Peroxynitrite-modified H3 Histone is Highly Immunogenic and Binds Circulating SLE Autoantibodies Better than Native DNA

Abstract

Peroxynitrite is a bifaceted reactive species. It can oxidize and nitrate proteins/nucleic acids/lipids and is involved in inflammation, apoptosis, cytotoxicity and autoimmune disorders of unknown etiology, including SLE. In this study, H3 histone exposed to peroxynitrite caused loss of tertiary structure, nitration of tyrosine residues and dityrosine formation. Experimentally produced antibodies against peroxynitrite-modified H3 histone showed specificity for the immunogen. However, cross-reactions with other nitrated proteins were also observed. We further investigated the binding of SLE autoantibodies with native DNA, native H3 histone and peroxynitrite-modified H3 histone to explore the possible role of modified-H3 histone in the initiation and/or progression of SLE in a subgroup of patients. The results showed preferential binding of SLE anti-nDNA autoantibodies to peroxynitrite-modified H3 histone. The visual detection of immune complex formation with native and peroxynitrite-modified H3 histone reiterated preferential binding of SLE autoantibodies with modified H3 histone. It may be concluded that anti-histone autoantibodies seen in a subgroup of SLE patients might be due to the immunogenicity of peroxynitrite-modified H3 histone.