The exposome as a driver of immune dysreglation in rheumatoid arthritis (360G-Wellcome-206899_Z_17_Z)

Polymorphisms in genes contribute about 50% of the risk for developing RA with the other half coming from factors such as diet, age, infection, traffic pollution and cigarette smoke. This may also be true of other chronic conditions such as Alzheimer's disease. In RA population studies show a potential interaction between cigarette smoke and PTPN 22, which has a polymorphic variant which increases susceptibility to RA and a broad range of other autoimmune chronic diseases. I will test the hypothesis that chemicals in cigarette smoke and traffic fumes (NO2) alter the function of PTPN 22 in leucocytes changing signalling through antigen receptors and perturbing the outcome of their activation to give rise to a pro-inflammatory phenotype which drives the development and perpetuation of RA. I will expose cell lines Jurkat (lymphocyte) and THP1 (macrophage) to cigarette smoke extract and to NO2. PTP's such as PTPN 22 are particularly susceptible to oxidative damage and I will assess the phosphatase activity of this enzyme, the phosphorylation of protein substrates it regulates and calcium signalling downstream. If time allows I will also expose primary neutrophils and T lymphocytes and investigate their functions in terms of reactive oxygen species generation and cytokine secretion.