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Modeling an autism risk factor in mice leads to permanent immune dysregulation

Hsiao, Elaine Y. and McBride, Sara W. and Chow, Janet and Mazmanian, Sarkis K. and Patterson, Paul H. (2012) Modeling an autism risk factor in mice leads to permanent immune dysregulation. Proceedings of the National Academy of Sciences of the United States of America, 109 (31). pp. 12776-12781. ISSN 0027-8424. PMCID PMC3411999. doi:10.1073/pnas.1202556109.

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Increasing evidence highlights a role for the immune system in the pathogenesis of autism spectrum disorder (ASD), as immune dysregulation is observed in the brain, periphery, and gastrointestinal tract of ASD individuals. Furthermore, maternal infection (maternal immune activation, MIA) is a risk factor for ASD. Modeling this risk factor in mice yields offspring with the cardinal behavioral and neuropathological symptoms of human ASD. In this study, we find that offspring of immune-activated mothers display altered immune profiles and function, characterized by a systemic deficit in CD4^+ TCRβ^+ Foxp3^+ CD25^+ T regulatory cells, increased IL-6 and IL-17 production by CD4^+ T cells, and elevated levels of peripheral Gr-1^+ cells. In addition, hematopoietic stem cells from MIA offspring exhibit altered myeloid lineage potential and differentiation. Interestingly, repopulating irradiated control mice with bone marrow derived from MIA offspring does not confer MIA-related immunological deficits, implicating the peripheral environmental context in long-term programming of immune dysfunction. Furthermore, behaviorally abnormal MIA offspring that have been irradiated and transplanted with immunologically normal bone marrow from either MIA or control offspring no longer exhibit deficits in stereotyped/repetitive and anxiety-like behaviors, suggesting that immune abnormalities in MIA offspring can contribute to ASD-related behaviors. These studies support a link between cellular immune dysregulation and ASD-related behavioral deficits in a mouse model of an autism risk factor.

Item Type:Article
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URLURL TypeDescription CentralArticle
Hsiao, Elaine Y.0000-0002-1633-588X
Mazmanian, Sarkis K.0000-0003-2713-1513
Additional Information:© 2012 National Academy of Sciences. Edited by Carla J. Shatz, Stanford University, Stanford, CA, and approved June 19, 2012 (received for review February 15, 2012. Published online before print July 16, 2012. The authors acknowledge the kind assistance of B. Deverman and G. Sharon for reviewing the manuscript, R. Sauza for caring for the animals, and M. Sadoshima for technical help. This work was supported by an Autism Speaks Weatherstone Fellowship (to E.Y.H.); National Institutes of Health Graduate Training Grant NIH/NRSA 5 T32 GM07737 (to E.Y.H. and J.C.); a Weston Havens Foundation grant (to S.K.M. and P.H.P.); a Caltech Innovation grant (to S.K.M. and P.H.P.); and a Congressionally Directed Medical Research Program Idea Development Award (to S.K.M. and P.H.P.). Author contributions: E.Y.H., S.W.M., J.C., S.K.M., and P.H.P. designed research; E.Y.H., S.W.M., and J.C. performed research; E.Y.H., S.W.M., J.C., and P.H.P. analyzed data; and E.Y.H., S.W.M., J.C., S.K.M., and P.H.P. wrote the paper. The authors declare no conflict of interest.
Funding AgencyGrant Number
NIH Predoctoral Fellowship5 T32 GM07737
Weston Havens FoundationUNSPECIFIED
Caltech Innovation Initiative (CI2)UNSPECIFIED
Congressionally Directed Medical Research ProgramUNSPECIFIED
Subject Keywords:immunity; neurodevelopment; prenatal programming; neuroimmunology
Issue or Number:31
PubMed Central ID:PMC3411999
Record Number:CaltechAUTHORS:20120924-131641114
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:34316
Deposited On:24 Sep 2012 21:04
Last Modified:09 Nov 2021 23:07

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