Modeling an autism risk factor in mice leads to permanent immune dysregulation.
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.
Biology Division, California Institute of Technology, Pasadena, CA 91125, USA. ehsiao@caltech.edu
Elaine Y
EY
Hsiao
Sara W
SW
McBride
Janet
J
Chow
Sarkis K
SK
Mazmanian
Paul H
PH
Patterson
D000818:Animals; D000943:Antigens, Differentiation / Q000276:immunology; D001321:Autistic Disorder / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D001522:Behavior, Animal; D002454:Cell Differentiation / Q000276:immunology; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000473:pathology; D006801:Humans; D007111:Immunity, Cellular; D020381:Interleukin-17 / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D051379:Mice; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000276:immunology* / Q000473:pathology; D012307:Risk Factors; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D014184:Transplantation, Homologous
D000943:Antigens, Differentiation; D020381:Interleukin-17; D015850:Interleukin-6