Pathogenesis of systemic sclerosis: altered B cell function is the key linking systemic autoimmunity and tissue fibrosis.
Systemic sclerosis (SSc) is characterized by autoimmunity and tissue fibrosis. There is a close association between specific autoantibodies and clinical features in patients with SSc. A number of studies have demonstrated that various cytokines, such as transforming growth factor-beta, modulate the synthesis of extracellular matrix by fibroblasts. However, it is not clear as to how autoimmunity and tissue fibrosis interact with each other. Recent studies have revealed that B cells play a critical role in various systemic autoimmune disorders. CD19 is a central regulator of B cell signaling threshold, and B cells from SSc patients exhibit an increased expression of CD19 that induces SSc-specific autoantibody production in transgenic mice. Furthermore, SSc patients have intrinsic B cell abnormalities characterized by decreased but activated memory B cells, which is possibly due to CD19 overexpression. Similarly, B cells from a tight-skin mouse, a model of SSc, show augmented CD19 signaling and chronic B cell activation. Remarkably, CD19 loss results in inhibition of chronic B cell hyper-reactivity and elimination of autoantibody production, which is associated with improvement in skin fibrosis and a parallel decrease in IL-6 production by B cells. Therefore, augmented cytokine production by B cells is a potential candidate for the induction of skin sclerosis. Alternatively, B cells may influence tissue fibrosis by regulating T cell activation and cytokine production through their antigen-presenting and co-stimulatory abilities. Thus, altered B cell function may result in tissue fibrosis, as well as autoimmunity, in SSc.
Hasegawa
Minoru
M
Department of Dermatology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan. minoruha@derma.m.kanazawa-u.ac.jp
Fujimoto
Manabu
M
Takehara
Kazuhiko
K
Sato
Shinichi
S
D000818:Animals; D018941:Antigens, CD19 / Q000502:physiology; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000502:physiology; D005355:Fibrosis; D006801:Humans; D008213:Lymphocyte Activation; D051379:Mice; D012595:Scleroderma, Systemic / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
D018941:Antigens, CD19; D016207:Cytokines