博士生课程固有免疫模式识别复习课件.ppt

What is an inflammasome and what does it do? Toll-Like Receptors (TLRs) There are six major clades of TLRs, each recognizing a general class of molecular patterns. Molecular tree of the vertebrate Toll-like receptors (TLRs). The evolution of vertebrate Toll-like receptors Toll-Like Receptors (TLRs): Basic Architecture ED TM CYT Leader Peptide Leucine Rich Repeats (LRR); BINDING Toll/interleukin 1 receptor (TIR) domain; SIGNALING Structural organization of human TLRs. ENDOTOXIN -Structural component of the outer leaflet of the outer membrane of Gram negative bacteria -Contains the O-antigenic polysaccharide determinant. -Presence of polysaccharide and lipid components. -Also termed Lipopolysaccharide (LPS). -The lipid component or Lipid A (glycophospholipid) is responsible for the biological activities of LPS (toxicity / fever) LPS (endotoxin) Outer membrane Peptidoglycan Inner membrane O-specific chain Core Region Lipid A LPS the toxic center of LPS The Basic Architecture of LPS Structure of Lipid A Lipid A is a glycophospholipid with phosphorylated D-glucosamines LBP and CD14 the first Endotoxin Receptors LPS-Binding Protein (LBP) -Plasma protein produced in the Liver. -Delivers LPS from the serum to macrophages. -Enhances the sensitivity of macrophages for LPS. CD14 -GPI-linked membrane protein (macrophages). -Also exists in a soluble form recruited to endothelial cells. -Works with LBP to bring LPS to the cell surface. No link between LBP/CD14 and intracellular signaling. However, LPS detection by immune cells results in an intracellular signaling response and production of TNF. Delivery of LPS to TLR4 by lipid transfer proteins Biological Activities LBP-CD14 Co-receptor(s) MD-2 TLR4 TLR signaling pathways ? The generation of inflammatory cytokines and chemokines The generation of antimicrobial peptides Initiation Signal-induced assembly of pathway components/invo