00f4e0b7277e0d1ec95d8c1150809de2 pmc_9699353.pdf 1966b9d2fef32a62e3f7f9914f9e4b13cfd3923b pmc_9699353.pdf 2614057eb02b287180640dfcf5ec08a4b1485dc3d72d6726db36ee766f80dbec pmc_9699353.pdf Title: Activation of the Monocyte/Macrophage System and Abnormal Blood Levels of Lymphocyte Subpopulations in Individuals with Autism Spectrum Disorder: A Systematic Review and Meta-Analysis Subject: Autism spectrum disorder (ASD) is a neurodevelopmental condition with a so far unknown etiology. Increasing evidence suggests that a state of systemic low-grade inflammation may be involved in the pathophysiology of this condition. However, studies investigating peripheral blood levels of immune cells, and/or of immune cell activation markers such as neopterin are lacking and have provided mixed findings. We performed a systematic review and meta-analysis of studies comparing total and differential white blood cell (WBC) counts, blood levels of lymphocyte subpopulations and of neopterin between individuals with ASD and typically developing (TD) controls (PROSPERO registration number: CRD CRD42019146472). Online searches covered publications from 1 January 1994 until 1 March 2022. Out of 1170 publication records identified, 25 studies were finally included. Random-effects meta-analyses were carried out, and sensitivity analyses were performed to control for potential moderators. Results: Individuals with ASD showed a significantly higher WBC count (k = 10, g = 0.29, p = 0.001, I2 = 34%), significantly higher levels of neutrophils (k = 6, g = 0.29, p = 0.005, I2 = 31%), monocytes (k = 11, g = 0.35, p < 0.001, I2 = 54%), NK cells (k = 7, g = 0.36, p = 0.037, I2 = 67%), Tc cells (k = 4, g = 0.73, p = 0.021, I2 = 82%), and a significantly lower Th/Tc cells ratio (k = 3, g = -0.42, p = 0.008, I2 = 0%), compared to TD controls. Subjects with ASD were also characterized by a significantly higher neutrophil-to-lymphocyte ratio (NLR) (k = 4, g = 0.69, p = 0.040, I2 = 90%), and significantly higher neopterin levels (k = 3, g = 1.16, p = 0.001, I2 = 97%) compared to TD controls. No significant differences were found with respect to the levels of lymphocytes, B cells, Th cells, Treg cells, and Th17 cells. Sensitivity analysis suggested that the findings for monocyte and neutrophil levels were robust, and independent of other factors, such as medication status, diagnostic criteria applied, and/or the difference in age or sex between subjects with ASD and TD controls. Taken together, our findings suggest the existence of a chronically (and systemically) activated inflammatory response system in, at least, a subgroup of individuals with ASD. This might have not only diagnostic, but also, therapeutic implications. However, larger longitudinal studies including more homogeneous samples and laboratory assessment methods and recording potential confounding factors such as body mass index, or the presence of comorbid psychiatric and/or medical conditions are urgently needed to confirm the findings.24pt Keywords: ASD; monocytes; lymphocytes; inflammation; immune Author: Gara Arteaga-Henríquez, Jorge Lugo-Marín, Laura Gisbert, Imanol Setién-Ramos, Mónica Martínez-Gallo, Ricardo Pujol-Borrell and Josep Antoni Ramos-Quiroga Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Tue Nov 22 05:46:06 2022 CET ModDate: Tue Nov 22 06:05:22 2022 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 16 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 881337 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- MRZZNX+URWPalladioL-Bold Type 1 Custom yes yes no 10 0 EIDDHY+URWPalladioL-Roma Type 1 Custom yes yes no 15 0 RPZIEW+URWPalladioL-Ital Type 1 Custom yes yes no 19 0 TRSMUE+CMSY10 Type 1 Builtin yes yes no 23 0 RREXSY+VnURWPalladioL Type 1 Custom yes yes no 27 0 XWOCXD+VnURWPalladioL-Bold Type 1 Custom yes yes no 32 0 IRWHZX+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 50 0 CKUPDE+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 53 0 GOCQIR+EURM10 Type 1 Builtin yes yes no 75 0 YXWWVK+URWPalladioL-BoldItal Type 1 Custom yes yes no 99 0 KNMFPI+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 112 0 KNMFPJ+PalatinoLinotype CID TrueType Identity-H yes yes yes 115 0 KNMFPK+PalatinoLinotype TrueType WinAnsi yes yes no 121 0 KNMFPM+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 124 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-08-25 02:29:53 CEST RepresentationInformation: pmc_9699353.