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.

异常的NF-κB激活是大多数B细胞恶性肿瘤的标志。在慢性淋巴细胞性白血病和原发性纵隔B细胞淋巴瘤中，有几种频率最高的B细胞恶性肿瘤中报道了NFKBIE基因的反复失活体细胞突变，该突变编码IκBε（一种抑制NF-κB的活性）。 NF-κB途径活化的一部分。的影响NFKBIE缺乏对B细胞的发育和功能的遗体，但还不清楚。在这里，我们显示Nfkbie缺陷小鼠表现出边缘区B细胞的扩增和B1 B细胞亚群的扩展。在生发中心（GC）依赖性免疫反应中，Nfkbie缺乏会通过以B细胞自主方式增加细胞增殖来触发GC B细胞扩增。我们还显示，Nfkbie缺乏会导致B1 B细胞亚群过度增殖，并在Toll样受体刺激后导致这些细胞中的NF-κB活化增加。Nfkbie缺乏症与突变MYD88信号转导合作，并在体外增强B细胞增殖。在老年小鼠中，Nfkbie的缺乏会导致寡克隆惰性B细胞淋巴细胞增生性疾病的发展，类似于单克隆B细胞淋巴细胞增多。总而言之，这些发现阐明了IκBε在微调B细胞发育和功能中的重要作用。