encounter with innate and adaptive immunity Flashcards
complement
proteins mainly produced by the liver (also by immune cells)
- consists fo a series of inactive precursor proteins
- activated by cleavage which then activates the next protein in the series
- products generated cause a range of effects
constitutively present in blood and tissue
- low concentrations of complement in CSF
what pathways is complement activated by
classical
alternative
lectin
anti-microbial roles of complement - lysis
the first is that it can cause lysis of bacteria
- and this involves complement proteins C5 to C9 and they join together to form the membrane attack complex or Mac.
- And that basically punches holes in bacterial membranes and that results in bacterial lysis
-and that’s due to water being able to flow into the cells, ions go out, you get osmotic Shock and It causes lysis.
antimicrobial roles of complement - opsonisation
○ the key complement factor involved there is c3b.
○ it coats the surface of microbes and that basically tags them for recognition by phagocytes.
○ phagocytes have a complement receptor on the surface - so microbes that are coated in c3b are easily recognized by phagocytes and they get phagocytosed and destroyed.
antimicrobial roles of complement - activation of the inflammatory response.
○ neutrophils need to leave the bloodstream and travel to the site of infection and that requires vasodilation for them to be able to escape from the blood stream Crossing endothelial wall.
○ And also they need to follow a chemotactic response to get to the site of infection
§ and that is a role of complements.
- So it’s important for the vasodilation and allowing the cells to leave the bloodstream.
-But also they provide the chemotactic factors and the signal for them to move to the site infection.
lectin activaition pathway of complement
MBL binds mannose on bacterial surface -> C4, C2 -> C3 convertase formation
classical activation pathway of complement
Antigen: antibody complexes -> C1, C4, C2 -> C3 convertase formation
alternative activation pathway of complement
C3b binds bacterial surface -> C3, factors B, D -> C3 convertase
after formation of C3 convertase, what leads to recruitment of inflammatory cells
cleavage of C3 exposes a highly reactive bond which mediates covalent binding to target surfaces
-> C4a, C3a, C5a -> recruitment of inflammatory cells
after formation of C3 convertase, what leads to opsonisation
cleavage of C3 exposes a highly reactive bond which mediates covalent binding to target surfaces
-> C3b - binds to complement receptors on phagocytes -> opsonisation
after the formation of C3 convertase, what leads to membrane attack complex lysis of bacteria
cleavage of C3 exposes a highly reactive bond which mediates covalent binding to target surfaces -> C3b -> Terminal complement components C5b, C6, C7, C8, C9
-> membrane attack complex lysis of bacteria
key components of the complement pathway - C3b
binds to microbial PAMPs -> opsonisation
- monocytes, macrophages and neutrophils have C3b receptors
- individuals that lack C3 suffer recurrent infections
key components of the complement pathway - C5a, C3a and C4a
inflammatory mediators
- C5a, C3a, C4a can act as anaphylatoxins (activate mast cells)
- chemotaxis (C5a particularly important)
- cause vascular permeability
key components of the complement pathway -membrane attack complex (components C5b - C9)
inserts into the bacterial cell membrane forming transmembrane channels which leads to osmotic lysis of gram negative bacteria
specific/ adaptive defence system
due to T lymphocytes and B lymphocytes
recognise pathogens using variable antigen-specific - cell surface receptors
- almost infinite number of different versions:
- each has a unique binding site for a different ligand
- generated by gene rearrangement
only those lymphocytes that are specific for components of infecting pathogen are selected
-> divide, proliferate and differentiate into effector lymphocytes
-> some proliferate into memory lymphocytes
T cells
2 main types - CD8 or CD4 glycoprotein markers
T cel receptors recognise peptide antigens ‘presented’ on the surface of cells - antigen needs to be presented bound to MHC cells
what are the 2 classes of MHC molecule that present peptide antigens to the 2 main types of T cells
MHC class I:
- present antigens of cytoplasmic origin to CD8 T cells
- cytotoxic cells (cell-mediated immunity)
MHC class II:
- present phagocytosed antigens of extracellular origin to CD4 T cells
-> differentiate into effector T helper cells
-> help B cells become antibody-producing plasma cells
-> hekp CD8 T cells to become cytotoxic T cells
-> activate macrophages
antigen characteristics determine whether presented on MHC-I or MHC-II
what do helper T lymphocytes do - pathway
- CD4 + helper T lymphocyte + APC with microbial antigen presented on MHC class II
leads to - cytokines
leads to -> activation of macrophages, inflammation, activation of T and B lymphocytes
cell-mediated immunity: cytotoxic T lymphocytes - pathway
