Increased Numbers of CD4<sup>+</sup> T-Cells in the Hypocretin/Orexin Region of Narcolepsy Type 1.

Shan, Ling; Fonville, Milo; Hoekstra, Mabel; Fronczek, Rolf; Smolders, Joost; Swaab, Dick F · Ann Neurol · 2026

basic_science · Level V

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Abstract

Narcolepsy type 1 (NT1) is presumed to be an autoimmune disorder caused by hypothalamic loss of hypocretin (Hcrt; orexin). In postmortem NT1 brains, we observed an 11-fold increase of CD4<sup>+</sup> T-cells in the Hcrt region compared with control hypothalami, without a corresponding rise in CD8<sup>+</sup> T-cells. CD4<sup>+</sup> and CD8<sup>+</sup> T-cell numbers were unchanged in other hypothalamic regions, including the paraventricular nucleus and median eminence, and in extra-hypothalamic areas such as the substantia nigra and locus coeruleus. Hcrt-region CD4<sup>+</sup> T-cells expressed the tissue-resident memory markers CD49a and CXCR6. These findings support the autoimmune hypothesis of NT1. ANN NEUROL 2026;99:1173-1178.

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