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-08-04 02:19:31 CEST 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Item: Title: Data Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Children: Item: Title: General Characteristics of Eligible Studies Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: WBC Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Neutrophils Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: Monocytes Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: Lymphocytes Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Item: Title: B Cells Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Item: Title: NK Cells Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Item: Title: T Cells Destination: 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edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@612679d6 Info: Title: Activation of the Monocyte/Macrophage System and Abnormal Blood Levels of Lymphocyte Subpopulations in Individuals with Autism Spectrum Disorder: A Systematic Review and Meta-Analysis Author: Gara Arteaga-Henríquez, Jorge Lugo-Marín, Laura Gisbert, Imanol Setién-Ramos, Mónica Martínez-Gallo, Ricardo Pujol-Borrell and Josep Antoni Ramos-Quiroga Subject: Autism spectrum disorder (ASD) is a neurodevelopmental condition with a so far unknown etiology. Increasing evidence suggests that a state of systemic low-grade inflammation may be involved in the pathophysiology of this condition. However, studies investigating peripheral blood levels of immune cells, and/or of immune cell activation markers such as neopterin are lacking and have provided mixed findings. We performed a systematic review and meta-analysis of studies comparing total and differential white blood cell (WBC) counts, blood levels of lymphocyte subpopulations and of neopterin between individuals with ASD and typically developing (TD) controls (PROSPERO registration number: CRD CRD42019146472). Online searches covered publications from 1 January 1994 until 1 March 2022. Out of 1170 publication records identified, 25 studies were finally included. Random-effects meta-analyses were carried out, and sensitivity analyses were performed to control for potential moderators. Results: Individuals with ASD showed a significantly higher WBC count (k = 10, g = 0.29, p = 0.001, I2 = 34%), significantly higher levels of neutrophils (k = 6, g = 0.29, p = 0.005, I2 = 31%), monocytes (k = 11, g = 0.35, p < 0.001, I2 = 54%), NK cells (k = 7, g = 0.36, p = 0.037, I2 = 67%), Tc cells (k = 4, g = 0.73, p = 0.021, I2 = 82%), and a significantly lower Th/Tc cells ratio (k = 3, g = -0.42, p = 0.008, I2 = 0%), compared to TD controls. Subjects with ASD were also characterized by a significantly higher neutrophil-to-lymphocyte ratio (NLR) (k = 4, g = 0.69, p = 0.040, I2 = 90%), and significantly higher neopterin levels (k = 3, g = 1.16, p = 0.001, I2 = 97%) compared to TD controls. No significant differences were found with respect to the levels of lymphocytes, B cells, Th cells, Treg cells, and Th17 cells. Sensitivity analysis suggested that the findings for monocyte and neutrophil levels were robust, and independent of other factors, such as medication status, diagnostic criteria applied, and/or the difference in age or sex between subjects with ASD and TD controls. Taken together, our findings suggest the existence of a chronically (and systemically) activated inflammatory response system in, at least, a subgroup of individuals with ASD. This might have not only diagnostic, but also, therapeutic implications. However, larger longitudinal studies including more homogeneous samples and laboratory assessment methods and recording potential confounding factors such as body mass index, or the presence of comorbid psychiatric and/or medical conditions are urgently needed to confirm the findings.24pt Keywords: ASD; monocytes; lymphocytes; inflammation; immune Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Tue Nov 22 05:46:06 CET 2022 ModDate: Tue Nov 22 06:05:22 CET 2022 ID: 0x1cf1477078b6ab0fdae811ae88d24147, 0x1cf1477078b6ab0fdae811ae88d24147 Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: XWOCXD+VnURWPalladioL-Bold FontSubset: true FirstChar: 178 LastChar: 226 FontDescriptor: FontName: XWOCXD+VnURWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: RPZIEW+URWPalladioL-Ital FontSubset: true FirstChar: 39 LastChar: 122 FontDescriptor: FontName: RPZIEW+URWPalladioL-Ital Flags: 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