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Developing a model of secondary IgA nephropathy


About This PhD Project

Project Description

Complement is a key humoral effector system when immune complexes are formed. On activation, split products are formed which attract inflammatory cells and enhance cellular responses. Complement activation has long been implicated in the renal damage brought on by IgA immune complex deposition. Mucosal sensitisation is very important in the pathogenesis of IgA nephropathy. Glomerular deposition of IgA immune complexes after mucosal sensitisation occurs in man and may progress to renal failure. These so-called secondary IgA nephropathies involving defined mucosal sensitisation can be meaningfully modelled in mice.

The project draws on strong local sets of expertise and will for the first time set up an in vivo model to study glomerular immune complex deposition after mucosal sensitisation. The project license to do this work is in place and is valid for the duration of the project.
We hypothesise that Complement activation is key in the glomerular deposition of immune complexes after mucosal sensitisation and in progression of inflammation.

The specific aims are to characterise glomerular and tubulointerstitial injury, and to evaluate mesangial cell proliferation and macrophage infiltration. We will attempt to target therapeutically the fibrotic response reactive to inflammation.

The individual objectives will be to i. achieve a systemic IgA response to orally delivered antigen (mucosal sensitisation); ii. visualise antigen specific IgA complexes in glomeruli in experimentally induced glomerular pathology, iii. characterise the role of Complement in glomerular pathology, and iv. target a specific molecule identified as part of preliminary work that is relevant to progression of secondary IgA nephropathy.

Overall, the project aims to increase our understanding of human kidney disease and how a particular form may be treated.

References

Pouria S, Barratt J. Secondary IgA nephropathy. Semin Nephrol. 2008; 28:27-37.
Daha MR, van Kooten C. Deposition of IgA in primary IgA nephropathy: it takes at least four to tango. Nephrol Dial Transplant 2013; 28: 794-797.
Kouser L, Paudyal B, Kaur A, Stenbeck G, Jones LA, Abozaid SM, Stover CM, Flauhat E, Sim RB, Kishore U. Human properdin opsonizes nanoparticles and triggers a potent pro-inflammatory response by macrophages without involving complement activation. Front Immunol 2018; 9:131-149.

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