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Immune activation of peripheral blood and mucosal CD3+ lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms
Abstract
Gastrointestinal pathology, characterized by lymphoid nodular hyperplasia and entero-colitis, has been demonstrated in a cohort of children with autistic spectrum disorder (ASD). Systemic and intestinal mucosal immune dysregulation was assessed in ASD children with gastrointestinal (GI) symptoms (n = 18), and typically developing controls (n = 27), including non-inflamed controls (NIC) and inflamed GI control children with Crohn's disease (CD), by analysis of intracellular cytokines in CD3+ lymphocytes. In both peripheral blood and mucosa, CD3+ TNFalpha+ and CD3+ IFNgamma+ were increased in ASD children compared with NIC (p < 0.004) and reached levels similar to CD. In contrast, peripheral and mucosal CD3+ IL-10+ were markedly lower in ASD children with GI symptoms compared with both NIC and CD controls (p < 0.02). In addition, mucosal CD3+ IL-4+ cells were increased (p < 0.007) in ASD compared with NIC. There is a unique pattern of peripheral blood and mucosal CD3+ lymphocytes intracellular cytokines, which is consistent with significant immune dysregulation, in this ASD cohort.
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“Elevated plasma cytokine levels (IL-1β, IL-6, IL-12p40 and TNFα) [82–84], altered immunoglobulin levels [85, 86], elevated levels of complement proteins [87], and increased chemokine levels (CCL2, CCL5 and CCL11) [88] are reported in the plasma of young children with AD compared with matched typically developing children.”
From Consensus Paper: Pathological Role of the Cerebellum in Autism (2012) · cites this paper as [84]
In the citing paper
“Increased pro-inflammatory (TNF-α and IL-6) but decreased regulatory (IL-10) cytokine production in mucosal lamina propria and epithelial lymphocytes was observed in ASD children with GI symptoms compared to typically developing controls matched on GI symptoms [21, 22].”
From Pilot study of probiotic/colostrum supplementation on gut function in children with autism and gastrointestinal symptoms (2019) · cites this paper as [22]
In the citing paper
“Our results are in agreement with previous findings of elevated TNF-α expression in children with ASD and GI symptoms [87] compared to non-inflamed controls that was similar to participants with Crohn’s disease [22].”
From Pilot study of probiotic/colostrum supplementation on gut function in children with autism and gastrointestinal symptoms (2019) · cites this paper as [22]
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“A number of studies have shown that TNFα, IFNγ, IL-1β and IL-12were increased in the peripheral blood of ASD patients (Zimmerman et al., 2005; Molloy et al., 2006; Ashwood and Wakefield, 2006).”
BackgroundConsensus Paper: Pathological Role of the Cerebellum in Autism
Fatemi, S. H., Aldinger, K. A., Ashwood, P., Bauman, M. L., Blaha, C. D., Blatt, G. J., Chauhan, A., Chauhan, V., Dager, S. R., Dickson, P. E., et al. (2012) · The Cerebellum · doi:10.1007/s12311-012-0355-9 · Cited by 723
Self-citationChauhan, A., & Chauhan, V. (2006) · Pathophysiology · doi:10.1016/j.pathophys.2006.05.007 · Cited by 656
The role of immune dysfunction in the pathophysiology of autism
Onore, C., Careaga, M., & Ashwood, P. (2012) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2011.08.007 · Cited by 635
“Analysis of intracellular cytokine production showed an increase in frequency of TNF-a+ T cells but reduced frequency of IL-10+ T cells in both peripheral and intestinal mucosal tissue in children with ASD (Ashwood et al., 2004; Ashwood and Wakefield, 2006).”
Self-citationEmerging Roles for the Gut Microbiome in Autism Spectrum Disorder
Vuong, H. E., & Hsiao, E. Y. (2017) · Biological Psychiatry · doi:10.1016/j.biopsych.2016.08.024 · Cited by 595
The immune response in autism: a new frontier for autism research
Ashwood, P., Wills, S., & Van de Water, J. (2006) · Journal of Leukocyte Biology · doi:10.1189/jlb.1205707 · Cited by 528
“neous production of proinflammatory, intracellular cytokines, most notably TNF- , when compared with aged-matched controls, including those with similar symptoms of constipation [44, 45].”
