Elevated Serum Levels of Interferon-Regulated Chemokines Are Biomarkers for Active Human Systemic Lupus Erythematosus

BACKGROUND: Systemic lupus erythematosus (SLE) is a serious systemic autoimmune disorder that affects multiple organ systems and is characterized by unpredictable flares of disease. Recent evidence indicates a role for type I interferon (IFN) in SLE pathogenesis; however, the downstream effects of IFN pathway activation are not well understood. Here we test the hypothesis that type I IFN-regulated proteins are present in the serum of SLE patients and correlate with disease activity. METHODS AND FINDINGS: We performed a comprehensive survey of the serologic proteome in human SLE and identified dysregulated levels of 30 cytokines, chemokines, growth factors, and soluble receptors. Particularly striking was the highly coordinated up-regulation of 12 inflammatory and/or homeostatic chemokines, molecules that direct the movement of leukocytes in the body. Most of the identified chemokines were inducible by type I IFN, and their levels correlated strongly with clinical and laboratory measures of disease activity. CONCLUSIONS: These data suggest that severely disrupted chemokine gradients may contribute to the systemic autoimmunity observed in human SLE. Furthermore, the levels of serum chemokines may serve as convenient biomarkers for disease activity in lupus

IFN-Regulated Chemokines Are Associated with SLE Disease Activity

<p>Shown are 20 serum analytes that exhibited significant positive (highlighted in yellow) or negative (highlighted in blue) correlation coefficients with clinical measures of SLE. The IFN gene score was calculated from 82 IFN-inducible transcripts measured by concurrent whole blood gene expression microarrays. The chemokine protein “score” was calculated using the seven IFN-regulated CC and CXC chemokines highlighted in red. * <i>p</i> < 0.05; ** <i>p</i> < 0.01; *** <i>p</i> < 0.001; **** <i>p</i> < 0.0001. <i>p</i>-Values were obtained by permutation testing.</p

Coordinate Dysregulation of Serum Protein Levels in SLE

<p>Hierarchical clustering was applied to protein levels of the identified analytes (“Serum Protein Levels”). Individual data points represent the log₂ ratio of the analyte concentration to the mean of control concentrations (scale shows linear fold-differences). “In Vitro Control PBMC Gene Expression” columns present gene expression microarray data obtained by incubating normal control PBMCs in vitro with medium alone or with type I IFN for 6 and 24 h. Data are normalized to control medium-alone conditions (scale depicts linear fold-differences). Grey boxes indicate missing data. Analytes induced by type I IFN in vitro (>2-fold and >500 expression unit mean difference) are highlighted in red font.</p

Visualizing Human Leukocyte Antigen Class II Risk Haplotypes in Human Systemic Lupus Erythematosus

Human leukocyte antigen (HLA) class I and class II alleles are implicated as genetic risk factors for many autoimmune diseases. However, the role of the HLA loci in human systemic lupus erythematosus (SLE) remains unclear. Using a dense map of polymorphic microsatellites across the HLA region in a large collection of families with SLE, we identified three distinct haplotypes that encompassed the class II region and exhibited transmission distortion. DRB1 and DQB1 typing of founders showed that the three haplotypes contained DRB1*1501/ DQB1*0602, DRB1*0801/ DQB1*0402, and DRB1*0301/DQB1*0201 alleles, respectively. By visualizing ancestral recombinants, we narrowed the disease-associated haplotypes containing DRB1*1501 and DRB1*0801 to an ∼500-kb region. We conclude that HLA class II haplotypes containing DRB1 and DQB1 alleles are strong risk factors for human SLE