Mechanisms of injury in experimental glomerulonephritis

Phoebe Sharp, Arthritis Research UK, Charles Pusey, Terence Cook, Ruth Tarzi
2015
Proliferative glomerulonephritis (GN), seen in patients with Goodpasture's disease or systemic lupus erythematosus (SLE), is characterised by glomerular infiltration of macrophages and T cells as well as proliferation of intrinsic renal cells. Significant insights into the pathogenesis of GN have been obtained through the use of experimental rodent models, such as nephrotoxic nephritis (NTN). In this thesis I have investigated the role of two important immunological molecules in NTN: Fas ligand
more » ... in NTN: Fas ligand (FasL) and Fc gamma receptor IIB (FcγRIIB). FasL is a well-known inducer of apoptosis in cells expressing its receptor Fas; however FasL also mediates non-apoptotic pro-inflammatory responses. FasL is widely expressed throughout the hematopoietic system but is also expressed within healthy and diseased kidney. I describe a novel role for FasL in the promotion of NTN independent from antibody and T cell responses. This pathological effect correlates with enhanced glomerular inflammation and appears to be dependent on FasL expression on both circulating leukocytes and intrinsic renal cells. Additionally, I have shown FasL-defective mesangial cells have impaired signalling through the IL-1R with a reduction in MCP-1 production. FcγRIIB is the sole inhibitory Fc receptor for IgG and is involved in the negative regulation of B cells and cellular activation. FcγRIIB is widely expressed throughout the hematopoietic system but is also expressed on mesangial cells within the kidney. FcγRIIB deficiency greatly exacerbates NTN. Here I use cell-specific deletion to demonstrate the critical importance of FcγRIIB expressed on myeloid cells rather than B cells in the protection from NTN. Further to this, I highlight a role for FcγRIIB on intrinsic renal cells, possibly mesangial cells, in the protection from NTN. Overall, these data widen our knowledge on the pathogenesis of GN and open up possibilities for finding future novel treatments.
doi:10.25560/22183 fatcat:6z4sct7ryfhzbhgvm7sx2xnxym