A single gene mutation causes some immune system cells to shut down at body temperature and sends others into overdrive in the cold, creating a mix of ailments that researchers say constitutes a new medical syndrome.
The discovery helps explain a mysterious set of symptoms that doctors didn’t realize were linked until a chance encounter between an allergist at the National Institutes of Health and a patient with a disfiguring rash running from head to toe. The study was published Wednesday in the New England Journal of Medicine.
The patient was also highly sensitive to cold, which he overlooked since it ran in his family. A genetic link to the potentially deadly condition known as cold urticaria had never before been shown, said Joshua Milner, chief of the allergic inflammation unit at the National Institutes of Allergy and Infectious Diseases. Tests on his family members and others with the condition uncovered a variety of ailments, including autoimmune disease and antibody deficiency.
“Every single person had the cold sensitivity, but the other symptoms were variable and overlooked,” Milner said in a telephone interview. “One person was literally getting gamma globulin,” infusions of a protein that is found in the blood and includes antibodies to fight infection, he said.
Discussions with investigators around the nation yielded two unrelated families with similar symptoms, including a wayward immune response against their own tissue and a dearth of the infection-fighting antibodies needed to stay healthy.
Further investigation on 27 family members allowed scientists to find the cause: deletions in a single gene known as PLCG2 that’s involved in switching immune system cells off and on.
“Investigating rare diseases gives researchers more clues about how the healthy immune system functions,” said Anthony Fauci, director of the NIAID, in a statement. “More importantly, identifying the genetic cause of these disorders opens up possibilities for better disease management and potentially a cure for people who may have spent their entire lives debilitated by severe and unexplained symptoms.”
The investigation was conducted by researchers at the U.S. National Institutes of Health in Bethesda, Md., University College London, Rady Children’s Hospital of San Diego and Yale University School of Medicine in New Haven, Conn.
One of the most intriguing findings was the significance of the gene deletion, which caused an enzyme responsible for activating immune system cells to be constantly left on. The over-stimulated immune system B cells appeared to shut down in response, failing to make all the antibodies needed to fight infection, Milner said.
“When something is on all the time, the result is to shut it down,” he said. “The enzyme is doing its job, but the cell says forget it and becomes unresponsive. It’s stunned.”
Once the cells are cooled down below body temperature, however, other immune defenses, known as mast cells, turned on without stimulation, he said.
“I don’t believe there is anything similar in the world of genetic disease when something is turned off abnormally at body temperature and is turned on abnormally in the cold,” Milner said. “It’s kind of wild to say the least. Somehow, this remarkable little tiny deletion renders a profound sensitivity to different temperatures.”
In these families, the mutation occurred a few generations back, Milner said. The researchers believe it may develop somewhat easily, and speculate that other people may have related conditions.
Several experimental drugs in development to treat cancer inhibit the pathway used by the gene, Milner said. It may be possible to block the signal so the mutated gene isn’t turned on all the time, allowing the remaining gene to work properly, he said. The researchers are pursuing the approach, he said.
“While these families appear to be relatively rare, the findings are potentially applicable to a broad patient population,” including patients with antibody problems, autoimmunity, and a rash known as granuloma, he said.