White blood cells are at the front line when it comes to protecting the body against attack. These immune-system cells can seek out and destroy invading microbes, but they are also a cause of disease when things go wrong.
The immune system goes awry in diseases such as rheumatoid arthritis and inflammatory bowel syndrome, when immune cells attack healthy tissue, causing the pain and inflammation associated with these disorders.
Much effort goes into understanding each step in the cascade of events that takes place when the immune system comes into play, and researchers at Trinity College in Dublin and the Royal College of Surgeons believe they have discovered a key component of this complex jigsaw puzzle.
The finding, by Professor Dermot Kelleher, Dr Yuri Volkov and colleagues in the department of Clinical Medicine TCD, and Dr Aideen Long at the RCSI, was important enough to make the cover of the June issue of Nature Immunology. The Health Research Board, Enterprise Ireland and the Wellcome Trust funded the research.
"The paper is about white blood cells and how they move to sites of inflammation, either to combat infection or when it is a case of arthritis," explains Kelleher. "We think we have identified a critical enzyme that makes them move."
When cells are damaged through injury or infection, they release substances that trigger an immune response. White cells respond by leaving nearby blood vessels and migrating to the injury. They squeeze between healthy cells to accomplish this, but researchers have an imperfect understanding of the complex biochemistry needed to do this.
It was known that a substance on the surface of the cell, called LFA-1, was central to the process that enabled white-cell migration. Signalling chemicals on the blood vessels activate LFA-1, which in turn attracts and assembles a complex of other molecules essential to allow white-blood-cell movement.
Included in this complex is an enzyme, PKC-Beta (1); the team discovered cell migration can't occur without it, and found an ingenious way to prove the importance of PKC-Beta (1) using genetic technologies.
They developed a white blood cell that did not produce the enzyme, then attempted to initiate an immune response by activating LFA-1. "That cell couldn't move," explains Kelleher.
The team then reinserted the gene, coupled to a jellyfish gene that expresses a green fluorescent protein, into the cells to see what change occurred. When PKC-Beta (1) was produced, the cell was able to move as normal.
The green protein was also expressed, and this marked out the engineered cells, making them easier to track. Volkov, who came to the Republic from the Institute of Immunology in Moscow, developed the essential expertise to reinsert the missing DNA in the white blood cells.
Understanding the importance of LFA-1 and PKC-Beta (1) gives drug researchers new opportunities in combating debilitating illnesses such as arthritis, says Kelleher. "If you are able to stop that event or some of the events it activates inside the cell then you could have a novel anti-inflammatory drug."
The greatest potential for new drug treatments is when targeting the events that follow PKC-Beta (1) activation, because PKC-Beta (1) is produced in many tissues, and blocking its action may have too powerful an effect, he adds.
There is now much discussion about whether PKC-Beta (1) represents the immune system's ignition or is just a spark plug, a key part of a wider system. "I'd say it is the spark plug: it is what lights the fuse and makes things come together," says Kelleher.