Biancone L, Andres G, Ahn H, DeMartino C, Stamenkovic I
Department of Pathology, Harvard Medical School, Massachusetts General Hospital, Boston, USA.
Kidney Int. 1995 Aug;48(2):458-68. doi: 10.1038/ki.1995.314.
Several forms of glomerulonephritis are induced by antibodies against self or foreign antigens. Normal B lymphocyte antibody production requires T cell costimulatory signals provided in part by T cell surface expression of gp39/CD40ligand (CD40L) that engages the B cell receptor CD40 and induces B cell differentiation and immunoglobulin class switching. We assessed the effect of disrupting the CD40L-CD40 costimulatory pathway, using a CD40-Ig fusion protein, on the development of membranous glomerulonephritis (MGN) in the mouse. MGN is induced by mouse antibodies that recognize and bind to exogenously administered rabbit anti-mouse renal tubular brush border (RbAMBB) IgG immobilized in the glomerular capillary wall. MGN did not occur in nude mice, showing the need of the T cell function. C57Bl/10 mice immunized with RbAMBB and treated with CD40-Ig fusion protein displayed a delayed autologous response and absence of MGN lesions, while control fusion proteins failed to prevent the development of the disease. These observations provide evidence that disruption of the CD40-CD40L costimulatory pathway can prevent the development of MGN by suppressing T cell-dependent antibody production.
几种形式的肾小球肾炎是由针对自身或外来抗原的抗体所诱发的。正常B淋巴细胞产生抗体需要T细胞共刺激信号，该信号部分由T细胞表面表达的gp39/CD40配体（CD40L）提供，CD40L与B细胞受体CD40结合并诱导B细胞分化和免疫球蛋白类别转换。我们使用一种CD40-Ig融合蛋白评估了破坏CD40L-CD40共刺激途径对小鼠膜性肾小球肾炎（MGN）发展的影响。MGN由小鼠抗体诱发，这些抗体识别并结合固定在肾小球毛细血管壁上的外源性给予的兔抗小鼠肾小管刷状缘（RbAMBB）IgG。MGN在裸鼠中不发生，这表明需要T细胞功能。用RbAMBB免疫并用CD40-Ig融合蛋白处理的C57Bl/10小鼠显示出自体反应延迟且无MGN病变，而对照融合蛋白未能预防该疾病的发展。这些观察结果提供了证据，即破坏CD40-CD40L共刺激途径可通过抑制T细胞依赖性抗体产生来预防MGN的发展。
