Heinrich Pette Institute - Leibniz Institute for Experimental Virology, Martinistrasse 52, 20251, Hamburg, Germany.
Department of Immune Modulation, University Hospital Erlangen, Hartmannstrasse 14, 91052, Erlangen, Germany.
Sci Rep. 2019 Mar 19;9(1):4853. doi: 10.1038/s41598-019-41269-z.
ANP32B belongs to a family of evolutionary conserved acidic nuclear phosphoproteins (ANP32A-H). Family members have been described as multifunctional regulatory proteins and proto-oncogenic factors affecting embryonic development, cell proliferation, apoptosis, and gene expression at various levels. Involvement of ANP32B in multiple processes of cellular life is reflected by the previous finding that systemic gene knockout (KO) of Anp32b leads to embryonic lethality in mice. Here, we demonstrate that a conditional KO of Anp32b is well tolerated in adult animals. However, after immune activation splenocytes isolated from Anp32b KO mice showed a strong commitment towards Th17 immune responses. Therefore, we further analyzed the respective animals in vivo using an experimental autoimmune encephalomyelitis (EAE) model. Interestingly, an exacerbated clinical score was observed in the Anp32b KO mice. This was accompanied by the finding that animal-derived T lymphocytes were in a more activated state, and RNA sequencing analyses revealed hyperactivation of several T lymphocyte-associated immune modulatory pathways, attended by significant upregulation of Tfh cell numbers that altogether might explain the observed strong autoreactive processes. Therefore, Anp32b appears to fulfill a role in regulating adequate adaptive immune responses and, hence, may be involved in dysregulation of pathways leading to autoimmune disorders and/or immune deficiencies.
ANP32B 属于进化保守的酸性核磷蛋白（ANP32A-H）家族。该家族成员被描述为多功能调节蛋白和原癌基因因子，可在多个层面上影响胚胎发育、细胞增殖、凋亡和基因表达。ANP32B 参与细胞生命的多个过程，这反映在先前的研究中，即全身性基因敲除（KO）Anp32b 会导致小鼠胚胎致死。在这里，我们证明条件性 KO Anp32b 在成年动物中是可以耐受的。然而，在免疫激活后，从 Anp32b KO 小鼠中分离的脾细胞强烈倾向于 Th17 免疫反应。因此，我们进一步在实验性自身免疫性脑脊髓炎（EAE）模型中对相应的动物进行了分析。有趣的是，在 Anp32b KO 小鼠中观察到更严重的临床评分。这伴随着发现动物来源的 T 淋巴细胞处于更活跃的状态，RNA 测序分析揭示了几个与 T 淋巴细胞相关的免疫调节途径的过度激活，伴随着滤泡辅助性 T 细胞（Tfh）数量的显著上调，这些途径可能共同解释了观察到的强烈自身反应过程。因此，Anp32b 似乎在调节适当的适应性免疫反应中发挥作用，因此可能参与导致自身免疫疾病和/或免疫缺陷的途径失调。
