Regulation of antibody production by the MSK-CREB pathway

The production of antibodies is a critical component of the response to infection and for effective vaccination responses. It must however be carefully controlled as the unwanted production of antibodies that react with self-components results in the development of autoimmune diseases. Antibodies are produced by B cells and each B cell has the potential to produce an antibody against a specific antigen. Antibody production is a complex process requiring several steps. First, antigen must be recognised by a naïve B cell. Following this, the B cells will proliferate and change the type of antibody class (or isotype) they produce to tailor it to the type of antigen or infection. At the same time they will increase the affinity of the antibody for the antigen. This is achieved via two processes; class switch recombination (CSR), which changes the isotype produced, and somatic recombination, which allows the generation of high affinity antibodies to the antigen. Defects in these processes have been identified in pathologies such as Common Variable Immune Deficiency. Understanding the molecular mechanism of CSR could also potentially contribute to the creation of better vaccines via boosting antigen specific antibody production. This project will look at how intracellular signalling mechanisms control this process. Specifically it will focus of on two enzymes, MSK1/2, that we have found in preliminary studies to play an important role in CSR. To further investigate the importance of these enzymes, in the project we will focus on MSK1/2 and their transcription factor substrate CREB, as well as the upstream pathways that activate them. Knockout mice for MSK1/2 and S133A knockin mice for CREB will be utilized for both in vivo and ex vivo studies of CSR and somatic hypermutation. The project will make use of a combination of in vivo studies to look a response to immunisation and proteomics to look at the changes in proteins with in the cell. Training will therefore be provided in vivo physiology as well as mass spectrometry and the bioinformatics analysis of the results.

Questions:

1.Explain interdisciplinary interface: Analysis of proteomic data will require both bioinformatic skills as well as knowledge of basic biology.

2.Does project require significant amount of quantitative skills? YES

3.Does project require significant amount of whole organism physiology skills? YES