week 6 390
U of L
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This 3 page Class Notes was uploaded by Mary-elizabeth Notetaker on Thursday September 29, 2016. The Class Notes belongs to bio 390 at University of Louisville taught by Shira Rabin in Fall 2016. Since its upload, it has received 7 views. For similar materials see Intro to Immunology. in Biology at University of Louisville.
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Date Created: 09/29/16
Week 6 Tuesday, September 27, 2016 1:02 PM Complement system- helps Abs lyse cells Bordet & erlich ○ Bacteriolysis of vibrio req'd 2 subs ○ Found Ps working w AB ○ "Completes" activity of AB 30+ Ps, iis Made by hepatocytes, macs, & some epithelial cells Steps: (list) 1. Initiators: C1q, MBL, ficolins 2. Convertase activators(C1r, C1s, C4b, C2a) & enzymeatic mediators(C3 convertase, C5 convertase) 3. Opsonins 4. Anaphylatoxins(inflamm) 5. Membrane attack complex(MAC) 6. complement receptors 7. Regulatory Steps described: - Activation(3 ways) i. Classical pathway(AB immune complexes)- initiated by AB binding 1) IgM or IgG binds antigen, complement binding site revealed 2) C1q binds antigen-bound AB and induces confo change in one C1r mol to activate it C1r then activates second C1r and 2 C1s mols C1 then cleaves C4, which splits into 2 parts and C4b binds cell surface(C4a leaves) C4b cleaves C2, C2b leaves Very short time where it can bind amino groups on cell memb w/thioester bond If doesn’t bind, will be hydrolyzed and becomes inactive(90% of them) C4b2a left (C3 convertase) C3 convertase cleaves C3 C3a leaves, C3b binds C4b2a --> C4b2a3B(C5 convertase) ..convergence at C5b ii. Lectin pathway (PAMP by lectins)- recognize glycoproteins on microbe surface 1. Soluble MBL(mannose binding lectin) binds to microbial glycoproteins 2. Docking sites for MBL are MASPs (MBL associated serine proteases) 3. MASPs cleave C4 and C2 to form C3 convertase(cleaves C3->C5 convertase)..convergence …MBL constitutively made by liver iii. Alternative pathway (spontaneous hydrolysisor pathogenic surfaces) A. Path 1 1. Small amts of C3 always being cleaved and bind target cell 2. Factor B binds to C3b 3. C3bB cleaved by Factor D 4. C3bBb= C3 convertase … fac's b & d, & properdin are small blood Ps 5. Properdin stabilizes C3 convertase 6. C3 convertase cleaves C3 proteins 4. C3bBb= C3 convertase … fac's b & d, & properdin are small blood Ps 5. Properdin stabilizes C3 convertase 6. C3 convertase cleaves C3 proteins 7. Forms C3bBbC3b=C5 convertase … convergence B. Path 2: Properdin initiated 1. Properdin binds surface 2. Recruits C3b and fac B a) Fac d cleaves fac b into Bb b) C3bBb= active C3 convertase c) Cleaves C3--> makes C3bPBb=C5 convertase…convergence C. Path 3: Clotting cascades stimulate cleavage of complement proteins Strong inflamm rxs could activate complement system C5b- leads to lysisin all pathways by bindingmembrane - C5b recruits C6, 7, 8, & 9.. Generates MAC and forms hole in membrane - CR1 receptor ○ Receptor on host cells allow for discrrete responses □ Erythrocytes(immune complexes to liver) Take dead microbes to liver for macrophages to bind PAMP to destroy □ Phagocytes(opsonization) Bind complement on dead microbe to destroy CR2(CD21) receptor on b cells □ Binds Cd3 on opsonized bacteria/antigens □ Provides secondary signals to b cells thru BCR □ CR2 binding Cd3 allows Lower concentrations of antigen to be sufficient for b cell activation C5aR & C3aR on granulocytes- bind anaphylatoxins C3a & C5a □ Stimulates release of IL1 cytokines(pro-inflamm)and degranulation from basophils, eosinophils,and neutrophils Complement enhances host defense ○ MAC-induced cell death ○ Promotion of inflamm ○ Promotion of opsonization- opsonized microbes are easier to ingest/destroy Taking of AB/complement and putting it all the way around microbes so covers slime and makes it easier for phagocyte to bind □ Opsonized immune complexes easier to clear □ If Ig Ag binds blood(solubleimmune complex of AB/antigen) needs cleared, so complement activaition occurs and C3b binds, which binds Erythrocyte and CR1, when enters liver, macrophages have many CR1 receptors so take AB/antigen complex and kills it Can cause renal damage from immune complex piling up Mediates innate to adaptive immunities ○ Mediates innate to adaptive immunities Inc uptake of antigens by APCs Can help stimulate t cells--> inc immune resp □ Mice w/out C3 gene have less CD4 & CD8 responses □ C5aR inhibitors-->fewer CD8 T cells □ Theory: Made C5a receptor to bind up inflamm proteins, then found higher numbers of activated t cells? Mediates end of immune resp ○ Disposal of apoptotic cells and bodies(C1q binds PS[phospholipid that flips to outer leaflet on cells to tell immune system they should be phagocytosed bc dead]) ○ Removal/disposal of immune complexes formed during responses(RBSs->liver) Regulation of complement activity ○ Passive- short half life(5 mins) of C3 convertase unless stabilized by properdin Destroying proteases bind more readily to host membs bc of acid in host cells than microbial--> destruction on host cells..much more inactive Cd3 on host cells ○ Active- self cells can inactivate C3b DAF(cell surface) C4BP, Fac H (soluble) ○ Inhibition of MAC attack Protectin(CD59) in membrane binds C5b678 complexes on host □ Prevent insertion into membrane □ Blocks C9 recruitment(so no memb holes) Complement deficiencies- immune complex disorders due to inadequate clearance ○ Greater freq od infections due to inefficient opsonization and phagocytosis Microbial invasion ○ S.Aureus- can evade complement