TLR signaling pathways in brain tissue from patients with autism
South Hall A
Monday, Oct 19, 2009, 1:00 PM - 2:00 PM
*A. K. AZHAGIRI
, C. LAWLER
, A. ZEA-VERA
, C. PARDO-VILLAMIZAR*
Neurol., Johns Hopkins Univ., Baltimore, MD;
Microbiology, Univ. del Valle, Cali, Colombia
Pathogenesis of autism has been associated with genetic and environmental factors. As part of the genetic and environmental interactions, immune factors and neuroimmune responses appear to play pathophysiological roles in autism. Innate immune mechanisms are involved in regulating synaptic/dendritic organization as well as neuronal dysfunction. Toll-like receptors (TLRs) and their associated pathways are involved in initiation and regulation of the innate immune response to diverse pathogen-associated molecular challenges. At least 10 TLRs are reported in humans and some of them are expressed in neurons and neuroglia in the central nervous system (CNS).
Assess role of TLR signaling pathways and examine patterns of expression in brains of patients with autism.
Expression profiles of TLR signaling pathway genes were assessed using PCR arrays. Brain tissues from 4 regions, mid-frontal (MFG), mid-temporal (MTG), anterior cingulate (ACG) and Occipital (OG) gyri from 7 autism (range 5-42 yrs, mean 14.6 years) and 10 control patients (range 5-20 yrs, mean 12.8 yrs) were studied. Selected TLRs were validated by immunoblot and immunocytochemistry.
Significant expression differences in at least 14 genes were observed. Most of the changes were in the MFG and ACG. Up regulation of gene expression occurred in the ACG, where genes such as TLR-2, IL-2, NFKB1 and TNFRSF1A, were significantly increased (p<0.05). In contrast, a different set of genes including SARM1 (p=0.01) and UBE2N (p=0.01) showed down regulation in the MFG. Immunocytochemical studies demonstrated that TLR-2 was localized mostly in astrocytes and microglia cells, a pattern almost identical to TLR-3. TLR-4 expression was observed mostly in microglial cells.
The expression variations observed reflect the status of neuroimmune responses in selected regions of the cerebral cortex. The ACG, an area of interest for social/behavioral changes in autism, displayed the most expression variations. The changes, in ACG, concur with previous observations of increased neuroimmune and neuroglial responses in autism. Two of the up-regulated genes, IL-2 and TLR-2, play roles in modulation of innate immunity and inflammation. Immunolocalization of TLR-2 in microglia and astrocytes indicate that TLRs are associated with neuroglial activation in patients with autism. In contrast, SARM1 and UBE2N, two genes down regulated in the MFG are associated with regulation of the number of neurons. This suggests their involvement in neurodevelopmental abnormalities such as those observed in some brain regions in autism.
Toll-like receptor (TLR)
Innate immune system
Bart Maclean Fund for Neuroimmunology Research-Project Restore
Peter Emch Fund for Autism Research
[Authors]. [Abstract Title]. Program No. XXX.XX. 2009 Neuroscience Meeting Planner. Chicago, IL: Society for Neuroscience, 2009. Online.
2009 Copyright by the Society for Neuroscience all rights reserved. Permission to republish any abstract or part of any abstract in any form must be obtained in writing by SfN office prior to publication.
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