New humanized HLA–DR4–transgenic mice that mimic the sex bias of rheumatoid arthritis

Abstract

Objective. To generate a mouse model that can mimic human rheumatoid arthritis (RA). A major difference between RA in humans and collagen-induced arthritis (CIA) in mice is the lack of sex bias and autoantibodies in the animal model. We used DRB1*0401-transgenic mice to understand the role of DR4 in susceptibility and sex bias in RA.Methods. A transgenic mouse was generated that lacked all endogenous mouse class II genes (AE o ) and expressed the RA susceptibility allele HLA-DRB1*0401. These transgenic mice were tested for incidence, severity, and sex distribution of CIA.Results. DRB1*0401.AE o mice developed CIA predominantly in females and produced rheumatoid factors, similar to the features of human RA. Another feature similar to human RA is the expression of class II molecules on antigen-presenting cells as well as T cells. Activated and sorted CD4؉ T cells can present DR4-restricted type II collagen (CII)-derived peptide in vitro, but cannot process the antigen. This suggests a role for these cells in epitope presentation locally in joints, which affects disease severity. After challenge with CII, female mice had higher cellularity and increased T cell proliferation and produced higher levels of proinflammatory cytokines than did the male mice.Conclusion. DR4.AE o mice expressed HLA similar to humans and displayed increased arthritis susceptibility in females, thus mimicking RA in humans. This model may be valuable for studying sex differences observed in humans and for understanding why autoimmunity is increased in women. These mice may also be useful for developing future therapeutic strategies.

Sex and rheumatoid arthritis: Mouse model versus human disease

“…The mouse model described by Taneja et al, which is reported elsewhere in this issue of Arthritis & Rheumatism (1), is the first to share similarities with human RA. The mice lack the classic endogenous mouse class II chains.…”

Effector T cells in rheumatoid arthritis: Lessons from animal models

“…Animal models of RA provided an unequivocal platform for dissecting the cellular and molecular immune-mediated nature of inflammatory joint diseases. With the aid of animal models, the role that CD4 + T cells play in disease induction and pathogenesis was solidified using genetic modifications in strains engineered to express a specific T cell receptor (TCR) [4][5][6], as well as humanised models modified to express alleles of human MHCII that have been associated with RA [7][8][9][10][11].…”

Rheumatoid Arthritis: Laboratory Models of the Disease

“…HLA-DR4 модель описана недавно, у мышей отсутствуют все гены II класса, но экспрессиру-ется РА-чувствительная аллель HLA-DRB1*0401 [51]. Заболевание моделируется преимуществен-но у самок.…”