In search of immune cellular sources of abnormal cytokines in the blood in autism spectrum disorder: A systematic review of case-control studies

Abstract

Abnormal cytokine levels in circulating blood have been repeatedly reported in autism; however, the underlying cause remains unclear. This systematic review aimed to investigate cytokine levels in peripheral blood compartments and identify their potential immune cellular sources in subjects with autism through comparison with controls. We conducted an electronic database search (PubMed, Scopus, ProQuest Central, Ovid, SAGE Journals, and Wiley Online Library) from inception (no time limits) to July 9, 2020, and identified 75 relevant articles. Our qualitative data synthesis focused on results consistently described in at least three independent studies, and we reported the results according to the PRISMA protocol. We found that compared with controls, in subjects with autism, cytokines IL-6, IL-17, TNF-α, and IL-1β increased in the plasma and serum. We also identified monocytes, neutrophils, and CD4+ T cells as potential sources of these elevated cytokines in autism. Cytokines IFN-γ, TGF-β, RANTES, and IL-8 were increased in the plasma/serum of subjects with autism, and IFN-γ was likely produced by CD4+ T cells and natural killer (NK) cells, although conflicting evidence is present for IFN-γ and TGF-β. Other cytokines—IL-13, IL-10, IL-5, and IL-4—were found to be unaltered in the plasma/serum and post-stimulated blood immune cells in autistic individuals as compared with controls. The frequencies of T cells, monocytes, B cells, and NK cells were unchanged in subjects with autism as opposed to controls, suggesting that abnormal cytokines were unlikely due to altered cell numbers but might be due to altered functioning of these cells in autism. Our results support existing studies of abnormal cytokines in autism and provide comprehensive evidence of potential cellular sources of these altered cytokines in the context of autism.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020205224, identifier [CRD42020205224].

Serum interleukin-17 A and homocysteine levels in children with autism

“…Alterations in cytokine profiles in children with ASD and notable changes in cytokines and their receptors are highlighted. Key cytokines and their receptors investigated in relation to childhood autism include IL-17 A, IL-1β, IL-2R, IL-4, IL-6, and various interleukins, each with diverse cellular origins and target cell types [ 41 , 42 ]. Consistent with previous studies, our results revealed elevated levels of IL-17 A in children with ASD, indicative of increased inflammation associated with ASD.…”

Differences of gut microbiota and behavioral symptoms between two subgroups of autistic children based on γδT cells-derived IFN-γ Levels: A preliminary study

“…However, results of the INF-γ levels in ASD from the previous studies were not always consistent. Both higher and lower levels of INF-γ have been found in blood samples and PBMCs of ASD [see the summarized results in the excellent systematic reviews ( 74 , 75 )]. In our clinical practice, we also find that a great heterogenicity exists in the INF-γ levels in ASD.…”

Analysis of potential biomarkers and immune infiltration in autism based on bioinformatics analysis

“…[36] In addition, we found that the proportions of neutrophils and resting mast cells in patients with ASD. On the one hand, neutrophils can produce a pro-inflammatory cytokine IL-17 [37,38] , which is related to neurodevelopmental disorders. However, an increase in neutrophil oxidative stress leads to a disorder of the enzyme antioxidant network in peripheral innate immune cells.…”