Researchers from the University of Alabama at Birmingham have discovered that there is a distinct group of cells in the immune system that induces and perpetuates inflammation in the gut.
They believe that the cells, a type of effector CD4 T cell, could serve as targets for new treatments to relieve — or even cure — inflammatory bowel disease (IBD).
Their findings also raise the possibility that the cells could be behind other disorders in which the immune system attacks healthy tissue, such as rheumatoid arthritis and type 1 diabetes.
A study paper on their work has now been published in the Journal of Experimental Medicine.
"Our hope is," says senior study author Laurie E. Harrington, who is an associate professor of cell, developmental, and integrative biology, "if we could treat these cells, it could be curative."
Crohn's disease and ulcerative colitis
IBD is a long-term condition in which the gastrointestinal tract, or the gut, becomes inflamed from constantly being attacked by the immune system.
There are two main types of IBD: ulcerative colitis, in which mainly the colon becomes inflamed; and Crohn's disease, in which inflammation can occur anywhere in the gastrointestinal tract between the mouth and the anus.
Autoimmunity and inflammation
Although scientists know that IBD is an autoimmune disease caused by a faulty immune response, the exact nature of the cells involved and the mechanisms of action remain unclear.
A mammal's immune system contains a very wide variety and number of cells that communicate with each other in an intricate network of signals.
Under "normal" conditions, the immune system targets and eliminates pathogens, such as viruses and bacteria, that might harm the body before they get a chance to do so. And, when the pathogens are fully disposed of, the immune attacks cease.
But sometimes the process can go wrong and the immune system attacks the individual's own cells as if they are pathogens.
This type of response is called autoimmunity and can lead to lasting inflammation and disease. We have a lot to learn about how autoimmunity works at the cellular and molecular level.
Prof. Harrington and her colleagues note, for example, that while CD4 T cells "are causally linked to autoimmune and chronic inflammatory disorders," we don't know which cell features are involved.
Studies of IBD have revealed that CD4 T cells produce high levels of a signaling molecule called interferon-gamma in the inflamed gut, but they are inconclusive about the molecule's role.
CD4 T cells
Immune cells form in bone marrow from undifferentiated cells called stem cells, which can divide and mature into virtually any type of working immune cell. The stem cells also have the ability to keep dividing perpetually.
As they differentiate, stem cells pass through the progenitor cell stage. Progenitor cells are similar to stem cells since their fate is not yet fixed, but there is a limit on how many times they can divide.
Effector CD4 T cells are immature immune cells that started out as stem cells but have paused at the progenitor stage. They can differentiate into several types of working immune cells. One of these is the T helper cell, which has been linked to IBD.
Using a mouse model of colitis, Prof. Harrington and her team identified a "discrete population of effector CD4 T cells that is able to both sustain and confer intestinal inflammation."
When the scientists transplanted them into healthy mice, the cells triggered and perpetuated the inflammatory condition.
Stem cell features
When the researchers analyzed the genetic signature of the effector CD4 T cells that caused colitis, they found that it had some stem cell features. The signature was "consistent with" self-renewal and the ability to escape a type of programmed cell death known as apoptosis.
The scientists also found that, like stem cells, the effector CD4 T cells were continually replenishing "interferon-gamma-producing cells in the inflamed intestine."
A final set of experiments identified an enzyme called glycosyltransferase that seems to switch on these stem cell features in the effector CD4 T cells.
"We think these cells could be in a number of auto-inflammatory diseases."
Prof. Laurie E. Harrington