BAFF Antagonist Attenuates the Development of Skin Fibrosis in Tight-Skin Mice

Abstract

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.

Regulation of B cell activating factor (BAFF) receptor expression by NF-κB signaling in rheumatoid arthritis B cells

“…BAFF is mainly secreted by monocytes, dendritic cells, and T cells. (Rahman et al, 2003;Rahman and Manser, 2004;Zhang et al, 2005;Matsushita et al, 2007). BAFF stimulation also results in prolonged survival of mature resting B cells (Do et al, 2000;Gross et al, 2001).…”

“…BAFF binds to three receptors, BAFF-R, transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), and B cell maturation Ag (BCMA) (Rahman et al, 2003;Rahman and Manser, 2004;Zhang et al, 2005;Matsushita et al, 2007;Kim et al, 2009). TACI and BCMA also bind a closely related cytokine, a proliferation-inducing ligand (APRIL).…”

“…B cell activating factor (BAFF), a member of the tumor necrosis factor family and also known as BLys, TALL-1, zTNF4, or THANK, is a critical cytokine in peripheral B cell survival during primary development and homeostasis (Rahman et al, 2003;Matsushita et al, 2007). BAFF is mainly secreted by monocytes, dendritic cells, and T cells.…”

Decreased levels of regulatory B cells in patients with systemic sclerosis: Association with autoantibody production and disease activity

“…Furthermore, B cell depletion therapy suppresses the development of skin fibrosis in the tight-skin mouse [3,4]. In addition, several recent studies have revealed a possible beneficial effect of antihuman CD20 antibody (rituximab) therapy for SSc patients [5].…”

The role of the acquired immune response in systemic sclerosis

“…This B cell activity was enhanced by B cell activation in the presence of anti-IgM and BAFF [32]. Interestingly, BAFF serum levels are increased in the tight-skin (TSK/+) mouse model and blockade of the BAFF/BAFF-receptor interaction can prevent the development of skin fibrosis, inhibit autoantibody generation, and increase the production of anti-fibrotic cytokines (i.e., IFN-γ) [67]. In a bleomycin-induced model of pulmonary fibrosis, BAFF neutralization or BAFF gene deletion resulted in attenuated fibrosis.…”