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...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1995-03, Vol.92 (6), p.2355-2359
Main Authors: Doudna, Jennifer A., Cech, Thomas R., Sullenger, Bruce A.
Format: Article
Language:English
Subjects:
Animals
Antibodies
Antibodies, Monoclonal
Antibody Specificity
Antigen-Antibody Complex
Autoantibodies
Autoantigens - blood
Autoantigens - immunology
Base Sequence
Biochemistry
DNA
Epitopes
Epitopes - analysis
Humans
Insulin
Insulin Resistance - immunology
Mice
Molecular Sequence Data
Molecules
Monoclonal antibodies
Nucleic Acid Conformation
Oligoribonucleotides
Plasmids
Receptor, Insulin - immunology
Receptors
Ribonucleic acid
RNA
RNA - chemistry
RNA - immunology
Rodents
Transcription, Genetic
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Summary: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 $\backsimeq$~ 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 useful in the treatment of autoimmune diseases.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.92.6.2355