炎症复合体通过识别微生物或宿主DNA诱发固有免疫反应

在感染和组织损伤过程中释放的核苷酸能被机体固有免疫系统识别。NALPS是一类NOD样蛋白受体（为CARTERPILLER蛋白家族成员），NALP3能够感受外源性、内源性的配体，腺病毒DNA被吞噬后，NALP3蛋白通过接头蛋白ASC来募集caspase-1来形成炎症复合体，参与caspase-1的活化与IL-1B前体的成熟过程，腺病毒衣壳蛋白无此作用。     

病毒固有免疫识别受体研究进展

固有免疫应答是机体抵御病毒入侵的第一道防线,其前提则是病毒固有免疫识别受体对病毒感染相关模式分子的识别.目前病毒固有免疫识别受体主要是Toll样受体家族和RIG样受体家族的成员.现就这些受体的特征及其在识别病毒感染相关模式分子过程中的作用作一综述.     

模式识别受体NLRC3的生物学效应及在免疫相关疾病中的研究进展

固有免疫系统是宿主抵御病原微生物攻击的第一道防线。可以快速识别并产生免疫反应，清除致病微生物。然而，强烈的免疫反应可能会导致过度炎症，甚至自身免疫性疾病。含胱天蛋白酶活化和募集结构域核苷酸结合寡聚结构域样受体3(NLRC3)位于细胞质中，是固有免疫系统的重要负调节因子，可以抑制体内过度的免疫反应。NLRC3既能够通过影响核因子κB(NF-κB)和干扰素基因刺激因子(STING)相关信号通路，减少促炎细胞因子的产生；还能通过干扰含pyrin结构域核苷酸结合寡聚结构域样受体家族蛋白3(NLRP3)炎性体复合体的组装和活性来抑制炎症反应。此外，还可以通过调控磷脂酰肌醇激酶3/哺乳动物雷帕霉素靶蛋白(PI3K/mTOR)等通路影响细胞的代谢、增殖、凋亡等生物学行为。NLRC3对细胞功能的这些调控作用，与感染性疾病、自身免疫性疾病和肿瘤等多种免疫相关性疾病的发生发展密切相关，通过调控NLRC3的表达可能成为治疗这些疾病的一个有效途径。     

CD100的分子生物学及其与疾病的关系

CD100是第1个被发现有免疫功能的脑信号蛋白分子,又称脑信号蛋白4D(Sema4D),在神经系统和免疫系统中发挥着重要作用。近年来随着对其研究的深入,发现CD100还与很多疾病的发生发展有重要关系,例如免疫性疾病、肿瘤、心血管疾病、肾炎、皮肤损伤等。本文主要综述了CD100的分子结构、受体、在免疫反应中的功能及与疾病的关系。     

自身免疫性疾病的基因治疗研究进展

自身免疫性疾病是危害人类健康的重要疾病.随着基因转移技术的发展,基因治疗在自身免疫性疾病中的研究取得了一定进展.通过选择合适的载体转导免疫调节分子、缺陷基因、激活因子、细胞凋亡受体以及诱导免疫耐受等方式来达到治疗目的 .与传统的治疗方法相比,基因治疗具有高效性、靶向性、副作用小等优点.近几年来自身免疫性疾病的基因治疗在临床前实验和临床实验阶段取得了很多成果.     

肿瘤坏死因子α诱导蛋白8家族的研究进展

肿瘤坏死因子α诱导蛋白8（TNFAIP8）是调控凋亡过程的重要分子之一.随着研究的不断深入,TNFAIP8蛋白在细胞凋亡、信号转导、肿瘤细胞增生、侵袭及转移等生命过程中具有重要的调节作用.TNFAIP8家族成员TIPE2是一个新发现的蛋白分子,通过对T细胞受体和Toll样受体信号途径实行负向调控,进而调节机体固有免疫应答和适应性免疫应答过程.TNFAIP8蛋白的多效应性及TIPE2在维持机体免疫动态平衡中的调控作用预示着TNFAIP8家族在免疫学及医学研究中可能极具应用价值.本文综述了TNFAIP8及TIPE2蛋白结构和生物学功能研究的最新认识,并介绍TNFAIP8及TIPE2表达异常与疾病发生的关系和临床意义.     

