Elevated immune response in the brain of autistic patients

Li, Xiaohong; Chauhan, Abha; Sheikh, Ashfaq M.; Patil, Sangita; Chauhan, Ved; Li, Xiumin; Ji, Lina; Brown, Ted; Malik, Mazhar N.

doi:10.1016/j.jneuroim.2008.12.002

Cited by 678 publications

(495 citation statements)

References 24 publications

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“…Various stimuli, such as the bacterial lipopolysaccharide (LPS) (14,17), have been shown to switch microglia into the M1 phenotype, denoted by the release of proinflammatory cytokines, interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF) (18), as well as the chemokines (C-C motif) ligand 2 (CCL2) and CCL5 (8,19), also found to be increased in brains of deceased patients with ASD. Immune dysfunction (18,(20)(21)(22) and inflammation of the brain (23)(24)(25) are now invoked in the pathogenesis of ASD.…”

mentioning

confidence: 99%

Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism

Patel

Tsilioni

Leeman

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

112

104

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We had reported elevated serum levels of the peptide neurotensin (NT) in children with autism spectrum disorders (ASD). Here, we show that NT stimulates primary human microglia, the resident immune cells of the brain, and the immortalized cell line of human microglia-SV40. NT (10 nM) increases the gene expression and release (P < 0.001) of the proinflammatory cytokine IL-1β and chemokine (C-X-C motif) ligand 8 (CXCL8), chemokine (C-C motif) ligand 2 (CCL2), and CCL5 from human microglia. NT also stimulates proliferation (P < 0.05) of microglia-SV40. Microglia express only the receptor 3 (NTR3)/sortilin and not the NTR1 or NTR2. The use of siRNA to target sortilin reduces (P < 0.001) the NT-stimulated cytokine and chemokine gene expression and release from human microglia. Stimulation with NT (10 nM) increases the gene expression of sortilin (P < 0.0001) and causes the receptor to be translocated from the cytoplasm to the cell surface, and to be secreted extracellularly. Our findings also show increased levels of sortilin (P < 0.0001) in the serum from children with ASD (n = 36), compared with healthy controls (n = 20). NT stimulation of microglia-SV40 causes activation of the mammalian target of rapamycin (mTOR) signaling kinase, as shown by phosphorylation of its substrates and inhibition of these responses by drugs that prevent mTOR activation. NT-stimulated responses are inhibited by the flavonoid methoxyluteolin (0.1–1 μM). The data provide a link between sortilin and the pathological findings of microglia and inflammation of the brain in ASD. Thus, inhibition of this pathway using methoxyluteolin could provide an effective treatment of ASD.

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mentioning

confidence: 99%

Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism

Patel

Tsilioni

Leeman

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

112

104

View full text Add to dashboard Cite

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“…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. 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).…”

Section: Immune Dysregulationmentioning

confidence: 87%

“…The notion of a more pro-inflammatory environment was supported by 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.…”

Section: Immune Dysregulationmentioning

confidence: 99%

The Role of the Immune System in Autism Spectrum Disorder

Meltzer

Water

2016

Neuropsychopharmacol

405

293

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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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“…Injections of IgG collected from mothers of children with ASD into pregnant rhesus monkeys during the first and second trimesters led to altered brain volume and social behavior development in the offspring [75]. Analyses of post-mortem brain tissues of ASD patients with ages ranging from children to adults have revealed microglia activation and increased cytokines including TNF-α and IL-6, suggesting ongoing neuroinflammation in the brains of ASD patients [76,77]. These findings indicate that immune responses may impact on ASD pathogenesis.…”

Section: Immune Dysregulation In Asdmentioning

confidence: 99%

Genetic architecture, epigenetic influence and environment exposure in the pathogenesis of Autism

2015

Sci. China Life Sci.

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Autism spectrum disorder (ASD) is a spectral neurodevelopment disorder affecting approximately 1% of the population. ASD is characterized by impairments in reciprocal social interaction, communication deficits and restricted patterns of behavior. Multiple factors, including genetic/genomic, epigenetic/epigenomic and environmental, are thought to be necessary for autism development. Recent reviews have provided further insight into the genetic/genomic basis of ASD. It has long been suspected that epigenetic mechanisms, including DNA methylation, chromatin structures and long non-coding RNAs may play important roles in the pathology of ASD. In addition to genetic/genomic alterations and epigenetic/epigenomic influences, environmental exposures have been widely accepted as an important role in autism etiology, among which immune dysregulation and gastrointestinal microbiota are two prominent ones. autism spectrum disorder, genetic architecture, genomic disorder, gene mutation, copy number variants, single nucleotide variants, genetic pathways, epigenetic influence, DNA methylation, chromatin remodeling, long non-coding RNAs, environment exposure, immune dysregulation, gastrointestinal microbiota Citation:Yu L, Wu YM, Wu BL. Genetic architecture, epigenetic influence and environment exposure in the pathogenesis of Autism. Sci China Life Sci, 2015, 58: 958-967,

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Elevated immune response in the brain of autistic patients

Cited by 678 publications

References 24 publications

Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism

Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism

The Role of the Immune System in Autism Spectrum Disorder

Genetic architecture, epigenetic influence and environment exposure in the pathogenesis of Autism

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