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【摘要】
Systemic sclerosis (scleroderma) is an autoimmune disease characterized by excessive extracellular matrix deposition in the skin. A direct role for B lymphocytes in disease development or progression has remained controversial, although autoantibody production is a feature of this disease. To address this issue, skin sclerosis and autoimmunity were assessed in tight-skin mice, a genetic model of human systemic sclerosis, after circulating and tissue B-cell depletion using an anti-mouse CD20 monoclonal antibody before (day 3 after birth) and after disease development (day 56). CD20 monoclonal antibody treatment (10 to 20 µg) depleted the majority (85 to 99%) of circulating and tissue B cells in newborn and adult tight-skin mice by days 56 and 112, respectively. B-cell depletion in newborn tight-skin mice significantly suppressed (43%) the development of skin fibrosis, autoantibody production, and hypergammaglobulinemia. B-cell depletion also restored a more normal balance between Th1 and Th2 cytokine mRNA expression in the skin. By contrast, B-cell depletion did not affect skin fibrosis, hypergammaglobulinemia, and autoantibody levels in adult mice with established disease. Thereby, B-cell depletion during disease onset suppressed skin fibrosis, indicating that B cells contribute to the initiation of systemic sclerosis pathogenesis in tight-skin mice but are not required for disease maintenance.
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Systemic sclerosis (SSc, scleroderma) is a connective tissue disease characterized by excessive extracellular matrix deposition in the skin and visceral organs.1,2 Although the molecular basis for SSc pathogenesis is unknown, hypergammaglobulinemia, polyclonal and memory B-cell hyperactivity, and altered B-cell homeostasis are found in SSc patients,3-5 with B-cell-associated transcripts up-regulated in lesional skin.6 Disease-specific autoantibodies reactive with DNA topoisomerase I, RNA polymerases, and fibrillin-1 further suggests that activated B cells contribute to disease pathogenesis.7-10 Moreover, B cells from SSc patients overexpress CD19,11 a signal transduction molecule that regulates B-cell responses to self and foreign antigens. A CD19 gene polymorphism also correlates with SSc susceptibility.12 Despite these findings, a role for B cells in SSc pathogenesis has remained controversial.13
The tight-skin (Tsk/+) mouse serves as a model for SSc,14 with increased synthesis and accumulation of collagen and other extracellular matrix proteins in the skin.15 Homozygous mice die in utero, whereas heterozygous Tsk/+ mice survive but develop skin fibrosis.16 A tandem duplication within the fibrillin-1 gene causes tissue hyperplasia and the SSc-like phenotype.17-21 However, there is also an immunological component to disease pathogenesis because CD4+ T cells, mast cells, and other immunocompetent cells contribute to skin fibrosis in Tsk/+ mice.22-25 For example, the infusion of bone marrow and spleen cells from tight-skin mice into normal mice induces a Tsk-like cutaneous phenotype and autoantibodies.22,26 Importantly, the adoptive transfer of enriched B or T cells alone into normal syngeneic mice does not cause skin fibrosis, whereas B cells alone increased autoantibody production.22 T helper 2 (Th2) cells and T-cell-secreted profibrogenic cytokines contribute specifically to the fibrotic processes in scleroderma.23,27,28 By contrast, CpG oligodeoxynucleotide or interleukin (IL)-12 inhibit skin sclerosis in Tsk/+ mice by stimulating a Th1 immune response.29,30 Transforming growth factor (TGF)-ß and IL-4 may contribute directly to skin fibrosis because they induce hyperresponsive collagen production in Tsk/+ fibroblasts.28,31 Reciprocally, skin fibrosis is prevented in Tsk/+ mice bearing IL-4, IL-4 receptor, STAT6, or TGF-ß gene mutations or by the administration of anti-IL-4 monoclonal antibody (mAb) to newborn Tsk/+ mice.27,28,32-34 Disrupting IL-4 rescues mice homozygous for the tight-skin mutation from embryonic death and also diminishes TGF-ß production by fibroblasts.33 The phenotypic characteristics of SSc patients and Tsk/+ mice are similar, except Tsk/+ mice have pulmonary emphysema and cardiac hypertrophy14 that are not inhibited by anti-IL-4 mAb, the absence of CD4+ T cells, or IL-4, IL-4 receptor, TGF-ß, or Stat6 deficiencies.23,27,32,34 Tsk/+ B cells also display a hyperresponsive phenotype, with enhanced CD19-induced i responses, higher levels of CD19 tyrosine phosphorylation,13,35 impaired CD22 regulation of signal transduction,36 and the production of autoantibodies against SSc-specific target autoantigens, such as topoisomerase I, RNA polymerase I, and fibrillin-1.37,38 There is also a correlation between the concentration of serum anti-topoisomerase I autoantibodies in Tsk/+ mice and histological and biochemical alterations in the skin.39 Likewise, human autoantibodies to fibrillin-1 activate normal human fibroblasts in culture through the TGF pathway to recapitulate the scleroderma phenotype.10 Thereby, CD19 deficiency in Tsk/+ mice down-regulates B-cell function, improves skin scleros
【关键词】 b-lymphocyte depletion fibrosis autoimmunity tight-skin systemic sclerosis
作者单位：From the Department of Dermatology,* Kanazawa University Graduate School of Medical Science, Kanazawa, Japan; the Department of Dermatology, Nagasaki University Graduate School of Biomedical Science, Nagasaki, Japan; and the Department of Immunology, Duke University Medical Center, Durham, North Car