CD8 + cytotoxic T lymphocyte + infected APC expressing microbial antigen on MHC class I
-> killing of infected cell
antibody-mediated immunity: B lymphocytes and antibodies
B cell + antibody > effector b lymphocytes , neutralisation of microbe phagocytosis, complement activation, neutralisation by agglutination
antibody-mediated immunity: B lymphocytes and antibodies - antibacterial roles
- neutralisation by agglutination:
- cause pathogen or protein such as a toxin to aggregate and thereby block binding to target/ action
- facilitate phagocytosis
- activation of complement
- block attachment (e.g. binds ligands essential for binding to host cell receptor)
what do bacteria need to evade in innate and adaptive immunity
- phagocytosis and killing by phagocytes
- antimicrobial activity of complement
- recognition and killing by antibodies and T cells
strategies for evading phagocyte recognition - contact with phagocyte prevented by a capsule
expression of a capsule prevents contact with the phagocyte
capsule can prevent C3b receptors on phagocytes from binding to C3b attached to bacterial cell wall
e.g. streptococcus, pneumoniae
evasion of phagocyte recognition (and complement activation and antibody binding)
possess capsules:
- loose, relatively unstructured, polymer coat
- mainly composed of polysaccharides
- protect form phagocyte recognition (shields PAMPs)
- prevent complement recognition/ activation (alternate pathway)
- prevent antibody binding by shielding antigens or resembling host polysaccharides ( will also prevent complement activation by classical pathway)
strategies for evading phagocyte recognition - opsonisation prevented by producing protein that binds antibodies
organisms produce proteins which prevent interaction between opsonising antibody and phagocyte
- block phagocytic process
strategies for evading phagocyte recognition - avoidance of phagocytic killing
- organism releases toxins e.g. staphylococci streptococci
- phagocyte killed by toxin
- organism may induce macrophage apoptosis
strategies for evading phagocyte recognition - resistance to killing
organisms resist killing by producing antioxidants e.g. catalase, superoxide dismutase, raise pH (urease), adaptation to low Fe and low Mg
resistance to phagocytic killing
- resistance to nitric oxide and reactive oxygen species: cell surface polysaccharides interact with/ detoxify reactive oxygen species
- avoid induction/reduce strenght of oxidative burst - resistance to defensins
- tough cell walls: refractory to lysosomal proteases and lysozyme
- resistant to low pH: urease and H+ transporters
- nutrient acquisition mechanisms
strategies for evading phagocyte recognition - phagolysosome fusion/ acidification inhibited
e.g. mycobacterium tuberculosis, salmonella
- organism escapes from phagosome/ phagolysosome and lives in the cytoplasmic compartment of the cell e.g. shigella sp. Listeria monocytogenes
surviving phagocytosis
- prevent phagocytosis - prevent contact, block phagocytosis, avoid opsonisation
- toxin productions
- escape phagosome before fuses with lysosome
- prevent phagosome-lysosome fusion/ acidification
- raise pH of phagosome
- reduce effectiveness of toxic compounds
surviving phagocytosis - reduce effectiveness of toxic compounds
- resistance to defensins
- production of catalase, SOD, flavohaemoglobin
- cell surface polysaccharides that intwract with/ detoxify oxygen radicals
- reduce strength of oxidative burst
- tough cell walls
- NO resistance
- resistance to low pH
- nutrient acquisition mechanisms
how do bacteria evade complement - prevention of complement opsonisation and killing by alternative pathway
sialic acid capsules: E coli K1, neisseria meningitidis
sialylation of LPS: N. meningitidis, N. gonorrhoea
silaylation of pili: N. meningitidis, N. gonorrhoea
how do bacteria evade complement - prevention of MAC mediated lysis
O- antigen mioety of lipopolysaccharide
- high affinity for C5b
MAC deposited away from cell membrane
how do bacteria evade complement - produce surface protein that prevents opsonisation
- M protein of streptococci acts as a receptor for factor H
- potentiates c3bBb dissociation
how do bacteria evade complement - -REVENT ANTIBODY RECOGNITION
- prevent activation of classical pathway
how do bacteria evade complement - produce a protease to destroy complement
reduces inflammatory signalling
- Group A streptococci secrete a C5a protease
-yersinisa: C3b and C5a proteases
neisseria meningitidis: alternative cleavage of C3 by NalP
how do bacteria evade complement - shedding of outer membrane vesicles
- blebbing
- prevent complement activation near bacteria
how do bacteria avoid the antibody response
- SlgA protease
- molecular mimicry: express antigen similar to host structues
- coating with host proteins: e.g. binding fibronectin, lactoferrin, transferrin, IgG
- antigenic variation
- phase variation
antigenic variation
changes in gene sequence leading to changes in the amino acid sequence of an antigen
phase variation
reversible on/ off switch resulting in variation in the level of expression of one or more antigens