BackgroundSelf-citationBlood–brain barrier and intestinal epithelial barrier alterations in autism spectrum disorders
Fiorentino, M., Sapone, A., Senger, S., Camhi, S. S., Kadzielski, S. M., Buie, T. M., Kelly, D. L., Cascella, N., & Fasano, A. (2016) · Molecular Autism · doi:10.1186/s13229-016-0110-z · Cited by 494
Autism Spectrum Disorders and the Gut Microbiota
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“The bidirectional communication between the gut and brain through neuroendocrine and neuroimmune pathways, autonomic nervous systems and microbial toxin production represents the gut-brain axis [90].”
BackgroundModeling an autism risk factor in mice leads to permanent immune dysregulation
Hsiao, E. Y., McBride, S. W., Chow, J., Mazmanian, S. K., & Patterson, P. H. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1202556109 · Cited by 340
“In addition, elevated levels of TNF-α– and IFN-γ–producing T cells are found in peripheral blood and gastrointestinal mucosa from autistic individuals (31).”
BackgroundWei, H., Zou, H., Sheikh, A. M., Malik, M., Dobkin, C., Brown, W. T., & Li, X. (2011) · Journal of Neuroinflammation · doi:10.1186/1742-2094-8-52 · Cited by 333
“TNF-a, IFN-g, IL-1b and IL-12 were found to be elevated in blood mononuclear cells, serum and plasma from autistic subjects [6,20-24].”
BackgroundBilbo, S. D., Block, C. L., Bolton, J. L., Hanamsagar, R., & Tran, P. K. (2017) · Experimental Neurology · doi:10.1016/j.expneurol.2017.07.002 · Cited by 329
“cyte responses to antigen, altered cytokine production, and an increased incidence of allergies and other autoimmune disorders (Ashwood and Wakefield, 2006; Ashwood et al., 2006; Blaylock, 2009; Blaylock and Strunecka, 2009; Derecki et al., 2010; Enstrom et al., 2010; Maezawa and Jin, 2010; Pardo et al., 2005).”
Differential monocyte responses to TLR ligands in children with autism spectrum disorders
Enstrom, A. M., Onore, C. E., Van de Water, J. A., & Ashwood, P. (2010) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2009.08.001 · Cited by 294
“(Ashwood et al., 2009; Ashwood and Wakefield, 2006; Cabanlit et al., 2007; Denney et al., 1996; Enstrom et al., 2009b; Garbett et al., 2008; Gupta et al., 1998; Li et al., 2009; Molloy et al., 2006; Sweeten et al., 2003; Vargas et al., 2005; Wills et al., 2007).”
Self-citationAltered T cell responses in children with autism
Ashwood, P., Krakowiak, P., Hertz-Picciotto, I., Hansen, R., Pessah, I. N., & Van de Water, J. (2011) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2010.09.002 · Cited by 281
Self-citationAssociations of impaired behaviors with elevated plasma chemokines in autism spectrum disorders
Ashwood, P., Krakowiak, P., Hertz-Picciotto, I., Hansen, R., Pessah, I. N., & Van de Water, J. (2011) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2010.10.025 · Cited by 279
“…plasma, and increased production of cytokines by peripheral bloodmononuclear cell (PBMC) cultures (Ashwood et al., 2008, 2009, 2010, in press-a,b; Ashwood and Wakefield, 2006; Enstrom et al., 2009a; Enstrom et al., 2010; Jyonouchi et al., 2001; Molloy et al., 2005; Onore et al., 2009; Vargas et…”
BackgroundSelf-citationAshwood, P., Enstrom, A., Krakowiak, P., Hertz-Picciotto, I., Hansen, R. L., Croen, L. A., Ozonoff, S., Pessah, I. N., & de Water, J. V. (2008) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2008.07.006 · Cited by 271
“In the autism literature, there are several studies that demonstrate an alteration or dysregulation of immune responses in autism compared with matched controls [Ashwood et al., 2004; Ashwood and Wakefield, 2006b; Cohly and Panja, 2005; Jyonouchi et al., 2005].”
