Immunity：研究者揭示X连锁的淋巴细胞异常增生症相关的分子机制

近日，来自加拿大的研究者通过研究揭示了和人类免疫系统疾病-X连锁的淋巴细胞异常增生症（XLP disease）相关的分子机制，相关研究成果刊登在近日的国际杂志Immunity上。研究者Veillette表示，他们研究发现SAP分子在多种类型的免疫细胞中扮演着重要的角色，而且，他们试图去理解为什么SAP是自然杀伤细胞的重要组分，自然杀伤细胞可以有效清除异常的血细胞。

自然杀伤细胞（NKC）对于免疫系统至关重要，而且可以对癌症和病毒感染细胞（尤其是白血病和淋巴瘤中的血细胞）有高度的反应，XLP病人有较高的患淋巴瘤的风险。直到现在，SAP增强NK细胞对异常效应血细胞产生效应的机制并不清楚，因此研究者通过研究发现，SAP是通过双重的机制来激活NK细胞功能的，一方面，SAP可以偶联必要的基因和酶来增强NK细胞的杀伤效应；另一方面，它可以抑制基因产生效应。

SAP与大多数XLP病人密切相关，另外，研究者的研究也阐明了SAP在其它疾病诸如狼疮和关节炎等中的作用。XLP疾病，即邓肯综合征，是一种全球性的影响男孩健康的致死疾病。疾病的病因在1998年被发现，如果被诊断发现没有及时治疗，70%的病人会在10岁之前死亡。

研究者的研究由加拿大卫生研究院等机构支持。

编译自：Molecular Mechanism Associated With Human Immune Disorder, XLP Disease, Explained

编译者：天使托

doi:10.1016/j.immuni.2012.03.023
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The Adaptor SAP Controls NK Cell Activation by Regulating the Enzymes Vav-1 and SHIP-1 and by Enhancing Conjugates with Target Cells

Zhongjun Dong, Dominique Davidson, Luis Alberto Pérez-Quintero, Tomohiro Kurosaki, Wojciech Swat, André Veillette

The adaptor SAP, mutated in X-linked lymphoproliferative disease, has critical roles in multiple immune cell types. Among these, SAP is essential for the ability of natural killer (NK) cells to eliminate abnormal hematopoietic cells. Herein, we elucidated the molecular and cellular bases of this activity. SAP enhanced NK cell responsiveness by a dual molecular mechanism. It coupled SLAM family receptors to the kinase Fyn, which triggered the exchange factor Vav-1 and augmented NK cell activation. SAP also prevented the inhibitory function of SLAM family receptors. This effect was Fyn independent and correlated with uncoupling of SLAM family receptors from the lipid phosphatase SHIP-1. Both mechanisms cooperated to enable conjugate formation with target cells and to stimulate cytotoxicity and cytokine secretion by NK cells. These data showed that SAP secures NK cell activation by a dichotomous molecular mechanism, which is required for conjugate formation. These findings may have implications for the role of SAP in other immune cell types.