TH1/Treg ratio may be a marker of autism in children with immune dysfunction

Nie, Zu-Qing; Han, Dong Wook; Zhang, Kun; Li, Meng; Kwon, Ho-Keun; Im, Sungbin; Xu, Li; Yang, Jichun; Li, Zhiwei; Huang, Xin-Wei; Wen, Jin‐Kun; Shu-Jun, Yang; Yin, Fang‐Fang; Shen, Chen; Ashwood, Paul; Kang, Chuanyuan; Cao, Xia

doi:10.1016/j.rasd.2022.102085

Cited by 8 publications

(9 citation statements)

References 48 publications

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“…In a study led by Jing He [11,22] on systemic lupus erythematosus (SLE), the disease activity was signi cantly reduced by LdIL-2 through the regulation of the relative numbers of Tfh, Th17, and Treg cells. Different works had indicated that in ammatory cytokines, CD4+, CD8 + T cells in immune organs and peripheral blood, as well as varies of immune cells in brain of BTBR mice were disordered in different levels compared with those in C57 mice, including our observation before [15,23,24]. Notably, several studies demonstrated that number of Treg cells had decreased while Th1 and Th17 cells which were associated with in ammation increased in BTBR mice [12].…”

Section: Discussionmentioning

confidence: 53%

“…Alhosaini [14] also meliorated the behavioral de cits of ASD through rebuilding the immune system of BTBR mice. In previous study, we also noticed the imbalance of Th/Treg cells may have potentiality as a diagnostic marker in ASD with immune dysfunction (Nie et al, 2023). All of these evidences suggest restoring the immune system is signi cantly effective for therapy of ASD in BTBR mice.…”

Section: Introductionmentioning

confidence: 74%

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LdIL-2 Treatment in ASD: A Novel Immunotherapeutic Approach Targeting Th/Treg Dysfunction and Neuroinflammation

Cao,

Li,

Kui

et al. 2024

Preprint

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There was a large part of children with Autism Spectrum Disorder (ASD) were accompanied with immune imbalances. In this study, we attempted to ameliorate the core symptoms of autism by correcting the immune imbalance, especially the T-cell subpopulation imbalance, in BTBR mice with autism through low-dose IL-2 (LdIL-2). We administered LdIL-2 (30,000 IU) subcutaneously to BTBR mice and observed changes in autistic behaviors in the mice before and after treatment. Behavioral tests of the mice included three-chamber test, self-grooming test, sniffing test, marble burying test, and open field test. We also analyzed the changes in peripheral Th/Treg ratios and cytokines, as well as the changes in M1/M2 ratios of microglia in the central nervous system in mice using flow cytometry. Neuroinflammatory proteins in cerebrospinal fluid were detected by proteomic analysis. In addition, we depleted CD25 + Treg cells with PC61 followed by LdIL-2 intervention to observe the role of Treg cells in LdIL-2-treated BTBR mice. We found that the core symptoms of autism in BTBR mice were significantly improved after LdIL-2 treatment. LdIL-2 not only increased the level of Treg cells, reversed the imbalance of Th17/Treg and Tfh/Treg, and improved the immune imbalance. Meanwhile, central nervous system inflammation was reduced in mice. In contrast, the effect of LdIL-2 on behavioral improvement was attenuated after depletion of Treg cells by PC61. This is the first attempt to treat ASD with LdIL-2. LdIL-2 is safe and effective in improving core symptoms and immune imbalance in autism. Improvement in core symptoms was associated with an increase in Treg cell levels in the peripheral blood of BTBR mice after treatment with LdIL-2. LdIL-2 may be a potential therapy for the treatment of core symptoms of autism.

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Section: Discussionmentioning

confidence: 53%

Section: Introductionmentioning

confidence: 74%

LdIL-2 Treatment in ASD: A Novel Immunotherapeutic Approach Targeting Th/Treg Dysfunction and Neuroinflammation

Cao,

Li,

Kui

et al. 2024

Preprint

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“…Children with ASD with gastrointestinal (GI) comorbidities exhibited elevated populations of peripheral Th17 cells compared with ASD children without GI comorbidities, whereas ASD children without GI comorbidities were characterized by increased Th2 and Th1 populations compared with normal children [ 45 ]. More recently, elevated levels of Th1, Th2, and Th17 subpopulations and decreased levels of Treg were reported in ASD-diagnosed children compared with control children [ 46 ]. In the VPA model for ASD in mice, an increased inflammatory response with evidence for neuroinflammation was also observed in males, suggesting similar deregulation of the immune system in the VPA model as well [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

Exogenous IL-17A Alleviates Social Behavior Deficits and Increases Neurogenesis in a Murine Model of Autism Spectrum Disorders

Willinger,

Friedland Cohen,

Turgeman

2023

IJMS

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Among the proposed mechanisms for autism spectrum disorders (ASD) is immune dysregulation. The proinflammatory cytokine Interleukine-17A (IL-17A) was shown to play a key role in mediating immune-related neurodevelopmental impairment of social behavior. Nevertheless, post-developmental administration of IL-17A was found to increase social behavior. In the present study, we explored the effect of post-developmental administration of IL-17A on ASD-like behaviors induced by developmental exposure to valproic acid (VPA) at postnatal day 4. At the age of seven weeks, VPA-exposed mice were intravenously injected twice with recombinant murine IL-17A (8 μg), and a week later, they were assessed for ASD-like behavior. IL-17A administration increased social behavior and alleviated the ASD-like phenotype. Behavioral changes were associated with increased serum levels of IL-17 and Th17-related cytokines. Exogenous IL-17A also increased neuritogenesis in the dendritic tree of doublecortin-expressing newly formed neurons in the dentate gyrus. Interestingly, the effect of IL-17A on neuritogenesis was more noticeable in females than in males, suggesting a sex-dependent effect of IL-17A. In conclusion, our study suggests a complex role for IL-17A in ASD. While contributing to its pathology at the developmental stage, IL-17 may also promote the alleviation of behavioral deficits post-developmentally by promoting neuritogenesis and synaptogenesis in the dentate gyrus.

