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Flashcards in Defence against Extracellular Pathogens Deck (24)
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Recap - outline features involved in defence with an extracellular pathogen

- Antibodies
- Macrophages
- Complement proteins


Explain basic principles of class switching

- 9 classes/ isotope based on the structure of the constant domain- this is determined by the 9 different genes which code for this
- Originally all B cells express mew gene that encodes the heavy chain associated with the whole IgM immunoglobulin
- When B cells activated, undergo class switching so they switch the gene used to encode the constant region of the heavy domain meaning a different isotope is expressed


Outline function of the Fc and Fab region

Fab- 2 arms of the antibody made up of the light and heavy chains- containing 2 antigen combining sites to bind to the epitope of the microbe
Fc- Constant region consisting of the 2 2 heavy domains
Sticks away for the surface of the microbe- therefore, can interact with other cells and molecules of the immune system
Fc Varies based on the isotope present and there are differences in distribution of isotopes
○ IgM, IgG- blood and tissues
○ IgG- transferred across placenta form maternal to foetal blood, giving immune protection to new-born babies
○ IgA- blood and mucosal secretions- can be transferred across mucosal epithelial cells so important in defence at these mucosal surfaces


Explain how the different antibody isotopes activate different defence processes

IgM IgG- complement activation
IgG, IgA- phagocyte binding- so more effective at ingesting and digesting microbes
IgE- mast cell binding- triggering release of inflammatory mediators
IgG- NK cell binding


What is complement

Complement: Works with/ complements activity of something else
- Present in the blood complementing defensive activity of antibodies
- Complement in blood is a collection of about 30 proteins- complement system of proteins
Produced by cells/ tissues and secreted into circulation and found in tissue fluids


How can the complement proteins work? (3 ways)

Range of function when activated (during infection):
- Act as activation enzymes: act on complement protein to activate another compliment protein
- Immune defensive molecules- punch holes in surface of microbes
- Control immune response (regulatory proteins) so it is activated and switched off appropriately- most of time complement proteins are in an inactive state (inappropriate induction of tissue damage and inflammation) and only active in process of infection


how is it activated and what does the complement pathway involve?

Once activated by infection an immune activation Occurs as a cascade/ chain reaction
Many steps involve splitting of complement proteins by enzymes (formed by complement proteins)
Main step C3--> C3a +C3b
By 2 C3 convertases


Outline the 3 pathways to make C3 convertase enzyme

- Classical pathway of complement activation- first to be discovered yet most recently evolved as involves antibodies
- Mannose binding lectin pathway- different pathway to make sae form of C3 convertase when antibodies not present
- Alternative pathway- 1st of pathways to evolve- involves complement proteins triggering their own activation


Explain classical pathway

IgM or IgG antibodies act with conplement protein complex C1q
C1Q: Complementary 6 units/ flowerheads which bind to the Fc regions of the antibodies when they are immobilised through binding with antigens on microbial surface
- Activation requires at least 2 of antigens bound but can be up to 6 as C1Q complement prptein has 6 flowerheads to bind with Fc region
- C1q associated with C1s are C1r proteins
- Upon binding of C1q with immunoglobulin C1s and C1r region are activated

IgG antibody- monomers- so requires at least 2 adjacent IgG antibodies to bind
IgM antibody- these are released from plasma cell as pentamers (5 immunoglobulin units) so 5 C1q flowerheads binds to 5 Fc sites

When activated C1r and C1s have an enzymatic activity that allows them to split into fragments 2 complement proteins (C4 and C2)
C4--> C4a + C4b
C2--> C2a + C2b
C4b and C2a conplex is a C3 convertase enzyme (split C3)


Explain Mannose binding lectin pathway

Mannose bonding- lectin: looks like C1Q- 6 units with 6 flowerheads and 6 stalks
- Don't bind to Fc region of antibodies
- Flowerheads bind to mannose residues in microbial carbohydrates (pattern recognition molecule) that binds directly to microbial structures
- Associated enzymes bonded to MBL (equivalent to C1s/C1r) called MASP- Mannose binding-lectin associated serine proteases 1 and 2
- Activated through MBL binding to microbial surfaces
- Split C4 and C2- leading to C4b2a (C3 convertase)


Why is redundancy common/ useful in the immune system when making C3 convertase

Redundancy common in immune system: multiple ways of achieving same end result
E.g. If no antibody available to bind to the microbial surface then MB-Lectin pathway activated also producing C3 convertase, or if are antibodies present CD3 convertase made through classical pathway- more efficient


Explain alternative pathway

- Uses complement proteins themselves to trigger their own activation
- Needs C3b to bind to microbial surfaces
- Binds another protein (factor B)
- Splits into fragments and b part of factor B that remains attached to C3b
- P (properdin) then binds onto that
--> C3bBbP (b part of C3, b fragment of factor B and P) produced as C3 convertase

- Tick over pathway: We always have a supply of C3b within cells as naturally produced from proteases- therefore we don't need a C3 convertase to initially produce this!
- C3b very unstable and rapidly degrades to inactive form unless bound to surface of microbe
- Hence, presence of microbe provides a surface for binding pf C3b, then Bb and P allowing production of C3 convertase


