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Research project on thrombotic microangiopathies

Thrombotic microangiopathies (TMAs) involve rare diseases with severe clinical symptoms that may be induced by autoimmune mechanisms. Common characteristics of these disorders affecting both children and young adults are thrombocytopenia and hemolytic anemia, potentially leading to death when untreated. Research results of the last few years revealed key pathogenetic components of TMAs, however basic mechanisms have not been clarified yet.

Atypical hemolytic uremic syndrome (aHUS) is related to the dysregulation of the alternative complement pathway evolving as a result of low penetrance mutations and risk polymorphisms or autoantibodies against complement factor H. Thrombotic thrombocytopenic purpura (TTP) primarily occurs due to the development of inhibitory autoantibodies against von Willebrand factor-cleaving protease (ADAMTS13) that was recently reported to be linked to certain HLA alleles. We studied the etiology and molecular pathogenesis of aHUS and TTP in affected patients and numerous healthy individuals. We revealed characteristics of pathogenic autoantibodies, such as epitope specificity, genetic and environmental (infective) linkage, by comparing patient and control samples. Furthermore, functional defects (due to mutations or autoantibodies) of new target molecules with potential role in the pathogenesis of TMAs were also studied as low penetrance of yet known disease predisposing mutations denotes additional pathogenetic constituents.

 

Significance of the project

Funding of the project helped to describe basic immunological mechanisms (genetic linkage of autoantibody development and the role of infections) and new molecular components of a rare, but potentially life-threatening disorder. Revealing characteristics of pathogenic autoantibodies (epitope specificity, mechanism of development) contributed to a better understanding of the pathogenesis of thrombotic microangiopathies, helped to clarify causality and hence facilitate planning of new interventional points. Analysis of new genetic variations identified by the successful execution of this project can also be utilized in prenatal diagnostics, as with the integration of the existing and new data, disease risk can be estimated more accurately. Newly described and characterized mutations help to assess disease recurrence risk in patients with end stage renal disease waiting for kidney transplantation.