CYTOTOXIC T-CELLS AND CSF-BRAIN BARRIER DAMAGE IN THE ASD BRAIN
- Matthew P. Anderson, United States of America
Abstract
Background and Aims
Autism spectrum disorder (ASD) affects 1 in 59 children in the US and yet, except for rare genetic causes, the etiology in most cases remains unknown. Increased inflammatory proteins and transcripts in the ASD brain reveals an activated innate immune response in a large proportion of cases. This study evaluates for adaptive immune cells and immune cell cytotoxic damage that could drive this innate immune response in ASD.
Methods
The quantity of immune cell subtype infiltrates, cytotoxic cellular debris, tissue loss and fibrosis are compared in ASD and control brains. Standard neuropathology diagnostics methods (histology and immunohistochemistry) are extended with automated image segmentation to quantify pathologic features.
Results
Multifocal perivascular lymphocytic cuffs have increased lymphocyte numbers in ~65% of ASD compared to control brains in males and females, in most brain regions, and in white and grey matter, and leptomeninges. CD3+ T-lymphocytes predominate over CD20+ B-lymphocytes and CD8+ over CD4+ T-lymphocytes in the ASD. Importantly, T-lymphocyte numbers correlate to the quantity of astrocyte-derived round membranous blebs, a known cytotoxic reaction to lymphocyte attack and a histologic feature so far unique to ASD. Consistent with an immune cell-mediated injury at perivascular CSF-brain barriers, a subset of white matter vessels has an expanded perivascular space with a jagged contour and increased collagen in ASD. Similar T-lymphocyte and astrocyte bleb pathology is also observed at pial and ependymal surfaces.
Conclusions
The findings suggest dysregulated cellular immunity may target damage of astrocytes at foci along the CSF-brain barrier in ASD.