The role of the complement system in the pathogenesis of IgA nephropathy

Immunoglobulin A nephropathy (IgAN) is a common cause of primary glomerulonephritis worldwide. The defining characteristic of IgAN is the presence of galactose deficient IgA1 (Gd-IgA1) containing immune complexes (ICs) in the glomerular mesangium, with subsequent mesangial cell proliferation and tubulointerstitial fibrosis, leading to end stage renal disease (ESRD). Although higher levels of Gd-IgA1 are commonly seen in patients with IgAN, this does not lead to development of glomerulonephritis in all patients. Indeed, the pathogenesis of IgAN is incompletely understood and glomerular IgA deposits may be seen in people with no evidence of renal disease. It is well documented that the deposited IgA originates from serum and that Gd-IgA1 is recognised by anti-glycan antibodies, (IgG and IgA). These antibodies combine with Gd-IgA1 to form circulating ICs that deposit in the mesangium and trigger mesangial cell proliferation and the release of cytokines. In the majority of IgAN kidney biopsies, C3 and other complement proteins are observed. The origin of these proteins is unclear. Changes in the level of serum complement proteins have been observed in IgAN suggesting disease-associated complement activation. To date, the role of complement in IgAN has not been clearly defined. This thesis aimed to investigate the role of complement in IgAN by measuring serum levels of IgA-complement ICs in IgAN using novel in-house ELISAs, developing a model of IgAN in a C3 gain-of-function (GOF) transgenic mouse, and assessing the human mesangial cell response to IgA1 containing high and low levels of IgA-complement ICs. I found that IgAN was associated with the presence of high serum levels of IgA-complement macromolecular complexes which was also observed in C3 GOF mice, and that high levels of these complexes were associated with severity of IgAN and more renal histological changes in mice. Moreover, exposing human mesangial cells to ICs containing high levels of IgA-complement ICs resulted in an exaggerated pro-inflammatory IL-6 cytokine response. These results support the hypothesis that in IgAN complement components bind directly to IgA in the circulation forming high molecular weight IgA-complement complexes which subsequently become trapped in the glomerular mesangium, leading to the activation of mesangial cells.