faulty tolerance toward the fetus by maternal NK cells during pregnancy could provide a mechanism for atypical development.
“an altered efficacy and faulty tolerance toward the fetus by maternal NK cells during pregnancy, thus compromising the privileged status of the fetus, could provide a mechanism for atypical development.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationcitationMany of these genes showed increased variability in the autism cohort, suggesting general dysregulation of the autistic immune system and a heterogeneous activation response.
“Many of these genes showed increased variability in the autism cohort, which suggests a general dysregulation of the autistic immune system and overall heterogeneous activation response.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Garbett et al, 2008 source
Not checked in the free run.
May combine two claims.
InterpretationcitationSimilar significant differences were seen in mothers, suggesting a broad influence of the genetic background of NK activity, especially since KIR/HLA complexes are expressed and active in the placenta.
“Similarly significant differences were seen following genotyping of the mothers, suggesting a broad influence of the genetic background of NK activity, especially given that KIR/HLA complexes are expressed and active in the placenta (Guerini et al, 2014;Parham, 2005).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationAmong upregulated genes in NK cells, annotations were highly enriched for NK activity and immune response and defense, while protein biosynthesis and metabolism were downregulated.
“Among all upregulated genes found in NK cells, annotations were highly enriched for NK activity and immune response and defense, while protein biosynthesis and metabolism were downregulated.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Enstrom et al, 2009b
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationNext-generation sequencing and genome-wide association studies generally find a complex and varied genomic landscape in autism.
“researchers have utilized the advanced techniques of next-generation sequencing and genome-wide association studies (GWAS) in an attempt to divine the genetic causes of autism, generally finding a complex and varied genomic landscape (Abrahams and Geschwind, 2008;Gaugler et al, 2014;Michel et al, 2012).”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationHLA-G interacts with natural killer cells as part of the innate immune system and is primarily expressed in placental tissues as part of immune tolerance during pregnancy.
“HLA-G interacts with natural killer cells as part of the innate immune system and is primarily expressed in placental tissues as part of immune tolerance during pregnancy (Carosella et al, 2008).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Carosella et al, 2008 source
Not checked in the free run.
May combine two claims.
PremisecitationA 1986 study found a reduced number of T cells in individuals with autism and an altered helper to suppressor T-cell ratio.
“A 1986 study found a reduced number of T cells in individuals with autism, as well as an altered helper to suppressor T-cell ratio (Warren et al, 1986)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Warren et al, 1986 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationA model proposes that a dysregulated immune system leads to increased metabolism and reactive oxygen species pre- and postnatally, with prenatal changes in proliferation, migration, and neuronal wiring, and postnatal mitochondrial dysfunction and ROS stress leading to abnormal synaptic formation.
“Lintas et al (2012) proposed a model whereby the dysregulated immune system leads to increased metabolism and reactive oxygen species (ROS) in both the pre-and postnatal environment.They suggest that such alterations would result in prenatal changes in proliferation, migration, and neuronal wiring, while postnatal mitochondrial dysfunction and ROS stress would lead to abnormal synaptic formation.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Lintas et al (2012) source
Not checked in the free run.
May combine two claims.
PremisecitationThe MET variant appears connected to an increase in 37/73 kDa maternal autoantibodies and a decrease in maternal IL-10.
“This MET variant also appears connected to both an increase in 37/73 kDa maternal autoantibodies and a decrease in maternal IL-10, suggesting another mechanism through which MET may associate with ASD as a susceptibility factor (Heuer et al, 2011).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Heuer et al, 2011 source
Not checked in the free run.
May combine two claims.
InterpretationreasoningThere appears to be a strong immunogenetic component to many examples of ASD, but no single thread.
“While there appears to be a strong immunogenetic component to many examples of ASD, there is no one single thread.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationThe CC and CG alleles at this MET site represent 1.76 and 1.59 relative risk over the GG allele, with an odds ratio of 1.64 for the C variant.
“Recent estimates at this site suggest that the CC and CG alleles represent a 1.76 and 1.59 relative risk, respectively, over the GG allele (Campbell et al, 2008), with an odds ratio of 1.64 for the C variant (Jackson et al, 2009).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationThese genes are heavily overrepresented in the KEGG natural killer cytotoxicity pathway and are highly expressed in NK and CD8 T cells.
“These genes are heavily overrepresented in the ontological KEGG natural killer cytotoxicity pathway, and are highly expressed in NK and CD8 T cells.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Gregg et al, 2008 source
Not checked in the free run.
May combine two claims.
PremisecitationAmong 90 continental Italian children with ASD, activating KIR/HLA complexes (aKIR2DS2) were increased and inhibitory KIR/HLA complexes (KIR 3DL1/HLA-Bw4-80I) were decreased relative to controls.
