Association of increased interferon‐inducible gene expression with disease activity and lupus nephritis in patients with systemic lupus erythematosus

Abstract

Objective. To study 5 type I interferon (IFN)-inducible genes (LY6E, OAS1, OASL, MX1, and ISG15) in patients with systemic lupus erythematosus (SLE) and to correlate expression levels with disease activity and/or clinical manifestations.Methods. Peripheral blood cells were obtained from 48 SLE patients, 48 normal controls, and 22 rheumatic disease controls, and total RNA was extracted and reverse transcribed into complementary DNA. Gene expression levels were measured by realtime polymerase chain reaction, standardized to a housekeeping gene, and summed to an IFN score. Disease activity was determined by the Safety of Estrogens in Lupus Erythematosus: National AssessmentSystemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) composite.Results. Each gene was highly expressed in SLE patients compared with normal controls (P < 0.0003) or disease controls (P < 0.0008 except for MX1). IFN scores were positively associated with the SELENA-SLEDAI instrument score (P ‫؍‬ 0.001), the SELENA-SLEDAI flare score (P ‫؍‬ 0.03), and the physician's global assessment score (P ‫؍‬ 0.005). Compared with patients without nephritis, lupus nephritis patients had higher IFN scores (overall P < 0.0001), especially during active renal disease. IFN scores were weakly associated with neurologic manifestations. Elevated IFN scores were positively associated with the current presence of anti-double-stranded DNA (anti-dsDNA) antibodies (P ‫؍‬ 0.007) or hypocomplementemia (P ‫؍‬ 0.007). LY6E expression levels distinguished active from inactive lupus nephritis (P ‫؍‬ 0.02) and were positively associated with proteinuria (P ‫؍‬ 0.009).Conclusion. The 5 IFN-inducible genes were highly expressed in SLE patients, and increased levels were correlated with disease activity defined by several methods. IFN scores, or LY6E levels, were elevated in lupus nephritis patients, especially during active renal disease, and in patients with anti-dsDNA antibody positivity and hypocomplementemia. IFN scores, or LY6E levels, may be useful as a biomarker for lupus nephritis therapy.Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by immune dysregulation resulting in the production of antinuclear and other autoantibodies, generation of circulating immune complexes, and activation of the complement system. The disease course of SLE is heterogeneous, affecting different individuals with a wide range of manifestations. Unpredictable flares and improvements may be observed. There is no specific single diagnostic test for SLE, and therapy is typically initiated after signs of

Sialic acid–binding Ig‐like lectin 1 expression in inflammatory and resident monocytes is a potential biomarker for monitoring disease activity and success of therapy in systemic lupus erythematosus

“…This is the first study to demonstrate a strong correlation between the frequencies of Siglec-1-positive monocyte subsets and clinical parameters, such as SLEDAI scores, complement factor levels, and titers of autoantibodies against dsDNA (which correlated only with the frequency of resident monocytes). Other than the correlation with titers of anti-dsDNA antibodies, our findings were consistent with the identification of other IFNinduced transcripts and their correlation with disease activity as described by Feng et al (9) and Kirou et al (8). Initial indications of the involvement of Siglec-1 in type I IFN-mediated pathophysiology arose in our global gene expression studies of purified monocytes from SLE patients and were comparable with previous findings in expression profiles generated with PBMCs from patients with SSc (24).…”

“…All SLE patients had active disease, and their mean score on the SLE Disease Activity Index (SLEDAI) (32) was 17 (range [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26]. SLE patients had a mean C-reactive protein (CRP) level of 5.7 mg/liter, and a mean erythrocyte sedimentation rate (ESR) of 40 mm/hour.…”

Markers of childhood lupus nephritis indicating disease activity

“…IFN-α that is highly expressed during active LN [45,46] inhibits the synthesis of C1q, and thus could contribute (in addition to anti-C1q antibodies) to the low levels of C1q in active LN, while the distinct cytokine milieu in inactive LN might favor the synthesis of C1q, which could explain the elevated levels observed in our study.…”

Biomarkers in systemic lupus erythematosus: challenges and prospects for the future

“…They further observed that the IFN signature correlated with more severe disease, such as cerebritis, nephritis, and hematological involvement, in those patients. Other investigators have subsequently reported similar findings, including significant associations of enhanced expression of IFN-inducible genes and/ or serum levels of IFN-inducible chemokines with increased disease activity, organ involvement, hypocomplementemia, and the presence of autoantibodies specific for dsDNA and RNAbinding proteins (Ro, U1-RNP, and Sm), in both adult and pediatric SLE patients [Bauer et al 2006;Bennett et al 2003;Feng et al 2006;Kirou et al 2005;Nikpour et al 2008;Vila et al 2007]. Two independent studies utilizing transcriptome analysis and traditional techniques [enzymelinked immunosorbent assay (ELISA) and flow cytometry] demonstrated that IP-10 and sialic acid-binding Ig-like lectin 1 (SIGLEC-1) were among the most prominent type 1 IFN-regulated genes/proteins [Biesen et al 2008;Rose et al 2012].…”