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Metalloprotease with ThromboSpondin type 1 repeats, member 13).7,8 Deficiency in ADAMTS13 leads to accu- mulation of hyper-active ultra-large VWF multimers that spontaneously interact with platelets. The resulting microthrombi block arterioles and capillaries, which leads to severe thrombocytopenia, hemolytic anemia and organ failure. The VWF cleaving protease ADAMTS13 consists of 14 domains: the metalloprotease (M), disintegrin-like (D), cysteine-rich (C) and spacer (S) domains, 8 throm- bospondin type 1 repeats (T1-8) and 2 CUB domains.9 It is known that the anti-ADAMTS13 autoimmune response in iTTP patients is polyclonal but 80-100% of patients possess autoantibodies targeting the cysteine-rich and spacer domain.7,10-12 The standard treatment for iTTP is plasma exchange (PEX), often in combination with immunosuppressive agents (mainly steroids and ritux- imab).8 Recently, the anti-VWF nanobody caplacizumab, used as front-line therapy together with PEX, hastened TTP recovery, opening promising perspectives to improve the prognosis of the disease.13,14 Splenectomy is only per- formed in the most severe patients, when other measures have failed.8,15
Since autoimmune diseases manifest differently among patients and have a chronic course with recurring acute bouts, biomarkers are identified that allow patient stratifi- cation to predict disease outcome and prognosis and to adapt specific treatment.16 Obviously, autoantibodies are useful biomarkers in autoimmune diseases and autoanti- body profiling has been shown to be valuable in stratify- ing patients with autoimmune disorders.17,18 On the one hand, autoantibody profiling approaches are based on the
binding of the patient autoantibodies to the disease caus- ing antigen (recombinant proteins, fragments of these, or peptides).19,20 Whereas, on the other hand, autoantibody profiling can be performed independently of the antigen using anti-idiotypic antibodies that recognize autoanti- bodies that bind to the antigen (Figure 1).21 Anti-idiotypic antibodies can be generated by immunizing mice with purified or cloned antigen-binding antibodies.22-24 Antibodies that bind to particular idiotopes involved in antigen binding can then be used to detect specific autoan- tibodies in patient plasma or serum.21 Finally, even if the disease-causing antigen is not known, antibody profiling can lead to the identification of disease-linked peptides using next-generation sequencing25 and mass spectrome- try26,27 of the total antibody response in autoimmune dis- ease patients.
Furthermore, iTTP is a chronic disease with a variable disease outcome and risk of relapse.28 Levels of ADAMTS13 activity, anti-ADAMTS13 autoantibody sub- types, ADAMTS13 antigen levels or a combination of these have been used to identify patient groups with a worse disease outcome or a higher risk of relapse.28-35 Although the outcome of the different studies varies, it has been shown, for example, that an ADAMTS13 activi- ty <10% during acute disease is linked with an increased risk of relapse,35 and that presenting anti-ADAMTS13 autoantibody and ADAMTS13 antigen levels predict prognosis.31 In addition, prognostic scoring systems based on clinical and/or laboratory parameters have been set up to predict severe cases and patients at risk; from 1987 with the Rose index,36,37 to more recently with the PLASMIC
Figure 1. Anti-idiotypic antibodies directed against different idiotopes in autoantibodies. A representative autoantibody is illustrated with the variable regions of heavy (VH) and light (VL) chains and the constant regions of heavy (CH) and light (CL) chains. Variable regions consist of framework regions and complemen- tarity determining regions (CDRs). The CDRs are unique among antibod- ies and consist of idiotopes that are involved in binding to the (self)-anti- gen (dark blue dots) and idiotopes that are not involved in binding to the (self)-antigen (light blue dots). All other regions are conserved regions (gray) between different antibodies, and make up the framework regions of the VH and VL and the constant regions of CH and CL chains. Anti- idiotypic antibodies (Abs) bind to idiotopes involved in (self)-antigen binding, shown in dark blue, whereas anti-idiotypic antibodies that bind to idiotopes not involved in binding to the (self)-antigen are shown in light blue. Anti-conserved region antibod- ies are in gray.
Anti-spacer idiotope profiles in iTTP patients
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