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Investigation of the role of neutrophils in the production of autoantigens in patients with rheumatoid arthritis

Spengler, Julia (2016)
Ph.D. thesis, University of Birmingham.

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In most patients with rheumatoid arthritis (RA), citrullinated autoantigens are targeted by autoantibodies (ACPA). However, the process leading to protein citrullination by peptidylarginine deiminases (PADs) in the joint remains unclear. In this thesis, I tested the hypothesis that generation of neutrophil extracellular traps (NETosis), can contribute to release of enzymatically active PADs and citrullinated autoantigens in inflamed joints.
I have shown that in vitro induced NETosis leads to release of citrullinated proteins and enzymatically active PADs both attached to NETs and free in the supernatant. In the SF from RA patients DNA levels correlated with neutrophil concentrations, and DNA levels and PAD activity were found to be increased compared with OA patients. Finally, I demonstrated the antigenicity of in vitro generated NETs and identified citrullinated histone H3 as a NET-component recognised by ACPA and RA sera.
Based on the findings in this thesis release of active PADs into SF by neutrophil cell death is a plausible explanation for the generation of citrullinated extracellular autoantigens. In ACPA positive RA patients the continuous production of these autoantigens combined with pre-existing ACPA may result in the formation of immune complexes and perpetuation of the inflammatory response.

Type of Work:Ph.D. thesis.
Supervisor(s):Scheel-Toellner, Dagmar and Cooper, Paul and Milward, Mike
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:School of Immunity and Infection
Subjects:QR180 Immunology
RA0421 Public health. Hygiene. Preventive Medicine
Institution:University of Birmingham
ID Code:6519
This unpublished thesis/dissertation is copyright of the author and/or third parties.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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