Amene Saghazadeh1, Bahar Ataeinia2, Kimia Keynejad3, Amirhussein Abdolalizadeh4, Armin Hirbod-Mobarakeh5, Nima Rezaei6. 1. aResearch Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; MetaCognition Interest Group (MCIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran. 2. aResearch Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Students' Scientific Research Center (SSRC), Tehran University of Medical Sciences (TUMS), Tehran, Iran; Border of Immune Tolerance Education and Research Network (BITERN), Universal Scientific Education and Research Network (USERN), Tehran, Iran. 3. Border of Immune Tolerance Education and Research Network (BITERN), Universal Scientific Education and Research Network (USERN), Tehran, Iran. 4. Students' Scientific Research Center (SSRC), Tehran University of Medical Sciences (TUMS), Tehran, Iran; MS Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran. 5. aResearch Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Border of Immune Tolerance Education and Research Network (BITERN), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Molecular Immunology Research Center, Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. 6. aResearch Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Molecular Immunology Research Center, Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Systematic Review and Meta-analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Boston, MA, USA. Electronic address: rezaei_nima@tums.ac.ir.
Abstract
BACKGROUND: Autism spectrum disorders (ASD) occur in 1.5% of the general population worldwide. Studies suggest that ASD might have more costs than diabetes and attention deficit and hyperactivity disorder by 2025. Dysregulation of the cytokine system is well-documented in ASD. We conducted a meta-analysis of studies providing data on circulating concentrations of pro-inflammatory cytokines in people with ASD compared with control subjects without ASD. METHODS: We identified potentially eligible studies by systematically searching electronic databases from inception to February 2018. RESULTS: Thirty-eight studies with total of 2487 participants (1393 patients with ASD and 1094 control subjects) were included in the meta-analysis; 13 for interferon (IFN)-γ, 17 for interleukin (IL)-1β, 22 for IL-6, 19 for tumor necrosis factor (TNF)-α, 4 for IL-1α, 6 for IL-2, 4 for IL-7, 8 for IL-8, 14 for IL-12, 3 for IL-15, 12 for IL-17, 3 for IL-18, 3 for IL-2 receptor, 3 for TNF-β, and 3 for IL-23. We found medium increases in levels of plasma IFN-γ (standardized mean difference, SMD = 0.53) and serum IL-1β (SMD = 0.56) and small increases in levels of blood IL-1β (SMD = 0.35), serum IL-6 (SMD = 0.30) and serum TNF-α (SMD = 0.31) for patients with ASD. Meta-regression analyses identified latitude as a negative moderator of the effect size (ES) of difference in mean levels of IFN-γ (R2 = 0.26) and TNF-α (R2 = 0.74). Also, difference in the mean age between patients and controls had a negative interaction with the ES of difference in mean levels of IL-1β. In contrast, there was a positive effect of the moderator of difference in the proportion of male subjects between patients and controls on the ES of difference in mean levels of IL-1β. We found no significant alterations in peripheral levels of other pro-inflammatory cytokines including IL-1α, IL-2, IL-2R, IL-3, IL-7, IL-8, IL-12, IL-12p40, IL-12p70, IL-15, IL-17, IL-18, IL-23, TBF-β, and TNFRI/II in patients with ASD. CONCLUSIONS: This meta-analysis provides evidence for higher concentration of pro-inflammatory cytokines IFN-γ, IL-1β, IL-6, and TNF-α in autistic patents compared with control subjects. Also, meta-regression analyses point to the interaction of latitude, age, and gender with peripheral alterations of associated pro-inflammatory cytokines.
BACKGROUND:Autism spectrum disorders (ASD) occur in 1.5% of the general population worldwide. Studies suggest that ASD might have more costs than diabetes and attention deficit and hyperactivity disorder by 2025. Dysregulation of the cytokine system is well-documented in ASD. We conducted a meta-analysis of studies providing data on circulating concentrations of pro-inflammatory cytokines in people with ASD compared with control subjects without ASD. METHODS: We identified potentially eligible studies by systematically searching electronic databases from inception to February 2018. RESULTS: Thirty-eight studies with total of 2487 participants (1393 patients with ASD and 1094 control subjects) were included in the meta-analysis; 13 for interferon (IFN)-γ, 17 for interleukin (IL)-1β, 22 for IL-6, 19 for tumor necrosis factor (TNF)-α, 4 for IL-1α, 6 for IL-2, 4 for IL-7, 8 for IL-8, 14 for IL-12, 3 for IL-15, 12 for IL-17, 3 for IL-18, 3 for IL-2 receptor, 3 for TNF-β, and 3 for IL-23. We found medium increases in levels of plasma IFN-γ (standardized mean difference, SMD = 0.53) and serum IL-1β (SMD = 0.56) and small increases in levels of blood IL-1β (SMD = 0.35), serum IL-6 (SMD = 0.30) and serum TNF-α (SMD = 0.31) for patients with ASD. Meta-regression analyses identified latitude as a negative moderator of the effect size (ES) of difference in mean levels of IFN-γ (R2 = 0.26) and TNF-α (R2 = 0.74). Also, difference in the mean age between patients and controls had a negative interaction with the ES of difference in mean levels of IL-1β. In contrast, there was a positive effect of the moderator of difference in the proportion of male subjects between patients and controls on the ES of difference in mean levels of IL-1β. We found no significant alterations in peripheral levels of other pro-inflammatory cytokines including IL-1α, IL-2, IL-2R, IL-3, IL-7, IL-8, IL-12, IL-12p40, IL-12p70, IL-15, IL-17, IL-18, IL-23, TBF-β, and TNFRI/II in patients with ASD. CONCLUSIONS: This meta-analysis provides evidence for higher concentration of pro-inflammatory cytokines IFN-γ, IL-1β, IL-6, and TNF-α in autistic patents compared with control subjects. Also, meta-regression analyses point to the interaction of latitude, age, and gender with peripheral alterations of associated pro-inflammatory cytokines.
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