Low-Density Granulocytes Link to Disease Activity, Organ Involvement, and Cytokine Production in Sjögren's Disease

Low-density granulocytes (LDGs) have been implicated in the pathogenesis of several autoimmune diseases, yet their role in Sjögren's disease (SjD) remains poorly understood. We enrolled 90 SjD patients and 30 healthy controls (HCs) and identified LDGs as CD14^-/lowCD15⁺ cells by flow cytometry, with intracellular interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) staining, and further analyzed CD16 as a maturation marker in LDGs and T helper 17 (Th17) cell frequency. LDG percentages were significantly elevated in active SjD compared with inactive patients (p < 0.001) and HCs (p < 0.0001), and correlated positively with EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) (r = 0.355, p = 0.0006), erythrocyte sedimentation rate (ESR) (r = 0.325, p = 0.0061), γ-globulin (r = 0.334, p = 0.0177), and Th17 frequency (r = 0.537, p = 0.0068). LDG expansion was accompanied by enrichment of immature CD16^-/low cells (r = -0.798, p = 0.0100). Patients with renal or pulmonary involvement showed higher LDG levels (p = 0.0004), and in SjD -associated interstitial lung disease (SjD-ILD) patients, LDG percentage showed a positive but non-significant trend with serum Krebs von den Lungen-6 (KL-6) levels (r = 0.497, p = 0.102). LDG levels decreased following treatment in longitudinally followed patients, and LDGs from active patients exhibited higher IL-6 and TNF-α production ratios relative to monocytes than those from inactive patients. Stratification by LDG levels revealed significant associations with disease activity, laboratory parameters, and organ involvement. These findings suggest that LDGs are associated with disease activity and organ involvement, may serve as potential biomarkers, and may contribute to the pathogenesis of SjD.