Self-citationEnstrom, A. M., Lit, L., Onore, C. E., Gregg, J. P., Hansen, R. L., Pessah, I. N., Hertz-Picciotto, I., Van de Water, J. A., Sharp, F. R., & Ashwood, P. (2009) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2008.08.001 · Cited by 257
Self-citationBrain IL-6 elevation causes neuronal circuitry imbalances and mediates autism-like behaviors
Wei, H., Chadman, K. K., McCloskey, D. P., Sheikh, A. M., Malik, M. N., Brown, W. T., & Li, X. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2012.01.011 · Cited by 267
Sanctuary, M. R., Kain, J. N., Chen, S. Y., Kalanetra, K., Lemay, D. G., Rose, D. R., Yang, H. T., Tancredi, D. J., German, J. B., Slupsky, C. M., et al. (2019) · PLOS ONE · doi:10.1371/journal.pone.0210064 · Cited by 255
“Increased pro-inflammatory (TNF-α and IL-6) but decreased regulatory (IL-10) cytokine production in mucosal lamina propria and epithelial lymphocytes was observed in ASD children with GI symptoms compared to typically developing controls matched on GI symptoms [21, 22].”
Self-citationImmune Dysfunction and Autoimmunity as Pathological Mechanisms in Autism Spectrum Disorders
Hughes, H. K., Ko, E. M., Rose, D. R., & Ashwood, P. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00405 · Cited by 253
Self-citationGastrointestinal issues in autism spectrum disorder
Hsiao, E. Y. (2014) · Harvard Review of Psychiatry · doi:10.1097/hrp.0000000000000029 · Cited by 209
de Theije, C. G. M., Wu, J., da Silva, S. L., Kamphuis, P. J. G. H., Garssen, J., Korte, S. M., & Kraneveld, A. D. (2011) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2011.07.013 · Cited by 212
“Furthermore, there were less IL-10 positive T cells present in both the periphery and the gut mucosa of ASD children with gastrointestinal symptoms, compared with non-inflamed controls and children with Crohn's disease (Ashwood and Wakefield, 2006).”
BackgroundMethodIntestinal Dysbiosis and Yeast Isolation in Stool of Subjects with Autism Spectrum Disorders
Iovene, M. R., Bombace, F., Maresca, R., Sapone, A., Iardino, P., Picardi, A., Marotta, R., Schiraldi, C., Siniscalco, D., Serra, N., et al. (2017) · Mycopathologia · doi:10.1007/s11046-016-0068-6 · Cited by 184
The Potential Role of Probiotics in the Management of Childhood Autism Spectrum Disorders
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The Role of Gut Dysbiosis in the Pathophysiology of Neuropsychiatric Disorders
Anand, N., Gorantla, V. R., & Chidambaram, S. B. (2022) · Cells · doi:10.3390/cells12010054 · Cited by 194
Immune Dysregulation in Autism Spectrum Disorder: What Do We Know about It?
Robinson-Agramonte, M. D. L. A., Noris García, E., Fraga Guerra, J., Vega Hurtado, Y., Antonucci, N., Semprún-Hernández, N., Schultz, S., & Siniscalco, D. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23063033 · Cited by 176
Evidence supporting an altered immune response in ASD
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Self-citationNeuroinflammation in autism spectrum disorders
El-Ansary, A. K., & AL-Ayadhi, L. Y. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-265 · Cited by 167
“A number of studies have also shown that inflammatory cytokines, including tumor necrosis factor (TNF) α, interferon (IFN) γ, IL1, IL6, IL8 and IL12, are elevated in blood mononuclear cells, serum, plasma and cerebrospinal fluid (CSF) of autistic subjects [2-8].”
BackgroundImmune Dysfunction in Autism: A Pathway to Treatment
Careaga, M., de Water, J. V., & Ashwood, P. (2010) · Neurotherapeutics · doi:10.1016/j.nurt.2010.05.003 · Cited by 166
Self-citationCan probiotics benefit children with autism spectrum disorders?
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Lack of Association between Measles Virus Vaccine and Autism with Enteropathy: A Case-Control Study
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“org A relevant point to be considered in the neuroimmune interactions occurring in autism is the fact that the intestinal mucosa of children with autism has a higher frequency of TNF-α+ T cells and lower frequency of IL-10+ T cells (148, 149).”
BackgroundAdvances in understanding the pathophysiology of autism spectrum disorders
Yenkoyan, K. B., Grigoryan, A., Fereshetyan, K., & Yepremyan, D. (2017) · Behavioural Brain Research · doi:10.1016/j.bbr.2017.04.038 · Cited by 151
“Several reports using different methods and small ASD patient populations have shown an increase in pro-inflammatory cytokines in peripheral blood [41].”