“The authors demonstrated that among a cohort of 90 continental Italian children with ASD, rates of activating KIR/HLA complexes (aKIR2DS2) were increased, while inhibitory KIR/HLA complexes (KIR 3DL1/HLABw4-80I) were decreased in the genome relative to controls.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Guerini et al (2014) source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIL-17 has an outsized role in other autoimmune conditions such as SLE and rheumatoid arthritis.
“This is especially so given the outsized role IL-17 has in other autoimmune conditions such as SLE and rheumatoid arthritis (Konya et al, 2015).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Konya et al, 2015 source
Not checked in the free run.
May combine two claims.
PremisecitationLower IgG1 levels were found in the serum of boys with ASD, with a negative correlation to communication as scored by the ADI-R.
“These findings are further supported by a recent report of lower IgG1 levels in the serum of boys with ASD, along with a similarly negative correlation to communication as scored by the ADI-R (Zaman et al, 2016).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Zaman et al, 2016 source
Not checked in the free run.
May combine two claims.
InterpretationcitationAge of the children is most likely a contributing factor to discrepancies in IgG levels, with IgG levels changing significantly and rapidly through the first decade of life.
“age of the children is most likely a contributing factor, with IgG levels changing significantly and rapidly through the first decade of life (Heuer et al, 2008).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Heuer et al, 2008 source
Not checked in the free run.
May combine two claims.
PremisecitationEnstrom et al found decreased plasma intracellular IL-23 in children with ASD, but no change in IL-17.
“Enstrom et al (2008) found decreased plasma intracellular IL-23 in children with ASD, but no such change in IL-17”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Enstrom et al (2008) source
Not checked in the free run.
May combine two claims.
PremisecitationPBMCs from children with ASD produce higher levels of TNF-α and IFN-γ but not IL-5, lending credence to a Th1-dominated response.
“In the context of dietary proteins and food hypersensitivity, PBMCs from children with ASD produce higher levels of TNF-α and IFN-γ but not IL-5, further lending credence to a Th1-dominated response (Jyonouchi et al, 2005;Jyonouchi et al, 2002).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationIL-23 induces IL-17, and IL-17 is important for inducing the MIA model of autism.
“Given that IL-23 induces IL-17 and the importance of IL-17 for inducing the MIA model of autism (Choi et al, 2016)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Choi et al, 2016 source
Not checked in the free run.
May combine two claims.
PremisecitationA later study indicated that a Th2-like response was present at birth and connected increased IL-4 to more severe autism.
“which was supported by a later study that indicated a Th2-like response was present at birth and connected increased IL-4 to more severe autism (Krakowiak et al, 2015).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Krakowiak et al, 2015
Not checked in the free run.
May combine two claims.
PremisecitationCD57+CD3- NK cells are terminally differentiated, have higher cytolytic capabilities, act as innate immune regulators, are less responsive to cytokines, and are connected to autoimmunity and immunodeficiency.
“These NK cells are functionally different than traditional, CD56 + NK cells-they are terminally differentiated and have higher cytolytic capabilities, and generally act as innate immune regulators despite being less responsive to cytokines and connected to autoimmunity and immunodeficiency (Lopez-Verges et al, 2010;Nielsen et al, 2013).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationA Th1-like response correlated with greater impairments and behavior aberrancies, and a Th2-like response correlated with better cognitive and adaptive function.
“A related study by the same team supported these findings using PHAstimulated PBMCs, and correlated a Th1-like response with greater impairments and behavior aberrancies and a Th2-like response to better cognitive and adaptive function (Ashwood et al, 2011b).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Ashwood et al, 2011b
Not checked in the free run.
May combine two claims.
InterpretationreasoningNK cells in ASD individuals appear to have baseline activity already at peak function, rendering them ill equipped for normal circulation and unable to respond further to stimulation.
“NK cells in ASD individuals appear to have a baseline level of activity that is already at peak function, rendering them ill equipped for normal circulation and unable to respond further to stimulation.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Enstrom et al, 2009b
Not checked in the free run.
May combine two claims.
InterpretationcitationEvidence strongly supports distinct roles for both maternal and patient autoantibodies in ASD, including an ability to affect structural brain development.
“The evidence strongly supports distinct roles for both maternal (Braunschweig et al, 2008;Croen et al, 2008b;Singer et al, 2008;Zimmerman et al, 2007) and patient (Henneberg et al, 1994;Libbey and Fujinami, 2010;Ryberg, 1982) autoantibodies in ASD, including an ability to affect structural brain development (Nordahl et al, 2013;Rossi et al, 2011).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Braunschweig et al, 2008
Not checked in the free run.
