Rheumatoid arthritis (RA) is an autoimmune disease that causes chronic inflammation of the synovial joints. It affects about 1.3 million people in the United States, or 0.6 percent of the population. Autoantibodies, which attack the body's own tissues, contribute to the inflammation experienced by RA patients.

Although these autoantibodies have been detected in the blood of RA patients, the molecules that stimulate the production of the antibodies, called autoantigens, have been more elusive. However, researchers supported in part by a grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) identified a potential autoantigen for RA, and in a study they published recently in the journal Arthritis and Rheumatism, they describe their further investigation into this autoantigen candidate.

Karin Lundberg, Ph.D., at the Imperial College of London, along with Ted Mikuls, M.D., of the University of Nebraska and Omaha Veterans Affairs Hospital, and their colleagues looked at a protein called alpha-enolase. This protein is highly conserved, which means that it has maintained its molecular structure and composition through evolution, making it very similar in bacteria and in humans.

The particular type of alpha-enolase that the team investigated in this study is called citrullinated alpha-enolase peptide, or CEP-1. When the protein is originally manufactured by the cell, it does not contain the amino acid citrulline, but a chemical reaction occurs to change or citrullinate the protein. This change may result from an environmental exposure, and it seems to affect the protein's function and structure, possibly causing the protein to unfold.

Antibodies known as anti-citrullinated protein antibodies, or ACPAs, which specifically recognize citrullinated proteins, are found in abundance in the blood plasma of RA patients. Because they are in evidence quite early in the disease, they are an important predictor of a severe, erosive form of RA, and testing for ACPAs is a powerful diagnostic tool.

By performing assays or tests that measure the concentration of substances in the blood plasma of RA patients, Drs. Lundberg, Mikuls, and colleagues determined that antibodies in these patients specifically recognized and attacked citrullinated (CEP-1) proteins.

The researchers then studied CEP-1 proteins from bacteria, specifically from the bacterium Porphyromonas gingivalis, which is responsible for periodontal or gum disease. This bacterium contains a citrullinated form of the alpha-enolase protein that is almost identical to the CEP-1 that occurs in the human body, and when assays were conducted, the antibodies in the RA patients' blood recognized the bacterial CEP-1 proteins the same way they recognized the body's own, as antigens. This is known as a cross-reaction.

Scientists have long suspected a link between RA and environmental factors, and this cross-reaction led the team to hypothesize that, for a subset of people with RA, an initial bacterial infection could prime the immune system for a later inflammation of normal tissue.

Further studies are necessary, but the work of these researchers provides evidence that CEP-1 may be important in the pathogenesis of RA in a certain group of patients. In addition, the similarity between human and bacterial enolase, and the cross-reactions of antibodies, may be important clues in the origin of the disease for this subset of people. Since early diagnosis and intervention with antirheumatic drugs has been shown to have a favorable effect on the course of the disease, the potential new biomarker represents an important advance in the diagnosis and treatment of this troubling chronic disease.

The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, a part of the 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 (toll-free call) or visit the NIAMS Web site at http://www.niams.nih.gov.


Reference: Lundberg K, Kinloch A, Fisher BA, et al. Antibodies to citrullinated alpha-enolase peptide 1 are specific for rheumatoid arthritis and cross-react with bacterial enolase. Arthritis Rheumatism. 2008 Oct; 58(10):3009-3019. PMID: 18821669

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