In Search of Cellular Immunophenotypes in the Blood of Children with Autism
Ashwood, P., Corbett, B. A., Kantor, A. B., Schulman, H., de Water, J. V., & Amaral, D. G. (2011) · PLoS ONE · doi:10.1371/journal.pone.0019299 · Cited by 151
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Immune-Glutamatergic Dysfunction as a Central Mechanism of the Autism Spectrum Disorders
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“This allows food antigens to enter the blood stream, resulting in a high incidence of food allergy, especially to gliadin and gluten [81].”
BackgroundImmune Abnormalities in Autism Spectrum Disorder—Could They Hold Promise for Causative Treatment?
Gładysz, D., Krzywdzińska, A., & Hozyasz, K. K. (2018) · Molecular Neurobiology · doi:10.1007/s12035-017-0822-x · Cited by 134
“The observed differences were maintained following stimulation [234].”
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Vojdani, A., Mumper, E. A., Granpeesheh, D., Mielke, L., Traver, D., Bock, K., Hirani, K., Neubrander, J. A., Woeller, K. N., O’Hara, N., et al. (2008) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2008.09.005 · Cited by 123
“Immune abnormalities in autism include changes in the numbers and activities ofmacrophages, Tcells, B cells andnatural killer (NK) cell activity (Ashwood et al., 2004; Ashwood et al., 2006; Ashwood and Wakefield, 2006; Stubbs et al.,1977;Warren et al.,1986,1987).”
Gut Microbiota, Inflammation, and Probiotics on Neural Development in Autism Spectrum Disorder
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Deficits in bioenergetics and impaired immune response in granulocytes from children with autism
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The Neurobiology of Lipid Metabolism in Autism Spectrum Disorders
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“Numerous investigators found cytokine and cytokine receptor differences between autistic and control children (Singh et al., 1991; Singh, 1996; Jyonouchi et al., 2001; Ashwood et al., 2004; Vargas et al., 2005; Molloy et al., 2006; Ashwood & Wakefield, 2006).”
BackgroundPotential biomarkers in psychiatry: focus on the cholesterol system
Woods, A. G., Sokolowska, I., Taurines, R., Gerlach, M., Dudley, E., Thome, J., & Darie, C. C. (2012) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2012.01543.x · Cited by 106
“In addition, immunological disturbances have been identified in the gastrointestinal tract in subgroups of children with ASD [145].”
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The Role of Microbiome in Brain Development and Neurodegenerative Diseases
Nandwana, V., Nandwana, N. K., Das, Y., Saito, M., Panda, T., Das, S., Almaguel, F. A., Hosmane, N. S., & Das, B. C. (2022) · Molecules · doi:10.3390/molecules27113402 · Cited by 117
“In comparison to controls, CD3+ T cells were observed to be more abundant in the duodenum and colon of children with ASD [76,77].”
ResultEvidence of parallels between mercury intoxication and the brain pathology in autism
Kern, J. K., Geier, D. A., AUDHYA, T. K., King, P. G., Sykes, L. K., & Geier, M. R. (2012) · Acta Neurobiologiae Experimentalis · doi:10.55782/ane-2012-1887 · Cited by 103
“2006, Ashwood and Wakefield 2006). Similarly, studies show elevated immune response in the brains and spinal cords of autistic patients. Li and colleagues (2009), for example, showed that proinflammatory cytokines (TNF-α, IL-6 and GM-CSF), Th1 cytokine (IFN-γ) and chemokine (IL-8) were significantly increased in the b…”
BackgroundMethodInfluentialMultiple inflammasome complexes are activated in autistic spectrum disorders
Saresella, M., Piancone, F., Marventano, I., Zoppis, M., Hernis, A., Zanette, M., Trabattoni, D., Chiappedi, M. A., Ghezzo, A., Canevini, M. P., et al. (2016) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2016.03.009 · Cited by 106
“ASD is associated with psychiatric and non-psychiatric comorbidities that include immune alterations, such as an increased production of proinflammatory cytokines by peripheral blood immune cells and mucosal lymphocytes from the ileal lymphoid tissue (Ashwood and Wakefield, 2006).”