- cites Croen et al, 2008b
Not checked in the free run.
- cites Singer et al, 2008 source
Not checked in the free run.
May combine two claims.
PremisecitationNumerous studies have demonstrated a correlation between cytokine levels and ASD status, and there is consensus that cytokines and chemokines are part of the altered immune environment in autism.
“Numerous studies have demonstrated a correlation between cytokine levels and ASD status, and while there is a consensus that cytokines and chemokines are part of the altered immune environment noted in autism (Depino, 2013;Enstrom et al, 2010)”
Quote in the paperSubstantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe research community has long noticed a correspondence between ASD and autoimmune diseases, with some suggesting that autism should be considered an autoimmune disorder.
“The research community has long noticed a correspondence between ASD and autoimmune diseases, with some suggesting autism should itself be considered an autoimmune disorder (Ashwood and Van de Water, 2004).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Ashwood and Van de Water, 2004 source
Not checked in the free run.
May combine two claims.
InterpretationcitationJust 30% of children with ASD had normal CD57+ NK cell levels, despite typical levels of CD56+ NK cells, suggesting that CD57+ cells are implicated in autism.
“Just 30% of children with ASD had normal CD57 + NK cell levels, despite typical levels of CD56 + NK cells, suggesting that it is the CD57 + cells that are implicated in autism.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Siniscalco et al, 2016
Not checked in the free run.
May combine two claims.
PremisecitationAl-Ayadhi and Mostafa and Akintunde et al found evidence of elevated IL-17 levels among children with ASD in serum and PHA-stimulated PBMCs, respectively.
“while Al-Ayadhi and Mostafa (2012) and Akintunde et al (2015) found evidence of elevated IL-17 levels among such children in serum and PHA-stimulated PBMCs, respectively.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Al-Ayadhi and Mostafa (2012)
Not checked in the free run.
- cites Akintunde et al (2015) source
Not checked in the free run.
May combine two claims.
PremisecitationAlthough there is a correlation between maternal and patient autoantibodies, there appear to be at least some differences in effect.
“although there exists a correlation between the two there does appear to be at least some differences in effect (Piras et al, 2014).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Piras et al, 2014 source
Not checked in the free run.
May combine two claims.
PremisecitationA 2008 study of over 250 children found a reduction of plasma IgG and IgM levels in young children with autism, with IgG levels negatively correlated with ABC scores regardless of ASD status.
“a 2008 study of over 250 children found a reduction of plasma IgG and IgM levels circulating in young children with autism, in particular IgG, the levels of which correlated negatively with scores on the ABC, regardless of ASD status (Heuer et al, 2008).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Heuer et al, 2008 source
Not checked in the free run.
May combine two claims.
PremisecitationLi et al found elevated levels of IL-8, IL-6, GM-CSF, TNF-α, and IFN-γ in autistic brain tissue, with no increase in IL-4 or IL-5, and claimed an increased Th1/Th2 ratio.
“Li et al (2009) who not only found elevated levels of the chemokine IL-8, pro-inflammatory cytokines IL-6, GM-CSF, and TNF-α, and the Th1 cytokine IFN-γ in autistic brain tissue, but also saw no increase in IL-4 or IL-5; as such, the authors claimed an increase in the Th1/Th2 ratio, suggesting that the Th1 arm is activated in autism.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Li et al (2009)
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationLouveau et al showed active lymphatic vessels connecting the CNS to the lymphatic system that may act as a conduit for neuroimmunological dysfunction.
“the recent groundbreaking work by Louveau et al (2015) showing active lymphatic vessels connecting the CNS to the lymphatic system that may possibly act as a conduit for neuroimmunological dysfunction.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Louveau et al (2015) source
Not checked in the free run.
May combine two claims.
PremisecitationInflammation and immune signaling dysregulation can strongly influence neuropsychiatric behavior beyond ASD, with roles in bipolar disorder and PTSD, and perhaps most emphatically in schizophrenia.
“Inflammation and immune signaling dysregulation can strongly influence neuropsychiatric behavior beyond just ASD (Haroon et al, 2012;Meyer and Feldon, 2009), with evidence pointing toward roles in bipolar disorder and PTSD (Jones and Thomsen, 2013), and perhaps most emphatically in schizophrenia (Brown et al, 2004b;Meyer and Feldon, 2009;Michel et al, 2012;Patterson, 2009).”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
InterpretationreasoningData on immune dysregulation in ASD are beginning to coalesce, but the heterogeneity of ASD phenotypes makes it difficult to explain different behavioral outcomes based solely on immune phenotype, and this may contribute to spurious conclusions.
