Age‐related differential oxidative modification of proteins may contribute to the differences in the onset of autoimmunity in MRL+/+ and MRL/lpr mice

Abstract

Despite the implication of reactive oxygen species (ROS) in systemic lupus erythematosus (SLE) pathogenesis, the contributory role of ROS, especially the consequences of oxidative modification of proteins by lipid peroxidation‐derived aldehydes (LPDAs) such as malondialdehyde (MDA) and 4‐hydroxynonenal (HNE) in eliciting an autoimmune response and disease pathogenesis remains largely unexplored. MRL/lpr mice, a widely used model for SLE, spontaneously develop a condition that has many similarities to human SLE, whereas MRL+/+ mice, with the same MRL background as MRL/lpr mice, show much slower onset of SLE. To assess if the differences in the onset of SLE in the two substrains could partly be due to differential expression of LPDAs and to provide evidence for the role of LPDA‐modified proteins in the pathogenesis of SLE, we determined the serum levels of MDA‐/HNE‐protein adducts, circulating immune complexes (CICs) and MDA‐/HNE‐protein adduct specific immune complexes, as well as various autoantibodies in 6‐, 12‐ and 18‐week old mice of both substrains. The results show age‐related increases in the formation of MDA‐/HNE‐protein adducts, CICs and MDA‐/HNE‐specific immune complexes, but MRL/lpr mice showed greater and accelerated response. This study also showed a strong association between increased MDA‐/HNE‐protein adducts and CICs, as well as highly positive correlation between increased MDA‐/HNE‐protein adducts and autoantibodies. More importantly, we observed that HNE‐mouse serum albumin adducts caused significant inhibition in ANA binding to nuclear antigens. These findings apart from supporting immunogenic potential of MDA‐/HNE‐protein adducts, also suggest that these LPDA‐modified proteins could be important sources of autoantibodies and CICs in these mice, and contribute to pathogenesis and progression of the disease. Supported by NIH ES016302.