BackgroundCathepsin D and apoptosis related proteins are elevated in the brain of autistic subjects
Sheikh, A. M., Li, X., Wen, G. Y., Tauqeer, Z., Brown, W. T., & Malik, M. N. (2009) · Neuroscience · doi:10.1016/j.neuroscience.2009.10.035 · Cited by 98
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“TH1 to TH2 cell type with decreased production of IL-2 and IFN-γ and increased production of IL-4 (31), others state that there is no clear cytokine polarization profile, and attempting to categorize the disease based on the traditional TH1/TH2 dichotomy may oversimplify and incorrectly characterize the immune dysfunc…”
BackgroundZhou, X., Chen, Y., Mok, K. Y., Zhao, Q., Chen, K., Chen, Y., Hardy, J., Li, Y., Fu, A. K. Y., Guo, Q., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1715554115 · Cited by 96
“Interestingly, previous studies show that alterations of genetic signatures in the peripheral circulatory system are associated with several brain disorders, including autism (76), Parkinson’s disease (77), and schizophrenia (78).”
BackgroundRose, S., Melnyk, S., Trusty, T. A., Pavliv, O., Seidel, L., Li, J., Nick, T. G., & James, S. J. (2011) · Autism Research and Treatment · doi:10.1155/2012/986519 · Cited by 93
“These results suggest that the loss of glutathione redox homeostasis and chronic oxidative stress may contribute to immune dysregulation in autism.”
BackgroundMalik, M. N., Sheikh, A. M., Wen, G. Y., Spivack, W. D., Brown, W. T., & Li, X. (2010) · Immunobiology · doi:10.1016/j.imbio.2010.03.001 · Cited by 92
Autism, asthma, inflammation, and the hygiene hypothesis
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The Promising Role of Probiotics in Managing the Altered Gut in Autism Spectrum Disorders
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Food allergy and autism spectrum disorders: Is there a link?
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Blood Markers in Detection of Autism
Stavridou, T., Driga, A. M., & Drigas, A. S. (2021) · International Journal of Recent Contributions from Engineering Science & IT (iJES) · doi:10.3991/ijes.v9i2.21283 · Cited by 81
“Studies [21], [22], observed that in children with autism, there is the presence of inflammation in the brain and increased plasma cytokine levels, such as interleukin (1α), -1β, IL-6, and IL-8.”
BackgroundNeuroinflammation in autism spectrum disorders: Exercise as a “pharmacological” tool
Toscano, C. V. A., Barros, L., Lima, A. B., Nunes, T., Carvalho, H. M., & Gaspar, J. M. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.07.023 · Cited by 91
The gut microbiota in neuropsychiatric disorders
Grochowska, M., Wojnar, M., & Radkowski, M. (2018) · Acta Neurobiologiae Experimentalis · doi:10.21307/ane-2018-008 · Cited by 77
“…immunochemistry and flow cy‑ tometry revealed infiltration of immune cells (e.g. lym‑ phocytes with proinflammatory phenotype CD3+ TNFα+ cells or CD3+ IFNγ+ cells, monocytes, NK cells) in the GI tract of autistic children (Ashwood and Wakefield 2006, Furlano et al. 2001, Torrente et al. 2002).”
BackgroundAnti-inflammatory cytokines in autism spectrum disorders: A systematic review and meta-analysis
Saghazadeh, A., Ataeinia, B., Keynejad, K., Abdolalizadeh, A., Hirbod‐Mobarakeh, A., & Rezaei, N. (2019) · Cytokine · doi:10.1016/j.cyto.2019.154740 · Cited by 82
Antibodies against Food Antigens in Patients with Autistic Spectrum Disorders
de Magistris, L., Picardi, A., Siniscalco, D., Riccio, M. P., Sapone, A., Cariello, R., Abbadessa, S., Medici, N., Lammers, K. M., Schiraldi, C., et al. (2013) · BioMed Research International · doi:10.1155/2013/729349 · Cited by 73
“…80131 Naples, Italy Correspondence should be addressed to Laura de Magistris; laura.demagistris@unina2.it Received 21 April 2013; Revised 18 June 2013; Accepted 27 June 2013 Academic Editor: David Bernardo Copyright © 2013 Laura de Magistris et al. This is an open access article distributed under…”
BackgroundIchim, T. E., Solano, F., Glenn, E., Morales, F., Smith, L., Zabrecky, G. P., & Riordan, N. H. (2007) · Journal of Translational Medicine · doi:10.1186/1479-5876-5-30 · Cited by 72
Similarities in features of autism and asthma and a possible link to acetaminophen use
Becker, K. G., & Schultz, S. T. (2009) · Medical Hypotheses · doi:10.1016/j.mehy.2009.08.033 · Cited by 69
“Gastrointestinal inflammation in autism [7] as well as pathological evidence of neuroinflammation involving activation of brain microglia has been shown [8].”
