Menu
Menu
MS is caused by destruction of the myelin sheath, the insulating material that wraps around nerves and conducts nerve impulses. Destruction occurs when the immune system mistakenly recognises myelin as a foreign invader and inappropriately mounts an immune response.
How the immune system works out whether a molecule is foreign, or part of our own body, is determined by a series of screening events in the body. One of the first steps is for immune cells to digest the molecule into small fragments, and then present them to the rest of the immune system using molecular “arms” holding them out from the cell. This helps the immune system to recognise and decide how to respond to a particular molecule.
One set of “arms” is a group of molecules called HLA-DR15. The exact molecular structure of HLA-DR15 differs between people, and might help determine if, and how, the immune system is activated to respond to particular molecules. For example, it might help the immune system decide whether to ignore or attack myelin. The structure of HLA-DR15 is determined by genetics, and interestingly, up to 60% of the genetic risk of developing MS is carried in our HLA-DR15 genes. Therefore, understanding the structure of the HLA-DR15 molecule, and how it interacts with other cells of the immune system could be key to understanding the mistaken immune response in MS.
The aim of this project is to better understand how HLADR15 presents self-proteins (such as proteins in the brain) to the immune system, compared to how it presents bacterial proteins. Dr Reid will begin determining the structure of HLADR15 when it binds these proteins, and the appropriate sensor molecule on the immune cells recognising them (known as the T cell receptor). This may pave the way for developing therapies that prevent or change the recognition of self, thus circumventing the immune attack on the myelin sheath.
In completing this study, Associate Professor Reid and his team generated a T cell receptor that recognises the HLA-DR15 protein when it was combined with RASCGRP2, a protein made naturally in our bodies. The interaction between HLA-DR15 and RASCGRP2 initially triggers the activation of T cells (a type of immune cell) that cause the inflammation at sites of disease in the brain and spinal cord of people living with MS. Associate Professor Reid and his team showed that this protein interaction is relatively weak, which is often the case in autoimmune responses.
The study also determined the 3D structure of the T cell receptor. Work is underway to determine the 3D structure of the T cell receptor when it is bound to the combined HLA-DR15 and RASCGRP2 proteins. Understanding how the T cell receptor interacts with these two combined proteins could lead to strategies for disrupting this interaction. Disrupting this interaction may stop T cell activation, which may prevent inflammation and tissue damage in the brain and spinal cord of people with MS.
Updated 31 March 2024
$25,000
2022
1 year
Past project
