Isoaspartyl Post-translational Modification Triggers Autoimmune Responses to Self-proteins

• Published in: The Journal of biological chemistry 1999-08, Vol.274 (32), p.22321-22327
• Main Authors: Mamula, M J, Gee, R J, Elliott, J I, Sette, A, Southwood, S, Jones, P J, Blier, P R
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Aspartic Acid - metabolism; Autoantibodies - blood; Autoimmunity; B-Lymphocytes - immunology; Binding, Competitive; Cytochrome c Group - immunology; Histocompatibility Antigens Class II - metabolism; Immune Tolerance; Isomerism; Lymphocyte Activation; Mice; Mice, Inbred MRL lpr; Molecular Sequence Data; Nuclear Magnetic Resonance, Biomolecular; Peptide Fragments - immunology; Protein Binding; Protein Processing, Post-Translational; Ribonucleoproteins, Small Nuclear - immunology; T-Lymphocytes - immunology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.274.32.22321

The normal functioning immune system is programmed to attack foreign pathogens and other foreign proteins while maintaining tolerance to self-proteins. The mechanisms by which tolerance is broken in the initiation of autoimmunity are not completely understood. In the present study, mice immunized with the murine cytochrome c peptide 90–104 showed no response by the B or T cell compartments. However, immunization with the isoaspartyl form of this peptide, where the linkage of Asp 93 to Leu 94 occurs through the β-carboxyl group, resulted in strong B and T cell autoimmune responses. Antibodies elicited by immunization with the isoaspartyl form of self-peptide were cross-reactive in binding to both isoforms of cytochrome c peptide and to native cytochrome c self-protein. In a similar manner, immunization of mice with the isoaspartyl form of a peptide autoantigen of human systemic lupus erythematosus (SLE) resulted in strong B and T cell responses while mice maintained tolerance to the normal aspartyl form of self-antigen. Isoaspartyl linkages within proteins are enhanced in aging and stressed cells and arise under physiological conditions. These post-translationally modified peptides may serve as an early immunologic stimulus in autoimmune disease.