High-resolution epitope mapping by HX MS reveals the pathogenic mechanism and a possible therapy for autoimmune TTP syndrome
Abstract
Acquired thrombotic thrombocytopenic purpura (TTP) is primarily caused by autoantibodies that inhibit the ability of ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) to proteolyze von Willebrand factor (VWF). The molecular mechanism of inhibition is not known. We used a hydrogen-deuterium exchange mass spectrometry (HX MS) method to determine at near-single-residue resolution the epitope of three monoclonal anti-ADAMTS13 autoantibodies isolated from TTP patients. Additional results show that the same autoantibody-binding epitope is responsible for ADAMTS13 binding to VWF to manage VWF proteolysis. These observations reveal the mechanism of autoimmune TTP and, together with the epitope determination, suggest a knowledge-based approach for finding a novel therapeutic.
- Publication:
-
Proceedings of the National Academy of Science
- Pub Date:
- August 2015
- DOI:
- 10.1073/pnas.1512561112
- Bibcode:
- 2015PNAS..112.9620C