NLRP3信号通路介导的睾丸固有免疫研究进展北大核心CSCD

NLR家族蛋白结构域-3(NLRP3)是一种胞浆传感器,是睾丸固有免疫模式识别受体家族的重要成员,能激活含半胱氨酸的天冬氨酸蛋白水解酶(caspase)和诱导IL-1β成熟。NLRP3与睾丸固有免疫过激导致的男性不育关系密切。因此,NLRP3有望成为极具价值的男性不育治疗靶标。本文总结了目前对NLRP3参与睾丸固有免疫的相关机制的研究结果,描述了NLRP3在睾丸组织内的广泛分布及功能,对调节睾丸NLRP3信号通路的抑制剂进行了汇总阐述,为NLRP3相关睾丸免疫问题提供更深入的见解。     

Toll样受体7作为新靶点在过敏性及自身免疫性疾病中的研究进展

Toll样受体(Toll-like receptors,TLRs)属于模式识别受体(pattern recognition receptors,PRRs)家族,通过迅速识别入侵微生物病原相关分子模式(pathogen-associated molecular patterns,PAMP)激活下游信号传导途径,引发机体的免疫反应,是连接固有免疫与适应性免疫的桥梁.目前在人类发现10种不同TLRs,分别命名为TLR1 ～TLR10.近年的研究显示,TLR7与过敏性疾病、自身免疫性疾病—过敏性哮喘、系统性红斑狼疮(systemic lupus erythematosus,SLE)等有密切的联系.TLR7的激活状态影响上述疾病的发生、发展和预后.这些证据预示TLR7可能作为潜在靶点为哮喘和SLE的治疗提供新的方向.     

Toll样受体4介导的抗病毒固有免疫研究进展

Toll样受体(TLR)是一类模式识别受体(PRR),人TLR分布在细胞表面或细胞内。不同TLR识别病原体的不同结构成分后,启动固有免疫反应。其中,TLR4在TLR家族中占有重要地位。它除了识别细菌的脂多糖(LPS)外,还可识别一些病毒的蛋白如水泡性口炎病毒的G糖蛋白、呼吸道合胞病毒的F蛋白。病毒包膜糖蛋白也是TLR4识别的配体。TLR4通过髓样分化因子88(My D88)和β干扰素TIR结构域衔接蛋白(TRIF)途径活化下游核因子κB(NF-κB)、干扰素调节因子3(IRF3)转录因子,产生细胞因子/趋化因子和1型干扰素等,在抗病毒免疫反应、免疫细胞分化及调节、发病机制、药物及疫苗研制等方面具有重要意义。     

雌激素及其受体与自身免疫性疾病

自身免疫性疾病有明显的性别差异，女性的发病率显著高于男性，表明雌激素影响这类疾病的发生。雌激素及其代谢产物水平、雌激素受体基因多态性、雌激素受体介导的信号通路等方面与自身免疫性疾病密切相关，雌激素及其受体在自身免疫性疾病治疗中发挥重要作用。     

NALP Inflammasomes: a central role in innate immunity

Inflammasomes are cytoplasmic multiprotein complexes that mediate the maturation of the proinflammatory cytokines interleukin-1β (IL-1β), IL-18, and possibly IL-33 by controlling the activation of the inflammatory caspases-1 and -5. Assembly of inflammasomes depends on NOD-like receptor (NLR) family members such as NALPs, NAIP, and IPAF. Various microbial and endogenous stimuli activate different types of inflammasomes. This article focuses on the Pyrin domain containing NLRs, known as NALP proteins. Recent findings provide exciting insights into how these proteins might be activated and also provide evidence of the critical role of the NALP inflammasomes in innate immunity and inflammatory diseases.     

The inflammasome: a danger sensing complex triggering innate immunity

The NOD-like receptors (NLR) are a family of intracellular sensors of microbial motifs and 'danger signals' that have emerged as being crucial components of the innate immune responses and inflammation. Several NLRs (NALPs and IPAF) form a caspase-1-activating multiprotein complex, termed inflammasome, that processes proinflammatory cytokines including IL-1beta. Amongst the various inflammasomes, the NALP3 inflammasome is particularly qualified to sense a plethora of diverse molecules, ranging from bacterial muramyldipeptide to monosodium urate crystals. The important role of the NALP3 inflammasome is emphasized by the identification of mutations in the NALP3 gene that are associated with a susceptibility to inflammatory disorders. These and other issues related to the inflammasome are discussed in this review.     

