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Interferon-induced gene expression in systemic lupus erythematosus reflects previous exposure to interferon alpha and is associated with increased disease activity and autoreactivity against RNA-binding proteins
Arthritis Res Ther volume 6, Article number: 91 (2004)
Both interferon (IFN) alpha and IFN-γ have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). Recently, microarray screens have demonstrated increased IFN-inducible gene (IFIG) expression in peripheral blood mononuclear cells of patients with active SLE. We investigated the relative roles of IFN-α and IFN-γ in gene expression and disease in SLE patients.
Quantitative real-time PCR was employed to identify IFIGs that are regulated by either IFN-α or IFN-γ. Peripheral blood mononuclear cells from 77 SLE patients were compared with those of 22 disease controls and 28 healthy donors (HD) for expression of three genes preferentially induced by IFN-α (PRKR, IFIT1, IFI44) and three genes preferentially induced by IFN-γ (IRF1, SERPING1, and GBP1) inducible genes. IFN-α and IFN-γ scores were then calculated for all individuals, based on the number of IFIGs overexpressed and the level of increased expression above the mean value for that gene in the HD group. IFNs in plasma were measured by ELISA and assayed for IFIG-inducing activity. Disease activity was assessed using the SLE disease activity index-2000 (SLEDAI-2K) and severity with the number of American College of Rheumatology (ACR) criteria fulfilled and the Systemic Lupus International Cooperating Clinics (SLICC) damage index. Sera were tested for autoantibodies to dsDNA, Sm, ribonucleoprotein, Ro, La, and antiphospholipid antibody (APLA).
Two IFN-α-inducible genes (PRKR and IFI44), but no IFN-γ inducible gene, showed higher expression in SLE than in disease controls (P = 0.005 and P = 0.01, respectively) or healthy donors (P = 0.01 and P = 0.03). Moreover, IFN-α scores were higher in SLE patients than in both control groups (P < 0.01), with 50% of SLE patients demonstrating a high IFN-α score (defined as ≥ 2). Plasma from all SLE patients contained high levels of IFN-α and some contained IFN-α-gene inducing capacity that was inhibited by anti-IFN-α antibody. Expression of IFN-α-regulated genes correlated with erythrocyte sedimentation rate (r = 0.33, P = 0.003), serum C3 (r = -0.3, P = 0.008), C-reactive protein (r = -0.3, P = 0.03), SLEDAI-2K (r = 0.22, P = 0.05), and SLICC damage index (r = 0.33, P = 0.003). It was also associated with a greater number of ACR criteria, Caucasian race, and renal disease. Interestingly, SLE patients had increased prevalence of autoantibodies to Ro (P = 0.0008) and to any RNA binding protein (one or more of Sm, ribonucleoprotein, Ro, La; P = 0.0002). In contrast, the prevalence of anti-dsDNA or APLA was not associated with IFN gene expression.
These data demonstrate that activation of the IFN-α pathway is a characteristic of SLE and that IFN-α is the predominant stimulus for IFIG expression in those patients. IFN-α-inducible genes are candidate biomarkers identifying patients with increased disease activity and define a subgroup of SLE patients with serum autoreactivity against RNA-binding proteins.
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Kirou, K., Lee, C., George, S. et al. Interferon-induced gene expression in systemic lupus erythematosus reflects previous exposure to interferon alpha and is associated with increased disease activity and autoreactivity against RNA-binding proteins. Arthritis Res Ther 6 (Suppl 3), 91 (2004). https://doi.org/10.1186/ar1406
- Systemic Lupus Erythematosus
- Peripheral Blood Mononuclear Cell
- Systemic Lupus Erythematosus Patient
- Healthy Donor
- Damage Index