Henderson, Scott Russell; (2018) Dissecting Mechanisms of Granuloma Formation in ANCA-Associated Vasculitis. Doctoral thesis (Ph.D), UCL (University College London).

Abstract

Anti-neutrophil cytoplasm antibodies (ANCA) are associated with a severe form of small vessel systemic vasculitis, in which they target two specific auto-antigens, proteinase-3 (PR3) and myeloperoxidase (MPO) found within neutrophils and monocytes. Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are the main clinical syndromes, both characterized by kidney and lung disease, but granulomatous inflammation is almost exclusively found in GPA, and unlike other manifestations, remains difficult to treat. In GPA patients, PR3 is the predominant ANCA auto-antigen and neutrophil membrane PR3 expression is increased. There has been limited understanding of why granulomata are restricted to this patient subgroup. I have investigated the role of PR3 in driving giant cell and granuloma formation by generating a novel in vitro model. Using extensive tissue culture and microscopy techniques I have been able to demonstrate that PR3 induces both giant cell and granuloma formation in GPA patients’ cells. Giant cells are the precursors to granulomata and I have demonstrated that in GPA patients, monocytes firstly fuse with the persistence of PR3 and then later recruit lymphocytes to form an organized granuloma-like structure. I have developed a unique method of quantifying granuloma formation and I have been able to show that GPA patients show a statistically significant greater rate of PBMC aggregation both spontaneously and in the presence of PR3 compared to MPA patients and healthy controls. I have explored the potential mechanisms of granuloma formation in this patient subgroup. Specifically, IL-6 may be important in driving granuloma formation in GPA patients and supports the notion of PR3-mediated process. PR3 cleaves protease-activated receptor 2 (PAR2) and I have shown that the presence of a PAR2 agonist further augments cell fusion. These findings support the role of PR3-mediated monocyte activation and fusion with additional T cell aggregation. In summary, I have developed a novel system to test giant cell and granuloma formation in GPA patients, a potential platform to evaluate new therapeutic treatments.

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