The immune system’s key role in cardiovascular disease: Leiden researchers explore what happens inside artery walls
Cardiovascular diseases
How can we keep our hearts and blood vessels healthy? To mark World Heart Day, researchers in Leiden explain how the immune system affects atherosclerosis. By uncovering what happens in artery walls, they hope to identify people at increased risk sooner and provide more targeted treatment.
‘A long time ago, we thought there was just one type of immune cell in artery walls affected by atherosclerosis, and that was it,’ Professor Ilze Bot says. ‘But it is nowhere near that simple.’ Researchers are finding more and more types of immune cells in affected artery walls. Some increase inflammation, while others help to reduce it.
Atherosclerosis is therefore not simply a passive build-up of fat. Our immune system also helps determine whether a thickened area in an artery remains stable for years or becomes fragile and eventually ruptures. If it ruptures, it can lead to a heart attack or stroke.
What is atherosclerosis?
Atherosclerosis develops when fatty particles build up in the inner wall of an artery. The body responds with inflammation, gradually creating a thickened area known as a plaque.
A plaque will usually remain stable for years. But if it ruptures, the body forms a blood clot to repair the damage. This clot can block an artery and cause a heart attack or stroke.
Ilze Bot, Amanda Foks and Laura Bosmans from the Leiden Academic Centre for Drug Research (LACDR) each study a different part of the immune system. Bot focuses mainly on mast cells, Foks studies how the immune system ages, and Bosmans examines dendritic cells, which direct other immune cells. Together, the three researchers are revealing more and more pieces of the same complex puzzle.
Why does a thickened area in an artery become unstable?
Bot has been studying mast cells for around twenty years. These immune cells are best known for their role in allergies and asthma, but they are also found in artery walls affected by atherosclerosis. They appear to be especially important in fragile areas.
‘Intervening in the immune system is not easy. You want to inhibit the harmful reaction in the artery wall, but without reducing the body’s defences against, for example, a virus.’
‘There are not very many mast cells,’ Bot says. ‘Even so, they can have a major effect. We see this in allergic reactions, for example, where mast cells play an important role.’ Mast cells can release substances that increase inflammation and make the artery wall more fragile. Bot and her colleagues are studying which signals activate these cells and how their activity could be reduced.
This has to be done very precisely. ‘It is not easy to intervene in the immune system,’ Bot says. ‘You want to reduce the harmful response in the artery wall without suddenly making someone less able to fight off a virus, for example.’
What happens to our immune system as we age?
The risk of a heart attack or stroke increases as we get older. However, researchers still do not know exactly how the immune system changes during the ageing process.
Amanda Foks studies age-associated B cells, among other things. She and her colleagues found these immune cells in the blood and affected artery walls of people with cardiovascular disease.
People with relatively high levels of these immune cells in their blood also appear to be at greater risk of having a first heart attack. This makes the cells interesting as a potential biomarker: a measurable sign that could help identify people at increased risk sooner. Her team is also investigating whether it is possible to target these cells and reduce their activity to slow the progression of atherosclerosis.
People with relatively high levels of age-related B cells in their blood appear to be at greater risk of a first heart attack.
Could we use the immune system as part of the treatment?
If immune cells contribute to atherosclerosis, they may also be part of the solution. Laura Bosmans is investigating the important role that dendritic cells may play. These cells act like traffic controllers for the immune system, directing other immune cells. They do this through what are known as immune checkpoints: molecular switches that can either increase or reduce inflammation.
Bosmans is studying the role this communication plays in atherosclerosis and whether harmful inflammation can be reduced selectively. This is important because suppressing the immune system more broadly can cause side effects. The challenge is to target only the harmful process in the artery wall.
The researchers are also looking for possible differences between men and women. A particular type of immune cell may be more important in one group than in the other. This could affect future treatments.
Earlier detection and more targeted treatment
New techniques are providing an increasingly detailed picture of which cells are present in different parts of the artery wall and how they affect one another. This makes the overall picture more complex, but it also helps researchers identify which interactions cause damage and where treatment could intervene.
Mast cells, age-associated B cells and dendritic cells: Bot, Foks and Bosmans are each tackling a different part of the same puzzle. Their research will not produce a new medicine tomorrow, but it could lay the foundations for new medicines and biomarkers.
The goal is clear: to identify people at increased risk sooner and tailor treatment more closely to what is happening in their artery walls. ‘Many people currently receive the same medication, even though that may not always be the best approach,’ Bot says. ‘Ultimately, the goal is personalised treatment.’