Role of peroxynitrite-modified biomolecules in the etiopathogenesis of systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease characterized by autoantibodies directed against various biomolecules. The initial immunogens that drive the development of SLE are unknown, but characteristics of the immune response in SLE suggest that it is an antigen-driven response, and a chromatin antigen could be one of the immunogens for the production of antinuclear antibodies (ANA) in SLE. Other factors implicated in the pathogenesis of SLE include nitrogen-free radicals such as nitric oxide and peroxynitrite. The free radical-mediated damage to proteins results in the modification of amino acid residues, cross-linking of side chains and fragmentation. The tyrosine residues in proteins are susceptible to attack by various reactive nitrogen intermediates, including peroxynitrite to form 3-nitrotyrosine (3-NT). The presence of nitrated proteins in vivo indicates that peptides derived from the proteolytic degradation of modified proteins could serve as neoantigens. Histones are highly conserved proteins that are rich in basic amino acids lysine and arginine. Autoantibodies against histones and anti-DNA antibodies are present in SLE. The anti-DNA autoantibodies coexist with anti-histone autoantibodies and may react with chromatin-associated histones and histone complexes. Elevated levels of reactive nitrogen species (RNS) in SLE patients suggest a possible role in the pathogenesis of the disease. The alteration of proteins resulting from photomodification or peroxynitrite could lead to the development of antibodies. Therefore, the modified proteins or photoadducts could have important implications in autoimmunity, and understanding the pathophysiology of peroxynitrite-modified biomolecules could lead to a better understanding of autoimmune phenomenon in SLE.