Early Immune Biomarkers Identified for Autism Subphenotype

The immune system dysregulation during pregnancy may lead to or exacerbate neurodevelopmental conditions such as autism.

According to recent findings published in Molecular Psychiatry, elevated maternal, mid-gestational levels of various cytokines and chemokines are associated with an increased risk for autism spectrum disorder (ASD) with concomitant intellectual disability (ID) in offspring.1

Behavioral neuroimmunology is a fast-growing field. Research efforts conducted throughout recent decades have revealed a generally adaptive relationship between the central nervous system (CNS) and the immune system. Their complex interdependence, however, includes immune system dysregulation that triggers pathophysiological changes of the CNS, which may then lead to or exacerbate neuropsychiatric conditions such as autism and related syndromes.2,3

The dynamic interaction between the CNS and the immune system is bidirectional, and the 2 systems communicate with one another through various signaling pathways. Cytokines in the periphery and within the brain parenchyma, for example, regulate neuronal function and behavior via immune and endocrine mechanisms.4,5 Beyond its influence on the CNS in adulthood, the immune system activation during the perinatal period causes lifelong changes in both brain function and behavior.6

In a large population-based, nested case-control study, the investigators examined the levels of 22 different cytokines in sera of pregnant mothers. Compared with control participants, elevated levels of proinflammatory cytokines including IL-1alpha, IL-6, and IFN-gamma were significantly associated with an increased risk for ASD with ID. The authors also noted that, “Although our findings may be indicative of an immune activation that affects developmental programming … several environmental toxicants such as heavy metals and pesticides can cause both neural and immune dysfunction and have been associated with increased risk of ASD.”1

The number of ASD diagnoses is on the rise. According to a 2014 report by the Centers for Disease Control and Prevention (CDC), this heritable disorder affects approximately 1 in 68 children in the United States and is almost 5 times more common among boys.7 In addition to rare de novo genetic variants contributing to an increased risk for autism,8 it’s becoming evident that inflammation during early fetal development can increase the risk of autism in offspring in humans, or offspring with autism-like behavior and molecular features in animal models.9

Autism is a highly heterogeneous condition. The aberrant immune system function and maternal inflammation modifies the neurodevelopmental trajectory of the fetus, but “this observed immunologic distinction between mothers of children with ASD+ID from mothers of children with ASD with no ID or developmental delay (DD) suggests that the intellectual disability associated with ASD might be etiologically distinct from DD without ASD,” the authors concluded.1

Researchers continue to examine the genetic, molecular, and behavioral differences among individuals with ASD in order to define diverse etiologies and varied phenotypes. This approach may ultimately help translate basic biomedical research into clinically beneficial personalized medicine approaches to treatment of ASD.10

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1. Jones KL, Croen LA, Yoshida CK, et al. Autism with intellectual disability is associated with increased levels of maternal cytokines and chemokines during gestation. Mol Psychiatry. 2016; doi: 10.1038/mp.2016.77. [Epub ahead of print]

2. Estes ML, McAllister AK. Immune mediators in the brain and peripheral tissues in autism spectrum disorder. Nat Rev Neurosci. 2015;16:469-486.

3. Young AM, Chakrabarti B, Roberts D, et al. From molecules to neural morphology: understanding neuroinflammation in autism spectrum condition. Mol Autism. 2016;7:9.

4. Louveau A, Harris TH, Kipnis J. Revisiting the mechanisms of CNS immune privilege. Trends Immunol. 2015;36:569-577.

5. Kelley KW, McCusker RH. Getting nervous about immunity. Semin Immunol. 2014;26:389-393.

6. Bilbo SD, Schwarz JM. Early-life programming of later-life brain and behavior: a critical role for the immune system. Front Behav Neurosci. 2009;3:14.

7. Baio J, et al. Prevalence of autism spectrum disorder among children aged 8 years – Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2010. MMWR. 2014;63(No. SS-2):1-21.

8. Geschwind DH, State MW. Gene hunting in autism spectrum disorder: on the path to precision medicine. Lancet Neurol. 2015;14:1109-1120.

9. Patterson PH. Maternal infection and immune involvement in autism. Trends Mol Med. 2011;17:389-394.

10. Constantino JN, Charman T. Diagnosis of autism spectrum disorder: reconciling the syndrome, its diverse origins, and variation of expression. Lancet Neurol. 2016;15:279-291.