Humoral immune response to ADAMTS13 in acquired thrombotic thrombocytopenic purpura

• Published in: Journal of thrombosis and haemostasis Vol. 9; no. 7; pp. 1285 - 1291
• Main Authors: POS, W., LUKEN, B. M., SORVILLO, N., HOVINGA, J. A. KREMER, VOORBERG, J.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.07.2011
• Subjects: ADAM Proteins - immunology; ADAMTS13; ADAMTS13 Protein; antibodies; Autoantibodies; Autoantibodies - blood; Complementarity; Epitope Mapping; Histocompatibility antigen HLA; HLA-DRB1 Chains; Humans; Immune response; Immune response (humoral); Immunity, Humoral; Immunoglobulin Heavy Chains - genetics; Immunoglobulin Variable Region - genetics; inspection; Mapping; Monoclonal antibodies; Protein Structure, Tertiary; Purpura, Thrombotic Thrombocytopenic - immunology; Residues; Risk Factors; Spacer; spacer domain; thromboembolism; Thrombosis; Thrombotic thrombocytopenic purpura; Von Willebrand factor
• ISSN: 1538-7933; 1538-7836; 1538-7836
• DOI: 10.1111/j.1538-7836.2011.04307.x

The apparently spontaneous development of autoantibodies to ADAMTS13 in previously healthy individuals is a major cause of thrombotic thrombocytopenic purpura (TTP). Epitope mapping studies have shown that in most patients antibodies directed towards the spacer domain of ADAMTS13 are present. A single antigenic surface comprising Arg660, Tyr661 and Tyr665 that contributes to the productive binding of ADAMTS13 to unfolded von Willebrand factor is targeted by anti‐spacer domain antibodies. Antibodies directed to the carboxyl‐terminal CUB1–2 and TSP2–8 domains have also been observed in the plasma of patients with acquired TTP. As yet it has not been established whether this class of antibodies modulates ADAMTS13 activity. Inspection of the primary sequence of human monoclonal anti‐ADAMTS13 antibodies suggests that the variable heavy chain germline gene segment VH1–69 is frequently incorporated. We suggest a model in which ‘shape complementarity’ between the spacer domain and residues encoded by the VH1–69 gene segment explain the preferential use of this variable heavy chain gene segment. Finally, a model is presented for the development of anti‐ADAMTS13 antibodies in previously healthy individuals that incorporates the recent identification of HLA DRB1*11 as a risk factor for acquired TTP.