Activation of the interferon‐α pathway identifies a subgroup of systemic lupus erythematosus patients with distinct serologic features and active disease

Abstract

Objective. Gene-expression studies have demonstrated increased expression of interferon (IFN)-inducible genes (IFIGs) in peripheral blood mononuclear cells (PBMCs) of many patients with systemic lupus erythematosus (SLE), with a predominant effect of type I IFN. This study examined the hypothesis that increased disease severity and activity, as well as distinct autoantibody specificities, characterize SLE patients with activation of the type I IFN pathway.Methods. Freshly isolated PBMCs from 77 SLE patients, 22 disease controls, and 28 healthy donors were subjected to real-time polymerase chain reaction for 3 IFIGs that are preferentially induced by IFN␣, and the data were used to derive IFN␣ scores for all individuals. Expression of IFIGs was significantly higher in SLE patients compared with disease controls or healthy donors. SLE patients with high and low IFN␣ scores were compared for clinical manifestations of disease, disease severity, disease activity, serologic features, and potential confounders, by bivariate and multivariate analyses.Results. SLE patients with a high IFN␣ score had a significantly higher prevalence of renal disease, a greater number of American College of Rheumatology criteria for SLE, and a higher Systemic Lupus International Collaborating Clinics damage index (SDI) score than did SLE patients with low IFN␣ scores. Patients with high scores showed increased disease activity, as measured by lower C3 levels, hemoglobin levels, absolute lymphocyte counts, and albumin levels, and a higher anti-double-stranded DNA (dsDNA) titer, erythrocyte sedimentation rate, and SLE Disease Activity Index 2000 score. The presence of antibodies specific for Ro, U1 RNP, Sm, and dsDNA, but not phospholipids, was significantly associated with a high IFN␣ score. Logistic regression analysis confirmed that renal disease, higher SDI scores, low complement levels, and presence of anti-RNA binding protein (RBP) autoantibodies were associated with a high IFN␣ score.Conclusion. Activation of the IFN␣ pathway defines a subgroup of SLE patients whose condition is characterized by increased disease severity, including renal disease, increased disease activity, reflected in complement activation, and autoreactivity to RBP.Systemic lupus erythematosus (SLE) is characterized by extensive defects of the immune system that culminate in the production of autoantibodies reactive with intracellular particles, consisting of nucleic acids and nucleic acid binding proteins. These autoantibodies contribute to the pathologic process underlying the protean clinical manifestations, ranging from skin rash and arthralgias to involvement of major organ systems, and often leading to renal, neurologic, or cardiovascular morbidity. The diversity of serologic and clinical manifestations observed among SLE patients presents important challenges in the diagnosis and management of the disease. In addition, this heterogeneity has hampered the ability of clinical trials to test the efficacy of promising therapeutic agents. Characterization of c...

A murine model of mixed connective tissue disease induced with U1 small nuclear RNP autoantigen

“…Plasmacytoid DCs can be induced to produce large amounts of type I interferons by TLR-9 agonists in conjunction with autoantibodies (30), and "classic" severe SLE, in which anti-RNP and anti-dsDNA responses occur, has been associated with a type I interferon-induced gene signature (13). These plasmacytoid DCs express TLR-7 and TLR-8, the human homologs to murine TLR-7 (23), in the same cellular compartment (and connected to the same downstream second signaling apparatus) as TLR-9 (31).…”

“…In a small series of mice, we have previously found that direct immunization of a susceptible animal with RNP antigen could induce MCTD-like serologic responses and clinical manifestations (12). However, reactivity to RNP components has recently been shown to correlate with the development of severe disease in lupus, including the development of GN (13). Reconciling the role of RNP antigens both in MCTD, a relatively mild lupus-like disorder that does not target the kidneys, and in severe kidney-targeted SLE has been difficult.…”

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

“…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.…”

Type I interferon signaling is involved in the spontaneous development of lupus-like disease in B6.Nba2 and (B6.Nba2 × NZW)F1 mice

“…[2][3][4] Most strikingly, gene expression profile analyses have shown that peripheral blood mononuclear cells from SLE patients harbor a signature resembling that of cells exposed to IFNab, and that this signature can distinguish SLE patients from patients with rheumatoid arthritis. 3,5 New Zealand hybrid mice are a well-studied mouse model of lupus-like disease. In these animals, the female F1 offspring of New Zealand black (NZB) crossed with New Zealand white (NZW) mice develops high levels of circulating autoantibodies against nuclear antigens such as DNA and histones, immune complex (IC) formation and deposition in the kidneys, and ultimately kidney failure due to damaged glomeruli.…”