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首页> 外文期刊>Immunity Ageing >The immunosenescence-related gene Zizimin2 is associated with early bone marrow B cell development and marginal zone B cell formation
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The immunosenescence-related gene Zizimin2 is associated with early bone marrow B cell development and marginal zone B cell formation

机译：免疫衰老相关基因Zizimin2与早期骨髓B细胞发育和边缘B区细胞形成有关

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We originally cloned and identified murine Zizimin2 (Ziz2, Dock11) as a guanine nucleotide exchange factor (GEF) for Cdc42 and demonstrated that it activated the formation of filopodia. Since its expression pattern is restricted in immune tissues and Rho GTPases such as Cdc42 function in B cell development and immune responses, we expected Ziz2 to also be associated with B cell development and immune responses. However, the function of Ziz2 has not yet been fully examined in vivo. We also recently discovered that Ziz2 expression levels in immune tissues were reduced with aging in the mouse, suggesting that its expression is also associated with the mechanisms of immuno-senescence. To gain insights into the mechanisms underlying immuno-senescence, we generated Ziz2 knock out (KO) mice and examined the functions of Ziz2 in B cell development and immune responses. We also obtained Zizimin3 (Ziz3; Dock10) KO mice and examined the functions of Ziz3. The results revealed that Ziz2 KO mice had a higher percentage of early bone marrow B cells (Fraction A), but a reduced fraction of marginal zone (MZ) B cells. In addition, an examination of B cell-specific Ziz2 KO mice revealed that Ziz2 was intrinsically required for MZ B cell development, but not for mature follicular B cells. However, immune responses against NP-CGG (T cell-dependent), TNP-LPS (T cell-independent, TI, type I), and TNP-Ficoll (TI, type II) were not altered in KO mice. We finally demonstrated that CD1d-positive MZ B cell region outside CD169-positive marginal metallophilic macrophages (MMM) was narrowed in Ziz2 KO mice. Furthermore, MMM morphology appeared to be altered in Ziz2 KO mice. In conclusion, we herein showed that Ziz2 was associated with early bone marrow B cell development, MZ B cell formation, MZ B number/localization around MZ, and MMM morphology which may explain in part the mechanism underlying immuno-senescence.
机译：我们最初克隆并鉴定了鼠Zizimin2（Ziz2，Dock11）作为Cdc42的鸟嘌呤核苷酸交换因子（GEF），并证明它激活了丝状伪足的形成。由于其表达模式在免疫组织和Rho GTP酶（如Cdc42在B细胞发育和免疫反应中）中受到限制，因此我们预期Ziz2也与B细胞发育和免疫反应有关。但是，Ziz2的功能尚未在体内进行全面检查。我们最近还发现，随着小鼠衰老，免疫组织中Ziz2的表达水平降低，这表明其表达也与免疫衰老的机制有关。为了深入了解免疫衰老的潜在机制，我们生成了Ziz2基因敲除（KO）小鼠，并研究了Ziz2在B细胞发育和免疫应答中的功能。我们还获得了Zizimin3（Ziz3; Dock10）KO小鼠，并检查了Ziz3的功能。结果显示，Ziz2 KO小鼠的早期骨髓B细胞百分比更高（组分A），但边缘区（MZ）B细胞的分数却降低了。此外，对B细胞特异性Ziz2 KO小鼠的检查显示，Ziz2本质上是MZ B细胞发育所必需的，而对于成熟的滤泡B细胞则不是。但是，在KO小鼠中，针对NP-CGG（T细胞依赖性），TNP-LPS（非T细胞依赖性，TI，I型）和TNP-Ficoll（TI，II型）的免疫反应没有改变。我们最终证明，Ziz2 KO小鼠体内CD169阳性边缘嗜金属巨噬细胞（MMM）以外的CD1d阳性MZ B细胞区域变窄。此外，MMM形态似乎在Ziz2 KO小鼠中发生了改变。总之，我们在本文中显示Ziz2与早期骨髓B细胞发育，MZ B细胞形成，MZ B数量/ MZ周围的定位以及MMM形态有关，这可能部分解释了免疫衰老的机制。

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