Cynthia de Bont Research

Research

Neutrophils are the most prevalent white blood cells in human blood, typically constituting about 70% of all white blood cells and function as the body’s first line of defence against invading pathogens. Neutrophils have several strategies to combat the invaders, such as engulfment of the pathogen and excreting antibacterial proteins. In 2004, NETosis was posed as an additional strategy to attack pathogens. During NETosis, the neutrophil expels its nuclear material into the extracellular space to form a dense and sticky network of DNA fibers to which neutrophil proteins such as histones, myeloperoxidase and neutrophil elastase are attached. This Neutrophil Extracellular Trap (NET) is the last effort of the neutrophil to capture pathogens and prevent them from spreading to other parts of the body.

Usually NETs are cleared by circulating DNases, but when the clearing is defective NETs might cause  blood vessels clogging and kidney dysfunction. Furthermore, improperly cleared NETs are associated with autoimmune diseases, such as systemic lupus erythematosus (SLE) and Rheumatoid Arthritis (RA).  These patients can form autoantibodies against NETs, causing an inflammation. A clear example of this are the antibodies against citrullinated residues present in most RA patients. A citrullinated residue is a post-translational modification of the arginine residue and is also present in NET associated proteins such as histone 3.

The goal of my project is both fundamental and translational. On the one hand I want to study the molecular pathways that lead to NET formation and the functions of proteins that are associated to the NETs, such as neutrophil proteases. On the other hand I try to define the role of NETs in autoimmune diseases such as SLE and RA ,by identifying the epitopes on NETs to which autoantibodies of RA and SLE patients are directed.

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