BackgroundJyonouchi, H., Geng, L., Streck, D. L., & Toruner, G. A. (2011) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2011.07.001 · Cited by 67
“Various subtle immuneabnormalities aswell as abnormalfindings of gut mucosa or array analysis of whole blood have been reported elsewhere (Ashwood and Wakefield, 2006; Gregg et al., 2008; Jyonouchi, 2009; Singh, 2009; Ashwood et al., 2011a; Enstrom et al., 2010; Ashwood et al., 2011b).”
BackgroundDecreased cellular IL-23 but not IL-17 production in children with autism spectrum disorders
Onore, C. E., Enstrom, A. M., Krakowiak, P., Hertz‐Picciotto, I., Hansen, R., de Water, J. V., & Ashwood, P. (2009) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2009.09.005 · Cited by 69
“Evidence of immune dysregulation has been observed in some individuals with ASD, including increased levels of pro-inflammatory cytokines in brain tissues, CSF and plasma, and increased production of pro-inflammatory cytokines by peripheral blood mononuclear cell (PBMC) cultures when compared to typically developing c…”
Self-citationAutism and immune factors: A comprehensive review
Stigler, K. A., Sweeten, T. L., Posey, D. J., & McDougle, C. J. (2009) · Research in Autism · doi:10.1016/j.rasd.2009.01.007 · Cited by 65
Alterations in plasma cytokine levels in chinese children with autism spectrum disorder
Hu, C., Xu, X., Xiong, G., Xu, Q., Zhou, B., Li, C., Qin, Q., Liu, C., Li, H., Sun, Y., et al. (2018) · Autism Research · doi:10.1002/aur.1940 · Cited by 68
Heuer, L., Braunschweig, D., Ashwood, P., Van de Water, J., & Campbell, D. B. (2011) · Translational Psychiatry · doi:10.1038/tp.2011.48 · Cited by 62
Self-citationInflammation and Mitochondrial Dysfunction in Autism Spectrum Disorder
Gevezova, M., Sarafian, V. S., Anderson, G., & Maes, M. H. J. (2020) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527319666200628015039 · Cited by 63
Ansari, M. A., Nadeem, A., Attia, S. M., Bakheet, S. A., Raish, M., & Ahmad, S. F. (2017) · Cellular Signalling · doi:10.1016/j.cellsig.2017.04.014 · Cited by 59
Hendouei, F., Moghaddam, H. S., Mohammadi, M. R., Taslimi, N., Rezaei, F., & Akhondzadeh, S. (2019) · Journal of Clinical Pharmacy and Therapeutics · doi:10.1111/jcpt.13076 · Cited by 61
Walker, S. J., Fortunato, J. E., González, L. G., & Krigsman, A. (2013) · PLoS ONE · doi:10.1371/journal.pone.0058058 · Cited by 58
“Abnormal gene expression in ASD tissues is consistent with previous reports of cellular and structural changes within the mucosa [11–13,15,16] accompanied by pro-inflammatory bias in mucosal CD3 lymphocyte cytokine profiles [10,31], and a more recent report of abnormal mucosal mRNA profiles in other ASD children who,…”
ResultInflammatory Activity in Autism Spectrum Disorder
Tonhajzerová, I., Ondrejka, I., Mestanik, M., Mikolka, P., Hrtánek, I., Mestanikova, A., Bujnakova, I., & Mokrá, D. (2015) · Advances in experimental medicine and biology · doi:10.1007/5584_2015_145 · Cited by 57
Detection of IL-17 and IL-23 in Plasma Samples of Children with Autism
Enstrom, A., Onore, C., Hertz-Picc, I., Hansen, R., Croen, L., Water, J. V. D., & Ashwood, P. (2008) · American Journal of Biochemistry and Biotechnology · doi:10.3844/ajbbsp.2008.114.120 · Cited by 51
“Immune abnormalities include increased inflammatory cytokines in the plasma and CNS, specifically neuroinflammatory cytokine interleukin-6 (IL-6) , proinflammatory cytokine tumor necrosis factor alpha (TNF )([4-6]) and chemoattractant cytokine macrophage chemotactic protein-1 (MCP-1)([7]).”
