Marcello M DiStasio1, Ikue Nagakura1, Monica J Nadler1, Matthew P Anderson1,2,3. 1. Department of Neurology and Pathology, Beth Israel Deaconess Medical Center, Boston, MA. 2. Boston Children's Hospital Intellectual and Developmental Disabilities Research Center, Harvard Medical School, Boston, MA. 3. Program in Neuroscience, Harvard Medical School, Boston, MA.
Abstract
OBJECTIVE: Autism spectrum disorder (ASD) affects 1 in 59 children, yet except for rare genetic causes, the etiology in most ASD remains unknown. In the ASD brain, inflammatory cytokine and transcript profiling shows increased expression of genes encoding mediators of the innate immune response. We evaluated postmortem brain tissue for adaptive immune cells and immune cell-mediated cytotoxic damage that could drive this innate immune response in the ASD brain. METHODS: Standard neuropathology diagnostic methods including histology and immunohistochemistry were extended with automated image segmentation to quantify identified pathologic features in the postmortem brains. RESULTS: We report multifocal perivascular lymphocytic cuffs contain increased numbers of lymphocytes in ~65% of ASD compared to control brains in males and females, across all ages, in most brain regions, and in white and gray matter, and leptomeninges. CD3+ T lymphocytes predominate over CD20+ B lymphocytes and CD8+ over CD4+ T lymphocytes in ASD brains. Importantly, the perivascular cuff lymphocyte numbers correlate to the quantity of astrocyte-derived round membranous blebs. Membranous blebs form as a cytotoxic reaction to lymphocyte attack. Consistent with multifocal immune cell-mediated injury at perivascular cerebrospinal fluid (CSF)-brain barriers, a subset of white matter vessels have increased perivascular space (with jagged contours) and collagen in ASD compared to control brains. CSF-brain barrier pathology is also evident at cerebral cortex pial and ventricular ependymal surfaces in ASD. INTERPRETATION: The findings suggest dysregulated cellular immunity damages astrocytes at foci along the CSF-brain barrier in ASD. ANN NEUROL 2019;86:885-898.
OBJECTIVE:Autism spectrum disorder (ASD) affects 1 in 59 children, yet except for rare genetic causes, the etiology in most ASD remains unknown. In the ASD brain, inflammatory cytokine and transcript profiling shows increased expression of genes encoding mediators of the innate immune response. We evaluated postmortem brain tissue for adaptive immune cells and immune cell-mediated cytotoxic damage that could drive this innate immune response in the ASD brain. METHODS: Standard neuropathology diagnostic methods including histology and immunohistochemistry were extended with automated image segmentation to quantify identified pathologic features in the postmortem brains. RESULTS: We report multifocal perivascular lymphocytic cuffs contain increased numbers of lymphocytes in ~65% of ASD compared to control brains in males and females, across all ages, in most brain regions, and in white and gray matter, and leptomeninges. CD3+ T lymphocytes predominate over CD20+ B lymphocytes and CD8+ over CD4+ T lymphocytes in ASD brains. Importantly, the perivascular cuff lymphocyte numbers correlate to the quantity of astrocyte-derived round membranous blebs. Membranous blebs form as a cytotoxic reaction to lymphocyte attack. Consistent with multifocal immune cell-mediated injury at perivascular cerebrospinal fluid (CSF)-brain barriers, a subset of white matter vessels have increased perivascular space (with jagged contours) and collagen in ASD compared to control brains. CSF-brain barrier pathology is also evident at cerebral cortex pial and ventricular ependymal surfaces in ASD. INTERPRETATION: The findings suggest dysregulated cellular immunity damages astrocytes at foci along the CSF-brain barrier in ASD. ANN NEUROL 2019;86:885-898.
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