Neonatal Cytokine Profiles Associated With Autism Spectrum Disorder
Open accessAbstract
Background Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that can be reliably diagnosed at age 24 months. Immunological phenomena, including skewed cytokine production, have been observed among children with ASD. Little is known about whether immune dysregulation is present before diagnosis of ASD.Methods We examined neonatal blood spots from 214 children with ASD (141 severe, 73 mild/moderate), 62 children with typical development, and 27 children with developmental delay as control subjects who participated in the Childhood Autism Risks from Genetics and the Environment study, a population-based case-control study. Levels of 17 cytokines and chemokines were compared across groups and in relation to developmental and behavioral domains.Results Interleukin (IL)-1β and IL-4 were independently associated with ASD compared with typical development, although these relationships varied by ASD symptom intensity. Elevated IL-4 was associated with increased odds of severe ASD (odds ratio [OR] = 1.40, 95% confidence interval [CI], 1.03, 1.91), whereas IL-1β was associated with increased odds of mild/moderate ASD (OR = 3.02, 95% CI, 1.43, 6.38). Additionally, IL-4 was associated with a higher likelihood of severe ASD versus mild/moderate ASD (OR = 1.35, 95% CI, 1.04, 1.75). In male subjects with ASD, IL-4 was negatively associated with nonverbal cognitive ability (β = -3.63, SE = 1.33, p = .04).Conclusions This study is part of a growing effort to identify early biological markers for ASD. We demonstrate that peripheral cytokine profiles at birth are associated with ASD later in childhood and that cytokine profiles vary depending on ASD severity. Cytokines have complex roles in neurodevelopment, and dysregulated levels may be indicative of genetic differences and environmental exposures or their interactions that relate to ASD.
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Several pre-clinical and clinical studies found increased levels of inflammatory markers in the systemic circulation of ASD individuals when compared to neurotypical controls, such as increased IL-1B and heightened systemic TNF-alpha.
“Several pre-clinical and clinical studies found increased levels of inflammatory markers in the systemic circulation of ASD individuals when compared to neurotypical controls, such as increased IL-1B [107, 108] and heightened systemic TNF-alpha [108–110].”
From Role of diet and its effects on the gut microbiome in the pathophysiology of mental disorders (2022) · cites this paper as [107]
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Role of diet and its effects on the gut microbiome in the pathophysiology of mental disorders
Horn, J., Mayer, D. E., Chen, S., & Mayer, E. A. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-01922-0 · Cited by 193 · see citing works
“Another study with germ-free mice found functional defects in microglia and as a result observed heightened levels of proinflammatory cytokines IL-1B, IL-6, and TNF-alpha [39], indicating an impairment in immune function.”
BackgroundUnderstanding environmental contributions to autism: Causal concepts and the state of science
Hertz‐Picciotto, I., Schmidt, R. J., & Krakowiak, P. (2018) · Autism Research · doi:10.1002/aur.1938 · Cited by 192 · see citing works
“Oxidative stress has been linked to ASD [Chauhan, Chauhan, Brown, & Cohen, 2004; Yao, Walsh, McGinnis, & Pratico, 2006], and skewed immune marker profiles have been described in newborns and children with ASD [Krakowiak et al., 2017a; Onore, Careaga, & Ashwood, 2012].”
BackgroundSelf-citationImmune dysfunction and neuroinflammation in autism spectrum disorder
Bjørklund, G., Saad, K., Chirumbolo, S., Kern, J. K., Geier, D. A., Geier, M. R., & Urbina, M. A. (2016) · Acta Neurobiologiae Experimentalis · doi:10.21307/ane-2017-025 · Cited by 188 · see citing works
“It was recently confirmed that persons with ASD in comparison to controls have cytokine functional impairment (Goines and Ashwood 2013, Krakowiak et al. 2015, Masi et al. 2015, Pecorelli et al. 2016).”
Vitamin D and autism, what’s new?
Cannell, J. J. (2017) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-017-9409-0 · Cited by 175 · see citing works
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 · see citing works
Advantages and Limitations of the Neonatal Immune System
Tsafaras, G., Ntontsi, P., & Xanthou, G. (2020) · Frontiers in Pediatrics · doi:10.3389/fped.2020.00005 · Cited by 168 · see citing works
“Increased IL-1β and IL-4 are associated with Frontiers in Pediatrics | www.frontiersin.org 6 January 2020 | Volume 8 | Article 5 severe ASD (94), while IL-10 and TGF-β are decreased in the circulation (95).”
