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Chpt 13 Complement


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What is the complement system?
The major effector of the humoral branch of the immune system.

The activity of blood serum that completes the action of antibody.
4 functions of complement
1. Lysis of cells, bacteria, viruses
2. Opsonization
3. Binding specific complement receptors to Trigger inflamm, regulation
4. immune complex clearance of
is complement heat stabile or labile?
labile; heating destroys its ability to lyse infected cells.
3 activation pathways:
1. Classical
2. Alternative
3. Lectin
How is the classical pathway initiated?
formation of Ag-Ab complex.
This induces a conformational change in the Fc region of the antibody to allow C1 to bind the complex (by antibody)
Step 2 of classical pathway

Special requirement:
C1 binds 2 Fc regions of antibody (that is complexed to antigen).

C1 must have 2 Fc regions accessible; IgM is much better at activating classical pathway than IgG
Step 3 of classical pathway
rapid hydrolysis of C3 into C3a and C3b.

initiates cascade that forms MAC
what is the mechanism of complement?
What allows C3b to act as an opsonin?
Internal thioester bond in C3 is activated when it's cleaved and it ends up on C3b so it has free sticky chemical group to bind to free OH or amine groups on cell membranes. (phagocytic cells)
Function of:
C3a --> anaphylatoxin; mediates inflammation

C3b --> opsonin for phagocytosis; coats immune complexes and particulate Ag.
For which pathways is Ab necessary?
Which are components of innate immunity?
ONLY Classical needs antibody.

Alternative and Lectin are innate.
Initiation of Alternative pathway:
Serum C3 just hydrolyzes very slowly into c3a/c3b. the sticky group on C3b then binds to groups on foreign molecules (bacteria, Ag).

Triggers a bunch of steps that results in MAC formation.
Which antibody needs to be in higher concentration to activate complement?
IgG much higher than IgM; need 2 binding sites for C1 to activate complement.
what can activate the alternative pathway?
pathogens, microbial particles, and even host self-cells that are recognized as non-self.
role of complement in viral neutralization:
C3b sticky ends bind to viruses in circulation; coats the surface and allows phagocytosis!
what is lectin?
an acute phase protein from inflammation. innate response produces this molecule to activate complement for lysis of bacteria.
what are the two steps of the Lectin activation pathway?
1. Lectin binds Mannose (carb) on bacterial surface.

2. Serine protease binds Lectin and activates cleavage of C2 and 4, and the complement cascade.
What is the point of convergence of the three activation pathways?
MAC formation.
how does c3b mediate opsonization?
Phagocytes have complement receptors. when complement proteins coat the surface of antigen, the proteins then bind receptors and activate the function.
what molecule polymerizes to form MAC?
How does MAC cause lysis of cells?
By forming a pore in their membrane, allows diffusion of ions across membrane and disrupts osmotic stability -> causes lysis
what are the 2 regulatory mechanisms of complement?
1. Inactivate complement components. Proteins cleave very unstable, short-lived intermediates to stop cascade.

2. Inactivate anaphylatoxin
What are the 6 consequences of complement activation?
1. Lysis of cells, GNB, and envel. virus
2. particulate Ag opsonization
3. Inflammatory activation
4. local clearance of Ag-Ab complex.
5. Viral neutralization
6. Systemic clearing of Ag-Ab complex.
How can innate immunity activate complement by all three pathways?
Microorganisms can activate Altern/lectin by their surface ag.

Classical can be activated by common surface molecules on ubiquitous microorganisms.
How can MAC lyse viruses?
It can insert pores into the viral envelope because it is made of plasma membrane (from the host)
What type of bacteria are more commonly lysed by MAC?
Gram negative - the peptidoglycan of Gram positive evades MAC insertion.
What is special about RBC lysis by MAC?
only requires one molecule of MAC;

nucleated cell lysis requires multiple MACs.
what are the two functions of C3a that mediate inflammation?
1. cause degranulation

2. chemotactic
How does c3a cause chemotaxis?
binds molecules already at the inflammatory site, induces binding of other neutrophils/monocytes to bind epithelial cells, extravasate, and arrive at inflamm site.
how does c3a mediate degranulation?
mast cells/basophils have receptors for it; binding induces degranulation.
How does C3A help C3B be a better opsonin?
anaphylatoxins induce upregulated c3b receptors on macrophages and phagocytic cells.
3 Methods of Complement neutralization of Viruses:
1. simply the fact aggregates formed from c3b-coating reduces the # of viral particles.

2. Complement coating prevents virus from binding host cells/infecting them.
3. Opsonization allows phagocytosis of virus-c3b aggregates.
Mac-lysis would cause spreading of Viral DNA; how is this prevented?
Coating virus w/ complement proteins allows phagocytosis, packaging the degraded virus and preventing spread.
2 ways to kill viruses with complement:
1. Phagocytosis (via opsonization)
2. Enveloped viruses get MAC-lysed
What is the result of insufficient levels of C1,2, or 4?
Insufficient levels of C3; insufficient complement
What role do RBCs play in immune complex-clearing?
Have CR1-receptor; this binds C3b-coated immune complexes, carry to spleen/liver. Then, Complex is stripped and phagocytosed; RBCs return to circulation.
Why do lupus patients have tissue damage?
produce too much immune complex;
produce too little c3b;

complexes persist (RBC don't bind if there's no c3b on complex) and activate MAC lysis instead of phagocytosis in spleen/liver
consequences of complement deficiency:
-recurrent bacterial infections
-tissue damage due to persistent Ag-ab complexes

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