test Browse by Author Names Browse by Titles of Works Browse by Subjects of Works Browse by Issue Dates of Works
       

Advanced Search
Home   
 
Browse   
Communities
& Collections
  
Issue Date   
Author   
Title   
Subject   
 
Sign on to:   
Receive email
updates
  
My Account
authorized users
  
Edit Profile   
 
Help   
About T-Space   

T-Space at The University of Toronto Libraries >
School of Graduate Studies - Theses >
Doctoral >

Please use this identifier to cite or link to this item: http://hdl.handle.net/1807/34029

Title: The Role of Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) in the Pathogenesis of Ankylosing Spondylitis
Authors: Haroon, Nigil
Advisor: Inman, Robert D.
Department: Medical Science
Keywords: Spondyloarthritis
HLA-B27
Endoplasmic Reticulum
Antigen presentation
Issue Date: 12-Dec-2012
Abstract: Ankylosing spondylitis (AS) is associated with HLA-B*2704 and B*2705 but not with HLA-B*2706 and B*2709. Genome wide studies recently identified ERAP1 as an important genetic association in AS and could be the missing link in the pathogenesis of AS. I studied the implications of the two known actions of ERAP1 on AS pathogenesis. For assessing the peptide trimming function, surface HLA-B27 and MHC-I free heavy chain (FHC) expression on peripheral blood mononuclear cells of AS patients were studied. Subsequently, in an in vitro system of C1R cells expressing different AS-associated and AS-neutral HLA-B27 subtypes, I studied the effect of ERAP1 suppression on HLA-B27 and FHC expression. To assess the cytokine receptor shedding function, I studied serum cytokine receptor level variation with ERAP1 polymorphisms and its relationship to disease activity in AS patients. Finally, I studied the effect of variants of ERAP1 and other members of the antigen presentation machinery on radiographic severity in AS patients. AS patients with the major allele of the ERAP1 rs27044 polymorphism had higher FHC expression on monocytes. In C1R cells ERAP1 suppression led to an increase in intracellular FHC (IC-FHC) and B27-peptide complexes identified by a special MARB4 antibody, but only in C1R cells expressing the AS-associated subtypes HLA-B*2704 and B*2705. ERAP1 variants had no effect on serum cytokine receptor levels. Baseline radiographic severity was associated with ERAP1 polymorphism in univariate analysis only. LMP2 variants were associated with baseline radiographic severity in multivariate analysis. ERAP1 affects peptide presentation and FHC formation by HLA-B27 and could be the missing link in the pathogenesis of AS. ERAP1 through its differential HLA-B27 subtype interaction could explain why certain subtypes of HLA-B27 are associated with AS while others are not. Larger studies are required to look closely at the effect of ERAP1 on radiographic severity and progression in AS.
URI: http://hdl.handle.net/1807/34029
Appears in Collections:Doctoral

Files in This Item:

File Description SizeFormat
Haroon_Nigil_201211_PhD_Thesis.pdf3.37 MBAdobe PDF
View/Open

Items in T-Space are protected by copyright, with all rights reserved, unless otherwise indicated.

uoft