The role of Type II Collagen in rheumatoid arthritis

December 02, 2005

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the joints, which gradually erodes the cartilage and bone. The agents of destruction include inflammatory cells, cytokines, and protein-degrading enzymes known as matrix metalloproteinases (MMPs). The vicious cycle begins when inflammatory cells infiltrate the tissue lining the joints and consume excess oxygen. In addition to unleashing MMPs, the oxidative stress provokes non-enzymatic glycation - a chemical binding of sugar molecules and proteins. Telltale signs of glycation have been found in blood, urine, and synovial fluid of RA patients.

The primary protein in cartilage, Type II Collagen (CII) is crucial to joint health and function. Yet, the involvement of CII in the process of joint inflammation has proven difficult to substantiate. To gain a clearer understanding of CII's role in the pathogenesis of RA, researchers at Queen Mary, University of London and others studied its behavior within an inflamed joint, when modified by oxidants linked to inflammation or by ribose, a five-carbon sugar common to all living cells. Featured in the December 2005 issue of Arthritis & Rheumatism (http://www.interscience.wiley.com/journal/arthritis), their findings support CII's potential contribution to antibody binding and RA's devastating progression.

For their investigation, the researchers collected blood serum samples from 31 RA patients. Between the ages of 65 to 93 years, the patients had disease in varying stages and were receiving different treatments. For control purposes, serum samples were also collected from 41 patients with other inflammatory joint diseases, including osteoarthritis and lupus, as well as back pain, osteoporosis, and gout. Both RA and non-RA samples were analyzed for their ability to bind to pure and natural CII, obtained from bovine cartilage, and to CII that had been chemically modified. The modified CII included three oxidants present in the rheumatic joint - hydroxyl radical, hypochlorous acid, and peroxynitrite - and ribose. The results were evaluated by a state-of-the-art 3-D fluorescent profile, followed by enzyme-linked immunosorbant assay (ELISA) and Western blotting.

Of the 31 RA serum samples analyzed, only 3 showed antibody binding to natural CII - affirming this protein as an innocent bystander in autoimmunity and its inflammatory toll on the joints. However, the percentage of samples that exhibited antibody binding increased 4-fold when tested with modified CII. In fact, 45 percent of all RA samples were assessed with moderate to strong antibody binding reactions. CII treated with hypochlorous acid was the most reactive, followed by CII treated with peroxynitrite, glycation, and hydroxyl radical, respectively. In contrast, only 1 non-RA sample showed strong antibody binding to modified CII.

"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," reflects the study's leading author, Ahuva Nissim, Ph.D. "We propose that the oxidative modification of CII creates a CII autoantigen." This hypothesis has important implications for the further study and enhanced understanding of the pathology of RA - a complex autoimmune disease.
-end-
Article: "Generation of Neoantigenic Epitopes After Posttranslational Modification of Type II Collagen by Factors Present Within the Inflamed Joint," Ahuva Nissim, Paul G. Winyard, Valerie Corrigall, Rewas Fatah, David Perrett, Gabriel Panayi, and Yuti Chernajovsky, Arthritis & Rheumatism, December 2005; 52:12; pp. 3829-3838.

Wiley

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