Research

REGULATION OF NEUTROPHIL GENE EXPRESSION IN INFLAMMATORY DISEASE & AGEING

Neutrophils are a type of white blood cell that normally protects us from infections. However, in inflammatory diseases such as rheumatoid arthritis (RA), neutrophils become activated and this results in chronic inflammation. The destructive molecules that neutrophils possess to kill bacteria instead attack healthy tissues and this leads to severe damage to joints, the hallmark of uncontrolled RA. No-one fully understands how these cells become activated in disease or the full clinical consequences of this activation. Furthermore, some patients respond very well to certain types of drugs (called biologics) but others do not. The reasons for this are unknown. One possible explanation for the variation in response to drugs may be that there are different ways to switch neutrophils on in RA. Alternatively, it is possible that genes of different patients dictate how effectively they respond to different types of treatments.

My research is trying to answer a number of questions:-

1) How are neutrophils switched on in RA, and which genes become 'activated'?

2) How are these genes switched off during successful treatment?

3) Are the same genes switched off when patients are successfully treated with different types of drugs?

REGULATION OF NEUTROPHIL EXTRACELLULAR TRAP FORMATION

Neutrophil extracellular traps (NETs) kill pathogens via the release of DNA and anti-microbial molecules (enzymes) in an extracellular mesh or “net”. NET release represents a novel form of cell death (NETosis) that can be induced by inflammatory agents (LPS, TNFα, IFNα) and micro-organisms. NETs may be a source of autoantigens in autoimmune diseases such as systemic lupus erythematosus (SLE) and RA where they contribute to the mis-direction of the immune system causing it to attack tissues in the body leading organ damage and nephritis. NETs cause the development of auto-antibodies that are a hallmark of RA and SLE. This new evidence creates new avenues for understanding the role of neutrophils inSLE and RA. Serum autoantibody profiles in SLE and RA are different: the former typically have high titres of "anti-dsDNA" and/or "anti-ANA", while the latter have high "ACPA". This suggests that either the molecular properties of NETs produced in SLE and RA are different and expose distinct autoantigens, or the host immune response to NETs in SLE and RA is different.

NEUTROPHIL METABOLOMICS

Neutrophils are phagocytic innate immune cells that play essential roles in host defence, but are also implicated in inflammatory diseases such as rheumatoid arthritis (RA) where they contribute to systemic inflammation and joint damage. We already know that gene expression in inflammatory neutrophils is different from that in healthy neutrophils. We are now discovering that metabolism - the process that all cells use to generate energy - is also different in inflammatory neutrophils compared to healthy neutrophils. Inflammatory neutrophils have higher rates of metabolism, in particular in a pathway that breaks down sugars to cause inflammation. We believe overactive neutrophil metabolism may be a new target for medical therapy.