Immunological Disarrangements in ASD Are Associated with Biological Processes and Homeostatic Mechanisms in ASD Rather Than Autoimmunity or Pathogenic Inflammation
Background: Interactions between the immune and central nervous system (CNS) are critical for maintenance of homeostasis and brain functions, including cognition. Immunological mechanisms have been hypothesized to play a role in the etiopathogenesis of autism spectrum disorder (ASD), based on observations of abnormalities in a variety of immune markers in serum samples or post-mortem tissues.
Objectives: To establish the immunological profiles in blood and cerebrospinal fluid (CSF) samples from pediatric subjects with ASD, in comparison with blood samples from typically developing children (TYP) in order to evaluate a pathogenic role of observed between-group differences and specific patterns.
Methods: A longitudinal study of clinical and immunological factors associated with ASD was carried out at the NIMH intramural program.106 subjects with autism (mean age 50.4±15.88 months) and 70 typically developing controls (mean age 38.53±15.34 months) were recruited for the study. Autism was diagnosed using the ADI-R and ADOS as well as clinical judgment. Regression history was also assessed using the Regression Validation Interview. Regression was defined as language loss and/or loss of social engagement. Blood and CSF were used to assess the immunological profile in subjects with autism while only blood was analyzed in typical developing controls. Studies to characterize patterns of immune activation and inflammation by flow cytometry, cytokine/chemokine profiling and microbial translocation were carried out.
- Although there was a significant increase in blood NK cells between ASD and controls, no evidence of activation of immune cells or dysregulation of T-regulatory cells was observed in ASD.
- Abnormally elevated levels of immune mediators such as CD40 ligand (CD40L) and epidermal growth factor (EGF) were found in blood of ASD patients while classical mediators of inflammation such as TNFa, IL6 and other cytokines were similar between ASD and control subjects.
- Cytokine/chemokine profiles in blood and CSF samples were clearly distinct, a result that suggests blood inflammation biomarkers are not suitable markers for assessment of CNS abnormalities in ASD.
- CSF cytokine/chemokine profiles demonstrated increases in monocyte-related mediators such as CX3CL1 (fractalkine), CCL2 (MCP-1) and FLT3-L, a finding that support the view that inductors of microglia activation are dominant in CSF of ASD subjects.
Conclusions: Our studies suggest that immunological abnormalities exist in ASD, but most appear to be related to genetic and environmental factors unrelated to autistic symptomatology. Evidence for a primary pathogenic role of immune dysfunction was generally absent in this cohort of young children with ASD.