Blockade of CD40/CD40 ligand interactions attenuates skin fibrosis and autoimmunity in the tight-skin mouse
Blockade of CD40/CD40 ligand interactions attenuates skin fibrosis and autoimmunity in the tight-skin mouse
复制标题
DOI：
10.1136/ard.2007.073387
复制
发表时间：
2008-06-01
影响因子：
27.4
通讯作者：
Sato, S.
中科院分区：
文献类型：
--
作者：
Komura, K.;Fujimoto, M.;Sato, S.
目的：探讨CD40/CD40配体（CD40L）相互作用与人系统性硬化症小鼠（TSK/+）皮肤纤维化和自身免疫的关系。方法：新生TSK/+小鼠腹腔注射小鼠抗cd40l单克隆抗体100 μ g /周。在光镜下测量8周龄雌性小鼠皮下厚度（定义为脂肪环下皮下疏松结缔组织层的厚度）。所有皮肤切片均取自上背部中线。采用酶联免疫吸附法检测血清抗拓扑异构酶1自身抗体水平、血清免疫球蛋白水平和血浆可溶性CD40L水平。为了分析淋巴细胞表面分子，用单克隆抗体对淋巴细胞的单细胞悬液进行染色。通过分别摄取[(3)H]标记的胸苷和溴脱氧尿苷来评估TSK/+ B细胞和成纤维细胞对抗cd40抗体的增殖。结果：抗CD40L单克隆抗体阻断CD40/CD40L相互作用可显著减少TSK/+小鼠皮肤纤维化（65%）和抗拓扑异构酶1自身抗体。抗cd40l单克隆抗体也能使TSK/+小鼠B淋巴细胞异常活化正常化，这在高γ -球蛋白血症中得到证实。此外，TSK/+小鼠CD4(+) T细胞上CD40L表达上调，血浆可溶性CD40L水平升高，表明CD40/CD40L相互作用增强。在TSK/+ B细胞和成纤维细胞中也观察到对CD40刺激的高反应性。结论：TSK/+小鼠的皮肤纤维化和自身免疫与CD40/CD40L相互作用密切相关。
Objective : To assess the association of CD40/CD40 ligand (CD40L) interactions with the development of skin fibrosis and autoimmunity in tight-skin (TSK/+) mouse, which is a mouse model for human systemic sclerosis.Methods: Newly born TSK/+ mice were treated with murine anti-CD40L monoclonal antibody (100 mu g intra-peritoneally weekly). Hypodermal thickness of 8-week-old female mice (defined as the thickness of a subcutaneous loose connective tissue layer beneath the panniculus carnosus) was measured under a light microscope. All skin sections were taken from the para-midline, upper back region. Serum anti-topoisomerase 1 autoantibody levels, serum immunoglobulin levels and plasma soluble CD40L levels were determined by enzyme-linked immunosorbent assay. For analysis of lymphocyte surface molecules, single cell suspensions of lymphocytes were stained by monoclonal antibodies. Proliferation of TSK/+ B cells and fibroblasts to anti-CD40 antibodies was assessed by the uptake of [(3)H]-labelled thymidine and bromodeoxyuridine, respectively.Results: The blockade of CD40/CD40L interactions by anti-CD40L monoclonal antibody significantly reduced cutaneous fibrosis (65%) and anti-topoisomerase 1 autoantibody in TSK/+ mice. Anti-CD40L monoclonal antibody also normalised B lymphocyte abnormal activation in TSK/+ mice, demonstrated by hyper-gamma-globulinaemia. Furthermore, augmented CD40/CD40L interactions in TSK/+ mice were suggested by upregulated expression of CD40L on CD4(+) T cells, elevated plasma soluble CD40L levels. The hyperresponsiveness to CD40 stimulation was also observed in TSK/+ B cells and fibroblasts.Conclusions: Cutaneous fibrosis and autoimmunity in TSK/+ mice are closely correlated with CD40/CD40L interactions.