Adaptive Cellular Immunity in the ASD Postmortem Brain

Background: Autism spectrum disorder (ASD) is estimated to affect 1 in 59 children by 8 years of age in the United States and yet, except for rare genetic causes, the etiology in most ASD cases remains unknown. The presence of increased inflammatory proteins and transcripts in the ASD brain indicates the innate immune response is activated in a large proportion of ASD cases.

Objectives: To evaluate for adaptive immune cells and damage typical of immune cell mediated cytotoxicity that could potentially drive an innate immune response in the ASD brain.

Methods: The quantity of immune cell subtype infiltrates, cytotoxic cellular debris, tissue loss and fibrosis were compared in ASD and control brains. Standard neuropathology diagnostics methods including histology and immunohistochemistry were extended with automated image segmentation to quantify identified pathologic features in the postmortem brains.

Results: Multifocal perivascular lymphocytic cuffs are found that contain increased numbers of lymphocytes in ~65% of ASD compared to control brains in males and females, across a range of ages, 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 brain. Importantly, the number of lymphocytes in these perivascular cuffs correlates to the quantity of astrocyte-derived round membranous blebs, a known cytotoxic reaction to targeted 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 have an expanded perivascular space (with jagged contours) and increased perivascular collagen in ASD compared to control brains. Similar T-lymphocyte and astrocyte bleb pathology is observed in subarachnoid and pial surfaces of the cerebral cortex in ASD.

Conclusions: The findings suggest dysregulated cellular immunity may target the damage of astrocytes at foci along the CSF-brain barrier in many cases of ASD.