Rheumatoid arthritis (RA) is a common, autoimmune inflammatory form of arthritis. It is characterized by chronic inflammation affecting the synovium (lining of the joint). As RA progresses, it causes erosions of cartilage and bone, and eventual destruction of joints. It is a very complex disease with many still unknown genetic and environmental factors involved. RA strikes women about three to four times more frequently than men. Understanding why this gender difference occurs has been hampered by the lack of a suitable laboratory mouse model.
Researchers at the Mayo Clinic have produced a new breed of transgenic mice with autoimmune responses similar to human RA. 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 experiment, mice were genetically modified with gene that confers susceptibility to developing classic RA.
This gene variant is linked to anti-cyclic citrullinated peptide (anti-CCP) autoantibodies, which develop before the onset of RA.
Mice were then injected with type II collagen that leads to a type of inflammatory arthritis. 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 very similar to humans. These included auto antibodies to type II collagen, increased expression of pathologic T cells, and production of proinflammatory cytokines (chemical messengers that are found in RA). 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.
Sex hormones such as estrogen and androgen play important roles in the regulation of immune and inflammatory responses. It is possible that changes in sex hormones could be used as a therapeutic option in the future. The presence of a suitable mouse model will certainly make further investigation easier into the factors that lead to gender differences in disease.
Taneja V, Behrens M, Mangalam A, Griffiths MM, Luthra HS, David CS. New Humanized HLA-DR4-Transgenic Mice That Mimic the Sex Bias of Rheumatoid Arthritis. Arthritis Rheum.56(1): 69-78.
This article was adapted in part from a press release by John Wiley & Sons, Inc.
