Quiz 3 - German - Barriers/Effectors II Flashcards
What is the complement system?
Immune surveillance system of plasma proteins that act in cascades to selectively kill extracellular pathogens and diseased tissue, promote inflammation, clear tissue damage, and regulate tissue homeostasis
What produces complement?
THE LIVER
What 3 pathways are in the complement system?
Classical pathway
Lectin pathway
Alternate pathway
The complement proteins act as what?
Pattern recognition system
*Also in cardiovascular circulation
What does complement do?
Goes around and covers everything
- If healthy cell - cell removes it and cascade is not initiated
- If unhealthy cell - it initiates a cascade pathway leading to destruction of that cell
**Complement monitors all cells in the body
____% of plasma globulin protein is complement.
15%
What are the initiators?
These initiate the complement pathways
- Classical: Antibody/C1q complexes
- Lectin: Mannose - binding lectins
- Alternate: C3, properdin
What are convertases?
C3b and C5b
-These are cleaved and function as opsonins (coat surfaces of pathogens)
Label pathogens/antigens
What are opsonins?
Coat pathogens/antigens and target for phagocytosis
What are anaphylatoxins?
Initiate and promote inflammation
What is the membrane attack complex?
Form the MAC pore
Group of peptides that form a pore in the cell surface
-This is how complement directly destroys pathogens
What do complement receptors do?
Initiate signaling
What are regulators?
Restrict or halt complement activity
- Proteins
- Proteases drive pathway progression
- Missing components cause pathogen susceptibility
What does a convertase do?
Protease that continuously cleaves its complement component
There are 3 complement pathways. Name them, what activates them, and put them in order of which one goes 1st.
1st - Alternative - pathogen surface creates local environment conducive to complement activation (coats everything)
2nd - Lectin - Mannose-binding lectins binds to pathogen surface
3rd - Classical - C-reactive protein OR antibody binds to specific antigen on pathogen surface
ALL pathways lead to what main event?
CLEAVAGE OF C3
When C3 is cleaved, what are the 2 products?
C3a and C3b
What does C3a do?
Acts as an anaphylatoxin
- Small fragment
- NO enzyme activity
- Signaling activity
What does C3b do?
Covalently binds to surface components of pathogen/cell
-Large fragment
-Enzyme activity
—Proteolytically active
- Opsonin
- Signaling activity
What is significant about C2?
This is the EXCEPTION
When cleaved, C2a binds the surface and C2b acts as the anaphylatoxin
What two antibodies are involved in the classical pathway?
IgM
IgG
What is the first component of complement in the classical pathway?
C1q
Tell me the beginning stages of the classical pathway.
Antibodies (IgM or IgG) bind to surface
C1q then comes down in between two antibodies and creates an activation cascade
What is the main difference b/t IgM and IgG?
IgM - PENTOMERIC - More binding sites for C1q (Higher binding affinity than IgG) - Highly concentrated in the blood - BLOODSTREAM PROTECTOR
IgG - Easily go into peripheral tissues
C1q has two subunits. Name them.
C1r and C1s
C1q binds to ______ IgM molecule(s).
C1q binds to _______ IgG molecule(s).
ONE IgM
TWO IgG
The binding of C1q to IgM/G activates ____, which cleaves and citrates the serine protease _______.
C1r
C1s
What proteolytic cleaves C4?
What is C4 and where is it found?
C1r and C1s
Protein floating around in periphery and vasculature
When C4 is cleaved, what are the products?
C4a and C4b
C4a is an anaphylatoxin
C4b is an opsonin and a protease
Once C4b sits down on the plasma membrane, what does it recruit?
C2
C2 is cleaved and what are the products and what happens?
C2a
C2b
*This is the EXCEPTION
C2a - Binds with C4b to create a cluster - THIS IS CALLED C4b2a - THIS CREATES C3 convertase
C2b - acts as the anaphylatoxin, but not a lot of known stuff about it
C4b2a is a C3 convertase. What does it do?
It continuously cleaves its complement component
It cleaves C3 into C3a and C3b
What does C3a do?
*What does C3b do?
C3a - Anaphylatoxin
C3b - COATS THE ENTIRE SURFACE OF THE PATHOGEN - Also, it can join the cluster to become: C3b2a3b - AKA: C5 convertase
What does the the C5 convertase (C4b2a3b) do?
Cleaves C5 into C5a and C5b
C5a - Anaphylatoxin
C5b - Opsonin - Opsonizes whole surface of pathogen
At what point in this cascade does actual biologic function occur?
Cleavage of C3. Once C3b sits down, a cell can be destroyed
Which convertase is shared by the lectin pathway?
C5 convertase
*The difference in the pathways is HOW they are inititiated
Tell me what pathogens have on their cell surface.
Pathogens express unique cell surface glycoproteins
*N-linked glycoproteins of yeasts contain many terminal mannose residues
**Glycoproteins of vertebrates have terminal sialic acid residues
How is the lectin pathway initiated?
