9. defence against extra cellular pathogens Flashcards
what is complement?
what do they act as?
a collection of proteins in circulation and tissue fluids that can complement the effects of antibodies
activation enzymes, defence molecules, regulatory proteins
what is the central event of complement activation?
splitting C3-> C3a+ C3b
what is the shape of a Cq1 and how does it bind and activate antibodies
what is similar about manose binding lectin
tulip flower 6 stalks
flower heads bind to Fc region on IgG- it can only bind when IgG is immobilised (bound to antigen)
at least two heads binding onto IgG triggers activation of C1r and C1s
IgMantibody – pentamer, 5Fc regions for C1q to bind to, so multiple heads bound to activate C1r and C1s
Manose binding lectin
Looks like C1q, flower heads of MBL bind to manose residues in microbial carbohydrates, pattern recognition molecule, binding activates MASP 1 and MASP2 which split C4 and C2 to generate C3 convertase enzyme
Membrane attack complex
Hole is punched
C5b binds then C6, C7, C8 binds then C9 comes and polymerise to form hole- osmotic lysis
classical pathway of complement
- IgM or IgG bound to antigens
- C1q binds to Fc regions-> activates C1r and C1s
- C4 and C2 converted to have C3 coverntase activity
(C4b2a)
if not antibodies availabile, MBL activates C3 convertase by MB lectin pathway- less efficient
activates MBL associated serine protease to covert C4 and C2 into C4b and C2a
alternative pathway
- a degree of C3 conversion occurs from spontaneous hydrolysis (enhanced by proteases or needs C3b from classical)
- allows C3 convertase formation without other components
- C3b unstable unless bound to microbe (then binds to factor B)
- C3b forms with factor B in presence of protease factor D= C3bBb: rapidly dissociates to other factors
then P binds= C3BbP
phagocytosis
types of cells and location
what do they have
macrophage: tissue resident cells from blood monocytes
neutrophils: circulate blood into sites of infection and inflammation
phagocytes express PRRs- binds to microbes
also have opsonin receptors
opsonisation
by acute phase proteins
C reactive (binds to phosphorylchlorine) and MBL (binds mannose residuces) opsonise for phagocytosis and activate complement
how can complements and antibodies opsonise for phagocytosis?
Microbe coated with antibodies, with Fc regions away, C3b complementary activation
Phagocyte have receptor FcR that bind to Fc regions of antibodies and also complement receptors for C3b
Increases binding and efficiently triggers phagocytosis
IgG and IgA can bind as have G gamma and A alpha receptors
phagocytosis mechanism
- interaction of microbe and opsonins with surface receptors of phagocyte triggers phagocytosis
- phagocyte moves along conc gradient of chemotactic agents via chemotaxis
- microbe engulfed into membrane bound vesicle= phagosome
- lysosome with lytic digestive enzymes fuse= phagolysosome
- microbe digested then exocytosed
- phagocytes produce reactive oxygen species- enters phagosome- degradation
how do neutrophils respond rapidly to inflammation stimuli
marginate to blood vessel walls, adhere to endothelial cells at sites of inflammation
extracellular digestion
if the parasite is too big, eosinophils have Fcr and Cr
(complement receptors and IgG and IgE receptors)
opsonisation of parasitic worms by antibodies and C3b to allow binding
cytoplasmic granules released (digestive)
mast cells and inflammation
mast cells have igh affinity of FcR and binds IgE from tissue fluid
become coated in IgE and become antigen specific
antigen binds to more than 2 IgE on mast cells (cross links/ bridges)-> inflammatory mediators released
also has Cr-> C3a and C5a trigger inflammatory mediator release (degranulation)
inflammatory mediators stored in granules (histamine, heparin, tryptase)
-synthesis of new mediators triggered on activation
released over long time
eg. leukotrienes, postaglandin, cytokines
the local inflammatory response
- vasodilation: increased volume of blood to tissue, decrease rate of blood flow so leucocytes move slowly through
- activation and flattening stage
leukocyte adhesion: edothelial cells activated to express adhesion molecules for leukocytes
capture and rolling: selectins on endothelial cells (E and P- selectin) bind to glycosylated proteins (mucins) on leukocytes
this allows leukocytes and chemokins to trigger integrin leukocyte expression intergrins on leukocyte bind to ligands in EC matrix and and vascular/interceullar adhesion molecules: allows beinding to tissue cells
3.extravasation leukocyte pass through endothelial cells (lose tight junctions) using intergrins (movement blood to tissue)
increase vascular permeability: allows leukocyte and plasma for antibodies and complement proteins to move into tissue
chemotaxis: directional movement leukocyte through tissue to site of infection in response to chemical signals
- immobilisation at site of infection and activation
