A recent study published in Medicina Clínica (Barcelona) has reported that patients with systemic lupus erythematosus (SLE) exhibit significantly elevated serum levels of Toll-like receptor 9 (TLR9), with higher TLR9 concentrations correlating with increased levels of the pro-inflammatory cytokines interleukin-10 (IL-10) and interferon-α (IFN-α). The findings further support the role of innate immune pathways in SLE pathogenesis.
The cross-sectional observational study evaluated serum TLR7 and TLR9 levels in patients with SLE and healthy controls and explored their association with previous viral infections, disease activity, and inflammatory cytokines. Clinical characteristics, disease activity, and infection history were documented, while serum TLR7, TLR9, IL-10, and IFN-α levels were quantified using enzyme-linked immunosorbent assay (ELISA).
The investigators found that serum TLR9 levels were significantly higher in patients with SLE than in healthy controls (P<0.001). In contrast, TLR7 levels did not differ significantly between the two groups, although they demonstrated a positive association with increasing age (P<0.001). Neither TLR7 nor TLR9 levels were associated with C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), anti-double-stranded DNA antibodies, extractable nuclear antigen (ENA) antibodies, antiphospholipid antibodies, disease activity, previous viral infections, or disease duration. Patients with antiphospholipid syndrome had significantly lower TLR7 levels (P=0.001).
Further analysis showed that elevated TLR9 levels were significantly associated with increased serum IL-10 and IFN-α concentrations (P<0.001), whereas TLR7 showed no significant association with IFN-α, although a trend toward higher TLR7 levels was observed in patients with elevated IL-10. Based on these findings, the authors concluded that TLR9 is upregulated in SLE and is associated with key inflammatory cytokines, while TLR7 expression appears to increase with age.
The findings are supported by another study conducted by Pati et al., which also highlighted the importance of TLR9 in SLE. In this case-control study involving 70 patients with SLE and age- and sex-matched healthy controls from eastern India, messenger RNA expression of TLR2, TLR4, TLR7, and TLR9 was evaluated using reverse transcription polymerase chain reaction (RT-PCR).
The study demonstrated significantly higher expression of both TLR2 (P<0.0001) and TLR9 (P=0.012) in patients with SLE compared with healthy controls. TLR9 expression was significantly greater in patients with lupus nephritis than in those without renal involvement (P=0.037) and showed a positive correlation with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores (Spearman’s r=0.47; P<0.0001). In contrast, TLR4 and TLR7 expression were not associated with disease susceptibility, clinical manifestations, or disease severity.
These findings reinforce the growing evidence implicating TLR9 in the immunopathogenesis of SLE. While the Medicina Clínica study links elevated circulating TLR9 levels with increased IL-10 and IFN-α, the study by Pati et al. further associates increased TLR9 expression with lupus nephritis and greater disease activity. The studies suggest that TLR9 may serve as a potential biomarker of immune activation and disease severity and could represent a promising therapeutic target in systemic lupus erythematosus.
References
- Grau García E, Leal Rodríguez S, Gómez-Lechón Quirós L, Román Ivorra JA. Increased TLR9 protein level and upregulated serum cytokines IL-10 and IFN1A in systemic lupus erythematous patients. Med Clin (Barc). 2026 Jul;166(7):107447.
- Pati A, Das BK, Panda AK. Elevated toll-like receptor 9 is associated with disease severity and kidney involvement in systemic lupus erythematosus. Hum Immunol. 2024 Nov;85(6):111104.