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


CONCLUSIONS
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.
Taneja
Veena
V
Mayo Clinic, Rochester, Minnesota 55905, USA. taneja.veena@mayo.edu
Behrens
Marshall
M
Mangalam
Ashutosh
A
Griffiths
Marie M
MM
Luthra
Harvinder S
HS
David
Chella S
CS
D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D020022:Genetic Predisposition to Disease; D015804:HLA-DR4 Antigen / Q000235:genetics* / Q000378:metabolism; D007596:Joints / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D012737:Sex Factors; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D013950:Thymus Gland / Q000378:metabolism / Q000473:pathology
D016207:Cytokines; D015804:HLA-DR4 Antigen