The Role of Filtered IgA in the Progression of IgA Nephropathy
thesisposted on 20.06.2017, 12:20 authored by Chee Kay Cheung
IgA nephropathy (IgAN) is the commonest primary glomerulonephritis worldwide, with 20-40% of patients developing progressive kidney disease. The most accurate predictors of prognosis are the presence of proteinuria and tubulointerstitial fibrosis, while the degree of mesangial IgA deposition is not a prognostic factor. These findings imply that tubular-specific factors play a key role in progressive IgAN. The aim of this thesis was to explore whether filtered IgA has a direct effect on proximal tubular epithelial cell (PTEC) activation and generation of pro-inflammatory and pro-fibrotic cytokines. The interaction between IgA and PTEC was initially investigated in vivo in Munich Wistar Frömter rats by multiphoton microscopy. These studies demonstrated that IgA, that crossed the glomerular filtration barrier, interacted with PTEC and underwent endocytosis via their apical surface. This process was greatly upregulated in a model of podocyte injury, resulting in increased amounts of filtered IgA. In vitro, human IgA1, and especially galactose-deficient polymeric IgA1, stimulated release of pro-inflammatory and pro-fibrotic cytokines from cultured human HK-2 PTEC. A mouse model of IgAN was optimised that developed both glomerular and tubulointerstitial inflammatory cell infiltration. Although glomerular deposition of complement component C3 was increased in the model, mice genetically deficient in key initiators of the lectin pathway, Collectin-11 (CL-11) or Mannose-binding lectin-associated serine protease-2 (MASP-2), were not protected from interstitial macrophage infiltration, while reductions in glomerular cell number and T cell infiltration were observed. These studies provide evidence for the first time that filtered IgA is able to interact with the proximal tubule and undergo endocytosis. IgA1, and especially galactosedeficient polymeric IgA1, stimulated a pro-inflammatory and pro-fibrotic response from PTEC that may contribute towards progressive IgAN. Understanding this interaction further may reveal novel targets for therapy in this condition. Deficiencies in CL-11 and MASP-2 did not protect against tubulointerstitial inflammation in a mouse model of IgAN, and further studies should concentrate on whether the alternative pathway is activated in this model.