Maternal neuronal antibodies associated with autism and a language disorder
Open accessAbstract
Neurodevelopmental disorders could be caused by maternal antibodies or other serum factors. We detected serum antibodies binding to rodent Purkinje cells and other neurons in a mother of three children: the first normal, the second with autism, and the third with a severe specific language disorder. We injected the serum (0.5–1.0ml/day) into pregnant mice during gestation and found altered exploration and motor coordination and changes in cerebellar magnetic resonance spectroscopy in the mouse offspring, comparing with offspring of mice injected with sera from mothers of healthy children. This evidence supports a role for maternal antibodies in some forms of neurodevelopmental disorder. Ann Neurol 2003;53:533–537
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Animal models have yielded many insights into the effects and mechanisms of inflammation and immune activation, as well as the role of toxic agents, in inducing autism-like behaviors in rodent and other species.
“animal models have yielded many intriguing insights into the effects and mechanisms of inflammation and immune activation, as well as the role of toxic agents, in inducing autism-like behaviors in rodent and other species [103, 104, 112–115, 207].”
From The contribution of environmental exposure to the etiology of autism spectrum disorder (2019) · cites this paper as [112]
Dalton et al. injected maternal serum containing anti-brain antibodies into pregnant mice daily between E10 and E17 and observed reduced exploration and motor control in the offspring compared with untreated dams.
“investigators injected maternal serum containing anti-brain antibodies into pregnant mice daily between E10 and E17, and observed reduced exploration and motor control in their offspring as compared with the offspring of untreated dams”
From The Role of the Immune System in Autism Spectrum Disorder (2017) · cites this paper as Dalton et al, 2003
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“Similar approaches have identified behavioral abnormalities in offspring following exposure of pregnant dams to serum antibodies from mothers of dyslexic children and from a mother with anti-Purkinje antibodies who had an autistic child (Dalton et al., 2003; Vincent et al., 2003).”
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“caused behavioral and motor abnormalities in mice exposed to the serum as embryos (Dalton et al., 2003).”
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Caspr2-reactive antibody cloned from a mother of an ASD child mediates an ASD-like phenotype in mice
Brimberg, L., Mader, S., Jeganathan, V., Berlin, R., Coleman, T. R., Gregersen, P. K., Huerta, P. T., Volpe, B. T., & Diamond, B. (2016) · Molecular Psychiatry · doi:10.1038/mp.2016.165 · Cited by 102 · see citing works
Autoantibodies in Autism Spectrum Disorders (ASD)
Wills, S., Cabanlit, M., BENNETT, J., Ashwood, P., Amaral, D. G., & de Water, J. V. (2007) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1381.009 · Cited by 98 · see citing works
Toward an immune-mediated subtype of autism spectrum disorder
McDougle, C. J., Landino, S. M., Vahabzadeh, A., O’Rourke, J., Zurcher, N. R., Finger, B. C., Palumbo, M. L., Helt, J., Mullett, J. E., Hooker, J. M., et al. (2015) · Brain Research · doi:10.1016/j.brainres.2014.09.048 · Cited by 95 · see citing works
Riva, D., Annunziata, S., Contarino, V. E., Erbetta, A., Aquino, D., & Bulgheroni, S. (2013) · The Cerebellum · doi:10.1007/s12311-013-0469-8 · Cited by 92 · see citing works
“Several recent immunological studies have suggested the involvement of cerebellum in the pathophysiology of autism [36–38].”
BackgroundPiras, I. S., Haapanen, L., Napolioni, V., Sacco, R., Van de Water, J., & Persico, A. M. (2014) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2013.12.020 · Cited by 88 · see citing works
“These results largely replicate previous findings, whereby mAbs have been found associated with high rates of language regression and poor expressive language scores (Dalton et al., 2003; Braunschweig et al., 2012).”
ResultImmune Dysregulation in Autism Spectrum Disorder
Hsiao, E. Y. (2013) · International Review of Neurobiology · doi:10.1016/b978-0-12-418700-9.00009-5 · Cited by 87 · see citing works
Martin, L. A., Goldowitz, D., & Mittleman, G. (2010) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2009.07073.x · Cited by 82 · see citing works
“…of ASD is self-generated or maternally derived pathogenic antibodies and several recent studies have shown that antibodies from children with ASD or their mothers target cell populations within the cerebellum including Purkinje cells (Dalton et al., 2003; Singer et al., 2006; Wills et al., 2009).”
