Cytokines in narcolepsy type 1: pathogenic relevance, biomarker potential, and future directions

Narcolepsy type 1 (NT1) is a central disorder of hypersomnolence characterized by the selective loss of hypocretin/orexin-producing neurons. Its pathogenesis is closely associated with HLA genetic susceptibility, environmental triggers, and T-cell-mediated autoimmune responses. In recent years, increasing attention has been paid to the role of cytokines in the immunopathology of NT1. This review summarizes current evidence regarding cytokines in NT1, including IL-6, TNF-α, IFN-γ, IL-8, MCP-1/CCL2, CCL3, IL-4, and IL-10, and critically evaluates their roles as potential pathogenic mediators, diagnostic biomarkers, disease-stage indicators, and markers of neuropsychiatric comorbidities. Current evidence suggests that IL-6, TNF-α, and IFN-γ may reflect peripheral pro-inflammatory responses and activation of the Th1/cytotoxic T-cell axis, whereas IL-4 and IL-10 may be associated with immunoregulatory balance and emotional symptoms. However, most available studies are limited by small sample sizes, single-center cohorts, and cross-sectional designs, and their findings are influenced by sample matrix, disease stage, age, medication exposure, obesity, and neuropsychiatric comorbidities, resulting in limited consistency and reproducibility. Therefore, no single cytokine currently qualifies as an independent diagnostic biomarker, disease-staging indicator, or therapeutic target for NT1. Future studies should integrate cytokine profiles with HLA/TCR background, cerebrospinal fluid hypocretin-1 levels, T-cell functional assays, disease stage, sample type, and neuropsychiatric phenotypes to construct multidimensional immune-phenotyping models for NT1.