Selection of an RNA molecule that mimics a major autoantigenic epitope of human insulin receptor.
Autoimmunity often involves the abnormal targeting of self-antigens by antibodies, leading to tissue destruction and other pathologies. This process could potentially be disrupted by small ligands that bind specifically to autoantibodies and inhibit their interaction with the target antigen. Here we report the identification of an RNA sequence that binds a mouse monoclonal antibody specific for an autoantigenic epitope of human insulin receptor. The RNA ligand binds specifically and with high affinity (apparent Kd congruent to 2 nM) to the anti-insulin receptor antibody and not to other mouse IgGs. The RNA can also act as a decoy, blocking the antibody from binding the insulin receptor. Thus, it probably binds near the combining site on the antibody. Strikingly, the RNA cross-reacts with autoantibodies from patients with extreme insulin resistance. One simple explanation is that the selected RNA may structurally mimic the antigenic epitope on the insulin receptor protein. These results suggest that decoy RNAs may be used in the treatment of autoimmune diseases.
Doudna
J A
JA
Department of Chemistry and Biochemistry, Howard Hughes Medical Institute, University of Colorado, Boulder 80309-0215.
Cech
T R
TR
Sullenger
B A
BA
D000818:Animals; D000911:Antibodies, Monoclonal; D000918:Antibody Specificity; D000936:Antigen-Antibody Complex; D001324:Autoantigens / Q000097:blood / Q000276:immunology; D001483:Base Sequence; D000939:Epitopes / Q000032:analysis*; D006801:Humans; D007333:Insulin Resistance / Q000276:immunology*; D051379:Mice; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D009843:Oligoribonucleotides; D010957:Plasmids; D012313:RNA / Q000737:chemistry / Q000276:immunology*; D011972:Receptor, Insulin / Q000276:immunology*; D014158:Transcription, Genetic
D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D001324:Autoantigens; D000939:Epitopes; D009843:Oligoribonucleotides; D012313:RNA; D011972:Receptor, Insulin