Characterized by chronic synovial tissue inflammation, increasing erosions of cartilage and bone, and eventual destruction of joints, rheumatoid arthritis (RA) is a complex and confounding autoimmune disease. It is associated with a variety of genetic and environmental factors and known to strike women about three times as frequently as men. A major obstacle to investigating this clear sex bias has been the lack of a laboratory rat or mouse that mimics human RA. Until now.
Researchers at the Mayo Clinic have produced a new breed of transgenic mice with autoimmune responses similar to human RA patients and increased incidence of the disease in females. Featured in the January 2007 issue of Arthritis & Rheumatism, this humanized mouse model may be valuable for not only studying sex differences in RA, but also for understanding why women are particularly vulnerable to autoimmunity and for developing future therapeutic strategies.
For this novel experiment, mice were genetically modified with a well-established RA susceptibility, the allele HLA-DRB1*0401. This gene variant is linked to anti-cyclic citrullinated peptide (anti-CCP) autoantibodies, which precede the onset of RA. Collagen-induced arthritis (CIA) in the mice was initiated by injection of type II collagen. These transgenic mice were then tested for incidence and severity of arthritic symptoms, as well as assessed for vulnerability to the disease by sex.
Of the transgenic mice that developed arthritis, all produced rheumatoid factors and anti-CCP autoantibodies strikingly similar to humans. These included auto antibodies to type II collagen (CII), increased expression of class II molecules T cells, and production of proinflammatory cytokines. In addition, female mice developed arthritis at a higher rate than the male mice, by a ratio greater than 3 to 1, and exhibited all the disease hallmarks at higher levels.
Commenting on this study's implications for further understanding and future treatment of RA, Maurizio Cutolo, M.D., a researcher with the Department of Rheumatology, the University of Genoa, Italy, considers its potential to shed light on the role of estrogen and androgen in the disease. "Sex hormone balance is a crucial factor in the regulation of immune and inflammatory responses," Dr. Cutolo notes. "Modulation of this balance should represent part of advanced biologic treatments for RA. Sharing the sex hormone effects of the human disease, the new humanized mouse may provide a better model with which to study the pathogenesis and treatment of arthritis."
Article: "New Humanized HLA-DR4-Transgenic Mice That Mimic the Sex Bias of Rheumatoid Arthritis," Veena Taneja, Marshall Behrens, Ashutosh Mangalam, Marie M. Griffiths, Harvinder S. Luthra, and Chella S. David, Arthritis & Rheumatism, January 2007; (DOI: 10.1002/art.22213).
Editorial: "Sex and Rheumatoid Arthritis: Mouse Model Versus Human Disease," Maurizio Cutolo, Arthritis & Rheumatism, January 2007; (DOI: 10.1002/art.22322).
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