Crohn's blamed on lazy immune cells

A MYSTERIOUS bowel disease thought to be caused by an over-exuberant immune system may paradoxically be triggered by immune cells that don't do enough in the early stages of bacterial infection.

Since some treatments for Crohn's disease aim to suppress the immune system, it's possible these drugs could be making things worse. The discovery by Anthony Segal of University College London and his colleagues is causing a stir among immunologists. Caetano Reis e Sousa at Cancer Research UK calls it "provocative", while Jean-Laurent Casanova at The Rockefeller University in New York says it is "a major breakthrough".

A similar mechanism may be at the root of a host of other "autoimmune" disorders, in which immune cells turn on the body's own tissue. Underactive immune cells could also explain why some of us are more prone to infectious diseases.

About 1 in 1000 people in the US and Europe have Crohn's. Symptoms include swollen, painful intestines and diarrhoea. Inflamed sections of gut often have to be surgically removed.

Segal and his colleagues got their first clue when they noticed a weaker immune response in people with Crohn's than in healthy people after both groups were injected with heat-killed Escherichia coli. The team reasoned that this lukewarm response might allow an infection to build up and eventually trigger a debilitating secondary immune response, resulting in Crohn's.

If this is the case, though, why does Crohn's only manifest itself in the intestine? After further experiments it became clear that the immune weakness only revealed itself when large numbers of killed E. coli were injected. As the bowel is one of the few places in the body where bacteria exist in huge numbers, Segal concluded that this is where the weakened immune response has its biggest impact. "It's only in the bowel that you routinely get massive loads of bacteria - and if these breach the intestinal wall it will cause an infection."

It still wasn't clear, however, what caused the weakened immunity in the first place. So Segal's team focused on cells called macrophages, the immune system's whistle-blowers. In people with Crohn's disease, they found that macrophages secrete lower levels of cytokines, the chemicals that rally other immune cells to infection sites (Journal of Experimental Medicine, DOI: 10.1084/jem.20091683).

The team concluded that ineffectual rallying of immune cells in people with defective macrophages is what allows intestinal bacteria to run amok in the early stages of an infection, setting in motion the series of events that leads to Crohn's disease.


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