Molecular properties of neutrophil extracellular traps (NETs) in rheumatoid arthritis (360G-Wellcome-200605_Z_16_Z)

Neutrophil extracellular traps (NETs) are nuclear chromatin structures covered in anti-microbial proteins that catch and kill pathogens. They are released from neutrophils in response to infection and represent an important and novel defense mechanism. The exposure of proteins and DNA within NETs can also trigger auto-immune responses, e.g. in systemic lupus erythematosis (SLE), where auto-antibodies to double-stranded DNA and cytoplasmic proteins contribute to disease pathology. Emerging evidence in rheumatoid arthritis (RA) suggests that NETs expose citrullinated neoepitopes (e.g. histones), and this may cause a loss of immune tolerance and development of antibodies to citrullinated proteins (ACPA), a hallmark of severe RA. This pilot study will test my novel hypothesis that NETs exposed by neutrophils from SLE and RA patients contain different proteins, thereby exposing different auto-antigens to the immune system. A series of proof-of-principle experiments will carry out comprehensive, quantitative analysis of the proteins decorating SLE and RA NETs, using immunofluorescence and quantitative proteomics. These experiments will provide the first insights into molecular properties of NET material in SLE and RA, and will allow me to generate a new hypothesis on the contribution of NETs to the development of auto-antibodies in these two diseases for an independent fellowship application.