Unexpected Immune Pathway Linked to Rheumatoid Arthritis
BOSTON — February 13, 2002 — Researchers at Joslin Diabetes Center have pinpointed a surprising set of factors contributing to joint destruction during arthritis development in mice. In doing so they have assigned an additional role to a well-known immunological pathway, the complement alternative route. Their discovery, reported in the February 20 issue of Immunity, provides new insight into the mechanisms underlying pathogenesis in rheumatoid arthritis and may stimulate a search for therapeutic agents designed to target the alternative pathway.
Rheumatoid arthritis is a chronic inflammatory disease, primarily of the synovial joints. It afflicts one to two percent of the population. The early stages of the disease are characterized by leukocyte invasion of the joint and overproduction of molecules that stimulate abnormal tissue growth and new blood vessel formation. Cartilage deterioration and attrition of the bone follow.
Complement is a system of circulating enzymes that is part of the body's response to illness or injury. The classic pathway of complement activation has always been regarded as the major effector for antibody action. A second complement pathway, one that is activated on microbial surfaces, is called the alternative. Until now, it was thought to function primarily in the absence of antibody-antigen complexes. Christophe Benoist and Diane Mathis, Harvard Medical School professors of medicine and heads of the Section on Immunology and Immunogenetics at Joslin Diabetes Center, working with HMS researchers Hong Ji, Koichiro Ohmura, Umar Mahmood, and David Lee, discovered that these accepted roles are not necessarily followed. Using a mouse model for rheumatoid arthritis, they found that antibody-antigen complexes also could stimulate the alternative complement pathway, rather than the classic, and initiate the cascade to joint destruction.
"It was no big surprise to anybody that complement would be involved because there are lots of indications of that in human disease, and also in animal models. But it was a really big surprise that the alternative pathway was involved," said Mathis. "The fact that it's the alternative pathway is most interesting because of the potential for new therapeutic targets. With this information we can target the disease much more precisely. It's also interesting because of what we think it's telling us about the mechanism of joint-specific disease."
Earlier research from the Benoist-Mathis lab using the model demonstrated that arthritis was a result of immune complex formation between an antibody and the protein, glucose-6-phosphate isomerase (GPI), which is present in all cells. This suggested that at least in some cases of arthritis, a joint-specific disease arises after an immune response against an antigen present throughout the body. Preliminary results suggest that this antigen complex is present also in at least some RA patients.
In the current study the researchers injected serum from arthritic mice into healthy mice. Healthy mice consistently developed arthritis within days following transfer of the anti-GPI:GPI complexes. The researchers found that, unlike other murine models of autoimmune disorders, disease developed in a broad variety of strains. This has allowed them to utilize mutant strains lacking genes encoding specific complement molecules. The researchers found that the proteins from the classical complement pathway were completely dispensable for arthritis development. However, when complement proteins along the alternative pathway were eliminated, the mice did not develop arthritis.
Additional experiments showed that a molecule involved in binding immunoglobin molecules, called the Fc receptor, was also vital for the processes that led to joint disease.
Rheumatoid arthritis has a variety of causes and clinical courses, complicating attempts to determine whether the disease arises primarily through autoimmune or inflammatory mechanisms. Regardless of the initiating event, Benoist and Mathis argue that inflammation and wasting of the joint — events that occur at a later stage — are brought about through a common set of molecular reactions, those that they have now uncovered.
The research was done in collaboration with Michael Carroll, Michael Brenner, Ralph Weissleder, and Craig Gerard, all of the Harvard Medical School.
