Background Anti-nuclear antibodies are essential features of SLE and are important markers for both diagnosis and pathogenesis. Anti-double stranded DNA (dsDNA) antibodies, which are routinely monitored to assess disease activity, can form immune complexes that activate complement (C) and promote renal pathology. Relatively less is known about the roles of autoantibodies against RNA binding proteins (RBPs) in pathogenesis and about the relationship between anti-dsDNA, anti-RBPs, complement activation, and expression of the interferon (IFN) gene signature (IGS). Analysis of data from two clinical trials of tabalumab in SLE (Illuminate 1 & 2, GSE88884) was undertaken to understand these inter-relationships.
Methods Microarray data from 1620 active (SLEDAI≥6), female SLE patients and accompanying laboratory measurements were analyzed. Gene set variation analysis (GSVA) determined enrichment of transcriptomic signatures in each patient. Linear regression analysis was used to determine relationships between IGS GSVA scores and C3 and/or C4 levels as well as autoantibody levels. Unbiased classification and regression trees (CART) were constructed to determine the highest predictors of IGS expression.
Results Patients were initially stratified by autoantibody positivity. Comparison of GSVA enrichment scores of a common IGS demonstrated that SLE patients positive for anti-RNP antibodies alone had greater enrichment of the IGS than those positive for anti-dsDNA alone. Similar results were noted for gene signatures of type I IFN, IFNα2, IFNβ, and IFNγ. In contrast, the TNF-induced gene signature was observed comparably in patients with anti-dsDNA or anti-RNP antibodies and an IL-1 gene signature was only observed in those with anti-dsDNA. By linear regression, IFN GSVA scores and C3 and C4 levels were significantly, inversely related in anti-dsDNA+ patients but not those with anti-RNP antibodies. Antibody levels correlated with decreased C levels in dsDNA+ patients. Additionally, IGS GSVA scores were increased in anti-dsDNA+ patients with low C3 or C4 compared to anti-dsDNA+ patients with high/normal C, but there was no significant difference in IGS expression in anti-RNP+ patients with the same stratification. CART analysis identified anti-RNP status as the highest predictor of the IGS GSVA score. Finally, 54.5% of SLE patients without IGS expression exhibited autoantibodies, but only 13.7% of SLE patients negative for autoantibodies expressed the IGS signature.
Conclusions Taken together, these data indicate that anti-RNP antibodies are associated with IGS expression more strongly than anti-dsDNA antibodies but are not related to the depression of C3 or C4. Furthermore, IGS expression is not required for autoantibody production, but autoantibodies are likely directionally related to the IGS signature.
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