Key Points
Anti-idiotypes to ADAMTS13 autoantibodies are part of the immune response in iTTP.
ITTP patients have shared ADAMTS13 autoantibodies but private anti-idiotypes.
Anti-idiotypes are capable of neutralizing their own and foreign ADAMTS13 autoantibodies.
Visual Abstract
Abstract
Rare immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a life-threatening disease resulting from a severe autoantibody-mediated ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motifs, member 13) deficiency. Acute iTTP episodes are medical emergencies, but when treated appropriately >95% of patients survive. However, at least half of survivors will eventually experience a relapse. How remission of an initial episode is achieved and factors contributing to reemergence of anti-ADAMTS13 Abs and a relapsing course are poorly understood. In acquired hemophilia and systemic lupus erythematosus, anti-idiotypic Abs counteracting and neutralizing pathogenic autoantibodies contribute to remission. We selected and amplified the splenic anti-idiotypic IgG1 Fab κ/λ repertoire of two relapsing iTTP patients on previously generated monoclonal inhibitory anti-ADAMTS13 Fabs by phage display to explore whether anti-idiotypic Abs have a role in iTTP. We obtained 27 single anti-idiotypic Fab clones, half of which had unique sequences, although both patients shared four H chain V region genes (VH1-69*01, VH3-15*01, VH3-23*01, and VH3-49*03). Anti-idiotypic Fab pools of both patients fully neutralized the inhibitor capacity of the monoclonal anti-ADAMTS13 Abs used for their selection. Preincubation of plasma samples of 22 unrelated iTTP patients stratified according to functional ADAMTS13 inhibitor titers (>2 Bethesda units/ml, or 1–2 Bethesda units/ml), with anti-idiotypic Fab pools neutralized functional ADAMTS13 inhibitors and restored ADAMTS13 activity in 18–45% of those cases. Taken together, we present evidence for the presence of an anti-idiotypic immune response in iTTP patients. The interindividual generalizability of this response is limited despite relatively uniform pathogenic anti-ADAMTS13 Abs recognizing a dominant epitope in the ADAMTS13 spacer domain.
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Footnotes
This work was supported by Schweizerischer Nationalfonds zur Förderung der wissenschaftlichen Forschung Grant 310030-185233 and by the Gesellschaft für Thrombosis- und Hämostaseforschung Congress Presidential Fund of 2017.
S.R.H. planned and carried out experiments, analyzed the data, and wrote the initial draft. M.S. and J.A.K.H. designed the project, supervised experiments, discussed data, and provided editorial help. The final version of the manuscript was approved by all authors.
The online version of this article contains supplemental material.
Abbreviations used in this article:
- ADAMTS13
- a disintegrin and metalloprotease with thrombospondin type 1 motifs, member 13
- BU
- Bethesda unit
- FRETS
- fluorescence resonance energy transfer system
- hTTP
- hereditary TTP
- iTTP
- immune-mediated thrombotic thrombocytopenic purpura
- SMC
- splenic mononuclear cell
- TPE
- therapeutic plasma exchange
- vWF
- von Willebrand factor
- Received September 3, 2021.
- Accepted March 29, 2022.
- Copyright © 2022 by The American Association of Immunologists, Inc.
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