Thesis Tom Arfman

Abstract

Citrullination comprises the enzymatic modification of peptidylarginine to peptidylcitrulline by peptidyl arginine deiminase (PAD) enzymes. The role of citrullination in innate immunity has particularly sparked scientific interest after the finding that histone citrullination is involved in formation of neutrophil extracellular traps (NETs). NETs function by trapping and killing pathogens, but can also exacerbate inflammatory diseases like sepsis. In addition citrullination drives the autoimmune response during rheumatoid arthritis, and has been implicated in several other autoimmune mediated disorders including immune-mediated thrombotic thrombocytopenic purpura (iTTP).
Recent advances are increasingly indicating that citrullination may act to promote blood coagulation through dysregulation of coagulation inhibitors and through protection of fibrin clots from lysis. Citrullination is therefore a post-translational modification (PTM) of specific interest in inflammatory diseases, autoimmune diseases and thrombosis.
However, the physiological functions of citrullination remain largely obscure, owing to unreliable citrullination detection in complex proteomes using mass spectrometry (MS). Citrullination induces a mass increase of 0.9840 Da, which closely resembles the mass increase associated with naturally occurring C13 and N15 isotopes. Furthermore, citrullination is a low-abundant modification, and enrichment strategies are essential for identification of citrullinated proteins.
The primary aim of this thesis is the development of novel approaches for detection and quantification of citrullination in human plasma. These methods are described in Chapter 3, 4 and 5, and we utilize these approaches to assess plasma protein citrullination in cancer (Chapter 3), COVID-19 (Chapter 4 and 5) and iTTP (Chapter 6).

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