BackgroundInfluentialXie, J., Huang, L., Li, X., Li, H., Zhou, Y., Zhu, H., Pan, T., Kendrick, K. M., & Xu, W. (2017) · Oncotarget · doi:10.18632/oncotarget.19326 · Cited by 152 · see citing works
“In terms of their potential use as an early biomarker for ASD recent studies have also reported cytokine changes can be detected in both amniotic fluid [16, 17] and neonatal blood [18] samples.”
BackgroundJoseph, R. M., O’Shea, T. M., Allred, E. N., Heeren, T., Hirtz, D., Paneth, N., Leviton, A., & Kuban, K. (2016) · Autism Research · doi:10.1002/aur.1644 · Cited by 146 · see citing works
“ASD risk has previously been found to increase with each week of decreasing gestational age among children born from 24 to 34 weeks gestation [Kuzniewicz et al., 2014].”
BackgroundPrenatal paracetamol exposure and child neurodevelopment: A review
Bauer, A. Z., Kriebel, D., Herbert, M. R., Bornehag, C.-G., & Swan, S. H. (2018) · Hormones and Behavior · doi:10.1016/j.yhbeh.2018.01.003 · Cited by 127 · see citing works
“…elevated in pregnant mothers whose children developed ASD (Jones et al., 2017; Goines et al., 2011), the children with ASD or ADHD themselves (Krakowiak et al., 2017; Donfrancesco et al., 2016; Masi et al., 2017; Han et al., 2017) and animal models of ASD and ADHD (Choi et al., 2016; Leffa…”
Immune 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 130 · see citing works
Biomarkers in autism spectrum disorders: Current progress
Shen, L., Liu, X., Zhang, H., Lin, J., Feng, C., & Iqbal, J. (2019) · Clinica Chimica Acta · doi:10.1016/j.cca.2019.12.009 · Cited by 124 · see citing works
Gustafsson, H., Sullivan, E. L., Nousen, E. K., Sullivan, C. A., Huang, E., Rincon, M. P., Nigg, J. T., & Loftis, J. M. (2018) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2018.06.011 · Cited by 109 · see citing works
Neuroinflammation in preterm babies and autism spectrum disorders
Bokobza, C., Steenwinckel, J. V., Mani, S., Mezger, V., Fleiss, B., & Gressèns, P. (2018) · Pediatric Research · doi:10.1038/s41390-018-0208-4 · Cited by 103 · see citing works
Heuer, L. S., Croen, L., Jones, K. L., Yoshida, C. K., Hansen, R. L., Yolken, R. H., Zerbo, O., DeLorenze, G. N., Kharrazi, M., Ashwood, P., et al. (2019) · Biological Psychiatry · doi:10.1016/j.biopsych.2019.04.037 · Cited by 101 · see citing works
“Several studies, including our own group, have examined newborn bloodspots for cytokine/chemokine differences as potential biomarkers for ASD (20, 21).”
BackgroundSelf-citationDevelopmental vitamin D and autism spectrum disorders: findings from the Stockholm Youth Cohort
Lee, B. K., Eyles, D. W., Magnusson, C., Newschaffer, C. J., McGrath, J. J., Kvaskoff, D., Ko, P., Dalman, C., Karlsson, H., & Gardner, R. M. (2019) · Molecular Psychiatry · doi:10.1038/s41380-019-0578-y · Cited by 101 · see citing works
“In rats, challenge of vitamin D-deficient placentas with poly(I: C) resulted in higher production of IL-6 and IL-1B in male fetuses [57].”
BackgroundModern Biomarkers for Autism Spectrum Disorder: Future Directions
Jensen, A., Lane, A. L., Werner, B. A., McLees, S. E., Fletcher, T. S., & Frye, R. E. (2022) · Molecular Diagnosis & Therapy · doi:10.1007/s40291-022-00600-7 · Cited by 92 · see citing works
“In a medium-sized retrospective study, women who had offspring who developed ASD were found to have mid-gestational elevations in cytokines [113], while another retrospective case-controlled study found that elevated interleukin (IL)-1β and IL-4 in neonatal blood spots was associated with an increased ASD risk [114].”
