Laboratoire I3 Immunologie, Immunopathologie, Immunothérapeutique, Centre National de la Recherche Scientifique Unité Mixte de Recherche 7211 et INSERM U959, Groupe Hospitalier Pitié-Salpétrière, Université Pierre et Marie Curie, F-75013 Paris, France.
J Immunol. 2011 Dec 15;187(12):6550-63. doi: 10.4049/jimmunol.1102022. Epub 2011 Nov 14.
Homeostasis of peripheral B cell subsets is disturbed during chronic hepatitis C virus (HCV) infection, leading to the occurrence of autoimmunity and B cell lymphoproliferation. However, mechanisms by which HCV causes lymphoproliferation remain controversial. We report in this article on the elevated number of clonal CD21(-/low)IgM(+)CD27(+) marginal zone (MZ)-like B cells, which correlates with autoimmunity and lymphoproliferation in HCV patients. We found an increase in autoreactive BCRs using V(H)1-69 and V(H)4-34 genes in CD21(-/low) MZ B cells. CD21(-/low) MZ B cells showed impaired calcium-mediated signaling, did not upregulate activation markers, and did not proliferate in response to BCR triggering. CD21(-/low) MZ B cells also were prone to dying faster than their CD21(+) counterparts, suggesting that these B cells were anergic. CD21(-/low) MZ B cells, in contrast, remained responsive to TLR9 stimulation. Gene array analyses revealed the critical role of Early growth response 2 and Cbl-b in the induction of anergy. Therefore, HCV patients who display high frequencies of unresponsive CD21(-/low) MZ B cells are more susceptible to developing autoimmunity and/or lymphoproliferation. These cells remain in peripheral blood controlled by functional anergy instead of being eliminated, and chronic antigenic stimulation through TLR stimulation may create a favorable environment for breaking tolerance and activating these cells.
外周 B 细胞亚群的稳态在慢性丙型肝炎病毒（HCV）感染期间受到干扰，导致自身免疫和 B 细胞淋巴增生的发生。然而，HCV 导致淋巴增生的机制仍存在争议。我们在本文中报告了 HCV 患者中克隆性 CD21(-/low)IgM(+)CD27(+)边缘区（MZ）样 B 细胞数量的增加，这与自身免疫和淋巴增生相关。我们发现使用 CD21(-/low) MZ B 细胞中的 V(H)1-69 和 V(H)4-34 基因，自身反应性 BCR 增加。CD21(-/low) MZ B 细胞表现出钙介导信号的受损，不会上调激活标志物，并且不会对 BCR 触发产生增殖反应。CD21(-/low) MZ B 细胞也比其 CD21(+)对应物更快死亡，表明这些 B 细胞是无反应性的。相比之下，CD21(-/low) MZ B 细胞仍然对 TLR9 刺激有反应。基因阵列分析显示 Early growth response 2 和 Cbl-b 在诱导无反应性中的关键作用。因此，显示无反应性 CD21(-/low) MZ B 细胞频率较高的 HCV 患者更容易发生自身免疫和/或淋巴增生。这些细胞仍受功能无反应性的控制而不会被消除，并且通过 TLR 刺激的慢性抗原刺激可能为打破耐受和激活这些细胞创造有利环境。
