Can diet influence immune tolerance?

The Mackay lab has a model of B cell immune tolerance, known as SWHEL. The SWHEL model is a cross between mice with B cells that express a B cell receptor (BCR) specific for the experimental antigen Hen Egg Lysozyme (HEL), and mice that express membrane HEL. In the resulting offspring, the HEL becomes the self-antigen and developing SWHEL B cells in the bone marrow are self-reactive B cells. The resulting SWHEL B cells are eliminated in the bone marrow through a process of negative selection in response to their BCR binding HEL. These SWHEL mice can be crossed with mice expressing a soluble version of HEL, secreted in the blood. In the resulting offspring, the self-antigen is circulating and binding of the SWHEL BCR to soluble HEL is not as strong. With a weaker SWHEL BCR interaction to soluble HEL, SWHEL self-reactive B cells can survive in the bone marrow but are negatively selected in the periphery or are anergised (neutralised and unable to be activated by HEL). This project will explore the following hypothesis: can diet (eg. high fat) prevent negative selection and therefore promote autoimmunity? To explore this, the above two models of B cell tolerance described will be fed with various diets and the impact of diet on the emergence of self-reactive B cells and their activation status will be investigated.

The aims of this project are to: • Determine whether diet can affect the emergence of self-reactive B cells. • Explore whether diet can interfere with negative selection and promote autoimmunity. • Dissect molecular mechanisms of immune tolerance affected by dietary intervention for the purpose of developing novel therapies promoting immune tolerance. The work involves animal models, flow cytometry, ELISA, histology and a number of omics methods.

No research group to date has explored the role of diet in this model. This approach is very novel, and as a recent review in Science suggests could lead to alternative therapeutic approaches for autoimmune diseases with huge clinical impact.