Using a humanized mouse model that mimics the effects of human rheumatoid arthritis (RA), researchers have discovered that protein growth factors called cytokines in the immune system have both pro- and anti-inflammatory responses to RA that help explain why some patients respond to current therapy and others don't. By pinpointing the unique immune mechanisms involved in different forms of RA, the scientists hope to guide physicians toward more precise individualized diagnosis of RA patients and more effective therapies that target specific forms of the disease.
The findings were published online on October 20 and are reported in the November issue of the Journal of Clinical Investigation. The research was conducted at the Lowance Center for Human Immunology at Emory University School of Medicine, and was led by rheumatologists Cornelia Weyand, MD, PhD, and Jorg Goronzy, MD, PhD. The study's first author was Thorsten M. Seyler.
Rheumatoid arthritis (RA) is a chronic and crippling inflammatory joint, bone and cartilage disease affecting more than 2.1 million Americans. An autoimmune disease, RA is characterized by an abnormal immune response in which the immune system attacks healthy tissue, causing inflammation of the lining of the joints, called the synovium.
For the last 20 years researchers, including those at Emory, have worked to identify pathways and molecules that play a role in RA, resulting in new therapies that target inflammatory growth factors and a marked improvement in treatment success. However, even though not all RA patients respond well to these therapies, they are applied universally, without accounting for differences in disease.
"We need to become much more sophisticated as rheumatologists in understanding that RA is not all the same disease and that when we treat it we will see very diverse results," said Dr. Weyand. "Rheumatologists need to develop diagnostic tools to capture differences in patients that have meaning for the course of disease and for our therapeutic actions."
Drs. Weyand and Goronzy have helped delineate three different subtypes of RA disease over the past ten years. In diffuse RA, T and B lymphocytes seem to infiltrate tissue randomly, resulting in autoimmune inflammation.
Many therapies currently used to treat RA patients are based on new knowledge about inflammatory cytokines -- growth factor-like proteins that stimulate the autoimmune process. Scientists have hypothesized that rheumatoid lesions produce excessive amounts of such growth factors, promoting lymphocyte proliferation and keeping alive the immune cells that drive inflammation and perpetuate the autoimmune disease state.
The Emory scientists set out to explore differences in immune responses by using their mouse model to study related types of cytokine protein known for helping B lympocytes survive and differentiate. Two of these proteins, known as APRIL (A proliferation inducing ligand) and BlyS (B-lymphcyte stimulator), are the targets of new experimental drugs currently in early phase clinical trials.
The conclusion? The factors APRIL and BlyS have multiple and complex effects in rheumatoid arthritis. In some types of disease they are critical in keeping the inflammatory structures working and functioning, while in other types of disease they seem to do just the opposite.
Other study authors included Yong W. Park, Seisuke Takemura, from Emory's Lowance Center for Human Immunology; Richard J. Bram, Department of Pediatrics and Adolescent Medicine, the Mayo Clinic; and Paul J. Kurtin, Department of Pathology, the Mayo Clinic.
The work was funded in part by the National Institutes of Health.