Regulation of arthritis by p53: critical role of adaptive immunity.
OBJECTIVE
The p53 tumor-suppressor protein is expressed in rheumatoid arthritis synovium, and loss of p53 function through somatic mutation can occur in longstanding disease. Previous studies demonstrated that p53 is protective in murine collagen-induced arthritis (CIA). To determine if adaptive immune responses or synovial effector functions are responsible for this effect, passive models of arthritis were studied in p53 wild-type and knockout mice.


METHODS
Models of passive CIA, passive K/BxN serum transfer arthritis, and active CIA were induced in DBA/1 p53(-/-) or p53(+) mice. Hind paws were evaluated for histologic evidence of inflammation and joint destruction. Synovial interleukin-6 and matrix metalloproteinases 3 and 13 gene expression was analyzed by real-time quantitative polymerase chain reaction. To evaluate T cell function in p53(-/-) mice, draining lymph node (LN) cells from mice immunized with type II collagen (CII) were evaluated in vitro.


RESULTS
Increased disease severity in p53(-/-) mice was confirmed in the standard CIA model. However, clinical arthritis, joint destruction, and synovial gene expression in the passive CIA and K/BxN serum transfer arthritis models were similar in p53(-/-) and p53(+) mice. To determine if the p53 effect was related to T cell function, LN cells from CII-immunized mice were isolated and stimulated with antigen in vitro. CII-stimulated T cell proliferation and interferon-gamma production were significantly higher in p53(-/-) mice. An independent assessment of Th1 function using the cutaneous delayed-type hypersensitivity model confirmed that p53(-/-) mice have enhanced T cell responses in vivo.


CONCLUSIONS
Adaptive immune responses, rather than antibody-mediated responses, in p53(-/-) mice account for increased disease severity in the active CIA model.
Simelyte
Egle
E
University of California, San Diego, School of Medicine, La Jolla, CA, USA.
Rosengren
Sanna
S
Boyle
David L
DL
Corr
Maripat
M
Green
Douglas R
DR
Firestein
Gary S
GS
D000818:Animals; D001168:Arthritis / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology; D051379:Mice; D023421:Models, Animal; D013601:T-Lymphocytes / Q000276:immunology; D016159:Tumor Suppressor Protein p53 / Q000276:immunology*
D016159:Tumor Suppressor Protein p53