title: Multiple domains of ADAMTS13 are targeted by autoantibodies against ADAMTS13 in patients with acquired idiopathic thrombotic thrombocytopenic purpura.
abstract: BACKGROUND
  Type G immunoglobulins against ADAMTS13 are the primary cause of acquired (idiopathic) thrombotic thrombocytopenic purpura. However, the domains of ADAMTS13 which the type G anti-ADAMT13 immunoglobulins target have not been investigated in a large cohort of patients with thrombotic thrombocytopenic purpura.
  
  
  METHODS
  Sixty-seven patients with acquired idiopathic thrombotic thrombocytopenic purpura were prospectively collected from three major U.S. centers. An enzyme-linked immunosorbent assay determined plasma concentrations of anti-ADAMTS13 type G immunoglobulins, whereas immunoprecipitation plus western blotting determined the binding domains of these type G immunoglobulins.
  
  
  RESULTS
  Plasma anti-ADAMTS13 type G immunoglobulins from 67 patients all bound full-length ADAMTS13 and a variant truncated after the eighth TSP1 repeat (delCUB). Approximately 97% (65/67) of patients harbored type G immunoglobulins targeted against a variant truncated after the spacer domain (MDTCS). However, only 12% of patients' samples reacted with a variant lacking the Cys-rich and spacer domains (MDT). In addition, approximately 37%, 31%, and 46% of patients' type G immunoglobulins interacted with the ADAMTS13 fragment containing TSP1 2-8 repeats (T2-8), CUB domains, and TSP1 5-8 repeats plus CUB domains (T5-8CUB), respectively. The presence of type G immunoglobulins targeted against the T2-8 and/or CUB domains was inversely correlated with the patients' platelet counts on admission.
  
  
  CONCLUSIONS
  This multicenter study further demonstrated that the multiple domains of ADAMTS13, particularly the Cys-rich and spacer domains, are frequently targeted by anti-ADAMTS13 type G immunoglobulins in patients with acquired (idiopathic) thrombotic thrombocytopenic purpura. Our data shed more light on the pathogenesis of acquired thrombotic thrombocytopenic purpura and provide further rationales for adjunctive immunotherapy.
authors.affiliation: The Children's Hospital of Philadelphia and The University of Pennsylvania Medical Center, 34th Street and Civic Center Boulevard, 816G Abramson Research Center, Philadelphia, PA 19104 USA. Zheng@email.chop.edu
authors.forename: X Long
authors.initials: XL
authors.lastname: Zheng
authors.forename: Haifeng M
authors.initials: HM
authors.lastname: Wu
authors.forename: Dezhi
authors.initials: D
authors.lastname: Shang
authors.forename: Erica
authors.initials: E
authors.lastname: Falls
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Skipwith
authors.forename: Spero R
authors.initials: SR
authors.lastname: Cataland
authors.forename: Charles L
authors.initials: CL
authors.lastname: Bennett
authors.forename: Hau C
authors.initials: HC
authors.lastname: Kwaan
mesh_terms: D051722:ADAM Proteins / Q000737:chemistry / Q000276:immunology*; D000071120:ADAMTS13 Protein; D000328:Adult; D000368:Aged; D001323:Autoantibodies / Q000276:immunology*; D000939:Epitopes / Q000276:immunology*; D005260:Female; D006801:Humans; D007074:Immunoglobulin G; D008297:Male; D008875:Middle Aged; D011697:Purpura, Thrombotic Thrombocytopenic / Q000276:immunology*; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D000939:Epitopes; D007074:Immunoglobulin G; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human