ResultArdalan, M., Chumak, T., Vexler, Z. S., & Mallard, C. E. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20092270 · Cited by 79 · see citing works
“Children with ASD have, for example, increased IL-9 in peripheral blood mononuclear cells [113] and peripheral cytokine profiles at birth have been associated with severity of ASD in childhood [114].”
BackgroundInflammatory mediators drive neuroinflammation in autism spectrum disorder and cerebral palsy
Than, U. T. T., Liêm, N. T., Nguyen, H.-P., Nguyen, X., Trinh, D. P., Hoang, D. H., Nguyen, P. A. T., & Dang, V. D. (2023) · Scientific Reports · doi:10.1038/s41598-023-49902-8 · Cited by 77 · see citing works
“…CP patients, indicating the neuro-inflammation in CNS of patients with ASD and CP. TNF-α, BAFF, IL-4, and IL-5 have been found at increased levels in the sera of patients with ASD compared to healthy controls, and these changes are associated with ASD severity 3,20,22,30–32 (Supplemental Table 1).”
BackgroundEvidence for an immune signature of prenatal alcohol exposure in female rats
Bodnar, T. S., Hill, L. A., & Weinberg, J. (2016) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2016.05.022 · Cited by 77 · see citing works
Liu, Z., Mao, X., Zhou, D., Pei, Y., Xu, R., Guo, M., Liu, K., Zhang, F., Chen, J., Su, C., et al. (2021) · Gut Microbes · doi:10.1080/19490976.2020.1854967 · Cited by 74 · see citing works
“The level of IL-1β, IL-4, IL-17α, IL-10, and TGF-β was significantly higher in ASD children compared with TDs (Figure 6(a)), consistent with the previous studies.(8,17,18) Several studies have suggested that host genetic can reshape the gut microbiome and its metabolites through aberrant immune activation.”
ResultMicroglia mediated neuroinflammation in autism spectrum disorder
Liao, X., Yang, J., Wang, H., & Li, Y. (2020) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2020.07.013 · Cited by 74 · see citing works
Patel, S., Dale, R. C., Rose, D. R., Heath, B. E., Nordahl, C. W., Rogers, S. J., Guastella, A. J., & Ashwood, P. (2020) · Translational Psychiatry · doi:10.1038/s41398-020-00976-2 · Cited by 70 · see citing works
Self-citationVolk, H. E., Park, B. Y., Holingue, C., Jones, K. L., Ashwood, P., Windham, G. C., Lurman, F., Alexeeff, S., Kharrazi, M., Pearl, M., et al. (2020) · Journal of Neurodevelopmental Disorders · doi:10.1186/s11689-020-09343-0 · Cited by 68 · see citing works
Self-citationPre- and Perinatal Ischemia-Hypoxia, the Ischemia-Hypoxia Response Pathway, and ADHD Risk
Smith, T. F., Schmidt‐Kastner, R., McGeary, J. E., Kaczorowski, J. A., & Knopik, V. S. (2016) · Behavior Genetics · doi:10.1007/s10519-016-9784-4 · Cited by 69 · see citing works
Postmortem Studies of Neuroinflammation in Autism Spectrum Disorder: a Systematic Review
Liao, X., Liu, Y., Fu, X. B., & Li, Y. (2020) · Molecular Neurobiology · doi:10.1007/s12035-020-01976-5 · Cited by 67 · see citing works
Yu, J. Z., & Kong, J. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2016.00609 · Cited by 66 · see citing works
“These neuroimmune abnormalities start from a very early stage of development and continue through the whole lifespan, which may influence neurodevelopment and nervous system function (Heuer et al., 2008; Krakowiak et al., 2015).”
BackgroundCroen, L., Qian, Y., Ashwood, P., Daniels, J. L., Fallin, M. D., Schendel, D., Schieve, L. A., Singer, A. B., & Zerbo, O. (2018) · Autism Research · doi:10.1002/aur.1979 · Cited by 67 · see citing works
Self-citationSocial impairments in autism spectrum disorder are related to maternal immune history profile
Patel, S., Masi, A., Dale, R. C., Whitehouse, A., Pokorski, I., Alvares, G. A., Hickie, I. B., Breen, E. J., & Guastella, A. J. (2017) · Molecular Psychiatry · doi:10.1038/mp.2017.201 · Cited by 63 · see citing works
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 65 · see citing works
“Changes in peripheral cytokine profiles at the time of birth, especially increased Interleukin (IL)-1b and IL-4 levels, have been associated with a higher risk of ASD diagnosis later on [Krakowiak et al., 2017].”
