Spotlight on Research 2010

April 2010 (historical)

Joint Tissue Findings Offer Potential Insight into Rheumatoid Arthritis

New research supported in part by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) looking directly at joint tissue in people with arthritis is giving investigators a better understanding of the antibodies involved in rheumatoid arthritis (RA), a condition in which chronic inflammation causes pain, stiffness and damage to the joints. Antibodies are molecules that participate in the immune system's protection of the body by recognizing harmful antigens such as viruses and bacteria. In RA, antibodies called autoantibodies are directed against a person's own healthy tissues.

Two autoantibodies – rheumatoid factor and anti-cyclic citrullinated peptide (anti-CCP) – circulating in the blood of many people with RA have been useful for diagnosing RA and predicting its severity, but scientists have little understanding of what these autoantibodies actually do in the joint, or whether the joints themselves might have clues to other antibodies contributing to the disease. To find some answers, NIAMS-supported researchers, Paul A. Monach, M.D., and Diane Mathis, Ph.D., and their colleagues conducted complex tests of joint tissue samples taken from 18 patients with RA. While their research didn't necessarily find a “third antibody,” the researchers did discover that antibodies that came out of the joints actually bound to a lot of products associated with joint cartilage and also to histones, intracellular proteins from the cell nucleus that associate with DNA in the formation of chromosomes. The histone deposits may be derived from cells that died and spilled their contents, which result from the disease condition. Furthermore, they found that cartilage in RA is actually coated with histones, regardless of whether RA was active or not.

Because normal joint tissue is rarely removed during surgery, the scientists compared their findings to those from samples from eight patients with osteoarthritis (OA, a form of arthritis not generally associated with autoantibodies). The differences between the OA and RA samples were striking; the OA cartilage samples were not covered in histones.

Right now, the scientists can't say whether histones sitting on the cartilage surface are binding to antihistone antibodies and contributing to inflammation, but that is a possibility, says Dr. Monach.

He says if histones are a contributor to joint damage, there are also other theories about their role. One is that they stimulate immune cells through a class of proteins called Toll-like receptors (TLRs). Another is that they may be key in a process that delivers potentially damaging enzymes to the cartilage surface.

Dr. Monach believes that following up on these and other hypotheses may eventually lead to the development of pharmaceuticals that would intervene in or block the process, and thereby slow down joint inflammation and damage in RA.

These findings were published in the Proceedings of the National Academy of Sciences.

The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (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 NIAMS, call the Information Clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS Web site at http://www.niams.nih.gov.

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Monach P, Hueber W, Kessler B, Tomooka B, BenBarak M, Simmons B, Wright J, Thornhill T, Monestier M, Ploegh H, Robinson W, Mathis D, Benoist C. A broad screen for targets of immune complexes decorating arthritic joints highlights deposition of nucleosomes in rheumatoid arthritis. Proceedings of the National Academy of Sciences USA. 2009 Sep 15;106(37):15867-72.