Immuno 4: Complement Cascade Flashcards by Chesney Oravec

Name the 3 activation pathways of the complement cascade in the order that they typically act.

Alternative
Lectin
Classical

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Which activation pathways are innate, and which are an acquired immune response?

Alternative and lectin are innate.

Classical is acquired.

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What is the primary opsinin created by the complement cascade activation pathways?

C3b

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Anaphylatoxins are one of three end products of the complement cascade. What do they do?

anaphylatoxins are inflammatory mediators that activate vascular endothelium (induce vascular permeability) and recruit phagocytes to the inflammatory site

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Opsinins are one of three end products of the complement cascade. What do they do?

mark pathogen surfaces for easier recognition, uptake, and destruction by phagocytes

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The membrane-attack complex (MAC) is one of three end products of the complement cascade. What does it do?

MAC is responsible for direct killing of pathogen by disruption of outer envelope, forming pores that result in cell lysis

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True or false: complement components are produced constitutively in the liver.

True

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How is complement opsonization different from antibody-mediated opsonization?

complement opsonization is permanent because the opsins are covalently bound to the pathogen

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Complement proteins are secreted from the liver in what form?

zymogen, or inactive; this is so that they’re always available but not active in the EC fluid and throughout the body

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Regarding these proteins, some have enzymatic activity, while others serve as membrane-binding proteins and opsonins.

Complement component proteins

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Complement proteins: What is the name of the complement protein that binds to antigen:antibody complexes and pathogen surfaces?

C1q

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Complement proteins: What is the name of the protein that binds to mannose on bacteria?

MBL

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Complement proteins: What are the names of the activating enzymes of the complement cascade?

C1r, C1s, C2a, Bb, D, MASP-2

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Complement proteins: What are the names of the membrane-binding proteins and opsonins?

C3b, C4b

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Complement proteins: What are the names of the peptide mediators of inflammation? Which is the most potent anaphylatoxin?

C5a, C3a, C4a.

C5a most potent

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Complement proteins: What are the names of the membrane-attack proteins?

C5b, C6, C7, C8, C9

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There are two versions of the C3 convertase enzyme that are responsible for cleaving component C3. Name them and the pathway that generates them.

C3b-Bb: alternative pathway

C4b-C2a: classical pathway predominantly, also lectin pathway

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The importance of C3b deposition is twofold: first: C3b is a component of the ___ convertase and eventually needed for MAC formation, and two: C3b and it breakdown products are the _____ that are permanently deposited on the surface of pathogens.

C5; opsonins

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The alternative activation pathway is a purely _____ pathway.

innate

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Turnover of C3 protein results in formation of two C3 fragments. They are:

C3a, an anapylatoxin

C3b, with exposed thioester bond

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If bound to a pathogen, C3b is a ligand for ___ __ binding, which when bound undergoes a conformational change making it susceptible to cleavage by ____ __.

factor B; factor D

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Cleavage of factor B by factor D on the surface of a pathogenic cell results in what products?

C3b-Ba and C3b-Bb (a convertase of the alternative pathway)

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If factor B binds to the surface of a host cell, will the alternative pathway be activated?

normally not; complement control proteins will prevent activation of the complement pathway

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What component proteins compose the C5 convertase enzyme for formation of the MAC?

C3b-Bb+C3b=C3b2-Bb=C5 convertase

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What is the role of the C5 convertase enzyme?

to cleave C5, into C5a (potent anapyloatoxin, acts on mast cells) and C5b

What does C5b bind to and form?

one copy each of C6 and C7; forms C5b67 complex: | C5b+C6+C7=C5b67

What is the function of the C5b67 complex?

to insert into the pathogen cell membrane, recruit C8, which then recruits 10-16 molecules of C9 which forms a pore in the membrane

What is it about membrane pores that cause death of the bacterium?

osmotic disintegrity of the cell that is formed with the addition of new pores

Mannose-binding protein (MBP) is associated with which complement activation pathway?

lectin

What does MBP bind to, and what does it serve as a ligand for?

binds to exposed mannose residues on the bacterial cell surface; then becomes ligand for Mannin-binding lectin Associated Serum Proteases (MASPs)

How do MASP proteins become enzymatically active, and what do they catalyze?

activated upon binding to MBP; cleave copies of C2 into C2a (large) and C2b (small), as well as cleave C4 into C4a (small) and C4b (large)

The classical pathway is initiated upon what event?

when complement component C1 binds to an antibody that has bound to its cognate antigen; recall that C1 has affinity for the Fc portion of antibodies

When the C1 component becomes active, ___ cleaves ___ and C1s then cleaves ___ and ___ proteins, thereby initiating the classical complement cascade.

C1r cleaves C1s; C2 and C4

Which antibody isotypes are the most efficient at activating the complement cascades?

IgM (clear champion) and IgG3

Why is IgM such an efficient activator of the complement cascade?

because it's a pentameric antibody, the C1q stalks can bind to several Fc regions at once; this conformational change to C1 initiates cleavage of C1r which is the first step toward activation

What is the mechanism of innate activation of the classical pathway?

during septic bacterial infections, liver produces and release C1 reactive protein which will bind to phosphocholine residues on the bacteria surface; this mimics an IgM molecule, so C1 binds it and the classical pathway becomes active

What is the role of complement receptors expressed on phagocytes?

to facilitate recognition and phagocytosis of pathogens

Why is complement an important component of the immune response?

some bacteria have learned how to avoid it, such as by developing a capsule--this encloses all surface structures of the bacteria, so phagocytes can't see it; but the complement is a way for phagocytes to can recognize pathogens that have been labeled with C3b

How many Fc receptors do phagocytes have for IgM?

zero. zilch. none.