Explain whole complement process

1) 2 IgG antibodies bound to antigens on surface of microbial membrane
2) C1q complex binds to the Fc region of IgM (at least 2 flowerheads bound)
3) Activates C1s and C1r : Splits C4 and C2 to form the C2aC4b C3 convertase
4) Splits C3 forming C3b- some binds to the membrane come binds to C3 convertase making C5 convertase
5) C5b generates, C6 and C7 come in- bind to microbial membrane
C8 inserts itself through microbial membrane and then ring of C9 come in forming tubular structure: causing hole in membrane


Explain how opsonisation is important in phagocytosis and give 3 e.g. of opsonin's

Opsonin's (make things tasty/ more palatable to phagocytes)
- E.g. Acute phase proteins are a class of opsonin produced in the liver when there is infection on the body (cytokine called interleukin 6 causes release of these proteins in large amounts)
- E.g. Mannan-binding lectin- dual role- triggers activation of complement through lectin pathway but also can act as opsonin to promote phagocytosis
E.g. C reactive protein coats surface of microbes and this facilitate binding of microbes to receptors for C reactive protein therefore this makes phagocytosis more efficient


Explain how antibodies and complement proteins are important in phagocytosis of extracellular pathogens

Microbe coated with antibodies binding to surface antigens with Fc regions sticking away from surface
Also complement activation so C3b stuck on microbe surface
Phagocytes have Fc receptors (alpha receptors for IgA antibody and gamma receptors for IgG antibody) and which bind to the Fc regions of antibodies
Phagocytes also have complement receptors which bind to C3b (complement protein )
Strong interaction between microbe and phagocyte, which very efficiently trigger signalling pathways of phagocytosis
Immune components working together are much more efficient than any one working alone:
- Antibodies and complement together make phagocytosis much more efficient- hence more microbes destroyed


What happens if pathogen too large to be phagocytosed e.g. parasitic worm?

Parasitic worms- much bigger than phagocytes (neutrophils, macrophages) so can't be engulfed
Eosinophils are therefore used- Eosinophils also have Fc and complement receptors which bind to C3b and antibodies on the surface of parasite
Spit out digestive proteins onto the surface of the microbe: Extracellular digestion


Explain isotopes of antibodies involved in phagocytosis and extracellular digestion

IgG and IgA class of antibodies are good at activating phagocytes
- As phagocytes contain Fc receptors that can bind to Fc region of these antibodies
- Gamma receptors can bind to IgG
- Alpha receptors can bind to IgA

Eosinophils also have Fc epsilon receptors so can bind to Fc region of IgE antibodies
Therefore if you have a parasitic infection often levels of IgE are high to mediate this type of response


Outline 2 methods of activating mast cells (redundancy)

- Mast cells don't circulate around body but sit in different tissues of the body
- Coated in Fc epsilon receptors so they soak up any IgE that comes into tissues on their surface (several thousand of these receptors binding IgE)
- Bind antigens to which IgE is specific
- If an antigen binds to at least 2 copies of IgE on mast cell surface we call this cross-linking or bridging the surface IgE
- Triggers mast cell activation


- Proteins derived from complement activation C3a or C5a
- Mast cells have receptors for these complement peptides- activate mast cell


What happens when mast cells are activated?

- Release mass of inflammatory mediators (chemicals which will promote processes of inflammation)
- E.g. Histamine, heparin, tryptase
- Degranulation of mast cells: Inflammatory mediators pre-formed and stored in granules of the mast cells, therefore released immediately upon mast cell activation
Additionally, activation causes production of new inflammatory mediators- from arachidonic acid, leukotriene-D4, prostaglandin- D2 and cytokines (TNF-a and IL4)


Where do inducers of inflammation come from

- C3a and C5a (complement peptides)
- mast cell products (histamine- immediate release and leukotrienes- delayed release)
- Prostaglandins (macrophages and mast cells)
- Cytokines (macrophages and mast cells)
- Chemokines


Collectively what do inflammatory mediators do?

Collectively these inflammatory mediators cause relaxing of smooth muscle around blood vessels- causing vasodilation
Hence more blood can get through tissue and we see reddening
Slower movement of leukocytes through blood vessels
Endothelial cells express adhesion molecules- which bind to the leukocytes causing them to exit blood flow at site of infection
Endothelial cells move apart form each other due to slackening of the tight junctions holding them together- increasing vascular permeability
--> cells and plasma containing antibodies and complement proteins can leek out into the tissue

Cells move through tissues in response to inflammatory mediators- chemotaxis (taxis=movement in response to chemicals)
Cells move to centre of site of infection where they can mediate defensive activities


Inducing cytokines of the acute phase response

Tumour necrosis factor


Key features of acute phase response

- Instead caused by production of cytokines by that trigger those features of acute phase response
- E.g. Act on hypothalamus of brain turning thermostat up- making you feel lousy but also has a antimicrobial affect as microbes prefer 37 degrees (normal body temperature) to reproduce
- E.g. Cytokines act on bone marrow to increase release of leukocytes into blood stream
- E.g. Act on liver to cause release of acute phase proteins e.g. C-reactive protein


Symptoms of acute phase response

- "feeling fluey"
- Symptoms include fever, headache, shivering, aching muscles, loosing appetite, tiredness
Known as the acute phase response