BackgroundSelf-citationEl-Ansary, A. K., Bacha, A. G. B., & AL-Ayadhi, L. Y. (2011) · Journal of Neuroinflammation · doi:10.1186/1742-2094-8-142 · Cited by 50
“A number of studies have also shown that inflammatory cytokines including tumor necrosis factor (TNF)a, interferon (IFN)a, IL1a, IL6, IL8 and IL12 are elevated in blood mononuclear cells, serum, plasma and cerebrospinal fluid (CSF) of autistic subjects [9-16].”
BackgroundA pilot dose finding study of pioglitazone in autistic children
Capano, L., Dupuis, A., Brian, J. A., Mankad, D., Genore, L., Adams, R. H., Smile, S., Lui, T., Odrobina, D., Foster, J. A., et al. (2018) · Molecular Autism · doi:10.1186/s13229-018-0241-5 · Cited by 48
Gut-to-Brain Axis in Autism Spectrum Disorders
Kraneveld, A. D., Szklany, K., de Theije, C. G. M., & Garssen, J. (2016) · International review of neurobiology · doi:10.1016/bs.irn.2016.09.001 · Cited by 47
A systematic review of gut‐immune‐brain mechanisms in Autism Spectrum Disorder
Azhari, A., Azizan, F., & Esposito, G. (2018) · Developmental Psychobiology · doi:10.1002/dev.21803 · Cited by 52
Autistic Spectrum Disorders as Functional Disconnection Syndrome
Melillo, R. J., & Leisman, G. (2009) · Reviews in the Neurosciences · doi:10.1515/revneuro.2009.20.2.111 · Cited by 46
Altered Sulfur Amino Acid Metabolism In Immune Cells of Children Diagnosed With Autism
Suh, J. H., Walsh, W. J., McGinnis, W. R., Lewis, A. T., & Ames, B. N. (2008) · American journal of biochemistry & biotechnology/American journal of biochemistry and biotechnology · doi:10.3844/ajbbsp.2008.105.113 · Cited by 45
“106 evidence of elevated levels of the pro-inflammatory cytokines, IL-4, and IL-6 [10].”
BackgroundCao, F., Yin, A., Wen, G. Y., Sheikh, A. M., Tauqeer, Z., Malik, M. N., Nagori, A., Schirripa, M., Schirripa, F. V., Merz, G., et al. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-223 · Cited by 44
“A number of studies including ours have demonstrated that cytokines including IL-6, IL-1β TNF-α and IFN-γ are elevated in the serum and brain tissue of autistic individuals [35-41].”
BackgroundRetractedPolyphenols in the management of brain disorders: Modulation of the microbiota-gut-brain axis
Serra, D., Almeida, L. M., & Dinis, T. C. P. (2019) · Advances in food and nutrition research · doi:10.1016/bs.afnr.2019.08.001 · Cited by 46
Ahmad, S. F., Nadeem, A., Ansari, M. A., Bakheet, S. A., Alshammari, M. A., & Attia, S. M. (2018) · Neurochemistry International · doi:10.1016/j.neuint.2018.09.006 · Cited by 44
“IL-10 levels are also reported to be low in children with ASD and show negative correlation with behavioral impairments in ASD subjects (https://www.sciencedirect.com/science/article/pii/ S0898656817301146?via%3Dihub, Jyonouchi et al., 2008; Ashwood and Wakefield, 2006; Ross et al., 2013).”
Fernell, E., Fagerberg, U. L., & Hellström, P. M. (2007) · Acta Paediatrica · doi:10.1111/j.1651-2227.2007.00298.x · Cited by 43
“Such a blunt inflammation has been suggested to elaborate cytokines, especially TNF and IFN (25,26).”
