20.500.12556/DiRROS-24106 Exhausted natural killer cells in adult IgA vasculitis Introduction. IgA vasculitis nephritis (IgAVN) manifests in up to 84% of adult patients with IgA vasculitis (IgAV) and is associated with an elevated risk of progression to chronic kidney failure. The underlying pathogenic mechanism of adult IgAVN in leukocytes remain largely uncharacterised. Although natural killer (NK) cells were investigated in paediatric IgAV, their specific role in the pathogenesis of adult IgAV has yet to be elucidated. Methods. RNA sequencing of leukocytes from adult IgAV patients and healthy controls (HC) was performed. NK cells’ cytotoxicity was assessed using calcein-AM stained K562 cells, and exocytosis was measured by LAMP-1/CD107a expression. Intracellular perforin and granzyme B were analyzed via flow cytometry, and cytokine secretion was measured by Luminex xMAP. Interferon-induced genes were validated with qPCR. Results. Principal component analysis (PCA) of leukocyte gene expression profiles distinguished IgAV patients from HC. Pathway enrichment analysis showed differences in patients’ subsets - Interferon signalling Reactome pathway was observed only in sample from patients with skin-limited IgAV (sl-IgAV) and was confirmed by increased expression of interferon-induced genes using qPCR. Only in samples from IgAVN patients enrichment of NK cell-mediated cytotoxicity KEGG pathway was found. NK cells from IgAVN patients showed significantly decreased cytotoxicity compared to samples from sl-IgAV patients (p = 2.53 × 10− 2). The % of CD107a+-NK cells significantly increased after stimulation in HC (p = 9.7 × 10− 3) and in sl-IgAV patient samples (p = 2.21 × 10− 2) while only a minor increase was observed in samples of IgAVN patients. IgAVN patients exhibited a decreased % of perforin+ NK cells compared to HC. Following phytohemagglutinin (PHA)/interleukin (IL)-2 stimulation, a significant reduction in intracellular perforin level was observed in HC (p = 2.53 × 10− 2), but not in IgAVN patients NK cells. Interferon (IFN)-ϒ and macrophage inflammatory protein (MIP)-1β were significantly decreased in NK cell culture supernatants from IgAVN patients (p = 2.64 × 10− 2 and p = 2.65 × 10− 2 respectively). Conclusion. Patients with IgAVN exhibited impaired cytotoxic and immunomodulatory functions of NK cells, along with a marked absence of interferon signaling in PBMCs. Further studies are needed to confirm if discrimination of patient subsets based on leukocyte samples might be of clinical use and if deregulated NK function might contribute to the pathogenesis of nephritis in adult IgAV. immunoglobulin A IgAVN IgA vasculitis RNA sequencing kidney diseases immunoglobulins killer cells adults imunoglobulin A IgAVN vaskulitis IgA sekvenciranje RNK ledvične bolezni immunoglobulini celice ubijalke odrasli true false false Angleški jezik Slovenski jezik Neznano 2025-11-12 14:15:04 2025-11-12 14:15:05 2025-11-13 08:25:11 0000-00-00 00:00:00 2025 0 0 Nasl. z nasl. zaslona; Opis vira z dne 19. 5. 2025; str. 1-13 Vol. 27, article no. 95 2025 0000-00-00 Zaloznikova Objavljeno apc 0000-00-00 0000-00-00 0000-00-00 616-097 1478-6362 10.1186/s13075-025-03559-y 236303107 RAZ_Bajzelj_Matija_2025.pdf RAZ_Bajzelj_Matija_2025.pdf 1 CA60B2DBCA487895C21272AF43E42BFF af7b68a0c14841eeafeaa467e1aa7e16a2cf4ea3136b87f243376d2e25d7ea8a 3c0a87c6-bfca-11f0-94a7-001a4af901a5 https://dirros.openscience.si/Dokument.php?lang=slv&id=35861 https://arthritis-research.biomedcentral.com/articles/10.1186/s13075-025-03559-y 1 9cefb396-bfc9-11f0-94a7-001a4af901a5 https://dirros.openscience.si/Dokument.php?lang=slv&id=35860 Univerzitetni klinični center Ljubljana 0 0 0