CD8 cytotoxic T-cell infiltrates and cellular damage in the hypothalamus in human obesity.

Autor: Ahrendsen JT; Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.; Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA., Nong Y; Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.; Neuroscience Therapeutic Focus Area, Regeneron Pharmaceuticals, Tarrytown, NY, USA., Huo Y; Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.; Neuroscience Therapeutic Focus Area, Regeneron Pharmaceuticals, Tarrytown, NY, USA., Steele J; Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA., Anderson MP; Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA. matthewanderson020@gmail.com.; Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA. matthewanderson020@gmail.com.; Neuroscience Therapeutic Focus Area, Regeneron Pharmaceuticals, Tarrytown, NY, USA. matthewanderson020@gmail.com.
Jazyk: angličtina
Zdroj: Acta neuropathologica communications [Acta Neuropathol Commun] 2023 Oct 09; Vol. 11 (1), pp. 163. Date of Electronic Publication: 2023 Oct 09.
DOI: 10.1186/s40478-023-01659-x
Abstrakt: Rare cases of paraneoplastic obesity in children suggest sporadic obesity might also arise from an adaptive immune cell-mediated mechanism. Since the hypothalamus is a central regulator of feeding behavior and energy expenditure, we quantified lymphocytic inflammation in this region in a cohort of obese and non-obese human post-mortem brains. We report that CD8-positive cytotoxic T-cells are increased in hypothalamic median eminence/arcuate nucleus (ME/Arc) and bed nucleus of the stria terminalis in 40% of obese compared to non-obese patients, but not in other hypothalamic nuclei or brain regions. CD8 T-cells were most abundant in individuals with concurrent obesity and diabetes. Markers of cytotoxic T-cell induced damage, activated caspase 3 and poly-ADP ribose, were also elevated in the ME/Arc of obese patients. To provoke CD8 cytotoxic T-cell infiltrates in ventromedial region of hypothalamus in mice we performed stereotactic injections of an adeno-associated virus expressing immunogenic green fluorescent protein or saline. AAV but not saline injections triggered hypothalamic CD8 T-cell infiltrates associated with a rapid weight gain in mice recapitulating the findings in human obesity. This is the first description of the neuropathology of human obesity and when combined with its reconstitution in a mouse model suggests adaptive immunity may drive as much as 40% of the human condition.
(© 2023. BioMed Central Ltd., part of Springer Nature.)
Databáze: MEDLINE
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