模式识别受体 2014(1)

Mice transgenic for TLR4 develop contact
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TLRs in disease: antagonism
TLR4 has been implicated in major inflammatory diseases Wim Van den Berg and colleagues Abdoolah-Roodaz S. et al., (2007) Arth Rheum 56, 2957-2967 Tenascin-C from connective tissue could be the TLR4 ligand Midwood K. et al., Nat Med (2009) 15, 774-781
1. Toll-like receptors (TLRs) 2.Байду номын сангаасRIG-I-like receptors (RLRs) 3. C-type lectin receptors (CLRs) 4. Nod-like receptors (NLRs)
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Toll-Like Receptors
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Lewis经多年的研究发现有一串的基因控制着果蝇体节的发育 基因可以分为四大类，由它们的先后作用，胚胎的构造逐步划分，渐趋 复杂，最后形成许多体节。
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Nobel prize for physiology or medicine 2011
Bruce Beutler Jules Hoffrmann Ralph Steinman • The Nobel prize in physiology or medicine 2011 was divided, one half jointly to Bruce A. Beutler and Jules A. Hoffmann "for their discoveries concerning the activation of innate immunity" and the other half to Ralph M精. 品St课ei件nman "for his discovery of the dendritic cell and its role in adaptive immunity"
molecular signatures of microbes 3. PRR triggering promotes APC activation and leads to T cell priming
Janeway Jr, C. A. (1989) Cold Spring Harb Symp Quant Biol.
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Inflammation
• Profound vascular change – blood vessels dilate • Extravasation of neutrophils – swelling • Pain
When inflammation goes wrong you get a whole range of horrible diseases
• 目前发现人类TLRs家族成员有11个,可以分别识别并结合多种 PAMPs
• TLRs 3, 7, 8 和 9 位于细胞质中， TLRs 1, 2, 4, 5, 6 and 10 位于细胞膜.
• TLRs是Toll／IL一1受体(Toll／Interleukin-1 receptors， TIR)超家族的成员，主要由位于胞膜外区的富含亮氨酸重复序 列(1eucine-rich repeat，LRR)结构域和胞内的TIR结构域组 成，LRR结构的主要功能是与配体识别并结合，而TIR结构域是 启动下游信号传导的关键。
TLRs,NLRs,DAMPs
向萌
复旦大学上海医学院生理与病理生理学系
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Nobel prize for physiology or medicine 1995
• The nobel prize in physiology or medicine 1995 was awarded jointly to Edward B. Lewis, Christiane Nüsslein-Volhard and Eric F. Wieschaus "for their discoveries concerning the genetic control of early embryonic development"
• PRRs识别结合的配体分子，即病原微生物某些共有的高度保守的分子 结构，称为病原相关分子模式(pathogen-associated molecular patterns。PAMPs)。例如细菌脂多糖、脂蛋白、肽聚糖、鞭毛蛋白、 非甲基化cpG，DNA、病毒双链RNA、真菌细胞壁等。
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PRRs: coupling innate and adaptive immunity
54:1-13
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• 固有免疫是生物体在长期进化过程中形成的防御机制，主要特点是固 有免疫细胞表面或胞内的受体可识别多种“非己”异物共同表达的模 式分子，经特殊的信号转导途径表达效应分子以产生免疫效应。
• 这种存在于固有免疫细胞的能识别病原微生物或宿主凋亡细胞的某些 共有的特定分子结构的受体称为模式识别受体(pattern recognition receptors，PRRs)，
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Bruce Beutler: spot the difference between these two mice...
C3H/HeJ LPS-resistant
C3H/HeN LPS-sensitive
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Human (but not mouse) TLR4 has histidines that co-ordinate
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Pattern recognition
Charlie Janeway
1. All bugs contain “pathogenassociated
molecular patterns” (PAMPs) not present in the host (e.g., dsRNA, LPS, peptidoglycan, β-glucan) 2. APC possess “Pattern Recognition Receptors” (PRR) that recognise these