BackgroundOsman, H. C., Moreno, R. J., Rose, D. R., Rowland, M. E., Ciernia, A. V., & Ashwood, P. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03106-7 · Cited by 64 · see citing works
“Neonatal blood spot data also shows dysregulated cytokine levels in children later diagnosed with ASD [36, 38].”
BackgroundSelf-citationOhja, K., Gozal, E., Fahnestock, M. L., Cai, L., Cai, J., Freedman, J. H., Switala, A., El-Baz, A. S., & Barnes, G. N. (2018) · NeuroMolecular Medicine · doi:10.1007/s12017-018-8488-8 · Cited by 65 · see citing works
The Communication Between the Immune and Nervous Systems: The Role of IL-1β in Synaptopathies
Pozzi, D., Menna, E., Canzi, A., Desiato, G., Mantovani, C., & Matteoli, M. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00111 · Cited by 63 · see citing works
Tsilioni, I., Patel, A., Pantazopoulos, H., Berretta, S., Conti, P., Leeman, S. E., & Theoharides, T. C. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1906817116 · Cited by 61 · see citing works
“Elevated levels of IL1β in neonatal blood from children with ASD were significantly associated with severity of the disease (59).”
BackgroundInflammation 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 61 · see citing works
CIFASD, A. T., Bodnar, T. S., Raineki, C., Wertelecki, W., Yevtushok, L., Plotka, L., Granovska, I. V., Zymak‐Zakutnya, N., Pashtepa, A. O., Wells, A., et al. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-1717-8 · Cited by 60 · see citing works
Buffolo, F., Petrosino, V., Albini, M., Moschetta, M., Carlini, F., Floss, T., Kerlero de Rosbo, N., Cesca, F., Rocchi, A., Uccelli, A., et al. (2021) · Cell Death & Disease · doi:10.1038/s41419-021-03465-6 · Cited by 60 · see citing works
Neuroimmune and Inflammatory Signals in Complex Disorders of the Central Nervous System
Liberman, A. C., Trías, E., Chagas, L. D. S., Trindade, P., Pereira, M. D. S., Refojo, D., Hedin‐Pereira, C., & Serfaty, C. A. (2018) · NeuroImmunoModulation · doi:10.1159/000494761 · Cited by 61 · see citing works
Zhang, W., Zhang, X., Zhang, Y., Qu, C., Zhou, X., & Zhang, S. (2019) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-019-09887-6 · Cited by 56 · see citing works
“IL-1β, as an important mediator of neuronal injury, also plays diverse roles in the CNS.”
BackgroundInfluentialPozzi, D., Rasile, M., Corradini, I., & Matteoli, M. (2020) · Translational Psychiatry · doi:10.1038/s41398-020-01027-6 · Cited by 55 · see citing works
Environmental Risk Factors in Autism Spectrum Disorder: A Narrative Review
Yenkoyan, K. B., Mkhitaryan, M., & Bjørklund, G. (2024) · Current Medicinal Chemistry · doi:10.2174/0109298673252471231121045529 · Cited by 56 · see citing works
Behavioral impact of maternal allergic-asthma in two genetically distinct mouse strains
Schwartzer, J. J., Careaga, M., Coburn, M., Rose, D. R., Hughes, H. K., & Ashwood, P. (2016) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2016.09.007 · Cited by 52 · see citing works
Self-citationThe X-Linked Intellectual Disability Protein IL1RAPL1 Regulates Dendrite Complexity
Montani, C., Ramos-Brossier, M., Ponzoni, L., Gritti, L., Cwetsch, A. W., Braida, D., Saillour, Y., Terragni, B., Mantegazza, M., Sala, M., et al. (2017) · Journal of Neuroscience · doi:10.1523/jneurosci.3775-16.2017 · Cited by 48 · see citing works
“Similarly, human patients with IL1RAPL1 mutations are characterized by strong ID and minor ASD symptoms (Carrie et al., 1999; Tabolacci et al., 2006; Bhat et al., 2008; Nawara et al., 2008; Piton et al., 2008; Behnecke et al., 2011; Franek et al., 2011; Youngs et al., 2012; Barone et al., 2013).”
