Abnormal germinal center reactions in systemic lupus erythematosus demonstrated by blockade of CD154-CD40 interactions
Abnormal germinal center reactions in systemic lupus erythematosus demonstrated by blockade of CD154-CD40 interactions
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DOI：
10.1172/jci200319301
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发表时间：
2003-11-01
影响因子：
15.9
通讯作者：
Lipsky, PE
中科院分区：
文献类型：
--
作者：
Grammer, AC;Slota, R;Lipsky, PE
为了确定CD 154-CD 40相互作用在活动性系统性红斑狼疮（SLE）患者表现出的B细胞过度活动中的作用，在人源化抗CD 154 mAb（BG 9588，5c 8）治疗前后检查了CD 19（+）外周B细胞。在治疗前，SLE患者表现出活化的B细胞，其表达CD 154、CD 69、CD 38、CD 5和CD 27。在抗CD 154 mAb治疗期间，表达CD 38、CD 5或CD 27的细胞从外周消失，在治疗后期间，表达CD 69和CD 154的细胞从外周消失。在治疗前，活动性SLE患者的循环中有CD 38（亮）免疫球蛋白分泌细胞，这在正常人中是没有发现的。治疗期间浆细胞亚群的消失与抗双链DNA抗体水平、蛋白尿和SLE疾病活动指数的降低相关。与该发现一致，体外培养的外周B细胞自发增殖并以抗CD 154 mAb抑制的方式分泌IG。最后，外周血中存在的CD 38（+）/（++）IgD（+）、CD 38（+）和CD 38（+）IgD（-）B细胞亚群也在人源化抗CD 154治疗后消失。总之，这些结果表明，活动性狼疮肾炎患者的外周B细胞室表现出异常，这与密集的生发中心活动一致，通过CD 154-CD 40相互作用驱动，并可能反映或有助于这些患者产生自身抗体的倾向。
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.