BackgroundT lymphocytes and cytotoxic astrocyte blebs correlate across autism brains
DiStasio, M., Nagakura, I., Nadler, M. J. S., & Anderson, M. P. (2019) · Annals of Neurology · doi:10.1002/ana.25610 · Cited by 78 · see citing works
Saint‐Martin, M., Joubert, B., Pellier‐Monnin, V., Pascual, O., Noraz, N., & Honnorat, J. (2018) · European Journal of Neuroscience · doi:10.1111/ejn.14081 · Cited by 83 · see citing works
“Furthermore, antibodies injected into pregnant mice were able to access the fetal brain and to affect its development (Dalton et al., 2003; Singer et al., 2009).”
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 88 · see citing works
Infection in the First 2 Years of Life and Autism Spectrum Disorders
Rosen, N. J., Yoshida, C. K., & Croen, L. (2007) · PEDIATRICS · doi:10.1542/peds.2006-1788 · Cited by 77 · see citing works
Carroll, L., Braeutigam, S., Dawes, J. M., Krsnik, Ž., Kostović, I., Coutinho, E., Dewing, J. M., Horton, C. A., Gómez‐Nicola, D., & Menassa, D. A. (2020) · The Neuroscientist · doi:10.1177/1073858420921378 · Cited by 75 · see citing works
Braunschweig, D., Golub, M. S., Koenig, C. M., Qi, L., Pessah, I. N., Van de Water, J., & Berman, R. F. (2012) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2012.08.002 · Cited by 71 · see citing works
Human gestational N‐methyl‐d‐aspartate receptor autoantibodies impair neonatal murine brain function
Jurek, B., Chayka, M., Kreye, J., Lang, K., Kraus, L., Fidzinski, P., Kornau, H.-C., Dao, L.-M., Wenke, N., Long, M., et al. (2019) · Annals of Neurology · doi:10.1002/ana.25552 · Cited by 59 · see citing works
Antibodies as Mediators of Brain Pathology
Brimberg, L., Mader, S., Fujieda, Y., Arinuma, Y., Kowal, C., Volpe, B., & Diamond, B. (2015) · Trends in immunology · doi:10.1016/j.it.2015.09.008 · Cited by 64 · see citing works
“When researchers gave these antibodies to pregnant mice and monkeys, they caused abnormal behavior in their offspring including increased motor activity, stereotypic behavior, anxiety-like behavior, and alterations in sociability [123–128].”
Maternal autoantibody related autism: mechanisms and pathways
Jones, K. L., & de Water, J. V. (2018) · Molecular Psychiatry · doi:10.1038/s41380-018-0099-0 · Cited by 71 · see citing works
“This interest was furthered by an intriguing pilot study in which sera from a mother of a child with ASD was injected into pregnant mice, producing alterations to exploratory behavior and motor coordination in the prenatally exposed offspring relative to controls [25].”
Maternal and fetal antibrain antibodies in development and disease
Fox, E., Amaral, D. G., & de Water, J. V. (2012) · Developmental Neurobiology · doi:10.1002/dneu.22052 · Cited by 63 · see citing works
“Plasma from one mother of multiple children with autism was injected into pregnant mice and the offspring demonstrated impaired exploratory behavior and motor coordination (Dalton et al., 2003; studies summarized in Table 1).”
BackgroundMethodKrämer, P., & Bressan, P. (2015) · Perspectives on Psychological Science · doi:10.1177/1745691615583131 · Cited by 66 · see citing works
“Indeed, if blood serum (which contains antibodies) from mothers of children with conditions such as autism (Dalton et al., 2003) or dyslexia (Vincent et al., 2002) is injected into pregnant mice, the mouse offspring shows altered brain growth and behavioral deficits, whereas this is not the case…”
BackgroundMartínez-Cerdeño, V., Camacho, J., Fox, E., Miller, E., Ariza, J., Kienzle, D., Plank, K., Noctor, S. C., & Van de Water, J. (2016) · Cerebral Cortex · doi:10.1093/cercor/bhu291 · Cited by 63 · see citing works
“independently identified by several groups (Dalton et al. 2003; Singer et al. 2008), and a particular pattern of reactivity that is unique to mothers of children with ASD has been identified (Braunschweig et al.”