BackgroundInfluentialAdvances in Biomarker Studies in Autism Spectrum Disorders
Shen, L., Zhao, Y., Zhang, H., Feng, C., Gao, Y. L., Zhao, D., Xia, S., Qi, H., Iqbal, J., Liu, X., et al. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-05542-4_11 · Cited by 48 · see citing works
Balestrieri, E., Cipriani, C., Matteucci, C., Benvenuto, A., Coniglio, A., Argaw-Denboba, A., Toschi, N., Bucci, I., Miele, M. T., Grelli, S., et al. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02244 · Cited by 48 · see citing works
“During the first trimester of pregnancy, the acute immune activation due to maternal viral infection increases the risk for having autistic children (50), and, at the time of birth, elevated levels of IL-1β and IL-4 in mothers have been associated to a subsequent diagnosis of ASD (51).”
BackgroundSweis, I. E., & Cressey, B. C. (2018) · Toxicology Reports · doi:10.1016/j.toxrep.2018.08.002 · Cited by 47 · see citing works
The Contribution of Inflammation to Autism Spectrum Disorders: Recent Clinical Evidence
Prata, J., Machado, A. S., von Doellinger, O., Almeida, M. I., Barbosa, M. A., Coelho, R. C., & Santos, S. G. (2019) · Methods in molecular biology · doi:10.1007/978-1-4939-9554-7_29 · Cited by 46 · see citing works
Early life exposures, neurodevelopmental disorders, and transposable elements
Lapp, H. E., & Hunter, R. G. (2019) · Neurobiology of Stress · doi:10.1016/j.ynstr.2019.100174 · Cited by 44 · see citing works
Re-emerging concepts of immune dysregulation in autism spectrum disorders
Erbescu, A., Papuc, S. M., Budișteanu, M., Arghir, A., & Neagu, M. T. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.1006612 · Cited by 48 · see citing works
“The increased expression of IL-1β and IL-4 indicate prenatal immune abnormalities, and thus support a potential contribution to ASD pathogenesis (83).”
BackgroundRaghavan, R., ZUCKERMAN, B. S., Hong, X., Wang, G., Ji, Y., Paige, D. M., DiBari, J., Zhang, C., Fallin, M. D., & Wang, X. (2018) · Autism Research · doi:10.1002/aur.2011 · Cited by 42 · see citing works
Serum levels of SOD and risk of autism spectrum disorder: A case‐control study
Wang, L., Jia, J., Zhang, J., & Li, K. (2016) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2016.04.004 · Cited by 41 · see citing works
“…admission, different variables are allegedly associated with risk of ASD, for example, thioredoxin (Zhang et al., 2015), brain-derived neurotrophic factor (BDNF) (Meng et al., 2016), inflammatory-related neuropeptides (Mostafa et al., 2016), and peripheral cytokine profile (Krakowiak et al., 2015).”
