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

Spengler, Julia (2017). Investigation of the role of neutrophils in the production of autoantigens in patients with rheumatoid arthritis. University of Birmingham. Ph.D.

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Abstract

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:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):