The role of lyp phosphatase in primary human macrophages AND cRel and its effect on class switch recombination, IRF4 induction and plasma cell differentiation during a T-independent immune response

Cawkwell, Lewis Blair (2013). The role of lyp phosphatase in primary human macrophages AND cRel and its effect on class switch recombination, IRF4 induction and plasma cell differentiation during a T-independent immune response. University of Birmingham. M.Res.

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Abstract

Project one: PTPN22 encodes the protein tyrosine phosphatase Lyp, a negative regulator of TCR signalling by dephosphorylation of Src family kinases. The C1858T substitution mutation in PTPN22 is associated with increased risk of autoimmune diseases. This project looked at the role of Lyp in primary human macrophages by using a competitive reversible inhibitor of Lyp protein activity. Lyp was found to be a negative regulator of reactive oxygen species production. Primary macrophages heterozygous for C1858T variant produced higher levels of pro-inflammatory cytokines. These novel findings provide insight into how C1858T is associated with inflammatory disease such as rheumatoid arthritis.
Project two: The NP-Ficoll immune response is a T-independent reaction, which results in significant extrafollicular foci formation. The NFκB member, cRel, is important in activated B cell proliferation, survival and also in class switch recombination (CSR) and IRF4 induction in vitro. IRF4 is essential in plasma cell differentiation as well as CSR. We found that after NP-Ficoll immunisation of mice, cRel -/- (KO) B cells produce far less plasma cells. Despite this, these cells did not exhibit defects in IRF4 induction or CSR. Therefore, B cell-intrinsic cRel loss still allows in vivo CSR, but cells appear not to proliferate and/or survive, resulting in a poor antibody response.

Type of Work:

Thesis (Masters by Research > M.Res.)

Award Type:

Masters by Research > M.Res.

Supervisor(s):