BackgroundInflammatory Biomarkers are Correlated with Some Forms of Regressive Autism Spectrum Disorder
Prosperi, M., Guiducci, L., Peroni, D., Narducci, C., Gaggini, M., Calderoni, S., Tancredi, R., Morales, M. A., Gastaldelli, A., Muratori, F., et al. (2019) · Brain Science · doi:10.3390/brainsci9120366 · Cited by 29
Ansari, M. A., Attia, S. M., Nadeem, A., Bakheet, S. A., Raish, M., Khan, T. H., Al‐Shabanah, O. A., & Ahmad, S. F. (2017) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2017.04.012 · Cited by 41
“Although the causes of ASD remain to be clarified, immune responses are believed to play a role in the pathogenesis of ASD (Ashwood and Wakefield, 2006).”
Medina, M. A., Andrade, V., Caracci, M. O., Ávila, M. E., Verdugo, D. A., Vargas, M. F., Ugarte, G. D., Reyes, A. E., Opazo, C., & Ferrari, G. V. D. (2018) · Translational Psychiatry · doi:10.1038/s41398-018-0093-y · Cited by 40
Autism Spectrum Disorders: From Immunity to Behavior
Careaga, M., & Ashwood, P. (2012) · Methods in Molecular Biology · doi:10.1007/978-1-62703-071-7_12 · Cited by 38
Self-citationA possible central mechanism in autism spectrum disorders, part 1.
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Role of NAD + , Oxidative Stress, and Tryptophan Metabolism in Autism Spectrum Disorders
Essa, M. M., Subash, S., Braidy, N., Al‐Adawi, S., Lim, C. K., Manivasagam, T., & Guillemin, G. J. (2013) · International Journal of Tryptophan Research · doi:10.4137/ijtr.s11355 · Cited by 41
Pierce, K., Glatt, S. J., Liptak, G. S., & McIntyre, L. L. (2009) · Annals of Clinical Psychiatry · doi:10.1177/104012370902100302 · Cited by 37
Gut–brain axis in the executive function of austism spectrum disorder
Román, P., Rueda‐Ruzafa, L., Cardona, D., & Cortés‐Rodríguez, A. E. (2018) · Behavioural Pharmacology · doi:10.1097/fbp.0000000000000428 · Cited by 36
Li, L.-J., Li, M., Li, Y., Feng, J.-J., Hao, F.-Q., & Zhang, L. (2012) · Marine Drugs · doi:10.3390/md10122648 · Cited by 35
Prandota, J. (2010) · Research in Autism · doi:10.1016/j.rasd.2010.03.009 · Cited by 34
Hashim, H. M., Abdelrahman, H. M., Mohammed, D. F., & Karam, R. A. (2012) · Research in Autism · doi:10.1016/j.rasd.2012.08.007 · Cited by 33
Ahmad, S. F., Ansari, M. A., Nadeem, A., Bakheet, S. A., Alqahtani, F., Alhoshani, A., Alasmari, F. F., Alsaleh, N. B., & Attia, S. M. (2020) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2020.172859 · Cited by 33
Metadata
- Authors
- Ashwood, P., & Wakefield, A. J.
- Affiliations
- University of California, Davis (US)
- Johnson Center for Child Health and Development (US)
- Corresponding author
- Ashwood, Paul
- ORCID
- Ashwood, Paul
- Venue
- Journal of Neuroimmunology
- Publisher
- Elsevier BV
- Published
- 2006-04
- Volume
- 173
- Issue
- 1-2
- Pages
- 126-134
- ISSN
- 0165-5728 (ISSN-L)
- OpenAlex
- W2033012158
- Cited by
- 202
- References
- 41
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 5 · 2023: 9 · 2022: 8 · 2021: 7 · 2020: 8 · 2019: 10 · 2018: 15 · 2017: 8 · 2016: 9 · 2015: 5 · 2014: 12 · 2013: 6 · 2012: 19
- FWCI
- 6.31
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neuroimmunology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Psychiatry and Mental health › Child Nutrition and Feeding Issues
- Keywords
- autism spectrum disorder, gastrointestinal symptoms, CD3+ T cells, intracellular cytokines, TNF-α, interferon-gamma, IL-10, IL-4, Crohn's disease, children
- MeSH terms
- Autistic Disorder, Child, Flow Cytometry, Gastrointestinal Diseases, Humans, Intestinal Mucosa, T-Lymphocytes, Cytokines, CD3 Complex
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