Science医学：红斑狼疮发病机制

　　

生物通报道 来自耶鲁大学医学院的科学家们在一项研究中获得了令人惊讶的发现，他们证实一种以促进天然抵抗细菌及真菌感染而闻名的酶复合物意料之外地抑制了红斑狼疮的形成。这一发现为开发出这一慢性虚弱性疾病治疗干预铺平了道路。相关研究在线发表在10月24日的《科学转化医学》（Science Translational Medicine）杂志上。

系统性红斑狼疮（SLE）是一种自身免疫性疾病，在这一疾病中免疫系统不仅没有消灭外来病原体，转而攻击了机体的健康组织，导致炎症以及关节和内部器官损伤。当前对于红斑狼疮的病因学还没有获得很好的了解，细胞死亡时产生的碎片被怀疑是疾病的病因。

耶鲁大学的研究人员将研究焦点放在了这一过程中一个称作NADPH氧化酶（Nox2）的关键酶复合物上，评估了它在红斑狼疮发病机制中的作用。

在这项研究之前，人们普遍认为Nox2有可能通过促进中性粒细胞胞外诱捕网(Neutrophil extracellular traps,NETs)生成过程中中性粒细胞的DNA释放来积极促进红斑狼疮形成。为了检测这一假说，耶鲁大学研究小组在缺乏Nox2蛋白的红斑狼疮易感小鼠中评估了疾病。与预期的相反，Nox2缺陷、中性粒细胞没有生成NETs的小鼠不仅仍然获得了红斑狼疮，而且是更为严重的疾病形式。惊讶于这一研究发现，研究人员意识到Nox2的正常功能是抑制而非促进红斑狼疮。

他们现将研究焦点放到了Nox2控制红斑狼疮的机制上。“Nox2显然具有对抗感染的重要作用，而红斑狼疮通常是由感染所触发。我们怀疑Nox2有可能是感染反应和狼疮复发之间的一个重要的连接。我们现在计划探究NADPH氧化酶发挥其作用的机制。这样做应该能够提获得关于该疾病原因的更多认识，”主要作者、耶鲁大学医学院医学与免疫生物学实验室教授Mark Shlomchik博士说。

这对于人类红斑狼疮病例的意义可能是巨大的。Shlomchik 解释说：“我们怀疑没有NADPH氧化酶，中性粒细胞可能以一种激活免疫系统的方式死亡。这或可帮助我们开发出促进NADPH氧化酶功能的治疗，由此抑制这一疾病。”

（生物通：何嫱）

生物通推荐原文摘要：

NADPH Oxidase Inhibits the Pathogenesis of Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by loss of tolerance to self nucleic acids. The source of autoantigen that drives disease onset and progression is unclear. A candidate source of autoantigen is the neutrophil extracellular trap (NET), which releases nucleic acids into the extracellular environment, generating a structure composed of DNA coated with antimicrobial proteins. On the basis of in vitro and patient correlative studies, several groups have suggested that NETs may provide lupus autoantigens. The observation that NET release (NETosis) relies on activity of the phagocyte NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase (Nox2) in neutrophils of both humans and mice provided a genetic strategy to test this hypothesis in vivo. Therefore, we crossed an X-linked nox2 null allele onto the lupus-prone MRL.Faslpr genetic background and assessed immune activation, autoantibody generation, and SLE pathology. Counter to the prevailing hypothesis, Nox2-deficient lupus-prone mice had markedly exacerbated lupus, including increased spleen weight, increased renal disease, and elevated and altered autoantibody profiles. Moreover, heterozygous female mice, which have Nox2 deficiency in 50% of neutrophils, also had exacerbated lupus and altered autoantibody patterns, suggesting that failure to undergo normal Nox2-dependent cell death may result in release of immunogenic self-constituents that stimulate lupus. Our results indicate that NETosis does not contribute to SLE in vivo; instead, Nox2 acts to inhibit disease pathogenesis, making this enzyme an important target for further study and a candidate for therapeutic intervention.