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Heterogeneity of injury in vasculitis: influence of anti neutrophil cytoplasm antibody IgG subclass and endothelial susceptibility.

Pankhurst, Tanya (2010)
Ph.D. thesis, University of Birmingham.

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Abstract

This study examined IgG subclass in ANCA associated vasculitis and glomerular endothelial cell (GEC) phenotype predisposes to injury. Using the flow model, interaction of neutrophils with normal immunoglobulin subclasses was compared to interaction with subclasses of ANCA IgG. Neutrophils were captured by normal IgG3>IgG1>IgG2/IgG4. Blockade of CD32 affected IgG3, CD16, IgG1/2. Neutrophils exposed to soluble ANCA IgG1/3 adhered to cytokine-activated endothelial cells, as did IgG4, not previously thought to bind constitutively expressed CD16/CD32. Fc blockade reduced binding. GEC were compared with human umbilical vein endothelial cells. Surface VCAM-1 was reduced on GEC and GEC demonstrated reduced leukocyte capture. RNA array analysis demonstrated a reduction in the GEC gene responsible for post translational modification of VCAM-1 to a sialoglycoprotein. VCAM-1 expression by GEC may be a protective mechanism to reduce inflammatory responses, potentially disrupted in disease. ANCA subclass and endothelial phenotype are important vasculitis pathogenesis: this may be useful in designing targeted therapy reducing overall immunsuppressive load. Additionally modification of specific adhesion molecule profiles on endothelial cells may enable alteration of conditions of one vascular bed whilst reducing impact on unaffected sites.

Type of Work:Ph.D. thesis.
Supervisor(s):Savage, Caroline and Nash, G. B. (Gerard B.)
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:Department of Immunity and Infection
Subjects:R Medicine (General)
QR180 Immunology
Institution:University of Birmingham
ID Code:718
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
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