Objective Previous studies suggest a link between high serum type I interferon (IFN) and lupus nephritis (LN). We determined whether serum IFN activity is associated with subtypes of LN and studied renal tissues and cells to understand the impact of IFN in LN. Methods 221 systemic lupus erythematosus (SLE) patients were studied. Serum IFN activity was measured by WISH bioassay. mRNA in-situ hybridization was used in renal tissue to measure expression of the representative IFN-induced gene, interferon-induced protein with tetratricopeptide repeats-1 (IFIT1), and the plasmacytoid dendritic cell (pDC) marker gene C-type lectin domain family-4 member C (CLEC4C or BDCA2). Podocyte cell line gene expression was measured by real-time PCR. Results Class III/IV LN prevalence was significantly increased in patients with high serum IFN compared with those with low IFN (OR=5.48, p=4.0x10-7). In multivariate regression models, type I IFN was a stronger predictor of class III/IV LN than complement C3 or anti-dsDNA antibody, and could account for the association of these variables with LN. IFIT1 expression was increased in all classes of LN, but most in the glomerular areas of active class III/IV LN kidneys. IFIT1 expression was not closely co-localized with pDCs. IFN directly activated podocyte cell lines to induce chemokines and proapoptotic molecules. Conclusion Systemic high IFN is involved in the pathogenesis of severe LN. We do not find co-localization of pDCs with IFN signature in renal tissue, and instead observe the greatest intensity of IFN signature in glomerular areas, which could suggest a blood source of IFN.
PS1:1 High type i interferon activity is associated with active class 3/4 lupus nephritis in european-american lupus patients independent of anti-dsdna antibodies