Isoaspartyl post-translational modification triggers autoimmune responses to self-proteins.
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 beta-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.
Mamula
M J
MJ
Section of Rheumatology, Yale University School of Medicine, New Haven, Connecticut 06520, USA. mark.mamula@yale.edu
Gee
R J
RJ
Elliott
J I
JI
Sette
A
A
Southwood
S
S
Jones
P J
PJ
Blier
P R
PR
D000595:Amino Acid Sequence; D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism*; D001323:Autoantibodies / Q000097:blood; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology; D001667:Binding, Competitive; D003574:Cytochrome c Group / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D007108:Immune Tolerance; D007536:Isomerism; D008213:Lymphocyte Activation; D051379:Mice; D019463:Mice, Inbred MRL lpr; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000276:immunology; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D017411:Ribonucleoproteins, Small Nuclear / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
D001323:Autoantibodies; D003574:Cytochrome c Group; D000949:Histocompatibility Antigens Class II; D010446:Peptide Fragments; D017411:Ribonucleoproteins, Small Nuclear; D001224:Aspartic Acid