TLR与慢性炎症性疾病

TLR与慢性免疫性 炎症性疾病,雷俊霞 中山大学中山医学院 2011，10,1、 病原相关分子模式 （pathogen associated molecular pattern，PAMP） 一类或一群特定的微生物病原体（及其产物）共有的某些非特异性、高度保守的分子结构，其可被非特异性免疫细胞所识别。如脂多糖、磷壁酸、肽聚糖、甘露糖等。,几个概念,2、模式识别受体 (pattern-recognition receptor，PRR) 是一类主要表达于天然免疫细胞表面、非克隆性分布、可识别一种或多种PAMP的识别分子。,几个概念,3. Toll样受体（Toll-like receptor，TLR） 属一类重要的信号转导型PRR，因其胞外段与一种果蝇蛋白Toll同源而得名，连接天然免疫和获得免疫的重要受体，现已发现13种。,几个概念,胞外区含一段保守序列，乃TLR识别微生物PAMP的区域；胞内区含有与IL-1R胞内信号转导区高度同源的结构域，此与信号转导有关。,TLR分子结构特征,TLR 配体,dsRNA内源mRNAPolyI:C,结核杆菌三酰基酯肽脑膜炎球菌可溶性成分,肽聚糖脂肽,大多数PAMP结构,HSP,Bruce A. Beutler,TLR 分布,单核/巨噬细胞、B、T、DC以及呼吸道和消化道上皮等免疫相关细胞。,TLR 的生物学功能,在天然免疫中的作用增强吞噬细胞和中性粒细胞的吞噬和杀伤力引起与免疫有关的细胞因子和趋化因子的释放介导一些抗微生物的肽类产生,TLR 的生物学功能,对特异免疫的影响诱导DC成熟，但也有相反实验结果可诱导向Th1/Th2分化，通过作用于DC或B细胞调控；或者直接作用于T细胞。诱导调节性T细胞（Treg)活化其它：影响免疫记忆的时间和强度，激活Tc等,TLR 与慢性免疫性炎症疾病,慢性免疫性炎症疾病自身免疫疾病：RA、SLE、多发性硬化、I型糖尿病、牛皮癣等对外界抗原过度反应引起的疾病：支气管哮喘等。,TLR 与慢性免疫性炎症疾病,TLR与RA和强直性脊柱炎：在患者PBMC和滑膜细胞均发现TLR2，4和相应配体表达升高；TLR可调节参与RA的关键细胞功能。触发促炎因子IL6，8， TNF-，趋化因子，ICAM-1和金属蛋白酶等；用TLR配体（DNA、polyI:C、坏死滑膜细胞RNA、CpG-DNA、肽聚糖） 可诱导或促进炎症；用抗TLR2抗体或infliximab和VIP下调TLR表达、信号激活或炎症因子表达，有治疗效果。此外，TLR的基因多肽性也有关。,TLR 与慢性免疫性炎症疾病,TLR与哮喘：一方面某些TLR及配体可改善哮喘症状：TLR9配体CpG-ODN可激活B细胞产生Ig，刺激DC产生Th1细胞因子和趋化因子，诱导IDO活性，减轻哮喘症状。DC上的TLR9激活可诱导调节性T细胞发育。呼吸道TLR2激活也可诱导向Th1极化，抑制Th2类细胞因子；但是也有结果与此相反。,TLR 与慢性免疫性炎症疾病,TLR与哮喘：另一方面某些TLR及配体与哮喘发生和加重有密切关系：呼吸道平滑肌细胞上TLR介导的促炎反应（如产生IL-8或噬酸性粒细胞趋化因子）加重哮喘。PolyI:C激发小气道上皮细胞TLR1，2，3表达上调和促炎反应。LPS对哮喘形成和程度存在剂量依赖关系，其暴露剂量可以决定机体产生炎症反应的类型。,TLR 与慢性免疫性炎症疾病,TLR与哮喘：TLR基因多态性或突变导致TLR构象和功能改变也参与哮喘发生：TLR2，4，6，9的某些等位基因被发现与哮喘发作倾向有关。,TLR与炎症性肠病（IBD）： 是一组慢性、特发性、复发性及组织破坏性的疾病, 包括溃疡性结肠炎(ulcerative colitis, UC)、克罗恩病(Crohns disease, CD),以肠粘膜的T细胞功能障碍和炎性细胞浸润为特征,并最终导致远端小肠和结肠粘膜的破坏,TLR 与慢性免疫性炎症疾病,TLR与炎症性肠病（IBD）：,constitutively or inducibly expressed throughout the wholeGI tract by a wide variety of cell types, including IEClineages, myofibroblasts, monocytes/macrophages, DCs andT cells healthy intestine:a) TLRs are present only in small amountsb) negative regulators maintain basal state of activation and prevent prolonged and excessive TLR signaling diseased intestine:a) distinct TLRs are significantly upregulated in certain cell subsets in intestinal mucosab) positive regulators initiate aberrant state of activation and allow uncontrolled TLR signaling,TLR expression and function between health and IBD,In the normal intestine, TLR2 and TLR4 are present only in small amounts on IEC and lamina propria mononuclear cells (LPMNCs) in vivo, minimizing recognition of the environment and maintaining a basal state of activation. Once host threats are encountered, these inhibitory mechanisms can be switched off, and positive regulators allow TLR signaling to elicit important immune responses, in the attempt to eliminate the danger. But sustained TLR hyperactivation may provoke chronic inflammation in IBD,TLR expression and function between health and IBD,Physiological effects of normal TLR signaling in the healthy GI tractIntegrity of commensal composition and commensal toleranceProtection of intestinal epithelial/mucosal barrier function, accelerated wound healingControl of Treg$Teff balance in the intestinal mucosa- Maintenance of commensal and mucosal homeostasisPathophysiological effects of aberrant TLR signaling in IBD Changes in commensal composition and commensal intolerance Impairment of intestinal epithelial/mucosal barrier function,delayed wound healing Promotion of Treg$Teff imbalance in the intestinal mucosa -Disturbance of commensal and mucosal homeostasis,TABLE 2. (Patho)physiology of TLRs in the Intestinal Mucosa,Primary genetic defects in TLR function, influencing IBD susceptibility/progressionTLR1-R80T: associated with UC pancolitis; cellular dysfunction unclearTLR2-R753Q: associated with UC pancolitis; impairs IEC restitution and communication (TFF3; GJIC;)TLR4-D299G: associated with increased susceptibility to IBD; interrupts LPS signalingTLR5-stop: associated with decreased susceptibility to IBD;reduces adaptive immune responses to flagellinTLR6-S249P: associated with decreased susceptibility to IBD proctitis; cellular dysfunction unclearTLR9-(-1237T/C), -(2848A/G): associated with CD-variants CARD15, IL23R, DLG5; cellular dysfunction unclear,TABLE 3. Gen