Rituximab does not reset defective early B cell tolerance checkpoints
Rituximab does not reset defective early B cell tolerance checkpoints
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DOI：
10.1172/jci83840
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发表时间：
2016-01-01
影响因子：
15.9
通讯作者：
Meffre, Eric
中科院分区：
文献类型：
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作者：
Chamberlain, Nicolas;Massad, Christopher;Meffre, Eric
1型糖尿病（T1D）患者在早期B细胞耐受检查点中显示出异常，导致大量自身反应性B细胞在其血液中积累。利妥昔单抗是一种抗CD20单抗，可消耗B细胞，已被证明可保护T1D患者的β细胞功能，并改善其他自身免疫性疾病，包括类风湿性关节炎和多发性硬化症。然而，抗B细胞治疗如何在这些病理中阻止自身免疫仍然是未知的。在此，我们分析了4例T1D患者治疗前和治疗后52周的单个成熟幼稚B细胞表达的抗体反应性，以确定利妥昔单抗是否重置早期B细胞耐受检查点。我们发现，抗B细胞治疗并没有改变自身反应性和多反应性B细胞的频率，在利妥昔单抗治疗后，所有患者的血液中的B细胞仍然升高。此外，治疗后自身反应性B细胞的有限增殖史表明，这些克隆是新产生的B细胞，而不是通过稳态扩增逃避耗竭并重新在外周增殖的自身反应性B细胞。我们的结论是，抗B细胞治疗可以通过B细胞耗竭提供自身免疫过程的暂时抑制。然而，自身反应性B细胞的补充可以解释许多自身免疫患者在抗B细胞治疗后复发的原因。
Type 1 diabetes (T1D) patients show abnormalities in early B cell tolerance checkpoints, resulting in the accumulation of large numbers of autoreactive B cells in their blood. Treatment with rituximab, an anti-CD20 mAb that depletes B cells, has been shown to preserve beta cell function in T1D patients and improve other autoimmune diseases, including rheumatoid arthritis and multiple sclerosis. However, it remains largely unknown how anti-B cell therapy thwarts autoimmunity in these pathologies. Here, we analyzed the reactivity of Abs expressed by single, mature naive B cells from 4 patients with T1D before and 52 weeks after treatment to determine whether rituximab resets early B cell tolerance checkpoints. We found that anti-B cell therapy did not alter the frequencies of autoreactive and polyreactive B cells, which remained elevated in the blood of all patients after rituximab treatment. Moreover, the limited proliferative history of autoreactive B cells after treatment revealed that these clones were newly generated B cells and not self-reactive B cells that had escaped depletion and repopulated the periphery through homeostatic expansion. We conclude that anti-B cell therapy may provide a temporary dampening of autoimmune processes through B cell depletion. However, repletion with autoreactive B cells may explain the relapse that occurs in many autoimmune patients after anti-B cell therapy.