A population of autoantibodies against a centromere-associated protein A major epitope motif cross-reacts with related cryptic epitopes on other nuclear autoantigens and on the Epstein-Barr nuclear antigen 1.
Autoimmune diseases arise from a host's immune response against self-antigens. The triggering events ultimately resulting in such a break of tolerance are largely unknown. It is also not known why certain molecular structures become autoantigenic. The hypothesis has long been proposed that autoimmune diseases arise from molecular mimicry followed by an epitope spreading mechanism. Recently we have shown that the anti-centromere-associated protein A (CENP-A) immune response is directed against an autoantigenic motif, G/A-P-R/S-R-R, that occurs three times in the N-terminal amino acids of CENP-A. In the present study we used mutational analyses with immobilized oligopeptide arrays to identify the amino acids in this motif that are responsible for antibody binding. In particular, we found that surprisingly mimotopes of this motif are present in a vast number of autoantigens and in the Epstein-Barr nuclear antigen 1. With affinity-purified antibodies we show that the antibodies against this motif are polyclonal and cross-react with several autoantigens. However, in these autoantigens this motif often represents a cryptic epitope explaining the obvious conflict between our results and the known high specificity of autoantibodies. The presence of such an ubiquitous structure on autoantigens suggests a novel peptide-driven mechanism for the evolution of autoantibodies.
Mahler
M
M
Institute of Molecular Genetics, University of Heidelberg, Im Neuenheimer Feld 230, 69120 Heidelberg, Germany.
Mierau
R
R
Schlumberger
W
W
Blüthner
M
M
D020816:Amino Acid Motifs / Q000235:genetics / Q000276:immunology; D000918:Antibody Specificity; D001323:Autoantibodies / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology*; D000076247:Centromere Protein A; D002868:Chromosomal Proteins, Non-Histone / Q000276:immunology*; D003429:Cross Reactions; D004252:DNA Mutational Analysis; D000939:Epitopes / Q000235:genetics / Q000276:immunology*; D019309:Epstein-Barr Virus Nuclear Antigens / Q000276:immunology*; D006801:Humans; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D017386:Sequence Homology, Amino Acid
D001323:Autoantibodies; D001324:Autoantigens; C000619700:CENPA protein, human; D000076247:Centromere Protein A; D002868:Chromosomal Proteins, Non-Histone; D000939:Epitopes; D019309:Epstein-Barr Virus Nuclear Antigens; D010455:Peptides; C417029:EBV-encoded nuclear antigen 1