Systemic lupus erythematosus (SLE) is a complex, inflammatory autoimmune disease that affects multiple organ systems. We used global gene expression profiling of peripheral blood mononuclear cells to identify distinct patterns of gene expression that distinguish most SLE patients from healthy controls. Strikingly, about half of the patients studied showed dysregulated expression of genes in the IFN pathway. Furthermore, this IFN gene expression ''signature'' served as a marker for more severe disease involving the kidneys, hematopoetic cells, and͞or the central nervous system. These results provide insights into the genetic pathways underlying SLE, and identify a subgroup of patients who may benefit from therapies targeting the IFN pathway.

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Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by activation of the type I interferon (IFN) pathway. Here we convincingly replicate association of the IFN regulatory factor 5 (IRF5) rs2004640 T allele with SLE in four independent case-control cohorts (P = 4.4 x 10(-16)) and by family-based transmission disequilibrium test analysis (P = 0.0006). The rs2004640 T allele creates a 5' donor splice site in an alternate exon 1 of IRF5, allowing expression of several unique IRF5 isoforms. We also identify an independent cis-acting variant associated with elevated expression of IRF5 and linked to the exon 1B splice site. Haplotypes carrying the variant associated with elevated expression and lacking the exon 1B donor site do not confer risk of SLE. Thus, a common IRF5 haplotype driving elevated expression of multiple unique isoforms of IRF5 is an important genetic risk factor for SLE, establishing a causal role for type I IFN pathway genes in human autoimmunity.

Systematic genome-wide studies to map genomic regions associated with human diseases are becoming more practical. Increasingly, efforts will be focused on the identification of the specific functional variants responsible for the disease. The challenges of identifying causal variants include the need for complete ascertainment of genetic variants and the need to consider the possibility of multiple causal alleles. We recently reported that risk of systemic lupus erythematosus (SLE) is strongly associated with a common SNP in IFN regulatory factor 5 (IRF5), and that this variant altered spicing in a way that might provide a functional explanation for the reproducible association to SLE risk. Here, by resequencing and genotyping in patients with SLE, we find evidence for three functional alleles of IRF5: the previously described exon 1B splice site variant, a 30-bp in-frame insertion/deletion variant of exon 6 that alters a proline-, glutamic acid-, serine-and threonine-rich domain region, and a variant in a conserved polyA؉ signal sequence that alters the length of the 3 UTR and stability of IRF5 mRNAs. Haplotypes of these three variants define at least three distinct levels of risk to SLE. Understanding how combinations of variants influence IRF5 function may offer etiological and therapeutic insights in SLE; more generally, IRF5 and SLE illustrates how multiple common variants of the same gene can together influence risk of common disease.interferon pathway ͉ systemic lupus erythematosus

We genotyped 525 independent North American white individuals with systemic lupus erythematosus (SLE) for the PTPN22 R620W polymorphism and compared the results with data generated from 1,961 white control individuals. The R620W SNP was associated with SLE (genotypic P=.00009), with estimated minor (T) allele frequencies of 12.67% in SLE cases and 8.64% in controls. A single copy of the T allele (W620) increases risk of SLE (odds ratio [OR]=1.37; 95% confidence interval [CI] 1.07-1.75), and two copies of the allele more than double this risk (OR=4.37; 95% CI 1.98-9.65). Together with recent evidence showing association of this SNP with type 1 diabetes and rheumatoid arthritis, these data provide compelling evidence that PTPN22 plays a fundamental role in regulating the immune system and the development of autoimmunity.

Objective. Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by unpredictable flares of disease activity and irreversible damage to multiple organ systems. An earlier study showed that SLE patients carrying an interferon (IFN) gene expression signature in blood have elevated serum levels of IFN-regulated chemokines. These chemokines were associated with more-severe and active disease and showed promise as SLE disease activity biomarkers. This study was designed to validate IFN-regulated chemokines as biomarkers of SLE disease activity in 267 SLE patients followed up longitudinally.Methods. To validate the potential utility of serum chemokine levels as biomarkers of disease activity, we measured serum levels of CXCL10 (IFN␥-inducible 10-kd protein), CCL2 (monocyte chemotactic protein 1), and CCL19 (macrophage inflammatory protein 3␤) in an independent cohort of 267 SLE patients followed up longitudinally over 1 year (1,166 total clinic visits).Results. Serum chemokine levels correlated with lupus activity at the current visit (P ‫؍‬ 2 ؋ 10 ؊10 ), rising at the time of SLE flare (P ‫؍‬ 2 ؋ 10 ؊3 ) and decreasing as disease remitted (P ‫؍‬ 1 ؋ 10 ؊3 ); they also performed better than the currently available laboratory tests. Chemokine levels measured at a single baseline visit in patients with a Systemic Lupus Erythematosus Disease Activity Index of <4 were predictive of lupus flare over the ensuing year (P ‫؍‬ 1 ؋ 10 ؊4 ).Conclusion. Monitoring serum chemokine levels in SLE may improve the assessment of current disease activity, the prediction of future disease flares, and the overall clinical decision-making.Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease defined by autoantibodies to nuclear components, immune complex deposition, and systemic vasculitis (1). Many organ systems are targeted, including the skin, joints, blood cells, kidneys, and nervous system. The disease affects 0.1% of the US population, with a striking 9:1 preponderance in women. The factors that contribute to the onset and progression of SLE are not well understood; however, genetic, environmental, and hormonal factors are likely to be important. SLE disease activity can be difficult to monitor, and flares are unpredictable, both in frequency and in severity. Certain clinical laboratory tests, including antidouble-stranded DNA (anti-dsDNA) antibody titers, complement factor levels, and the erythrocyte sedimen-

BackgroundSystemic 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 FindingsWe 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.ConclusionsThese 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.

Recent studies have shown increased expression of interferon (IFN)-regulated genes in the peripheral blood cells of patients with systemic lupus erythematosus. A similar interferon signature has been observed in affected muscle tissue from patients with dermatomyositis (DM), but it has not yet been determined if this signature extends to the peripheral blood in DM. We performed global gene expression profiling of peripheral blood cells from adult and juvenile DM patients and healthy controls. Several interesting groups of genes were differentially expressed in DM, including genes with immune function, and others that function in muscle or are involved in mitochondrial/oxidative phosphorylation. Investigation of type I IFN-regulated transcripts revealed a striking interferon signature present in most DM patients studied. Levels of type I IFN-regulated proteins were also elevated in DM serum samples. Furthermore, both the transcript and serum protein IFN signatures were associated with disease activity. These data suggest that the IFN signature may be a useful marker for DM disease activity, and that sampling peripheral blood may be a more practical alternative to muscle biopsy for measuring this signature.