BAFF antagonist attenuates the development of skin fibrosis in tight-skin mice.
The tight-skin (TSK/+) mouse, a genetic model for systemic sclerosis (SSc), develops cutaneous fibrosis and autoimmunity. Although immunological abnormalities have been demonstrated in TSK/+ mice, the roles of B-cell-activating factor belonging to the tumor necrosis factor family (BAFF), a potent B-cell survival factor, have not been investigated. Serum BAFF levels in TSK/+ mice were examined by ELISA. Newborn TSK/+ mice were treated with BAFF antagonist, and then skin fibrosis of 8-week-old mice was assessed. Serum BAFF levels were significantly elevated in TSK/+ mice. Remarkably, BAFF antagonist inhibited the development of skin fibrosis, hyper-gamma-globulinemia, and the autoantibody production in TSK/+ mice. The skin from TSK/+ mice showed upregulated expressions of fibrogenic cytokines, such as IL-6 and IL-10, while BAFF antagonist significantly suppressed them. Reciprocally, BAFF antagonist augmented antifibrogenic cytokines, such as IFN-gamma, in the skin of TSK/+ mice. Furthermore, TSK/+ B cells with BAFF stimulation had a significantly enhanced ability to produce IL-6. The results suggest that BAFF/BAFF receptor system is critical for the development of skin fibrosis in TSK/+ mice and could be a potent therapeutical target.
Matsushita
Takashi
T
Department of Dermatology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
Fujimoto
Manabu
M
Hasegawa
Minoru
M
Matsushita
Yukiyo
Y
Komura
Kazuhiro
K
Ogawa
Fumihide
F
Watanabe
Rei
R
Takehara
Kazuhiko
K
Sato
Shinichi
S
D000818:Animals; D001323:Autoantibodies / Q000378:metabolism; D053264:B-Cell Activating Factor / Q000037:antagonists & inhibitors* / Q000097:blood / Q000235:genetics* / Q000502:physiology; D053265:B-Cell Activation Factor Receptor / Q000378:metabolism*; D001402:B-Lymphocytes / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005355:Fibrosis / Q000235:genetics* / Q000473:pathology; D005786:Gene Expression Regulation; D005838:Genotype; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D012867:Skin / Q000473:pathology*
D001323:Autoantibodies; D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D016207:Cytokines