Varfolomeev Eugene, Kischkel Frank, Martin Flavius, Seshasayee Dhaya, Wang Hua, Lawrence David, Olsson Christine, Tom Lucrece, Erickson Sharon, French Dorothy, Schow Peter, Grewal Iqbal S, Ashkenazi Avi
Department of Molecular Oncology, Genentech Inc., South San Francisco, California 94080, USA.
Mol Cell Biol. 2004 Feb;24(3):997-1006. doi: 10.1128/MCB.24.3.997-1006.2004.
APRIL (a proliferation-inducing ligand) is a member of the tumor necrosis factor (TNF) superfamily. APRIL mRNA shows high levels of expression in tumors of different origin and a low level of expression in normal cells. APRIL shares two TNF receptor family members, TACI and BCMA, with another TNF homolog, BLyS/BAFF. BLyS is involved in regulation of B-cell activation and survival and also binds to a third receptor, BR3/BAFF-R, which is not shared with APRIL. Recombinant APRIL and BLyS induce accumulation of B cells in mice, while BLyS deficiency results in severe B-cell dysfunction. To investigate the physiological role of APRIL, we generated mice that are deficient in its encoding gene. APRIL(-/-) mice were viable and fertile and lacked any gross abnormality. Detailed histological analysis did not reveal any defects in major tissues and organs, including the primary and secondary immune organs. T- and B-cell development and in vitro function were normal as well, as were T-cell-dependent and -independent in vivo humoral responses to antigenic challenge. These data indicate that APRIL is dispensable in the mouse for proper development. Thus, BLyS may be capable of fulfilling APRIL's main functions.
增殖诱导配体（APRIL）是肿瘤坏死因子（TNF）超家族的成员。APRIL信使核糖核酸（mRNA）在不同起源的肿瘤中表达水平较高，而在正常细胞中表达水平较低。APRIL与另一种TNF同源物B淋巴细胞刺激因子（BLyS）/B细胞活化因子（BAFF）共有两个TNF受体家族成员，即跨膜激活剂和钙调素及环磷酰胺调节因子（TACI）和B细胞成熟抗原（BCMA）。BLyS参与B细胞活化和存活的调节，并且还与第三种受体B细胞成熟抗原受体（BR3）/BAFF受体（BAFF-R）结合，而该受体并非APRIL所共有。重组APRIL和BLyS可诱导小鼠体内B细胞积聚，而BLyS缺陷则导致严重的B细胞功能障碍。为了研究APRIL的生理作用，我们培育出了编码基因缺陷的小鼠。APRIL基因敲除（-/-）小鼠能够存活且可育，没有任何明显异常。详细的组织学分析未发现包括初级和次级免疫器官在内的主要组织和器官有任何缺陷。T细胞和B细胞的发育及体外功能正常，对抗原刺激的T细胞依赖性和非依赖性体内体液反应也正常。这些数据表明，在小鼠中，APRIL对于正常发育并非必需。因此，BLyS可能能够履行APRIL的主要功能。