- Mannose binding lectins (MBL)
- Ficolins
What does the lectin pathway recruit?
Mannose binding lectins (MBL) Associated Serine Proteases [MASP]
—MASP-1
—MASP-2
**The MASPs are to the lectin pathway as the C1s/C1r are to the classical pathway
Serine proteases (MASPs) cleave complement protein _____.
C4
MBL binds with high affinity to _____ and fructose residues.
Mannose
Ficolins bind ___________ containing acetylated sugars.
Oligosaccharides
Once MASPs are bound, what happens?
C4 comes in and is cleaved
THE REST OF THE PATHWAY IS THE SAME AS THE CLASSICAL PATHWAY
Third pathway is the alternative pathway. What happens there?
C3 is spontaneously hydrolyzed
LOOK AT ONE NOTE FOR DRAWING
LOOK AT ONE NOTE FOR PATHWAY DRAWINGS.
SERIOUSLY
What do anaphylatoxins do?
Act on blood vessels to increase vascular permeability and cell-adhesion molecules
Help with inflammation
Increased permeability allows increased fluid leakage
—This allows for migration of macrophages, PMNs, and lymphocytes is increased. Microbicidal activity of macrophages and PMNs are increased
What do anaphylatoxins activate?
Immune cells
- Macrophage
- Neutrophil
- Basophil
- Eosinophil
- Mast cells
*They interact with discrete receptors on innate immune cells
How does opsonization neutralize pathogens and target them for phagocytosis?
C3b all over bacterium
-Macrophage has C3b and C5a receptors all over
Macrophage binds the C3b on bacterium
WHEN ONLY C3b BINDS TO CR1, BACTERIA ARE NOT PHAGOCYTOSED
-This prevents macrophages from destroying self-cells
When C5a binds, the macrophages have the green light to phagocytose via CR1
T/F - C3b and C5a are NECESSARY for macrophage phagocytosis.
TRUE
Receptor questions
CR1 - Bind what? Functions? Cell types?
CR3 - “
C5a - “
CR1
- C3b, C4bi
- Stims phagocytosis (req’s C5a)
- Macrophages, RBCs, WBCs
CR3
- iC3b
- Stims phagocytosis
- WBCs
C5a
- C5a
- Binding of C5a activates G protein
- Endothelial cells, mast cells, phagocytes
Tell me how the MAC is formed.
C5b recruits C6 and C7
Then, C8 is recruited, and the C5b678 complex is created
Then ~20 C9s are recruited
C9 perforates into the membrane and forms the MAC
-This puts large lesions into the membrane
—With more C5b on the surface, more MAC is formed and pathogen is killed
How is the MAC regulated?
Human cells have CD59 that binds the C5b678 complex and PREVENTS recruitment of C9 to form the MAC pore
Why is opsonization and convertase activity regulated?
This is obviously critical since C3b and C5b need to be removed from self-cells to avoid too frequent self-destruction
How is C3b opsonizaiton and convertase activity regulated?
Factors H and I
Factor H and Factor I (From vasculature)
These cleave off C3b into a number of different sub components which leads to an insoluble/inactive C3b
-When properdin binds, it prevents the binding of Factor H and Factor I
How is C3b opsonization and convertase activity regulated?
DAF and MCP
DAF and MCP (On healthy human cells)
- Decay-Accelerating Factor
- Membrane Co-Factor Protein
DAF - Removes Bb component from C3b, and prevents the C3 pathway from moving on
MCP - Removes Bb component by binding, recruits factor I, and leads to cleavage of iC3b
OVERVIEW
Classical Pathway
Initiated by C-reactive protein or antibodies
C1q interacts with pathogen surface or antibodies on pathogen surface
C1r and C1s
Pathway starts
OVERVIEW
Lectin Pathway
Initiated by mannose binding lectin (MBL) or ficolins
These recognize and bind carbs on pathogen surface
MASP-1 and MASP-2
Pathway starts
OVERVIEW
Alternative Pathway
C3 undergoes spontaneous hydrolysis (via H2O) and C3b is put all over everything
Pathways starts
Leads to MAC
C3 convertases:
Classical and lectin - ??
Alternative - ??
Classical and lectin - C4b2a
Alternative - iC3Bb, C3bBb
C5 convertases:
Classical and lectin - ??
Alternative - ??
Classical and lectin - C4b2a3b
Alternative - (C3b)2Bb
What do anaphylatoxins do?
Vasodilation
Chemotactic factors
-Recruit induced immune system
Drive phagocytosis
Drive degranulation
What does C3b do?
Targets a cell for destruction
Creates the C5 convertase
-Forms the MAC
What is the difference b/t iC3b and C3b?
- C3b sits down on any surface
- iC3b is insoluble and floats around
What prevents the MAC complex from forming?
CD59
