Spotlight on Research 2016

August 2016

Immune Cellís Role in Rheumatoid Arthritis-Induced Bone Loss Revealed

Investigators supported in part by the NIHís National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) have uncovered a mechanism by which B cells, the antibody-producing cells of the immune system, contribute to bone degradation in rheumatoid arthritis (RA). The study showed that B cells produce a molecule called RANKL, which stimulates the generation of bone-destroying cells called osteoclasts. The findings, which were reported in Arthritis and Rheumatology, suggest that targeting B cells and the RANKL pathway could be an effective strategy for preserving bone in people with the disease.

RA is an autoimmune disorder in which the immune system, which normally protects the body, mistakenly attacks the joints, creating inflammation and pain. If unchecked, the disease can erode the cartilage and bone in the joint, resulting in reduced mobility and impaired quality of life. There is no cure for RA, but medicines that dampen inflammation help ease the discomfort and reduce joint damage. Joint replacement surgery is also an option in severe cases.

Microscope image of the joint tissue from RA patient.

Joint tissue from patients with rheumatoid arthritis contains high numbers
of B cells (white) that produce high levels of RANKL (green) and stimulate
osteoclasts (red). Credit: Jennifer H. Anolik, M.D., Ph.D., University
of Rochester.

In healthy people, bone degradation and bone formation balance one another to maintain healthy bones. In people with RA, bone degradation often predominates, leading to fragile bones that are prone to fractures.

The mechanisms that underlie bone loss in RA are complex. Inflammatory molecules, which bathe the joints of people with the disease, stimulate the production of bone-degrading osteoclasts. In addition, evidence points to an important role for B cells—depleting B cells in RA patients with a drug called rituximab was found to reduce structural damage to the joints and relieve symptoms.

B cells contribute to joint inflammation in RA patients by generating autoantibodies—antibodies that attack the bodyís own proteins. However, scientists had noticed little correlation between the levels of these antibodies and severity of symptoms. This suggested that B cells were contributing to the disease in other ways, as well. Understanding the mechanisms involved could help improve clinical care by providing scientists with the foundation for developing new treatments.

To better understand B cellsí role, researchers led by Jennifer H. Anolik, M.D., Ph.D., of the University of Rochester, focused on a signaling molecule called RANKL. Earlier work had shown that RANKL promotes bone degradation by stimulating the production of osteoclasts from immature cells called osteoclast precursors (OCPs). Dr. Anolikís team wondered if B cells could be contributing to bone damage in RA by generating the molecule.

To test the idea, the scientists examined B cells in blood from RA patients and healthy controls for the presence of RANKL. They found that the cells, especially a subset called memory B cells, produce the molecule. Memory B cells from people with RA produced about twice as much RANKL as those from controls.

Memory B cells help protect people from catching an infectious disease more than once. Upon a second exposure, the cells "remember" the microbe and quickly launch an attack, stopping the infection in its tracks. RA patients have high levels of memory B cells as a result of the autoimmune assault that characterizes the disease, suggesting that the RANKL they produce may significantly contribute to bone damage.

To see if memory B cells in blood invade the joints of RA patients, the researchers next examined samples of synovial fluid, the viscous liquid that lubricates the joints. They found higher levels of memory B cells in the fluid compared to blood, and the cells produced higher levels of RANKL. These results suggested that B cell-produced RANKL may be boosting levels of osteoclasts in the joints, causing bone erosion.

Laboratory experiments in which the researchers cultured B cells from RA patients together with OCPs provided support for the idea. B cells from RA patients stimulated the formation of five times as many osteoclasts as did B cells from healthy controls. Blocking RANKLís activity in these co-cultures resulted in a much more modest effect on osteoclast formation, revealing an essential role for the molecule in the process.

"We know that depleting B cells in RA patients helps preserve healthy joints and eases pain, but the potential downside is the loss of protective immunity these cells provide," said Dr. Anolik. "Our aim is to identify the specific B cell subsets and molecular pathways involved in the cellsí harmful effects so that we can begin to find ways to selectively target them. The ultimate goal is to develop new treatments with fewer unwanted side effects."

This work was supported by the NIHís NIAMS (grants UH2-AR067690, R01-AR048697 and R01-AR063650) and National Institute of Allergy and Infectious Diseases (grants U19-AI563262 and P01-AI078907). The Bertha and Louis Weinstein Research Fund and the New York State Stem Cell Science program also contributed support.

Kirstie Saltsman, Ph.D.

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Production of RANKL by Memory B Cells: A Link Between B Cells and Bone Erosion in Rheumatoid Arthritis. Meednu N, Zhang H, Owen T, Sun W, Wang V, Cistrone C, Rangel-Moreno J, Xing L, Anolik JH. Arthritis Rheumatol. 2016 Apr;68(4):805-16. doi: 10.1002/art.39489. PMID: 26554541

The mission of the NIAMS, a part of the U.S. Department of Health and Human Services' National Institutes of Health, is to support research into the causes, treatment and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about the NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS website at http://www.niams.nih.gov.