“Data from various studies regarding immune dysregulation in ASD are beginning to coalesce, but given the heterogeneity of ASD phenotypes, it remains difficult to explain different behavioral outcomes based solely on immune phenotype, and this may contribute to spurious conclusions.”
Quote in the paperSubstantial claim- Rests on an assumption: ASD comprises heterogeneous phenotypes that make it difficult to explain behavioral outcomes solely from immune phenotype.
Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Premisenone givenMany KIRs are genetically linked to ASD.
“NK cells interact with activating and inhibitory KIRs, many of which are genetically linked to ASD.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.
Interpretationnone givenRegulators of the immune system have long been featured prominently among the genetic components of autism and are likely to continue to be so.
“Regulators of the immune system have long been featured prominently among the genetic components of autism and are likely to continue to do so as we learn more about the myriad interactions taking place between the immune system and the brain.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisenone givenOther genetic factors in ASD include the oncogene MET.
“Other genetic factors include the oncogene MET and members of the diverse family of HLA genes.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationnone givenThe postnatal environment echoes the prenatal lines of development, with anti-brain antibodies and systemic inflammation providing evidence of anomalies in immune regulation in a subpopulation of children with ASD.
“The postnatal environment echoes those lines of development, with anti-brain antibodies and systemic inflammation providing evidence of anomalies in immune regulation in a subpopulation of children with ASD.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.
Premisenone givenPro-inflammatory cytokines such as IL-6 and IL-17 have been implicated in this process, but the mechanisms remain under investigation.
“Pro-inflammatory cytokines such as IL-6 and IL-17 have been implicated in this process, but the mechanisms remain under investigation.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisenone givenNatural killer cells engage both activating and inhibitory KIRs.
“NK cells interact with activating and inhibitory KIRs, many of which are genetically linked to ASD.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationSchizophrenia and autism share many immune similarities, including a subset of patients with an etiology based in maternal infection and immune activation.
“Schizophrenia and autism share many immune similarities, including a subset of patients with an etiology based in maternal infection and immune activation (Bauman et al, 2014;Boksa, 2010;Brown et al, 2004a;Meyer et al, 2005Meyer et al, , 2007;;Patterson, 2009;Urakubo et al, 2001).”
Quote in the paperNot a substantial claim0 of 3 sources checked
The paper relies on this without support.
Findings from animal models of maternal immune activation and maternal autoantibody transfer are informative about the pathogenesis of human ASD.
“Animal models of MIA have been particularly significant in underscoring the importance of maternal immune regulation.”
“animal models have been repeatedly utilized to bolster the findings of maternal anti-brain autoantibodies, suggesting a directly causative effect”
The paper relies on this without support.
ASD can be divided into immune-related subphenotypes that are meaningful for diagnosis and treatment.
“it is the heterogeneity within this disorder that has brought to light much of the current thinking regarding the subphenotypes within ASD and how the immune system is associated with these distinctions”
The paper relies on this without support.
ASD comprises heterogeneous phenotypes that make it difficult to explain behavioral outcomes solely from immune phenotype.
“given the heterogeneity of ASD phenotypes, it remains difficult to explain different behavioral outcomes based solely on immune phenotype”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
A well-established non-genetic model system for studying ASD pathophysiology is the prenatal maternal immune activation (MIA) model.
“A well-established non-genetic model system for studying ASD pathophysiology is the prenatal maternal immune activation (MIA) model [114–116].”
From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [116]
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- Authors
- Meltzer, A., & Van de Water, J.
- Affiliations
- University of California, Davis (US)
- ORCID
- Meltzer, Amory
- Venue
- Neuropsychopharmacology
- Published
- 2016-08-18
- Volume
- 42
- Issue
- 1
- Pages
- 284-298
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC5143489
- OpenAlex
- W2515862236
- Semantic Scholar
- a877d7d9d3d51ab3253406fddfd39c82460073d0
- Cited by
- 533
- References
- 160
- Citations by year
- 2026: 48 · 2025: 41 · 2024: 67 · 2023: 57 · 2022: 81 · 2021: 62 · 2020: 77 · 2019: 49 · 2018: 28 · 2017: 20 · 2016: 2
- FWCI
- 3.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute of Environmental Health Sciences (R01ES015359, P01ES011269)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD079125)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- autism spectrum disorder, immune dysfunction, maternal infection, prenatal immune activation, maternal-fetal immune interaction, neuroinflammation, neurodevelopmental risk factors
- MeSH terms
- Autism Spectrum Disorder, Animals, Autoantibodies, Brain, Female, Humans, Inflammation, Pregnancy, Pregnancy Complications, Infectious, Prenatal Exposure Delayed Effects
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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