New research reveals the ability of type II collagen (CII) to act as an autoantigen in the inflamed joints of patients with rheumatoid arthritis (RA),¹ possibly contributing to the cycle of chronicity associated with the disease. The finding may also help identify new target-specific drugs for RA, according to the authors.

Published in the December issue of Arthritis & Rheumatism, the study found that when CII is modified by conditions found within the inflamed joint, it acts as an autoantigen in RA. "Although collagen-induced arthritis is a commonly accepted model for RA, it has proved difficult to substantiate the involvement of autoimmunity to CII in the pathogenesis of RA," explains lead investigator Ahuva Nissim, PhD, of Queen Mary's School of Medicine and Dentistry at the University of London, UK. "Our finding demonstrated the role of chemical posttranslational modifications by reactive oxidants in inducing neoantigenicity within CII."

According to Dr. Nissim, these reactive oxidants originated from inflammatory cells that infiltrated the inflamed synovial membrane and consumed increased amounts of oxygen, resulting in the generation of reactive oxidants. "We have demonstrated autoimmune reactivity against CII modified by oxidative reactions and demonstrated that CII is an autoantigen in RA after it is modified by conditions found within the inflamed joint," Dr. Nissim says, pointing out that "this finding can help us target drugs specifically to the inflamed joints."

For the study, researchers compared blood serum samples from 31 RA patients (aged 65 to 93 years) in varying stages of disease who were receiving different treatments, and 41 patients presenting other inflammatory joint diseases. The investigators modified native CII with the oxidants present in the rheumatoid joint that are found in acute and chronic inflammation, including hydroxyl radical, hypochlorous acid, and peroxynitrite.

Since nonenzymatic oxidative reactions by glycation are evident in RA, CII was also glycated with ribose. The investigators then analyzed their modifications by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and 3-dimensional fluorescence, followed by enzyme-linked immunosorbent assay (ELISA) and Western blotting, using sera from patients with RA and other inflammatory and noninflammatory joint diseases as probes.

Only one RA serum sample showed strong binding to native CII, affirming that this protein is an innocent bystander in autoimmunity and takes an inflammatory toll on the joints. However, binding to modified CII was shown to be increased in 14 of 31 RA sera. In fact, 45% of all RA samples showed moderate to strong antibody binding reactions, the study found.

Among the non-RA serum samples, only one yielded a strong reaction to modified CII, and 5 of the 41 were moderate binders, the study showed. Samples that demonstrated the strongest binding to modified CII in ELISA also exhibited strong binding to various fragmented or aggregated forms of CII in Western blots, as well as strong binding to the fragmented CII present in RA synovial fluid.

"The present findings support the possibility that chemical modification of self-antigens, in RA in particular and in inflammation in general, is the cause of formation of neoepitopes," conclude the researchers.

Reference

1. Nissim A, Winyard PG, Corrigall V, et al. Generation of neoantigenic epitopes after posttranslational modification of type II collagen by factors present within the inflamed Joint. Arthritis Rheum. 2005;52:3829-3838.