The role of CD4 T cell subsets in autoimmune anti-myeloperoxidase glomerulonephritis

2017-02-15T05:00:52Z (GMT) by Gan, Poh-Yi
My PhD project was to provide novel insights into the role of CD4 cells and their subsets in glomerulonephritis (GN) associated with autoimmunity to myeloperoxidase (MPO) using animal models. This thesis comprises a background review of this form of GN followed by the series of published manuscripts resulting from my research. Each manuscript chapter begins with a literature review surrounding the hypothesis of the manuscript and details of the contribution of the candidate. To gain insights into the development of autoimmunity to MPO I demonstrated that AIRE has an essential role in the generation of central tolerance to MPO. Consequently, AIRE-/- mice develop enhanced MPO autoimmunity and glomerular injury in a model of anti MPO induced GN (Tan et al., 2013). To evaluate the role of cell mediated autoimmunity to MPO in the development of focal segmental necrotising GN, I set up an murine model of anti MPO autoimmunity in agammaglobulinemic µMT mice, comparing the development of glomerular injury between MPO and OVA immunized mice administered passive ANCA. Immunodepletion of CD4 cells prevented the augmentation of injury seen in MPO immunized mice. Both these studies provide proof of concept that MPO specific CD4 cells direct DTH type injury inducing focal necrotising GN (Gan et al., 2013). To assess the role of key T helper (Th) subsets driving cell mediated glomerular injury, I first demonstrated my capacity to evaluate the relative contributions of Th1 and Th17 CD4 subsets in a model of experimental anti GBM GN. In this model, Th17 induces early neutrophil accumulation while Th1 responses drive established disease which is counter-regulated by Th17 cells (Odobasic et al., 2011). With experience gained in dissecting the relative contributions of Th subsets orchestrating anti GBM GN, I next examined the role of IL-17A in autoimmune anti MPO GN. As the limited time course of this model permits only studies of the early disease, it was hypothesised that Th17 cells direct injurious anti MPO autoimmunity. MPO immunised WT mice developed significant focal necrotizing GN, while MPO immunised IL-17A-/- mice were protected. This was the first demonstration of a role for IL-17A in the recruitment of DTH effectors in glomeruli and the associated injury in autoimmune anti MPO vasculitis and GN (Gan et al., 2010). Finally, in theme with examining Th subsets in autoimmune anti MPO GN, the interactions between mast cells (MCs) and Tregs were determined. During the induction of autoimmunity to MPO, MCs migrate to lymph nodes draining MPO immunisation sites where they were found to interact with Tregs. These interactions regulate and facilitate peripheral tolerance to diminish the severity of subsequently induced anti MPO mediated GN. Studies with IL-10-/- MCs show that MC production of IL-10 is responsible for this immunodmodulation (Gan et al., 2012). In conclusion, this thesis examines the loss of tolerance to MPO and the subsequent contribution of regulatory and effector T cell pathways in the pathogenesis of autoimmune MPO ANCA GN. It is hoped that these published manuscripts will help in definition of new therapeutic targets and facilitate the development of more targeted and less toxic therapeutic interventions for an important disease that badly needs better therapies.