BackgroundChen, Y., Liu, S., Xu, H., Zheng, H., Bai, C., Pan, W., Zhou, H., Liao, M., Huang, C., & Dong, Q. (2019) · Toxicology · doi:10.1016/j.tox.2019.02.016 · Cited by 41 · see citing works
Sato, A., Kotajima‐Murakami, H., Tanaka, M., Katoh, Y., & Ikeda, K. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.821455 · Cited by 42 · see citing works
Basheer, S., Venkataswamy, M. M., Christopher, R., van Amelsvoort, T., Srinath, S., Girimaji, S. C., & Ravi, V. (2018) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2018.05.002 · Cited by 40 · see citing works
Carpita, B., Marazziti, D., Palego, L., Giannaccini, G., Betti, L., & Dell’Osso, L. (2019) · Current Medicinal Chemistry · doi:10.2174/0929867326666190328151539 · Cited by 40 · see citing works
Cytokine expression profiles in Autism spectrum disorder: A multi-center study from Turkey
Kütük, M. Ö., Tufan, A. E., Gökçen, C., Kılıçaslan, F., Karadağ, M., Mutluer, T., Yektaş, Ç., Coban, N., Kandemır, H., Büber, A., et al. (2020) · Cytokine · doi:10.1016/j.cyto.2020.155152 · Cited by 38 · see citing works
Nour‐Eldine, W., Ltaief, S. M., Manaph, N. P. A., & Al‐Shammari, A. R. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.950275 · Cited by 39 · see citing works
“The inclusion criteria were the following: (1) original articles; (2) case-control studies; (3) sample type: peripheral blood, plasma, or serum; (4) analysis of immune cell percentages; (5) analysis of cytokine levels in plasma, serum, or bloodspot; (6) analysis of cytokine levels in immune cells at baseline or after…”
BackgroundMethodProtti, M., Mandrioli, R., & Mercolini, L. (2020) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2020.113597 · Cited by 38 · see citing works
Pichitpunpong, C., Thongkorn, S., Kanlayaprasit, S., Yuwattana, W., Plaingam, W., Sangsuthum, S., Aizat, W. M., Baharum, S. N., Tencomnao, T., Hu, V. W., et al. (2019) · PLoS ONE · doi:10.1371/journal.pone.0214198 · Cited by 37 · see citing works
Nuclear Factor Kappa B in Autism Spectrum Disorder: A Systematic Review
Liao, X., & Li, Y. (2020) · Pharmacological Research · doi:10.1016/j.phrs.2020.104918 · Cited by 37 · see citing works
Saad, K., Abdallah, A. M., Abdelrahman, A. A., Al-Atram, A. A., Abdel-Raheem, Y. F., Gad, E. F., Abo‐Elela, M. G. M., Elserogy, Y., Elhoufey, A. A., Nigm, D. A., et al. (2020) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2020.109999 · Cited by 37 · see citing works
Research Progress on the Role of Vitamin D in Autism Spectrum Disorder
Wang, J., Huang, H., Liu, C., Zhang, Y., Wang, W., Zou, Z., Yang, L. F., He, X., Wu, J.-T., Ma, J., et al. (2022) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2022.859151 · Cited by 38 · see citing works
Gene × environment interactions in autism spectrum disorders
Keil, K. P., & Lein, P. J. (2022) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/bs.ctdb.2022.11.001 · Cited by 37 · see citing works
Microglia M2A Polarization as Potential Link between Food Allergy and Autism Spectrum Disorders
Kalkman, H. O., & Feuerbach, D. (2017) · Pharmaceuticals · doi:10.3390/ph10040095 · Cited by 37 · see citing works
“Indeed, in neonatal blood spots collected from ASD patients and normally developing control children, the presence of elevated concentrations of IL1β and IL4 were independently associated with ASD [48].”
BackgroundT cell populations in children with autism spectrum disorder and co-morbid gastrointestinal symptoms
Rose, D. R., Yang, H. T., Careaga, M., Angkustsiri, K., de Water, J. V., & Ashwood, P. (2020) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2020.100042 · Cited by 39 · see citing works
Self-citationInflammation, Dopaminergic Brain and Bilirubin
Jayanti, S. D., Verde, C. D., Tiribelli, C., & Gazzin, S. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241411478 · Cited by 38 · see citing works
Air Pollution during Pregnancy and Childhood Autism Spectrum Disorder in Taiwan
Wang, S.-Y., Cheng, Y., Guo, H., & Tseng, Y.-C. (2021) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph18189784 · Cited by 35 · see citing works
Prenatal Tetanus, Diphtheria, Acellular Pertussis Vaccination and Autism Spectrum Disorder
Becerra-Culqui, T. A., Getahun, D. T., Chiu, V. Y., Sy, L. S., & Tseng, H. F. (2018) · PEDIATRICS · doi:10.1542/peds.2018-0120 · Cited by 35 · see citing works
Blaylock, R. L., Strunecká, A., Patočka, J., & Strunecký, O. (2018) · Surgical Neurology International · doi:10.4103/sni.sni_407_17 · Cited by 35 · see citing works
“Studies of autistic patients report elevations of particular cytokines and the presence of antibrain antibodies.[73,133,259]”
BackgroundCross-genetic determination of maternal and neonatal immune mediators during pregnancy
Traglia, M., Croen, L., Jones, K. L., Heuer, L. S., Yolken, R. H., Kharrazi, M., DeLorenze, G. N., Ashwood, P., de Water, J. V., & Weiss, L. A. (2018) · Genome Medicine · doi:10.1186/s13073-018-0576-8 · Cited by 33 · see citing works
“Elevated peripheral cytokine profiles in pregnancy [31] and at birth have been associated with ASD diagnosis in childhood [32, 33].”
