A protein that helps keep immune system cells from mistakenly swallowing and destroying healthy cells has been linked to an inherited disorder with symptoms similar to severe food poisoning, according to researchers at the School of Medicine and the University of Newcastle in the United Kingdom.
The results make it possible to genetically screen patients for one form of atypical hemolytic uremic syndrome (atypical HUS), a rare but potentially life-threatening condition linked to excessive blood clots and kidney failure.
Normal HUS, often in the headlines because of food-related outbreaks, is caused by consumption of a toxic form of the bacteria E. coli and includes an additional symptom: bloody diarrhea.
“Based on what we’ve discovered, atypical HUS patients would be susceptible to more damage anytime they have tissue injury,” said John Atkinson, M.D., the Samuel Grant Professor of Medicine. “In a heart attack, for example, these people might get 20 percent to 30 percent more tissue damage. There are new drugs coming on the market that may help us limit this damage.”
The new study, published in the Oct. 17 edition of the Proceedings of the National Academy of the Sciences, links atypical HUS to membrane cofactor protein (MCP), which researchers in Atkinson’s laboratory discovered in 1985.
“In most situations, when you find a new protein, you just genetically disable or remove the protein in the mouse,” Atkinson said. “That can’t be done here because in the mouse, this protein is only expressed on the head of sperm, while in humans it’s found throughout the body. So we didn’t have a model to look at and were trying to find the first human deficiencies of this, not knowing where or how to look.”
The answer came from Timothy Goodship, M.D., a nephrologist at the University of Newcastle. Goodship’s group was studying a registry of families in which more than one member had atypical HUS, and had learned that mutations in three families were linked to an area in human DNA where Atkinson’s group had found the gene for MCP.
“It turned out that a mutation in two of the families was a mutation that we’d already made trying to figure out how the protein worked,” Atkinson said. “So in a matter of minutes I knew that these were likely not to be just the random genetic variations that we all have.”
Atkinson and Goodship put together a theory about what happens in atypical HUS and developed recommendations for clinicians.
From Atkinson’s research, they knew that MCP deactivates C3, a protein that coats cells to make it easier for immune system cells known as macrophages to operate. Invading cells lack MCP and therefore do not have this protection, so the macrophages swallow and destroy them.
Atkinson compares MCP’s role to that of a sentry protecting the castle (a healthy cell) from excessive damage.
“This is a way of protecting self from being damaged too much at an inflammatory site or at an infection site,” Atkinson said. “You’re going to let some damage occur to get over the infection or injury, but you’d like to minimize that damage.”
In atypical HUS, MCP either is missing or is present in levels too low to prevent collateral damage from immune system responses. This doesn’t present a problem until a patient’s immune system is sufficiently provoked by an infection or an injury.
“The bloodstream and, for some reason, the kidney take the brunt of the out-of-control immune response,” Atkinson said.
Kidney transplants, which provide patients with kidney cells with normal MCP levels, have in some cases relieved the most life-threatening symptoms of atypical HUS. Patients with the condition may be treatable with new drugs currently in development that block excessive inflammation just as MCP does.
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