The BCL-6 proto-oncogene controls germinal-centre formation and Th2-type inflammation
The BCL-6 proto-oncogene controls germinal-centre formation and Th2-type inflammation
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DOI：
10.1038/ng0697-161
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发表时间：
1997-06-01
期刊：
影响因子：
30.8
通讯作者：
DallaFavera, R
中科院分区：
文献类型：
--
作者：
Ye, BH;Cattoretti, G;DallaFavera, R
BCL - 6原癌基因启动子区域的结构改变是与非霍奇金淋巴瘤相关的最常见基因改变，非霍奇金淋巴瘤是一种常起源于生发中心B细胞的恶性肿瘤。BCL - 6基因编码一种锌指转录抑制因子，通常在生发中心内的B细胞和CD4(+)T细胞中表达，但其确切功能尚不清楚。我们发现BCL - 6缺陷的小鼠表现出正常的B细胞、T细胞和淋巴器官发育，但在T细胞依赖性抗体应答方面存在选择性缺陷。这种缺陷包括完全缺乏亲和力成熟，原因是滤泡B细胞无法增殖并形成生发中心。此外，BCL - 6缺陷小鼠在多个器官中发生炎症反应，其特征是嗜酸性粒细胞浸润以及携带IgE的B淋巴细胞浸润，这是典型的Th2介导的超免疫反应。因此，BCL - 6作为一种转录开关发挥作用，控制生发中心的形成，并且可能还调节特定的T细胞介导的反应。淋巴瘤中BCL - 6表达的改变代表了正常导致B细胞增殖和生发中心形成的通路失调。
Structural alterations of the promoter region of the BCL-6 proto-oncogene represent the most frequent genetic alteration associated with non-Hodgkin lymphoma, a malignancy often deriving from germinal-centre B cells. The BCL-6 gene encodes a zinc-finger transcriptional repressor normally expressed in both B cells and CD4(+) T cells within germinal centres, but its precise function is unknown. We show that mice deficient in BCL-6 displayed normal B-cell, T-cell and lymphoid-organ development but have a selective defect in T-cell-dependent antibody responses. This defect included a complete lack of affinity maturation and was due to the inability of follicular B cells to proliferate and form germinal centres. In addition, BCL-6-deficient mice developed an inflammatory response in multiple organs characterized by infiltrations of eosinophils and IgE-bearing B lymphocytes typical of a Th2-mediated hyperimmune response. Thus, BCL-6 functions as a transcriptional switch that controls germinal centre formation and may also modulate specific T-cell-mediated responses. Altered expression of BCL-6 in lymphoma represents a deregulation of the pathway normally leading to B cell proliferation and germinal centre formation.