BackgroundSelf-citationHuman pluripotent stem cell (hPSC) and organoid models of autism: opportunities and limitations
Kilpatrick, S., Irwin, C. L., & Singh, K. K. (2023) · Translational Psychiatry · doi:10.1038/s41398-023-02510-6 · Cited by 34 · see citing works
Ross, F. C., Mayer, D. E., Gupta, A., Gill, C. I. R., Rio, D. D., Cryan, J. F., Lavelle, A., Ross, R. P., Stanton, C., & Mayer, E. A. (2023) · Biological Psychiatry · doi:10.1016/j.biopsych.2023.10.018 · Cited by 35 · see citing works
Trained Innate Immunity Not Always Amicable
Włodarczyk, M., Druszczyńska, M., & Fol, M. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20102565 · Cited by 33 · see citing works
“Analysis of the cytokine profile at birth revealed elevated IL-1β and IL-4 levels, which can be considered as a prenatal immune challenge, followed by the development of ASD symptoms later in childhood [163,164].”
BackgroundZhou, J., Tong, J., Ru, X., Teng, Y., Geng, M., Yan, S., Tao, F., & Huang, K. (2023) · BMC Medicine · doi:10.1186/s12916-023-03173-2 · Cited by 32 · see citing works
“Krakowiak et al. [79] found that neonatal IL-4 was associated with increased odds of mild/moderate autism ASD and that high IL-4 was negatively related to nonverbal cognitive abilities in male subjects with ASD.”
BackgroundThe influence of asthma on neuroinflammation and neurodevelopment: From epidemiology to basic models
Tamayo, J. M., Osman, H. C., Schwartzer, J. J., & Ashwood, P. (2023) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2023.12.003 · Cited by 30 · see citing works
“…Autism Risks from Genetics and the Environment (CHARGE) study found that IL-4 and IL-1 β were elevated in newborn blood spots of children later diagnosed with ASD, with IL-4 associated with increased odds of severe ASD (odds ratio 1.40; confidence intervals 1.03 – 1.91) (Krakowiak et al., 2017).”
InfluentialSelf-citationMaternal Immune Activation and Autism in Offspring: What Is the Evidence for Causation?
Gardner, R. M., Brynge, M., Sjöqvist, H., Dalman, C., & Karlsson, H. (2024) · Biological Psychiatry · doi:10.1016/j.biopsych.2024.11.009 · Cited by 30 · see citing works
Cohort-guided insights into gene–environment interactions in autism spectrum disorders
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Role of Maternal Immune Factors in Neuroimmunology of Brain Development
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- Authors
- Krakowiak, P., Goines, P. E., Tancredi, D. J., Ashwood, P., Hansen, R. L., Hertz-Picciotto, I., & Van de Water, J.
- Affiliations
- University of California, Davis (US)
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2017-03
- Volume
- 81
- Issue
- 5
- Pages
- 442-451
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC4753133
- OpenAlex
- W1409858176
- Cited by
- 249
- References
- 65
- Citations by year
- 2026: 15 · 2025: 14 · 2024: 34 · 2023: 32 · 2022: 35 · 2021: 16 · 2020: 27 · 2019: 26 · 2018: 28 · 2017: 12 · 2016: 10
- FWCI
- 10.02
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (P01 ES11269 and R01 ES015359)
- U.S. Environmental Protection Agency through the Science to Achieve Results (STAR) (R829388, R833292)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- autism spectrum disorder, IL-1β, IL-4, immune dysregulation, ASD severity, biomarkers, nonverbal cognitive ability, developmental delay, chemokines, brain development
- MeSH terms
- Autism Spectrum Disorder, Child, Preschool, Female, Humans, Male, Severity of Illness Index, Biomarkers, Interleukin-4, Case-Control Studies, Cytokines, Interleukin-1beta
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