OBJECTIVES: Huntington's Disease (HD) is a debilitating neurodegenerative condition characterized by motor, cognitive and psychiatric abnormalities. Immune hyperactivity and dysregulation are common in HD. In addition to the central nervous system, HD patients exhibit systemic innate immune activation and inflammation, which has been shown to contribute to the pathogenic effects of the Huntingtin gene mutation. Upregulation of inflammatory mediators including interferon gamma (IFN-γ) and interleukin (IL)-8 has been observed in animal Huntington's disease models. However, studies on HD patients remain limited. METHODS: In this study, serum samples from 58 HD patients and 59 age- and gender-matched healthy control individuals were analysed using a bead-based assay, that enabled simultaneous measurement of 13 cytokines and chemokines. Additionally, publicly available transcriptomic data from brain tissues of HD patients and controls were examined. RESULTS: Our results confirm that IL-8 protein levels are significantly higher in HD patients compared to non-HD controls, with the highest levels observed in the moderate HD group. In the control group, we found significant positive correlations between IL-8 levels and both IL-17A and IL-10. However, these correlations were not observed in HD patients, where IL-8 levels were notably positively correlated with pro-inflammatory markers including IFNγ and IL-23. Interestingly, IL-17A levels demonstrated a negative correlation with disease parameters, including CAG trinucleotide repeat expansion and disease burden score. Furthermore, cytokines and chemokines such as IFNγ and monocyte chemoattractant protein 1 (MCP-1
CCL2) demonstrated positive correlations with the same disease parameters. In-depth analysis of publicly available bulk RNAseq, and single-nucleus RNA-sequencing (snRNAseq) data from two key HD-affected brain regions- the prefrontal cortex and striatum revealed that IL-8 expression is significantly increased in cortex samples from individuals with HD compared to non-HD controls. Moreover, snRNAseq data in the striatum showed higher IL-8 expression in HD patients than in non-HD controls, with a predominant expression in microglia. CONCLUSION: Overall, our findings support an upregulation of IL-8 in patients with HD, evident in both central degenerating brain regions, and peripheral blood samples. We identified unique immunological signatures associated with the severity of HD and provide potential biomarkers that may reflect immune-pathological mechanisms in HD patients.