Autoantibodies in autoimmune-mediated thrombotic thrombocytopenic purpura: from mechanistic insights towards the first steps in targeted therapy

More than 2.5% of the population is affected by autoantibody-driven autoimmune diseases. The mechanism of autoantibody-induced deficiency of the autoantigen is different for every autoimmune disease. However, there is only one general treatment for all those diseases and that is systemic immune suppression. As a consequence, side effects, morbidity and mortality are high in these patients. An unmet need in the field is the availability of targeted immune therapies to neutralize the pathogenic autoantibodies. A targeted therapy can only be developed when the exact mechanism on how autoantibodies cause autoantigen deficiency is known. A targeted neutralization of the pathogenic antibodies could then be realized by specific drugs like anti-idiotypic antibodies or small molecules. Immune–mediated thrombotic thrombocytopenic purpura (iTTP) is a rare and life-threatening autoimmune disease caused by a severe deficiency in the plasma metalloprotease ADAMTS13 (A Disintegrin and Metalloprotease with Thrombospondin Type 1 repeats, member 13). Hyperactive ultra-large von Willebrand factor (UL-VWF) multimers in circulation cannot be cleaved when this metalloprotease is absent or dysfunctional. Consequently, microthrombi are formed by spontaneous binding of UL-VWF multimers to platelets, depriving organs from oxygen supply. The immune response in iTTP patients is polyclonal with an immunodominant epitope in the ADAMTS13 spacer domain. The exact mechanism how anti-ADAMTS13 autoantibodies induce ADAMTS13 deficiency is unknown. Unravelling this mechanism is, however, an unmet need to allow development of a targeted therapy for iTTP patients. The aim of the current project is to identify which group of anti-ADAMTS13 autoantibodies are the pathogenic ones and cause ADAMTS13 deficiency. Blocking the specific group of pathogenic antibodies would lead to the first steps in developing a targeted therapy for iTTP.

Keywords:autoandibodies

Disciplines:Biochemistry and metabolism, Medical biochemistry and metabolism, Cardiac and vascular medicine