Background: IgA vasculitis nephritis (IgAVN) is found in up to 84% of adult with IgA vasculitis (IgAV) and is associated with poor prognosis. Pathogenic mechanism has been poorly explored in adult IgAV. Natural killer (NK) cells were found to be decreased in number in paediatric IgAV and patients with IgA nephropathy, however they have been much less characterized in adult with IgAV.

Objectives: Our aim was to investigate NK cells cytotoxic and immunomodulatory function in adults with IgAV and the association with renal involvement.

Methods: RNA sequencing analysis was conducted in leukocytes of 6 treatment-naïve patients (3 with skin-limited (sl) IgAV and 3 with IgAVN) and 3 healthy controls (HC). NK cells isolated from 10 IgAVN patients, 6 sl-IgAV patients and 12 HC were activated overnight with IL-2, and Calcein-AM release from stained K562 cells co-cultured with NK was assayed to measure NK cytotoxic ability. Cytotoxic granule release from NK cells was examined by determining exposed lysosomal membrane protein (LAMP-1)/CD107a and intracellular perforin in 5 IgAVN patients, 4 sl-IgAV patients and 5 HC with flow cytometry. Cytokines interferon‐gamma (IFN‐γ), granzyme B, granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage inflammatory protein (MIP)-1α and MIP-1β, tumour necrosis factor α (TNF α), interleukin-10 (IL-10) and interleukin-8 (IL-8) were measured in cell culture supernatants by multiplex assays, Luminex. NK cell stimulatory cytokines IL-15 and IL-18 were measured in sera of 59 adult IgAV patients and 22 HC.

Results: Gene set enrichment analysis of RNA sequencing data showed the enrichment of NK cell-mediated cytotoxicity pathway gene sets specifically in IgAVN patients as we found the downregulation of prototypic NK cell marker CD56, NK cells activating receptors (KLRC1, KLRC2, KLRD1) as well as effector enzymes (granzyme B, M and H, perforin 1) mediating cytotoxic functions in IgAVN patients. The number of NK cells and their subtypes (CD56 ^bright CD16 ⁺ , CD56 ^bright CD16 ^- , CD56 ^dim CD16 ⁺ , CD56 ^dim CD16 ^- ) were not significantly changed between IgAVN patients, sl-IgAV and HC. NK cells isolated from IgAVN patients showed significantly decreased cytotoxicity in calcein-AM release assay as compared to sl-IgAV (p = 0.0253). The % of CD107a-positive NK cells significantly increased after stimulation with PHA-P and IL-2 in HC (p=0.0097) and in sl-IgAV patients (p=0.0221) while only a minor increase was observed in IgAVN patients (p=0.635), suggesting exhaustion of NK cells in IgAVN patients, as their cytotoxic activity did not increase upon stimulation. We observed a significant reduction of intracellular perforin in HC (p=0.0253), but not in IgAVN patients after stimulation. Significantly elevated serum levels of NK cell activating cytokines, IL-15 and IL-18 in IgAV patients compared to healthy controls (HC) indicate the presence of NK cell activators, shedding light on the potential NK cells exhaustion in IgAVN. IFN‐γ, the most distinctive NK cell cytokine and MIP-1β were significantly decreased in IgAVN patients’ cell culture supernatants compared to HC.

Conclusion: Impaired NK cell cytotoxic and immunomodulatory functions might contribute to immune system dysregulation in adult IgAV.

REFERENCES: NIL.

Acknowledgements: NIL.

Disclosure of Interests: None declared.

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.