Getting to grips with autoimmunity
Why does the body attack itself? EU-funded researchers have discovered new details about how faults in a specific gene trigger such activity, increasing our understanding of the roots of autoimmune diseases like arthritis and lupus and raising hopes of finding new treatment approaches.
© Vercoulen, 2018
Our immune system normally keeps us healthy by getting rid of unwanted invaders such as bacteria and viruses. The main soldiers in this immune army are special cells known as T cells, which spot and destroy infectious agents. But sometimes they can turn on healthy cells, attacking and destroying normal tissues and causing inflammation and damage. This is known as autoimmune disease.
Hundreds of thousands of people in Europe are affected by autoimmune disorders such as arthritis, lupus and inflammatory bowel disease, and rates are rising. But there are few effective long-term treatments, and little is known about the underlying triggers that cause T cells to attack healthy tissue.
Thats where the EU-funded AUTOIMMUNITY RASGRP1 project comes in.
T cells are the bad guys in autoimmunity, says researcher Yvonne Vercoulen of project coordinator Universitair Medisch Centrum Utrecht in the Netherlands. So we wanted to know what happens inside a T cell when things go wrong and they turn on us.
To understand what happens during the development of autoimmune disease, Vercoulen has been studying a gene called RasGRP1, which is switched on in T cells to make a protein also called RasGRP1. This molecule plays an important role in sending signals within T cells, prompting them to attack infected cells while leaving healthy cells unharmed.
Changes in the RasGRP1 gene cause changes in the protein, making it work in a different way. Some alterations might make it more active, others will reduce its activity, and some will have no effect at all.
People from families affected by autoimmune disorders are known to have changes in their RasGRP1 genes that make the protein less active, so it isnt as effective at keeping T cells under control. But little was known about how specific changes affect the function of the protein, or how these variations might increase the risk of developing an autoimmune disease.
Vercoulen who received funding through the EUs Marie Skłodowska-Curie fellowship programme investigated the effect of small alterations in the DNA of the RasGRP1 gene, known as SNPs, on the function of the resulting protein. Initially she was studying human immune cells grown in the lab but then began to use new genetic engineering technology known as CRISPR to look at fresh T cells from human donors.
Vercoulen and her colleagues were able to look at the impact of each of these DNA changes on RasGRP1 and see how it affected the activity of T cells. They found that one specific genetic variation had a dramatic impact on how the RasGRP1 protein responds to changes in acidity.
When a T cell receives an activation signal, the interior of the cell becomes less acidic so the RasGRP1 protein changes shape and becomes active. Changing one particular region of the gene means that the protein no longer responds to the acidity change and is not activated. This work sheds important light on the biological processes underpinning T cell activation and increases our understanding of the roots of autoimmune disease.
From autoimmunity to cancer
Vercoulen and her team are now investigating ways of manipulating the levels of RasGRP1 activity in T cells, with the hope of finding new approaches for treating autoimmune diseases. They are also looking at the behaviour of RasGRP1 and T cells around cancer cells, which are often ignored by the immune system.
The findings of this project are still being used for follow-up research, says Vercoulen, pointing out that RasGRP1 is implicated in bowel cancer and leukaemia. The implications of our understanding of how RasGRP1 activity is regulated will be very relevant in the future for immune disease, as well as different types of cancer.