A New Concept of ANCA-Associated Vasculitis (ANCA)

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:

• To delineate whether ANCA can bind their target epitopes on PR3 and MPO when these are in complex with Eap and SPIN
• To identify ANCA-specific B cells, isolate and immortalize them, thereby generating ANCA B cell lines. These B cell lines will be used to:
• Elucidate whether ANCA B cells can phagocytose and present PR3/Eap and MPO/SPIN complexes to S. aureus specific-T cells.

The metrics and milestones to measure the success are the products of the different aims:

• Aim 1. For sufficient support of the hypothesis, the majority (>50%) of sera from AAV-patients should still recognize PR3 and MPO when they are in complex with Eap and SPIN respectively.
• Aim 2. In light of the challenging techniques involved in generating immortalized antigen-specific B cell lines, the aim will be to produce anti-PR3 and anti-MPO B cell lines from at least three different patients.
• Aim 3. Stimulation of T cells by immortalized B cells with Eap-PR3 or SPIN-MPO-complexes should lead to considerably more pronounced T and B cell activation (measures of T and B cell activation being at least twice as high) compared to stimulation with PR3 or MPO only.

• 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). doi.org/10.1038/s41584-022-00786-4
  Read more

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.