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Immune & Cytokine Dysregulation Associated With Behavioral Deficits In A Mouse Model Of Autism

IFN-Gamma, IL-4 and IL-5 - Mothers Bearing Autistic Children

A new report in the Proceedings of the National Academy of Sciences of the USA (PNAS) indicates that cellular and cytokine immune dysregulation may contribute to the autism spectrum disorder (ASD)-related behavioral deficits in a mouse model of an autism.

Recent evidence indicates the involvement of an abnormal immune system activity in the pathogenesis of autism and the autism spectrum disorder (ASD).

In recent reports,  predominantly in the mothers of ASD children, a higher incidence of allergy or autoimmune diseases, and increased serum levels of interleukin (IL)-4, IL-5 and interferon (IFN)-gamma  have been observed.

In the PNAS study, Elaine Hsiao and colleagues from the California Institute of Technology, Pasadena, CA used a mouse model exhibiting many features of autism, and specifically the maternal immune activation (MIA) model.

In this model, pregnant mice were injected with synthetic, double-stranded RNA, poly(I:C), to initiate a proinflammatory antiviral response. Previous studies indicate that MIA induces in the offspring some major behavioral and neuro-pathological symptoms of autism, including reduced social interaction, abnormal communication and stereotyped/repetitive behavior.

The investigators found that offspring of immune-activated mothers had decreased Tregs and hyper-responsive CD4+ cells, suggesting a chronic, proinflammatory phenotype. This was characterized by increased IL-6 and IL-17 production by CD4+ T cells, and elevated levels of peripheral Gr-1+ CD11b+ neutrophilic and monocytic cells.

Interestingly, and as discussed by the authors, previous research indicates that increased IL-4 levels correlate with greater deficits in communication, whereas high IL-8, IL-12p40, IL-6, and IL-1beta plasma levels are linked to stereotypy, hyperactivity, and lethargy scores in ASD children.

According to the authors, their observations may provide further insights into the mechanisms and relationships between brain dysfunction and altered immunity in the manifestation of abnormal behavior, and how prenatal challenges can program long-term postnatal immunity, health, and disease.

SOURCE:  Proc Natl Acad Sci U S A, 2012, 109:12776. Epub 2012 Jul 16.

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