文章：

Nfkbie缺失导致老年小鼠更易发生B细胞淋巴增殖性疾病

Nfkbie-deficiency leads to increased susceptibility to develop B-cell lymphoproliferative disorders in aged mice

原文发布日期：2020-03-13

DOI: 10.1038/s41408-020-0305-6

类型: Article

开放获取: 是

英文摘要：

Aberrant NF-κB activation is a hallmark of most B-cell malignancies. Recurrent inactivating somatic mutations in the NFKBIE gene, which encodes IκBε, an inhibitor of NF-κB-inducible activity, are reported in several B-cell malignancies with highest frequencies in chronic lymphocytic leukemia and primary mediastinal B-cell lymphoma, and account for a fraction of NF-κB pathway activation. The impact of NFKBIE deficiency on B-cell development and function remains, however, largely unknown. Here, we show that Nfkbie-deficient mice exhibit an amplification of marginal zone B cells and an expansion of B1 B-cell subsets. In germinal center (GC)-dependent immune response, Nfkbie deficiency triggers expansion of GC B-cells through increasing cell proliferation in a B-cell autonomous manner. We also show that Nfkbie deficiency results in hyperproliferation of a B1 B-cell subset and leads to increased NF-κB activation in these cells upon Toll-like receptor stimulation. Nfkbie deficiency cooperates with mutant MYD88 signaling and enhances B-cell proliferation in vitro. In aged mice, Nfkbie absence drives the development of an oligoclonal indolent B-cell lymphoproliferative disorders, resembling monoclonal B-cell lymphocytosis. Collectively, these findings shed light on an essential role of IκBε in finely tuning B-cell development and function.
 

摘要翻译： 

异常的NF-κB激活是大多数B细胞恶性肿瘤的标志。NFKBIE基因（编码NF-κB诱导活性的抑制因子IκBε）反复发生的失活体细胞突变，据报道存在于多种B细胞恶性肿瘤中，其中在慢性淋巴细胞白血病和原发性纵隔B细胞淋巴瘤中频率最高，并部分解释了NF-κB通路的激活。然而，NFKBIE缺陷对B细胞发育和功能的影响在很大程度上仍不清楚。本文中，我们发现Nfkbie缺陷小鼠表现出边缘区B细胞的扩增和B1 B细胞亚群的增多。在生发中心依赖性免疫应答中，Nfkbie缺陷通过以B细胞自主方式增加细胞增殖，引发生发中心B细胞的扩增。我们还发现，Nfkbie缺陷导致B1 B细胞亚群的过度增殖，并在Toll样受体刺激后增强这些细胞中NF-κB的激活。Nfkbie缺陷与突变型MYD88信号传导协同作用，并在体外增强B细胞增殖。在老年小鼠中，Nfkbie缺失驱动了寡克隆惰性B细胞淋巴增生性疾病的发展，类似于单克隆B细胞淋巴细胞增多症。总之，这些发现揭示了IκBε在精细调节B细胞发育和功能中的重要作用。

原文链接：

Nfkbie-deficiency leads to increased susceptibility to develop B-cell lymphoproliferative disorders in aged mice