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.

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Countries
Countries
  Algeria
  Argentina
  Australia
  Austria
  Bangladesh
  Belarus
  Belgium
  Benin
  Bolivia
  Brazil
  Bulgaria
  Burkina Faso
  Cambodia
  Cameroon
  Canada
  Cape Verde
  Chile
  China
  Colombia
  Costa Rica
  Croatia
  Cyprus
  Czech Republic
  Denmark
  Ecuador
  Egypt
  Estonia
  Ethiopia
  Faroe Islands
  Finland
  France
  French Polynesia
  Georgia


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Published: 20 June 2018  
Related theme(s) and subtheme(s)
Health & life sciencesMedical research
Human resources & mobilityMarie Curie Actions
Research policySeventh Framework Programme
Countries involved in the project described in the article
Netherlands
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Getting to grips with autoimmunity

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© 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.

That’s 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.”

Revealing research

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 isn’t 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 EU’s 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.”

Project details

  • Project acronym: AUTOIMMUNITY RASGRP1
  • Participants: Netherlands (Coordinator)
  • Project number: 328666
  • Total costs: € 259 745
  • EU contribution: € 259 745
  • Duration: September 2009 to January 2015

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