A Mouse Model for the Immune Dysregulation Subtype of Autism
By guest blogger & TACA Physician Advisory Member: Dr. Cindy Schneider
A landmark paper was published this week in the Proceedings of the National Academy of Sciences. Researchers at the California Institute of Technology have successfully created an animal model for autism.[i] By injecting mice with synthetic double-strand RNA, they were able to precipitate an inflammatory process that profoundly and permanently affected the immune and nervous systems of their offspring, mimicking the immune dysregulation autism phenotype. In a subgroup of individuals with autism, pro-inflammatory chemicals called cytokines are elevated and the pattern of immune response leans toward allergies, autoimmune disease, and inflammation rather than toward a normal, more controlled response to environmental immune triggers.[ii] [iii] Dr. Elaine Hsiao and colleagues found that one dose of a double-stranded RNA that mimics viral infection given in the first trimester caused a decrease in T regulatory cells (the immune cells that put the brakes on immune reactions), an increase in the inflammatory cytokines IL-6 and IL-17, and a permanent pro-inflammatory state. These abnormalities correlated with behavioral changes in the mice reminiscent of behaviors seen in individuals with autism. The offspring of mice that underwent maternal immune activation (MIA) had a higher level of anxiety, more repetitive behaviors such as excessive grooming and compulsive burying of marbles, vocalized less and in unusual ways, and were less social when given the opportunity to interact with other mice.
In the second stage of this research, scientists irradiated both MIA offspring and control mice, a process that destroyed their ability to produce stem cells. They then gave them bone marrow transplants from either MIA offspring or control offspring. When normal mice received stem cells from affected mice, they remained healthy. When MIA offspring (mice with immune dysregulation) underwent bone marrow transplant, their autism behaviors reduced significantly, regardless of whether the stem cells were from donors without immune dysregulation or from MIA offspring with significant immune abnormalities.
This finding is extremely important for many reasons. First of all, the potential for stem cell therapy is real, although not ready for prime time in humans. Secondly, this work provides strong evidence that maternal immune activation is a significant risk factor for development of the immune autism phenotype in the mouse model, but is not alone sufficient for development of the condition. Ongoing environmental triggers appear to be necessary for the development of the murine (mouse) equivalent of autism with immune pathology.
Interestingly, bone marrow transplant significantly improved anxiety and stereotypic behaviors in affected mice as well as their immune abnormalities, but did not have a significant impact on their social impairment.
This study sheds light on previous observations that maternal immune activation is a risk factor for having a child who develops autism. Comi et al reported an increased risk of autism in the children of mothers with autoimmune diseases, as have many others.[iv] [v] Maternal antibodies against fetal brain tissue have been identified in a subgroup of mothers of children with autism[vi] and a study of all Danish children born between 1980 and 2005 revealed a very significant association between autism and maternal viral infection in the first trimester. [vii]
In light of the increasing evidence of maternal immune activation in at least one autism phenotype, the wisdom of influenza vaccination in pregnancy should be re-evaluated and pre-conceptual counseling of high risk women should ideally include screening for inflammation and autoimmune diseases.
Cindy Schneider, MD
Center for Autism Research and Education
For more information about TACA’s Physician Advisory board including biographies:
[i] Hsiao EY et al. (2012) Modeling an autism risk factor in mice leads to permanent immune dysregulation. Proc Natl Acad Sci Published ahead of print July 16, 2012 doi: 10.1073/pnas.1202256109.
[ii] Goines P, Van de Water J (2010) The immune system’s role in the biology of autism. Curr Opin Neurol 23:111-117.
[iii] Onore C, Careaga M, Ashwood P (2012) The role of immune dysfunction in the pathophysiology of autism. Brain Behav Immun 26: 383-392.
[iv] Comi AM, Zimmerman AW, Frye VH, et al (1999) Familial clustering of autoimmune disorders and evaluation of medical risk factors in autism. J Child Neurol 14:388-394.
[v] Atladottir HQ et al (2009) Association of family history of autoimmune diseases and autism spectrum disorders. Pediatrics 124:687-694.
[vi] Zimmerman AW (2007) Maternal antibrain antibodies in autism. Brain Behav Immun 21:351-357.
[vii] Atladottir HQ et al (2010) Maternal infection requiring hospitalization during pregnancy and autism spectrum disorders. J Autism Dev Disord 40:1423-1430.