Ankylosing enthesitis associated with up-regulated IFN-gamma and IL-17 production in (BXSB x NZB) F(1) male mice: a new mouse model.
We found that in contrast to (BXSB x NZB) F(1) female mice that spontaneously develop severe systemic lupus erythematosus (SLE), male (BXSB x NZB) F(1) mice are not prone to SLE, but instead develop seronegative ankylosing enthesitis in ankle/tarsal joints only when caged in groups, with the incidence reaching 83% at 7 months of age. This ankylosis is microscopically characterized by a marked proliferation of fibroblast-like cells positive for bone morphogenetic protein (BMP)-2 in association with heterotropic formation of cartilages and bones in hyperplastic entheseal tissues and subsequent fusion of tarsal bones. Elevated potentials of popliteal lymph node T cells producing interleukin (IL)-17 and interferon (IFN)-gamma were significantly associated with joint ankylosis, suggesting the involvement of these cytokines in effector phase mechanisms of the disease, including up-regulated BMP signaling pathways. There was no difference in serum autoantibody levels between affected and unaffected mice. Parental BXSB and NZB strains of both sexes did not develop the disease even when caged in groups, indicating that the disease develops under the control of susceptibility genes derived from both parental strains. These results indicate that (BXSB x NZB) F(1) male mice are a suitable model for clarifying genetic, environmental and molecular mechanisms underlying ankylosing enthesitis and related diseases.
Department of Pharmacy, Kanazawa Medical Center, National Hospital Organization, Kanazawa, Ishikawa, Japan.
Yasuharu
Y
Abe
Mareki
M
Ohtsuji
Naomi
N
Ohtsuji
Qingshun
Q
Lin
Hiromichi
H
Tsurui
Susumu
S
Nakae
Toshikazu
T
Shirai
Katsuko
K
Sudo
Sachiko
S
Hirose
D000818:Animals; D000974:Antibodies, Antinuclear; D004195:Disease Models, Animal; D007371:Interferon-gamma / Q000378:metabolism*; D020381:Interleukin-17 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008814:Mice, Inbred NZB; D011859:Radiography; D013167:Spondylitis, Ankylosing / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013601:T-Lymphocytes / Q000378:metabolism; D013643:Tarsus, Animal / Q000000981:diagnostic imaging / Q000473:pathology; D015854:Up-Regulation
D000974:Antibodies, Antinuclear; D020381:Interleukin-17; D007371:Interferon-gamma