title: The splenic autoimmune response to ADAMTS13 in thrombotic thrombocytopenic purpura contains recurrent antigen-binding CDR3 motifs.
abstract: Acquired thrombotic thrombocytopenic purpura (TTP) is the consequence of a severe ADAMTS13 deficiency resulting from autoantibodies inhibiting ADAMTS13 or accelerating its clearance. Despite the success of plasma exchange the risk of relapse is high. From 2 patients (A and B), splenectomized for recurrent episodes of acquired TTP, the splenic B-cell response against ADAMTS13 was characterized through generation of human monoclonal anti-ADAMTS13 autoantibodies (mAbs) by cloning an immunoglobulin G (IgG)4κ- and IgG4λ-Fab library using phage display technology and by Epstein-Barr virus transformation of switched memory B cells (CD19+/CD27+/IgG+). Sequence analysis of the anti-ADAMTS13 IgGs of both patients revealed that the VH gene use was limited in our patients to VH1-3 (55%), VH1-69 (17%), VH3-30 (7%), and VH4-28 (21%) and contained 8 unique and thus far not reported heavy-chain complementarity determining region 3 motifs, of which 4 were shared by the 2 patients. The discovery of several highly similar anti-ADAMTS13 autoantibodies in 2 unrelated TTP patients suggests that the autoimmune response is antigen driven, because the probability that such similar immunoglobulin rearrangements happen by chance is very low (< 10(-9)).
authors.affiliation: Department of Hematology and Central Hematology Laboratory, Hemostasis Research Laboratory and.
authors.forename: Monica
authors.initials: M
authors.lastname: Schaller
authors.affiliation: Institute of Immunology, Inselspital, Bern University Hospital and the University of Bern, Bern, Switzerland; and.
authors.forename: Monique
authors.initials: M
authors.lastname: Vogel
authors.affiliation: Children's Hospital, Friedrich Schiller University, Jena, Germany.
authors.forename: Karim
authors.initials: K
authors.lastname: Kentouche
authors.affiliation: Department of Hematology and Central Hematology Laboratory, Hemostasis Research Laboratory and.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Lämmle
authors.affiliation: Department of Hematology and Central Hematology Laboratory, Hemostasis Research Laboratory and.
authors.forename: Johanna A
authors.initials: JA
authors.lastname: Kremer Hovinga
mesh_terms: D051722:ADAM Proteins / Q000276:immunology*; D000071120:ADAMTS13 Protein; D000328:Adult; D000936:Antigen-Antibody Complex / Q000737:chemistry; D001323:Autoantibodies / Q000737:chemistry* / Q000378:metabolism*; D015551:Autoimmunity / Q000276:immunology; D002648:Child; D005260:Female; D006801:Humans; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011697:Purpura, Thrombotic Thrombocytopenic / Q000276:immunology* / Q000378:metabolism / Q000601:surgery; D012074:Remission Induction; D013154:Spleen / Q000276:immunology* / Q000378:metabolism; D013156:Splenectomy
chemical_list: D000936:Antigen-Antibody Complex; D001323:Autoantibodies; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human