Lec 2- innate immunity part 1 Flashcards
Innate immunity
- The first line of defence are always ready for action
- Physical barriers- skin, mucosal surfaces (epithelial cells); prevents the entry of pathogens
- Breach of the physical barriers can lead to infection
- This is activates Innate immunity: first response mechanism- instant; 2nd response- hours or days later
- Sequence of events depends on pathogens- type and route of entry
- How efficient is innate immunity- not really known
Innate immunity- graph
RED LINE- NO innate immunity -The number of micro-organism is exponentially growing because without the innate immunity the adaptive immunity can’t be triggered so in effect you have no immune response
GREEN LINE- No adaptive -Initial dealings with infection are good due to the effectiveness of the innate immunity however over time we cannot eradicate the infection due to no adaptive immunity
Innate immunity- Defence depends on WHAT the pathogens produce
IF EXOTOXIN IS RELEASED -This usually occurs in cholera
-Defence is anti-bodies and cytokines
IF ENDOTOXIN IS RELEASE -Occurs in the plague
- TLR and complement defend against this
- IF DIRECT CYTOPATHIC EFFEC -This occurs in influenza virus
- We use interferons to defend this
Innate immunity- Defence depends on WHERE the pathogens are
1) EXTRACELLULAR (intersitial space, blood and lymph)
- defence mechanisms include complement, macrophages and neutrophils
- act against all main microbes including worms
2) EXTRACELLULAR (epithelial surface)
- Active against gonorrhoea, thrush and worms
- Defence is anti-microbial peptides
3) INTRACELLULAR cytoplasmic
- Active against virus, protozoa
- Defence include NK cells
4) INTRACELLULAR VESICULAR
- Active against; mycobacteria
- Defence includes activated macrophages
Complement
- Complement is a collection of soluble and membrane-bound proteins
- Made by the liver constitutively (no stimulus required)
- Found in blood, lymph, extracellular fluids
- Many complement components are proteases: Zymogens (i.e. a pro-enzyme; inactive form)
- These require activation- a cascade of enzymatic reactions that occur upon infection
Complement- C3 component
- There are >30 proteins in the complement system
- C3 is the most important
- People deficient in C3 are very unwell
- When we cleve C3 we create C3a and C3b
- C3a will go and recruit phagocytes
- C3b tags bacteria via opsonisation for destruction
3 different pathways of activation: alternative pathways
-We have different pathways so we can have upregulation
- Pathogen surface creates local environment conductive to complement activation –>
- First to act –>
- Complement activation
- Cleavage of C3 to C3a and C3b; covalently bound to surface components of pathogens (Generates C3 convertase)
This leads to 3 responses
1) recruitment of inflammatory cells
2) Opsonization of pathogens, facilitating uptake and killing by phagocytes
3) Perforation of pathogen cell membrane Leading to death of pathogen
3 Different activation pathways: lectin pathway
- Mannose binding lectin binds to pathogens surface
- 2nd to act
- Complement activation
- Cleavage of C3 to C3a and C3b; covalently bound to surface components of pathogens (Generates C3 convertase)
This leads to 3 responses
1) recruitment of inflammatory cells
2) Opsonization of pathogens, facilitating uptake and killing by phagocytes
3) Perforation of pathogen cell membrane Leading to death of pathogen
3 different activation pathways: classical pathway
- C-reactive protein or antibody binds to specific antigen on pathogen surface
- 3rd to act
- Complement activation
- Cleavage of C3 to C3a and C3b; covalently bound to surface components of pathogens (Generates C3 convertase)
This leads to 3 responses
1) recruitment of inflammatory cells
2) Opsonization of pathogens, facilitating uptake and killing by phagocytes
3) Perforation of pathogen cell membrane Leading to death of pathogen
The alternative pathway: in more detail
- we have C3 –>
- Spontaneous generation of iC3- increases in vicinity of pathogen (C3 + H20 = iC3)
- Another complement component call B will then coma along and attach to iC3
- When B and iC3 attach this changes the shape of B allowing D (another component) to attach
- This causes the B section to split in 2 with Ba moving off and Bb being attached to iC3 giving iC3Bb (D moves off as well)
- iC3Bb is C3 covertase -C3 will then bind to iC3Bb, C2 then becomes cleaved into C3a and C3b
- C3b will then opsonise then near by pathogen surface
Pathogen coating with C3b
- Formation and action of C3 convertase and C3bBb (like iC3Bb but attached to pathogen surface) of the alternative pathway at pathogen surface
- Positive feedback of C3 convertase production amplifies response
- More C3 convertase = more C3b -C3b binds to the pathogen and coats its surface
Regulation of complement activation
- Properdin stabilises C3 convertase C3Bb on a pathogen surface
1) Properdin (factor P); plasma protein maintains C3bBb activity by preventing cleavage - Extends the lifetime of C3 convertase (increases Half-life) a positive control mechanism
Regulation of complement activation: 2)
2) Factor H and factor I are plasma proteins factor H binds C3b and makes it susceptible to cleavage by Factor I
- iC3b is not a C3 convertase but still tags the pathogen for destruction
- Essential negative control to prevent C3 depletion and over activation- very important
Regulation of complement activation: 3)
3) decay accelerating factor (DAF) and membrane co-factor protein (MCP) are membrane proteins
- DAF binds C3bBb causing Bb to dissociate and inactivate
- MCP also increases susceptibility to factor I
- Factor H and MCP work in a similar manner
- Factor H can bind to cell surfaces via sialic acid
Phagocytosis
- Phagocytosis is the first cellular defence in innate immunity
- Complement activation leads to deposition of C3b on the b bacterial surface (C3b covers bacteria)
- CR1 receptors on macrophages binds to C3b on bacteria -Endocytosis of the bacterium by the macrophage
- Macrophage membrane fuse creating a membrane-bounded vesicle, the phagosome
- Lysosomes fuse with the phagosomes forming the phagolysosome
- Complement activation, opsonisation and phagocytosis keep bacterial numbers low at the start of infection
Complement activation and bacterial cell lysis
- C3b binds C3 convertase to make C3b2Bb- a C5 convertase
- C5 convertase activity results in assembly of membrane attack complex (MAC) from C9
- C5 convertase turns C5 into C5a and b
- C5b causes itself to bind with C6, C7, C8 -C9 will then bind to this complex which is the pore
- This punches a hole in the pathogen membrane, causing loss of osmotic control causing cell lysis
Regulation of complement activation 4)
- On the cells of pathogens complement components C5
- 9 assemble a complex that perforates the cell membrane
- On a human cell CD59 binds to C5b678 complex and prevents recruitment fo C9 to form the pore
4) protectin (CD59)- prevents the formation of the MAC in human cells preventing pore formation and cell lysis - Patients deficient in CD59 can develop complications leading to paroxysmal nocturnal hemoglobinuria (PNH)
Complement activation induces inflammatory response
- Anaphylatoxins (C3a and C5a) action on blood vessels to increase vascular permeability
- This increased permeability allows increased fluid leakage from blood vessels and extravasation of complement and other plasma proteins at site of infection (more complement components and plasma proteins)
- Also increases migration of monocytes and neutrophils from blood into tissue is increased, microbial activity of macrophages and neutrophils is also increased
