Grammer Amrie C, Slota Rebecca, Fischer Randy, Gur Hanan, Girschick Hermann, Yarboro Cheryl, Illei Gabor G, Lipsky Peter E
Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland 20892, USA.
J Clin Invest. 2003 Nov;112(10):1506-20. doi: 10.1172/JCI19301.
To determine the role of CD154-CD40 interactions in the B cell overactivity exhibited by patients with active systemic lupus erythematosus (SLE), CD19+ peripheral B cells were examined before and after treatment with humanized anti-CD154 mAb (BG9588, 5c8). Before treatment, SLE patients manifested activated B cells that expressed CD154, CD69, CD38, CD5, and CD27. Cells expressing CD38, CD5, or CD27 disappeared from the periphery during treatment with anti-CD154 mAb, and cells expressing CD69 and CD154 disappeared from the periphery during the post-treatment period. Before treatment, active-SLE patients had circulating CD38 (bright) Ig-secreting cells that were not found in normal individuals. Disappearance of this plasma cell subset during treatment was associated with decreases in anti-double-stranded DNA (anti-dsDNA) Ab levels, proteinuria, and SLE disease activity index. Consistent with this finding, peripheral B cells cultured in vitro spontaneously proliferated and secreted Ig in a manner that was inhibited by anti-CD154 mAb. Finally, the CD38(+/++)IgD(+), CD38(+++), and CD38(+)IgD(-) B cell subsets present in the peripheral blood also disappeared following treatment with humanized anti-CD154. Together, these results indicate that patients with active lupus nephritis exhibit abnormalities in the peripheral B cell compartment that are consistent with intensive germinal center activity, are driven via CD154-CD40 interactions, and may reflect or contribute to the propensity of these patients to produce autoantibodies.
为了确定CD154 - CD40相互作用在活动性系统性红斑狼疮（SLE）患者所表现出的B细胞过度活化中的作用，在用人源化抗CD154单克隆抗体（BG9588，5c8）治疗前后对CD19⁺外周血B细胞进行了检测。治疗前，SLE患者表现出表达CD154、CD69、CD38、CD5和CD27的活化B细胞。在用抗CD154单克隆抗体治疗期间，表达CD38、CD5或CD27的细胞从外周血中消失，而在治疗后阶段，表达CD69和CD154的细胞从外周血中消失。治疗前，活动性SLE患者有循环中的CD38（明亮）Ig分泌细胞，而正常个体中未发现这种细胞。治疗期间这种浆细胞亚群的消失与抗双链DNA（抗dsDNA）抗体水平、蛋白尿和SLE疾病活动指数的降低相关。与此发现一致，体外培养的外周血B细胞以一种被抗CD154单克隆抗体抑制的方式自发增殖并分泌Ig。最后，外周血中存在的CD38（⁺/⁺⁺）IgD⁺、CD38（⁺⁺⁺）和CD38⁺IgD⁻ B细胞亚群在用人源化抗CD154治疗后也消失了。总之，这些结果表明活动性狼疮性肾炎患者在外周血B细胞区室中表现出异常，这些异常与生发中心的强烈活动一致，是由CD154 - CD40相互作用驱动的，并且可能反映或促成这些患者产生自身抗体的倾向。
