Desai-Mehta A, Lu L, Ramsey-Goldman R, Datta S K
Department of Medicine, Northwestern University Medical School, Chicago, Illinois 60611, USA.
J Clin Invest. 1996 May 1;97(9):2063-73. doi: 10.1172/JCI118643.
We investigated the role of the costimulatory molecules, CD40 and its ligand CD40L, in the pathogenesis of human SLE. In comparison to normal subjects or patients in remission, PBMC from active lupus patients had a 21-fold increase in the frequency of CD40L-expressing, CD4+T cells. However, the expression of CD40L induced in either lupus or normal T cells by mitogenic stimulation could be down-regulated equally well by CD40 molecules on autologous B cells. Active lupus patients also had a 22-fold increase in percentage of CD8+ T cells expressing CD40L, consistent with their unusual helper activity in SLE. Surprisingly, patients with active lupus had a 20.5-fold increase in B cells that spontaneously expressed high levels of CD40L, as strongly as their T cells. Although lupus patients in remission had low levels of CD40L+ cells in the range of normal subjects, mitogen-induced upregulation of CD40L expression in the T and B cells was markedly greater than normal, suggesting an intrinsic defect. A mAb to CD40L blocked significantly the ability of lymphocytes from lupus patients with active and established disease to produce the pathogenic variety of antinuclear autoantibodies in vitro, bolstering the possibility of anti-CD40L immunotherapy for lupus. Future studies on the hyperexpression of CD40L could elucidate a regulatory defect in the pathogenic T and B cells of lupus.
我们研究了共刺激分子CD40及其配体CD40L在人类系统性红斑狼疮（SLE）发病机制中的作用。与正常受试者或病情缓解的患者相比，活动期狼疮患者的外周血单个核细胞（PBMC）中表达CD40L的CD4⁺T细胞频率增加了21倍。然而，有丝分裂原刺激在狼疮T细胞或正常T细胞中诱导的CD40L表达，可被自体B细胞上的CD40分子同样有效地下调。活动期狼疮患者中表达CD40L的CD8⁺T细胞百分比也增加了22倍，这与它们在SLE中异常的辅助活性一致。令人惊讶的是，活动期狼疮患者中自发表达高水平CD40L的B细胞增加了20.5倍，与T细胞一样强烈。虽然病情缓解的狼疮患者中CD40L⁺细胞水平与正常受试者相当，但有丝分裂原诱导的T细胞和B细胞中CD40L表达上调明显高于正常水平，提示存在内在缺陷。一种抗CD40L单克隆抗体显著阻断了活动期和确诊疾病的狼疮患者淋巴细胞在体外产生致病性抗核自身抗体的能力，支持了抗CD40L免疫疗法治疗狼疮的可能性。未来关于CD40L过度表达的研究可能会阐明狼疮致病性T细胞和B细胞中的调节缺陷。
