Some people just can’t help themselves. They wash their hands over and over, scrubbing their skin raw. Or they lock and relock doors, pull out their own hair, or obsessively rearrange the contents of their closet. Now, a study of mice suggests that faulty immune cells prompt such compulsive behaviors. The results raise the possibility of treating obsessive-compulsive disorder by targeting the immune system rather than the brain.
Mice are fastidious, regularly cleansing their bodies from nose to tail. But animals with a defective version of the gene Hoxb8 groom themselves so much that they tear out patches of fur and develop skin sores. The behavior resembles a type of obsessive-compulsive disorder called trichotillomania, in which people tug out their own hair.
The Hox family of genes is best known for helping to organize the embryo’s body, but Hoxb8 has several effects. The protein encoded by the gene functions in neural development, so mice lacking it have abnormal spinal cords and sensory ability, including pain sensitivity. This defect could in theory provoke the rodents to wash excessively, although molecular geneticist Mario Capecchi of the University of Utah School of Medicine in Salt Lake City and colleagues note that Hoxb8-lacking mice also obsessively groom other mice. That suggests that overcleaning is not a sensory problem but a behavioral one originating in the brain.
When Capecchi and colleagues began looking for the Hoxb8-making cells in the mouse brain, they expected to find that the source was neurons that control grooming. To their surprise, the only cells producing Hoxb8 were microglia, immune cells that guard against pathogens. Although some microglia start out in the brain, others are born in the bone marrow and move in. Overall, adult mice with faulty Hoxb8 harbored about 15% fewer microglia in the brain than normal.
To test whether defective microglia provoke mice to feats of extreme cleanliness, the researchers performed bone marrow transplants. Transferring marrow from Hoxb8-lacking mice into healthy rodents provoked compulsive grooming, the researchers report  in the 28 May issue of Cell. And when mice deficient in Hoxb8 received marrow from healthy animals, they cut back on their ablutions. Before this finding, “nobody would say you can cure a [pathological] behavior with a bone marrow transplant,” Capecchi says.
The sensory disruptions resulting from a lack of Hoxb8 don’t trigger abnormal grooming, the team concludes. When the researchers deleted Hoxb8 only from spinal cord cells, the animals displayed reduced sensitivity to pain, but they didn’t clean themselves to excess. By contrast, when the team removed Hoxb8 only from the blood-making cells that spawn microglia, the mice washed too much. Previous studies have implied a link between the immune system and obsessive-compulsive disorder and other neuropsychiatric conditions, Capecchi says. “Here, we say there is a direct connection.”
Now, the researchers are testing trichotillomania patients to determine whether they carry mutations in the Hoxb8 gene.
“This is important work,” says developmental biologist Jacqueline Deschamps of the Hubrecht Institute in Utrecht, the Netherlands. “The localization of a bone marrow origin of such a behavioral disturbance is a landmark.” To determine whether the results apply to humans, researchers should check for microglia in dissected brains from patients with obsessive-compulsive disorder, says neuroscientist Aye Mu Myint of Ludwig-Maximilians University in Munich, Germany.
Still, Capecchi says that even if the microglia link holds in humans, expensive and risky bone marrow transplants are a poor alternative for current obsessive-compulsive disorder treatments, which include behavioral therapy and drugs such as fluoxetine (Prozac). Developing drugs to alter microglia activity could be a better option.