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“…The neuroimmune‐inflammatory hypothesis of ASD has received a great deal of attention, as numerous researchers have pointed to an immune system imbalance in ASD patients (Croonenberghs et al, 2002; Ormstad, Bryn, Saugstad, et al, 2018; Warren et al, 1986). Numerous original studies (Croonenberghs et al, 2002; Nie et al, 2023; Xu et al, 2015), meta‐analyses (Masi et al, 2015; Zhao et al, 2021), and gene network analyses based on meta‐analysis‐generated genes, mRNA and protein data (Gevezova et al, 2023) demonstrate an activated immune response system (IRS) in ASD with increased production of macrophage and T helper (Th)1, Th2, and Th17 cytokines, such as tumor necrosis factor‐ (TNF)‐α, migration inhibitory factor (MIF), interleukin (IL)‐1, IL‐6, IL‐8, IL‐7, IL‐12p70, CCL11, and monocyte chemoattractant protein‐1 (MCP‐1), IL‐1 receptor antagonist (IL‐1RA), and interferon (IFN)‐γ. Furthermore, some meta‐analyses found that children with ASD have significantly elevated C‐reactive protein (CRP) (Gardner et al, 2021; Nadeem, Hussain, & Sajid, 2020; Yin et al, 2020) along with decreased α‐2‐macroglobulin, ceruloplasmin, and transferrin (Chauhan et al, 2004; Gardner et al, 2021; Hergüner et al, 2012) and increased cortisol (Corbett et al, 2010; Spratt et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, some meta‐analyses found that children with ASD have significantly elevated C‐reactive protein (CRP) (Gardner et al, 2021; Nadeem, Hussain, & Sajid, 2020; Yin et al, 2020) along with decreased α‐2‐macroglobulin, ceruloplasmin, and transferrin (Chauhan et al, 2004; Gardner et al, 2021; Hergüner et al, 2012) and increased cortisol (Corbett et al, 2010; Spratt et al, 2012). Additionally, it has been reported that in ASD, the activity of T regulatory (Treg) cells was significantly reduced together with lowered concentrations of IL‐1RA and IL‐10, two immunoregulatory cytokines which are essential components of the compensatory immunoregulatory response system (CIRS) (Ashwood, 2023; Nie et al, 2023; Saghazadeh et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

The tryptophan catabolite or kynurenine pathway in autism spectrum disorder; a systematic review and meta‐analysis

Almulla,

Thipakorn,

Tunvirachaisakul

et al. 2023

Autism Research

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Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social communication and interaction, as well as rigid and unchanging interests and behaviors. Several studies have reported that activated immune‐inflammatory and nitro‐oxidative pathways are accompanied by depletion of plasma tryptophan (TRP), increased competing amino acid (CAAs) levels, and activation of the TRP catabolite (TRYCAT) pathway. This study aims to systematically review and meta‐analyze data on peripheral TRP, CAAs, TRYCAT pathway activity, and individual TRYCATs, including kynurenine (KYN) and kynurenic acid (KA) levels, in the blood and urine of ASD patients. After extensively searching PubMed, Google Scholar, and SciFinder, a total of 25 full‐text papers were included in the analysis, with a total of 6653 participants (3557 people with ASD and 3096 healthy controls). Our results indicate that blood TRP and the TRP/CAAs ratio were not significantly different between ASD patients and controls (standardized mean difference, SMD = −0.227, 95% confidence interval, CI: −0.540; 0.085, and SMD = 0.158, 95% CI: −0.042; 0.359), respectively. The KYN/TRP ratio showed no significant difference between ASD and controls (SMD = 0.001, 95% CI: −0.169; 0.171). Blood KYN and KA levels were not significantly changed in ASD. Moreover, there were no significant differences in urine TRP, KYN, and KA levels between ASD and controls. We could not establish increases in neurotoxic TRYCATs in ASD. In conclusion, this study demonstrates no abnormalities in peripheral blood TRP metabolism, indoleamine 2,3‐dioxygenase enzyme (IDO) activity, or TRYCAT production in ASD. Reduced TRP availability and elevated neurotoxic TRYCAT levels are not substantial contributors to ASD's pathophysiology.

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TH1/Treg ratio may be a marker of autism in children with immune dysfunction

Cited by 8 publications

References 48 publications

LdIL-2 Treatment in ASD: A Novel Immunotherapeutic Approach Targeting Th/Treg Dysfunction and Neuroinflammation

LdIL-2 Treatment in ASD: A Novel Immunotherapeutic Approach Targeting Th/Treg Dysfunction and Neuroinflammation

Exogenous IL-17A Alleviates Social Behavior Deficits and Increases Neurogenesis in a Murine Model of Autism Spectrum Disorders

The tryptophan catabolite or kynurenine pathway in autism spectrum disorder; a systematic review and meta‐analysis

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