Defence against Extracellular Pathogens Flashcards
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
