LOCAL AND SYSTEMIC IMMUNE REGULATION BY LIVER AND PLASMA PROTEIN GLYCOSYLATION

Bibliographic Details
Main Author:	Oswald, Douglas Martin
Language:	English
Published:	Case Western Reserve University School of Graduate Studies / OhioLINK 2020
Subjects:	Immunology Pathology
Online Access:	http://rave.ohiolink.edu/etdc/view?acc_num=case1575642172980456

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spelling	ndltd-OhioLink-oai-etd.ohiolink.edu-case15756421729804562021-08-03T07:13:36Z LOCAL AND SYSTEMIC IMMUNE REGULATION BY LIVER AND PLASMA PROTEIN GLYCOSYLATION Oswald, Douglas Martin Immunology Pathology Virtually every mammalian protein expressed at the cellular surface or secreted into solution contains at least one site of glycosylation. Glycosylation can modify the properties of these molecules in profound ways, changing both general characteristics and specific interactions. Many cell-cell communications are mediated by glycans or glycosylated proteins, as they often are direct targets of receptors or modify receptor binding. Glycan interactions are particularly important in the immune system, where they are associated with endogenous functioning of immune cells and signaling as well as in pathogen interactions. Prior work has established that plasma protein glycosylation changes in response to various inflammatory conditions and pathology. These changes are consistent, and many have been found to be predictive of disease outcomes. What role these glycans play in the mediation of disease, however, is unknown. One specific plasma glycan that is widely studied is the IgG Fc glycan. IgG Fc glycosylation is also a strong predictor of disease. In contrast to plasma protein glycosylation, there are many biological effects known to be mediated by IgG Fc glycosylation. The sialylation of this glycan enables anti-inflammatory functions of IgG. Fucosylated IgG is also less able to mediate antibody dependent cellular toxicity. The mechanism by which IgG glycosylation is controlled are not understood. Prior work has established that the sialylation of IgG is independent of the B cells that produce it and that the molecule can be modified post secretion by circulatory enzyme. This novel mechanism of glycosylation, termed extracellular glycosylation, is a rich vein for understanding the modification and roles of plasma protein glycans in health and disease.We utilize a genetic mouse model in which the glycosyltransferase ST6Gal1 has been specifically removed from hepatocytes (hepatocyte conditional knockout of ST6Gal1, H-cKO) to investigate the effects mediated by the glycosylation of liver proteins both systemically and locally. In addition to the loss of the α2,6 sialic acid linkages on liver proteins, the H-cKO mouse displays broad changes in plasma protein glycosylation. Local to the site of deletion, there is a dysregulation of liver inflammation, believed to stem from metabolic changes in the liver leading to fatty liver disease and some systemic inflammatory signatures. The mouse is additionally susceptible to various models of inflammatory disease that are dependent on T cell priming by macrophages, including Asthma and EAE. This systemic dysregulation is linked mechanistically to a loss of α2,6 sialylated plasma proteins via changes in splenic immune cell CD22 signaling and an increase in T cell activation. It was theorized that the loss of liver origin ST6Gal1 would ablate extracellular IgG sialylation, but we determined, using the H-cKO mouse, that IgG sialylation occurs independently of liver or B cell ST6Gal1. Finally, we use measurements of human plasma protein glycosylation to predict cardiovascular disease in HIV positive patients. These four studies represent four different investigations into the control of plasma protein glycosylation in the regulation of inflammation and build toward multiple mechanisms by which glycans can be not only predictive of disease but also implicated in pathogenesis. 2020-01-28 English text Case Western Reserve University School of Graduate Studies / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=case1575642172980456 http://rave.ohiolink.edu/etdc/view?acc_num=case1575642172980456 restricted--full text unavailable until 2022-01-17 This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection	NDLTD
language	English
sources	NDLTD
topic	Immunology Pathology
spellingShingle	Immunology Pathology Oswald, Douglas Martin LOCAL AND SYSTEMIC IMMUNE REGULATION BY LIVER AND PLASMA PROTEIN GLYCOSYLATION
author	Oswald, Douglas Martin
author_facet	Oswald, Douglas Martin
author_sort	Oswald, Douglas Martin
title	LOCAL AND SYSTEMIC IMMUNE REGULATION BY LIVER AND PLASMA PROTEIN GLYCOSYLATION
title_short	LOCAL AND SYSTEMIC IMMUNE REGULATION BY LIVER AND PLASMA PROTEIN GLYCOSYLATION
title_full	LOCAL AND SYSTEMIC IMMUNE REGULATION BY LIVER AND PLASMA PROTEIN GLYCOSYLATION
title_fullStr	LOCAL AND SYSTEMIC IMMUNE REGULATION BY LIVER AND PLASMA PROTEIN GLYCOSYLATION
title_full_unstemmed	LOCAL AND SYSTEMIC IMMUNE REGULATION BY LIVER AND PLASMA PROTEIN GLYCOSYLATION
title_sort	local and systemic immune regulation by liver and plasma protein glycosylation
publisher	Case Western Reserve University School of Graduate Studies / OhioLINK
publishDate	2020
url	http://rave.ohiolink.edu/etdc/view?acc_num=case1575642172980456
work_keys_str_mv	AT oswalddouglasmartin localandsystemicimmuneregulationbyliverandplasmaproteinglycosylation
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LOCAL AND SYSTEMIC IMMUNE REGULATION BY LIVER AND PLASMA PROTEIN GLYCOSYLATION

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