IGA1 O-Glycosylation and IGA Nephropathy

2019-07-17T08:06:10Z (GMT) by David H. J. Wimbury
IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide diagnosed by observing deposition of IgA in the mesangium of a renal biopsy. It is known that levels of abnormally glycosylated IgA1 with a reduction in galactose at the hinge region (galactose-deficient IgA1, Gd-IgA1) are elevated in the disease in both circulation and mesangial deposits. Gd-IgA1 is seen as auto-antigenic and leads to immune complex formation which can be deposited in the kidneys leading to renal injury. Higher levels of Gd-Ig1 ave also been linked t progressive forms of IgAN. While much research effort has been devoted to the study of Gd-IgA1 in IgAN, the biological basis for this aberrancy is still not well understood. This project aimed first to examine how genetic variation can influence O-glycosylation of the IgA1 hinge region. Secondly, how the mechanism behind IgA1 hinge region O-glycosylation can be altered during maturation of IgA1 producing B cells. Thirdly, how IgA1 hinge region O-glycosylation can be modulated by the action of cytokines and chemokines. This work has for the first time identified a disparity in serum Gd-IgA1 levels between Caucasian and Chinese populations; in both health and IgAN. Gender differences in serum Gd-IgA1 levels in IgAN have also been observed for the first time. A haplotype of C1GALT1, the gene for the galactose-adding C1GalT1 enzyme, associated with higher serum Gd-IgA1 levels has also been discovered. Maturation-dependent transcriptional regulation of glycosylation enzymes in B cells has been confirmed, and the C1GALT1 haplotype was found to strongly affect C1GALT1 transcript levels. Novel cytokines were also found to be able to modulate Gd-IgA1 production in IgA1 producing cells. The work in this thesis serves to further elucidate control of the mechanism behind O-glycosylation at the IgA1 hinge region and provides new research questions in the study of IgAN.

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