Our gut, like that of most mammals, is filled with thousands of species of bacteria, many of which are helpful and aid in the development of a normal, healthy immune system. Gut-residing bacteria can also play a role in disorders of the immune system, especially autoimmune disorders in which the body attacks its own cells.
Diane Mathis and Christophe Benoist
It turns out that rheumatoid arthritis is one such disorder. Researchers in the laboratories of Christophe Benoist and Diane Mathis at Harvard Medical School and Dan Littman at New York University made this discovery while working in mice prone to arthritis.
“In the absence of all bacteria, these mice didn’t develop arthritis, but the introduction of a single bacterium was enough to jump-start the immune process that leads to development of the disease,” says Mathis, an HMS professor of pathology.
The findings appear in the June 25 issue of the journal Immunity.
The researchers began by raising arthritis-prone mice in a germ-free environment. The mice had much lower levels of arthritis-causing autoantibodies than mice raised in a non-germ-free facility. The germ-free mice also showed strong attenuation in the onset and severity of clinical arthritis.
At three weeks of age, some mice were transferred to a non-germ-free facility and the researchers introduced segmented filamentous bacteria into their systems. When they introduced this normally-occurring bacteria into the mice, the animals rapidly began producing autoantibodies and developed arthritis within four days.
First author Hsin-Jung Wu emphasizes that these bacteria do not cause the mice to “catch” arthritis. “It’s more that they have the genetic susceptibility, and this bacterium creates an environment that allows this genetic susceptibility to play out,” says Wu, a postdoctoral researcher at Harvard Medical School. “It’s an interaction between genetics and the environment.”
The team mapped out the complex chain of events leading to arthritis. The segmented filamentous bacteria cause the animals to produce more of a particular subset of T cells. The immune system reacts to the activity of the T cells as if to a foreign threat and produces autoantibodies that trigger the devastating disease.
One surprising finding was that bacteria in the gut could influence the development of an autoimmune disease affecting tissues distant from the gut. Diseases such as irritable bowel syndrome have been linked to gut-residing bacteria, but this study is unique in showing the mechanism by which a bacterium in the gut can influence the development of an autoimmune response that ends in inflammation and pain in the joints.
The team will continue to use this mouse model of arthritis to answer questions about the link between the disease and autoimmune response. Next, they plan on tackling the molecular explanation of how these bacteria promote the development of this particular subset of T cells and to explore connections with other autoimmune diseases, in particular type-1 diabetes.
This research was funded by the National Institutes of Health.
Written by Mary Bates
Immunity 32, 1-13, June 25, 2010
“Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells”
Hsin-Jung Wu, PhD (a,b); Ivaylo I. Ivanov, PhD (c); Jaime Darce, PhD (a,b); Kimie Hattori, (a,b); Tatsuichiro Shima, (e); Yoshinori Umesaki, (e); Dan R. Littman, MD, PhD (c,d); Christophe Benoist, MD, PhD (a,b,f); and Diane Mathis, PhD (a,b,f)
HARVARD MEDICAL SCHOOL CONTACT:
Harvard Medical School has more than 7,500 full-time faculty working in 11 academic departments located at the School’s Boston campus or in one of 47 hospital-based clinical departments at 17 Harvard-affiliated teaching hospitals and research institutes. Those affiliates include Beth Israel Deaconess Medical Center, Brigham and Women’s Hospital, Cambridge Health Alliance, Children’s Hospital Boston, Dana-Farber Cancer Institute, Forsyth Institute, Harvard Pilgrim Health Care, Hebrew SeniorLife, Joslin Diabetes Center, Judge Baker Children’s Center, Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital, McLean Hospital, Mount Auburn Hospital, Schepens Eye Research Institute, Spaulding Rehabilitation Hospital, and VA Boston Healthcare System.