Molecule Key to Joint Inflammation Identified, May Lead to Improved Arthritis Treatments

Researchers have identified a factor that controls immune cells’ entry into joints, which leads to arthritis in diseases such as systemic lupus erythematosus (SLE). Though they are studying other factors in the process, they believe these findings could lead to new treatments that are more effective in preventing arthritis.

“Inflammatory arthritis is caused when immune cells are recruited from the blood into the joint in a highly regulated process controlled by chemoattractants and adhesion receptors,” said Andrew Luster, MD, PhD, senior investigator of the study, “Complement C5a receptor is the key initiator of neutrophil adhesion igniting immune complex–induced arthritis.” It was published in the journal Science Immunology.

“When the disease has become symptomatic, it is difficult to determine the initial steps that set off the recruitment of immune cells into the joint and the specific roles of the different chemoattractants. Our study was designed to more fully understand this process,” Luster said in a press release.

Joint inflammation and arthritis result from a chain of events set off by antibodies binding to structures in the joint. The reaction is known as type III hypersensitivity, and an earlier step involves immune cells — called neutrophils — migrating into the joints. Researchers believe binding antibodies triggers the release of cytokines, which are immune mediators sent out to recruit neutrophils.

To better understand the recruitment process, the research team at Massachusetts General Hospital Center for Immunology and Inflammatory Diseases used an imaging technique, called multiphoton intravital microscopy, to follow the real-time development of arthritis in a mouse model.

They discovered that once antibodies bind inside the joint, a molecule called complement C5a is needed for neutrophils to adhere to joint surfaces and migrate into the joint. C5a, an innate immune system component, was first seen inside the joint, then on the inner walls of nearby blood vessels. In that position, the molecule can directly interact with neutrophils, which carry a C5a receptor, allowing the cells to pass from the bloodstream into the joint. The process is “known to set off the inflammatory cascade,” the release said.

Once the neutrophils have entered the joint, immune molecules, such as interleukin-1 (IL-1), are generated to attract more immune cells to the site. There are medications that prevent IL-1 signaling, but they do not target the process’ earliest step.

“The control of immune cell entry into the joint represents a major point at which new therapies could be developed to reduce the symptoms of inflammatory arthritis,” said Luster, who is also chief of the hospital’s Division of Rheumatology, Allergy and Immunology and the Harrison Professor of Medicine at Harvard Medical School.

“Imaging of the joint could help evaluate the mechanism of a drug’s therapeutic effect, and if a process turns out to be mediated by more than one chemoattractant, understanding the mechanism would allow the rational design of combination therapies to completely shut down critical steps in the process.”

The team hopes to continue studying the process, analyzing whether other molecules interact with C5a to help transport it from the joint into blood vessels. They also plan to track the movement of other immune cell types, such as T-cells and B-cells, which are involved in the process’ later stages.