Inflammasomes: guardians of cytosolic sanctity

Summary:  The innate immune system is critical in recognizing bacterial and viral infections to evoke a proper immune response. Certain members of the intracellular nucleotide-binding and oligomerization domain (NOD)-like receptor (NLR) family detect microbial components in the cytosol and trigger the assembly of large caspase-1-activating complexes termed inflammasomes. Autoproteolytic maturation of caspase-1 zymogens within these inflammasomes leads to maturation and secretion of the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18. The NLR proteins ICE protease-activating factor (IPAF), NALP1b (NACHT domain-, leucine-rich repeat-, and PYD-containing protein 1b), and cryopyrin/NALP3 assemble caspase-1-activating inflammasomes in a stimulus-dependent manner. Bacterial flagellin is sensed by IPAF, whereas mouse NALP1b detects anthrax lethal toxin. Cryopyrin/NALP3 mediates caspase-1 activation in response to a wide variety of microbial components and in response to crystalline substances such as the endogenous danger signal uric acid. Genetic variations in Nalp1 and cryopyrin/Nalp3 are associated with autoinflammatory disorders and increased susceptibility to microbial infection. Further understanding of inflammasomes and their role in innate immunity should provide new insights into the mechanisms of host defense and the pathogenesis of autoimmune diseases.     

NALP1:一种新的参与炎症和凋亡的胞内蛋白

NALP1(NACHT leucine-rich-repeat protein 1)属于NLRs(NOD-like receptors)家族中一员,主要参与炎症体(inflammasome)的组装活化以及凋亡体(apoptosome)的诱导形成,从而在炎症反应和细胞凋亡的调节机制中发挥着重要的生物学作用。此外,鉴于NALP1在神经变性性疾病、血液疾病、自身炎症性疾病以及感染性疾病中差异性表达以及致病性作用,将为NALP1相关疾病提供新的诊断和治疗依据。     

NALP1 influences susceptibility to human congenital toxoplasmosis, proinflammatory cytokine response, and fate of Toxoplasma gondii-infected monocytic cells

NALP1 is a member of the NOD-like receptor (NLR) family of proteins that form inflammasomes. Upon cellular infection or stress, inflammasomes are activated, triggering maturation of proinflammatory cytokines and downstream cellular signaling mediated through the MyD88 adaptor. Toxoplasma gondii is an obligate intracellular parasite that stimulates production of high levels of proinflammatory cytokines that are important in innate immunity. In this study, susceptibility alleles for human congenital toxoplasmosis were identified in the NALP1 gene. To investigate the role of the NALP1 inflammasome during infection with T. gondii, we genetically engineered a human monocytic cell line for NALP1 gene knockdown by RNA interference. NALP1 silencing attenuated progression of T. gondii infection, with accelerated host cell death and eventual cell disintegration. In line with this observation, upregulation of the proinflammatory cytokines interleukin-1β (IL-1β), IL-18, and IL-12 upon T. gondii infection was not observed in monocytic cells with NALP1 knockdown. These findings suggest that the NALP1 inflammasome is critical for mediating innate immune responses to T. gondii infection and pathogenesis. Although there have been recent advances in understanding the potent activity of inflammasomes in directing innate immune responses to disease, this is the first report, to our knowledge, on the crucial role of the NALP1 inflammasome in the pathogenesis of T. gondii infections in humans.     

NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder

Mutations within the NALP3/cryopyrin/CIAS1 gene are responsible for three autoinflammatory disorders: Muckle-Wells syndrome, familial cold autoinflammatory syndrome, and CINCA. The NALP3 protein is homologous to NALP1, which is a component of the inflammasome, a molecular platform that activates the proinflammatory caspases-1 and -5. NALP3 (and other members of the NALP family) lacks the C-terminal, CARD-containing sequence of NALP1, and its role in caspase activation is unclear. Here, we report that NALP2 and NALP3 associate with ASC, the CARD-containing protein Cardinal, and caspase-1 (but not caspase-5), thereby forming an inflammasome with high proIL-1beta-processing activity. Macrophages from Muckle-Wells patients spontaneously secrete active IL-1beta. Increased inflammasome activity is therefore likely to be the molecular basis of the symptoms associated with NALP3-dependent autoinflammatory disorders.     

A coding polymorphism in NALP1 confers risk for autoimmune Addison's disease and type 1 diabetes

Variants in the gene encoding NACHT leucine-rich-repeat protein 1 (NALP1), an important molecule in innate immunity, have recently been shown to confer risk for vitiligo and associated autoimmunity. We hypothesized that sequence variants in this gene may be involved in susceptibility to a wider spectrum of autoimmune diseases. Investigating large patient cohorts from six different autoimmune diseases, that is autoimmune Addison's disease (n=333), type 1 diabetes (n=1086), multiple sclerosis (n=502), rheumatoid arthritis (n=945), systemic lupus erythematosus (n=156) and juvenile idiopathic arthritis (n=505), against 3273 healthy controls, we analyzed four single nucleotide polymorphisms (SNPs) in NALP1. The major allele of the coding SNP rs12150220 revealed significant association with autoimmune Addison's disease compared with controls (OR=1.25, 95% CI: 1.06-1.49, P=0.007), and with type 1 diabetes (OR=1.15, 95% CI: 1.04-1.27, P=0.005). Trends toward the same associations were seen in rheumatoid arthritis, systemic lupus erythematosus and, although less obvious, multiple sclerosis. Patients with juvenile idiopathic arthritis did not show association with NALP1 gene variants. The results indicate that NALP1 and the innate immune system may be implicated in the pathogenesis of many autoimmune disorders, particularly organ-specific autoimmune diseases.     

Silica crystals and aluminum salts regulate the production of prostaglandin in macrophages via NALP3 inflammasome-independent mechanisms

Particulates such as silica crystal (silica) and aluminum salts (alum) activate the inflammasome and induce the secretion of proinflammatory cytokines in macrophages. These particulates also induce the production of immunoglobulin E via a T helper 2 (Th2) cell-associated mechanism. However, the mechanism involved in the induction of type 2 immunity has not been elucidated. Here, we showed that silica and alum induced lipopolysaccharide-primed macrophages to produce the lipid mediator prostaglandin E? (PGE?) and interleukin-1β (IL-1β). Macrophages deficient in the inflammasome components caspase 1, NALP3, and ASC revealed that PGE? production was independent of the NALP3 inflammasome. PGE? expression was markedly reduced in PGE synthase-deficient (Ptges?/?) macrophages, and Ptges?/? mice displayed reduced antigen-specific serum IgE concentrations after immunization with alum or silica. Our results indicate that silica and alum regulate the production of PGE? and that the induction of PGE? by particulates controls the immune response in vivo.     

NALP3 is not necessary for early protection against experimental tuberculosis

In vitro, Toll-like receptors (TLR)2, 4 and 9 as well as NOD-like receptor 2 critically determine macrophage responses to Mycobacterium tuberculosis (Mtb) infection. However, in low-dose experimental murine tuberculosis, single or multiple deficiencies in TLRs 2, 4, 9 or NOD2 have little, if any, impact on early mycobacterial growth containment, granuloma formation and survival. Here, we analyzed the relevance of NALP3, one component of the danger-signaling inflammasome, for (i) Mtb-induced cytokine secretion in vitro and in vivo, (ii) restriction of Mtb replication in infected organs and (iii) granuloma formation. In the absence of functional NALP3, there was no IL-1β and IL-18 production in Mtb-infected dendritic cells and macrophages in vitro, whereas secretion of IL-1α, IL-12p40 and TNF remained unaffected. After three weeks of infection, NALP3-deficient as well as IL-18-deficient mice were as capable as wildtype mice of restricting Mtb loads at a plateau level within well-differentiated granulomas. In conclusion, despite its involvement in cytokine processing, NALP3 is not essential for induction of protective immunity to Mtb.