BackgroundHeuer, L., Braunschweig, D., Ashwood, P., Van de Water, J., & Campbell, D. B. (2011) · Translational Psychiatry · doi:10.1038/tp.2011.48 · Cited by 62 · see citing works
“injected into gestating mice and shown to elicit behavioral deficits in the offspring.(12) In another study, 11 mothers of children with ASD and their affected children were found to have consistent patterns of antibody reactivity against rat prenatal brain proteins.”
Hyperbaric oxygen therapy might improve certain pathophysiological findings in autism
Rossignol, D. A. (2006) · Medical Hypotheses · doi:10.1016/j.mehy.2006.09.064 · Cited by 62 · see citing works
“Finally, maternal neuronal antibodies might play a role in the development of autism in some children [91].”
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
Rossi, C. C., de Water, J. V., Rogers, S. J., & Amaral, D. G. (2011) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2011.02.011 · Cited by 56 · see citing works
Coutinho, E., Menassa, D. A., Jacobson, L. W., West, S. J., Domingos, J., Moloney, T. C., Lang, B., Harrison, P. J., Bennett, D., Bannerman, D. M., et al. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1751-5 · Cited by 56 · see citing works
“To explore the long-term sequelae of in utero exposure to these antibodies, we used our established mouse maternal-to-fetal transfer model [9, 15] using human IgG preparations from two patients with CASPR2-antibody encephalitis and from three healthy individuals.”
MethodSelf-citationAutism spectrum disorder: Trends in research exploring etiopathogenesis
Gyawali, S., & Patra, B. N. (2019) · Psychiatry and Clinical Neurosciences · doi:10.1111/pcn.12860 · Cited by 59 · see citing works
“Maternal antibodies or other serum factors could cause neurodevelopmental disorders.(33) A case–control study with serum samples of 49 mothers of ASD-affected children and 73 controls found a higher maternal seropositivity for anti-Yo antibodies (34.”
BackgroundImmunologic and neurodevelopmental susceptibilities of autism
Pessah, I. N., Seegal, R. F., Lein, P. J., LaSalle, J., Yee, B. K., Van De Water, J., & Berman, R. F. (2008) · NeuroToxicology · doi:10.1016/j.neuro.2008.02.006 · Cited by 51 · see citing works
“(Dalton et al., 2003) demonstrated maternal IgG antibody reactivity to adult rat cerebellar Purkinje cells in a mother of multiple children with ASD.”
BackgroundInfluentialEdmiston, E., & de Water, J. V. (2015) · CNS Drugs · doi:10.1007/s40263-015-0279-2 · Cited by 49 · see citing works
Gupta, S., Samra, D., & Agrawal, S. (2010) · Journal of Clinical Immunology · doi:10.1007/s10875-010-9402-9 · Cited by 48 · see citing works
“However, Dalton and associates [5] were the first to demonstrate the presence of antibodies in”
Cannabidiol for the treatment of autism spectrum disorder: hope or hype?
Pedrazzi, J. F. C., Ferreira, F. R., Silva-Amaral, D., Lima, D. D. A., Hallak, J. E. C., Zuardi, A. W., Bel, E. A. D., Guimarães, F. S., Costa, K. C. M., Campos, A. C., et al. (2022) · Psychopharmacology · doi:10.1007/s00213-022-06196-4 · Cited by 52 · see citing works
“These factors may promote behavioral abnormalities with similarities to autism, including inadequate activation of proinflammatory cytokines and abnormal immune response (Dalton et al. 2003; Kirsten et al. 2010).”
BackgroundClinical clues for autoimmunity and neuroinflammation in patients with autistic regression
Scott, O., Shi, D., Andriashek, D., Clark, B., & Goez, H. (2017) · Developmental Medicine & Child Neurology · doi:10.1111/dmcn.13432 · Cited by 47 · see citing works
“Dalton et al.20 isolated neuronal autoantibodies from the serum of a mother of three children, of whom one had ASD and another had severe language delay.”
BackgroundInfluentialA 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 47 · see citing works
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 45 · see citing works
Coutinho, E., Jacobson, L. W., Pedersen, M. G., Benros, M. E., Nørgaard‐Pedersen, B., Mortensen, P. B., Harrison, P. J., & Vincent, A. C. (2017) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2016-315251 · Cited by 45 · see citing works
Self-citationEtiopathogenesis of autism spectrum disorders: Fitting the pieces of the puzzle together
Gentile, I., Zappulo, E., Militerni, R., Pascotto, A., Borgia, G., & Bravaccio, C. (2013) · Medical Hypotheses · doi:10.1016/j.mehy.2013.04.002 · Cited by 42 · see citing works
“[137] identified antibodies capable of opsonizing the Purkinje cells and other rodent neurons in the serum of a mother of an autistic child.”
