The potentially life-threatening disease anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is characterized by autoantibodies against proteinase 3 (PR3) and myeloperoxidase (MPO). Despite decades of research, the trigger that initially breaks tolerance and causes ANCA-production remains unknown. This project will provide crucial insight into AAV-pathogenesis that can subsequently be used to develop more effective treatments e.g. by eradicating S. aureus or tolerizing the involved antigen-specific immune cells.
This project proposes a novel hypothesis regarding the onset of autoimmunity in AAV: tolerance to PR3 and MPO is broken through complex formation with the S. aureus proteins Eap and SPIN, enabling ANCA B cells to present S. aureus peptides and recruit the help of S. aureus-specific T cells. It aims to investigate this hypothesis by focusing on the following three objectives:
The metrics and milestones to measure the success are the products of the different aims:
Scherer, H.U., van der Woude, D. & Toes, R.E.M. From risk to chronicity: evolution of autoreactive B cell and antibody responses in rheumatoid arthritis. Nat Rev Rheumatol 18, 371–383 (2022). https://doi.org/10.1038/s41584-022-00786-4
This project will provide crucial insight into AAV-pathogenesis that can subsequently be used to develop more effective treatments. If S. aureus indeed triggers vasculitis as described above, then eradicating this bacterium could prevent onset of disease (e.g. in genetically at-risk family members), and in patients with established disease, it could diminish debilitating disease flares. Furthermore, it would allow the development of tolerizing therapies aimed at inhibiting the T cells reacting to Eap and SPIN that form the starting point of the disease.