Cytokines and fetal development in autism

As discussed in Chap. 5, epidemiologic studies have marshaled considerable evidence that maternal infection increases the risk of schizophrenia in the offspring. This evidence includes studies of viral, bacterial and parasitic infections. Moreover, objective measures of infection, including elevated anti-influenza antibodies or certain cytokines in the blood of pregnant women, are associated with increased schizophrenia risk in the offspring. Epidemiologic studies of a similar scale for autism spectrum disorders (ASD) have lagged behind those in schizophrenia. Therefore, it was a major step forward when Atladotiir et al. (2010) mined the records of >10,000 autism cases in the Danish Historic Birth Cohort and found a significant association with maternal viral infection in the first trimester. A new paper by Morsi Abdallah and colleagues at the Aarhus Univ. Sch. Of Public Health in Denmark just coming out in Brain, Behavior, and Immunity makes use of locally archived samples of amniotic fluid. The major conclusions of this new study are that an increased risk for ASD in the offspring is associated with elevated levels of the chemokine MCP-1 (monocyte chemotactic protein-1; also known as CCL2). What is the meaning of the association with the chemokine MCP-1? This protein is one of a large family of cytokines that controls leukocyte migration. In addition, chemokines mediate communication between neurons and glia, and they could be involved in the altered immune state in autism, where they are elevated in both the brain and the periphery (Goines and Van de Water, 2010). Since the composition of the amniotic fluid is thought to emanate more from fetal than maternal sources, it is possible that the elevated MCP-1 reflects an inflammatory-like state in the fetal brain, perhaps following maternal infection or other obstetrical problems. In animal models of the maternal infection risk factor, my group and others have found that cytokines are significantly elevated in both the fetal brain and the placenta (Meyer et al., 2008; Hsiao and Patterson, 2011). MCP-1 is known to up- regulate IL-6, which is elevated in human autism and is critical for the autism-like behaviors seen in the maternal infection mouse model (Smith et al., 2007; Patterson, 2011). MCP-1 is also associated with autoimmune diseases. Other findings of interest in the Abdallah paper that are not emphasized by the authors are that ASD cases are more likely to be diagnosed with congenital malformation and to have an Apgar score below 7 (meaning poor motor signs]. These associations are consistent with problems during gestation, and have been previously linked to ASD. Such gestational complications are, of course, consistent with maternal infection, particularly the congenital malformations. Also adding to this accumulating evidence of the importance of the fetal environment in autism are large twin studies showing higher concordance for ASD in dizygotic twins than in siblings, as I cited in a prior post (reviewed by Szatmari, 2011). Another important link between cytokines during fetal development is the finding by Goines et al. (Molecular Autism 2:13, ’11) that there is an association between elevated cytokines in the mother’s serum and increased risk for autism in the offspring. This correlation was also found for elevated maternal cytokines and schizophrenia outcome in the offspring (Alan Brown’s work).

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