How do antibodies serve as opsinins?

if a phagocyte recognizes antibody-labeled material, it phagocytoses that material and destroys it

CR1 is found on what immune cell?

phagocytes

CR3 and CR4 recognize ____, a breakdown product of iC3, and are found on ____.

iC3b; phagocytes

Erythrocytes express ____ on their surface in order to help transport small _____ _____ to liver/spleen.

CR1; immune complexes

The complement cascade is a ____ feedback loop regulated by what two forms?

Positive; passive and active regulation

Rapid hydrolysis of the reactive thioester bonds following cleavage of complement components is an example of what type of regulation?

passive

True or false: Active regulation of the complement depends on C3 inhibitor.

False - depends on C1 inihibtor

What is the mechanism of action of C1INH (C1 inhibitor)?

binds to C1r:C1s, forcing it to dissociate from C1q

Is C1INH soluble or insoluble?

soluble

What is the deficiency, cause, presentation, and treatment of hereditary angioneurotic edema (HANE)?

- C1INH deficiency; low serum C2 and C4 levels - caused by overproduction of anaphylatoxins - presents with episodic systemic edema, most often around lips because this area is heavily vascularized - treated by monthly injection of C1INH

C4-binding protein (C4BP) binds to ___ of the ____ convertase of the ____ pathway.

C4b; C3 convertase; classical

How does factor H regulate?

binds C3b, making susceptible to factor I cleavage (inactivates C3b and C4b)

How does factor I inactivate C3b and C4b?

it's a protease that cleaves the proteins once Factor H/MCP/CR1 (for C3b) or C4BP (for C4b) has made them susceptible: C3b-->iC3b (opsinin for use elsewhere, not in complement activation) C4b-->inactive

Deficiency of factor I results in what?

extended C3 convertase activity and up-production, eventually leading to depletion of C3 which prevents activation of complement cascades when needed

What are the 3 membrane-bound proteins that serve to protect host cells by way of deactivating the C3 convertase?

DAF - decay accelerating factor MCP - membrane co-factor protein CR1 - complement receptor 1

What is the function of DAF?

dissociates C3 convertase

What is the function of MCP?

binds C3b/C4b making them susceptible to cleavage by factor I

What is the function of CR1?

binds C3b/C4b making them susceptible to cleavage by factor I

What is CD59 and what does it do?

aka protectin; binds to the C5b-6-7-8 complex and prevents polymerization of C9; located on host cell membranes to prevent MAC pore formation

Deficiency of the phosphoinositol glycolipid tail that anchors DAF and CD59 to host cell membranes results in what?

clinical disease where patients suffer from episodes of intravascular RBC lysis, aka paroxymal nocturnal hemoglobinuria

What is the function of factor P?

stabilizes alternative C3 convertase

List the 3 primary products of the complement cascade.

C3b (most important) Membrane Attack Complex Anaphylatoxin

What is the last of the membrane attack complex complements to coalesce?

What Complement molecules are included in the membrane attack complex?

C5b-C9

In the classical complement pathway, the C1 molecule is made up of:

6 stalks of C1q and small C1r and C1s subunits

Inherited deficiency of mannose-binding lectin would result in the greatest reduction in C3b deposition through which pathway of complement activation?

Lectin Pathway

Inherited deficiency of factor D would result in the greatest reduction in C3b deposition through which pathway(s) of complement activation?

Alternative Pathway

Inherited deficiency of C2 would result in the greatest reduction in C3b deposition through which pathway(s) of complement activation?

Classical and Lectin Pathways

C1r and C1s catalyze the cleavage of what two complement proteins for the classical pathway?

C2 & C4

What are the multiple roles of the products of C5 cleavage?

C5b is a component of the membrane attack complex in the alternative pathway. C5a goes on to become an anaphylatoxin and a chemotaxin in the classical pathway.

Inherited deficiency of which component would result in the inability to activate the classical complement cascade (in an acquired manner) while leaving the alternative and lectin pathways in tact?

C1 - recall that it mediates cleavage of C4 and C2 for use in making the C3 convertase

Genus Neisseria is especially sensitive to which product of the complement cascade?

Membrane attack complex

Would you expect gram-positive and gram negative bacteria to be equally susceptible to killing by membrane attack complex?

No, gram-positive bacteria would be more resistant because of their thicker cell wall.

Which host cells are most susceptible to damage in patients that have a deficiency of C4BP, factor H, factor I, DAF, or MCP?

erythrocytes, because they have high surface area and no nucleus to alter gene expression for membrane repair or anything like that

Deficiency of c-reactive protein results in decreased deposition of complement C3 protein through which pathway?

Classical pathway

Deficiency of MAC components results in heightened susceptibility to only one pathogen. What is it?

Neisseria - this is weird because for most pathogens, the C3 attack process is the most significant killer

Would you expect Gram-negative or Gram-positive to be more resistant to attack by the MAC?

Gram-positive, because they have a thicker cell wall presenting a greater challenge for the MAC to permeate the cell