BackgroundTrajkovski, V., Ajdinski, L., & Spiroski, M. Z. (2018) · doi:10.31235/osf.io/vrt3b · Cited by 42 · see citing works
“Serum antibodies binding to rodent Purkinije cells and other neurons were detected in a mother of 3 children (the first normal, the second with autism, and the third with a severe specific language disorder), which supports the role of maternal antibodies in some forms of neurodevelopmental disorder ( 22 ).”
BackgroundBeyond the brain: A multi-system inflammatory subtype of autism spectrum disorder
Thom, R. P., Keary, C. J., Palumbo, M. L., Ravichandran, C. T., Mullett, J. E., Hazen, E. P., Neumeyer, A. M., & McDougle, C. J. (2019) · Psychopharmacology · doi:10.1007/s00213-019-05280-6 · Cited by 41 · see citing works
Brain Abnormalities in Language Disorders and in Autism
Herbert, M. R., & Kenet, T. (2007) · Pediatric Clinics of North America · doi:10.1016/j.pcl.2007.02.007 · Cited by 39 · see citing works
Vincent, A. C. (2010) · Journal of Clinical Immunology · doi:10.1007/s10875-010-9401-x · Cited by 38 · see citing works
“Maternal antibodies to unknown neuronal antigens have also been proposed as a possible disease mechanism in some cases of autism [12].”
BackgroundSelf-citationAutoimmunity in psychotic disorders. Where we stand, challenges and opportunities
Mané-Damas, M., Hoffmann, C., Zong, S., Tan, A., Molenaar, P. C., Losen, M. H., & Martínez‐Martínez, P. (2019) · Autoimmunity Reviews · doi:10.1016/j.autrev.2019.102348 · Cited by 38 · see citing works
Autism‐specific maternal anti‐fetal brain autoantibodies are associated with metabolic conditions
Krakowiak, P., Walker, C. K., Tancredi, D. J., Hertz‐Picciotto, I., & de Water, J. V. (2016) · Autism Research · doi:10.1002/aur.1657 · Cited by 37 · see citing works
“Interestingly, impairments in MET signaling have also been linked to type 2 and gestational diabetes in several animal studies [Araujo et al., 2012; Demirci et al., 2012; Fafalios et al., 2011; Mellado-Gil et al., 2011].”
BackgroundMaternal antibodies and developing blood–brain barrier
Kowal, C., Athanassiou, A., Chen, H.-Y., & Diamond, B. (2015) · Immunologic research · doi:10.1007/s12026-015-8714-5 · Cited by 39 · see citing works
- Authors
- Dalton, P., Deacon, R., Blamire, A., Pike, M., McKinlay, I., Stein, J., Styles, P., & Vincent, A.
- Affiliations
- University of Oxford (GB)
- John Radcliffe Hospital (GB)
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2003-03-24
- Volume
- 53
- Issue
- 4
- Pages
- 533-537
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- OpenAlex
- W2105371617
- Cited by
- 204
- References
- 20
- Citations by year
- 2025: 1 · 2024: 5 · 2023: 9 · 2022: 5 · 2021: 9 · 2020: 10 · 2019: 12 · 2018: 9 · 2017: 9 · 2016: 10 · 2015: 15 · 2014: 10 · 2013: 14 · 2012: 11
- FWCI
- 4.08
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Health Sciences › Medicine › Neurology › Autoimmune Neurological Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- maternal antibodies, autism spectrum disorder, specific language impairment, Purkinje cells, cerebellum, neurodevelopmental disorders, mouse offspring, motor coordination, maternal-fetal immune transfer
- MeSH terms
- Adult, Animals, Autistic Disorder, Child, Dyslexia, Postural Balance, Female, Humans, Immunoglobulin G, Immunoglobulin M, Immunity, Maternally-Acquired, Magnetic Resonance Imaging, Male, Motor Activity, Magnetic Resonance Spectroscopy, Pregnancy, Purkinje Cells, Mice
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