Understanding the origins of pathogenic IgA in IgA nephropathy. (360G-Wellcome-099117_Z_12_Z)

In IgA nephropathy (IgAN), serum and mesangial IgA is enriched for IgA1 molecules that are polymeric, display low antibody affinity and are poorly galactosylated at their hinge region. These features are typical of IgA normally produced at mucosal surfaces and this contrasts with that usually present in the systemic compartment. However, in IgAN, numbers of polymeric IgA1-producing plasma cells are reduced at mucosal sites and increased in systemic sites. This Fellowship will test the hypothesis that in patients withIgAN, polymeric, poorly galactosylated IgA1 is synthesised by a population of mucosally-primed IgA+ B cells which mis-traffic to the systemic circulation. I aim to identify the population of IgA+ B cells which produces poorly galactosylated polymeric IgA1 in patients with IgAN and healthy controls. I will use flow cytometry to isolate IgA+ plasmablasts and will carry out microarray analysis and Q-PRC to establish important cell phenotypes particularly relating to O-glycosyltransferase, J-chain expression and homing characteristics. I will immortalise specific cell populations to allow study