Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7276, Université de Limoges, 87025 Limoges, France;
Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7276, Université de Limoges, 87025 Limoges, France; Centre Hospitalier Universitaire Dupuytren, Centre de Référence des Amyloses, 87042 Limoges, France; and.
J Immunol. 2014 Aug 1;193(3):1171-83. doi: 10.4049/jimmunol.1302868. Epub 2014 Jun 25.
The IgH intronic enhancer region Eμ is a combination of both a 220-bp core enhancer element and two 310-350-bp flanking scaffold/matrix attachment regions named MARsEμ. In the mouse, deletion of the core-enhancer Eμ element mainly affects VDJ recombination with minor effects on class switch recombination. We carried out endogenous deletion of the full-length Eμ region (core plus MARsEμ) in the mouse genome to study VH gene repertoire and IgH expression in developing B-lineage cells. Despite a severe defect in VDJ recombination with partial blockade at the pro-B cell stage, Eμ deletion (core or full length) did not affect VH gene usage. Deletion of this regulatory region induced both a decrease of pre-B cell and newly formed B cell compartments and a strong orientation toward the marginal zone B cell subset. Because Igμ H chain expression was decreased in Eμ-deficient pre-B cells, we propose that modification of B cell homeostasis in deficient animals was caused by "weak" pre-B cell and BCR expression. Besides imbalances in B cell compartments, Ag-specific Ab responses were not impaired in animals carrying the Eμ deletion. In addition to its role in VDJ recombination, our study points out that the full-length Eμ region does not influence VH segment usage but ensures efficient Igμ-chain expression required for strong signaling through pre-B cells and newly formed BCRs and thus participates in B cell inflow and fate.
IgH 内含子增强子区域 Eμ 是一个 220bp 核心增强子元件和两个 310-350bp 侧翼支架/基质附着区域（MARsEμ）的组合。在小鼠中，核心增强子 Eμ 元件的缺失主要影响 VDJ 重组，对类别转换重组的影响较小。我们在小鼠基因组中进行了全长 Eμ 区域（核心加 MARsEμ）的内源缺失，以研究发育中的 B 细胞谱系细胞中的 VH 基因库和 IgH 表达。尽管 VDJ 重组存在严重缺陷，在 pro-B 细胞阶段出现部分阻断，但 Eμ 缺失（核心或全长）并不影响 VH 基因的使用。该调控区的缺失诱导了前 B 细胞和新形成的 B 细胞区室的减少，并强烈偏向边缘区 B 细胞亚群。由于 Eμ 缺陷前 B 细胞中 Igμ H 链表达减少，我们提出，缺陷动物中 B 细胞稳态的改变是由“弱”前 B 细胞和 BCR 表达引起的。除了 B 细胞区室的失衡外，携带 Eμ 缺失的动物的抗原特异性 Ab 反应没有受损。除了在 VDJ 重组中的作用外，我们的研究还指出，全长 Eμ 区域不会影响 VH 片段的使用，但确保了 Igμ 链表达的有效性，这是通过前 B 细胞和新形成的 BCR 进行强信号所必需的，从而参与 B 细胞流入和命运。
