博士生课程固有免疫模式识别课件

Innate Immunity monocytemonocyte macrophagemacrophage bacteriabacteria The most ancient defense Physical in this case pattern of terminal sugars on cell surfaces Recognizing mannose-containing molecular patterns found on microbes but not on vertebrate cells directing complement attack Mannose-binding lectin Mannose binding protein (MBP) lPart of C-type lectin superfamily lAssociates with and activates serine proteases: MASP-1 and MASP-2 lAfter binding to pathogen surface this complex activates lectin pathway of complement system, C2 and C4 MB-LECTIN MASP = MBL- associated serine protease MBL mannose MB-LECTIN ANOTHER VERSION POINTS OUT TOTALITY OF CLEAVED C3 FUNCTIONS lBind to phorphorylcholine (PC) on bacteria, other microorganisms, damaged host cell membranes PC found in teichoic acids, capsular carbohydrates, and lipopolysaccharides Requires Ca+ lFunction directly as opsonins (enhancer of phagocytosis) lFunction indirectly by binding to C1q of classical complement pathway and activate complement cascade C-reactive protein (CRP) and serum amyloid protein (SAP) (belongs to a family of pentameric protein called pentraxins) binding to polysaccharidepolysaccharide 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/involvement of an adaptor molecule Protein kinase-mediated phosphorylation Initiation of an enzyme cascade: MAP kinase pathway (in many cell types) NFB pathway (a powerful transcriptional factor) generate cytokines, adhesion molecules 22