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55 Cards in this Set

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Name the 4 possible outcomes of compelment activation.
1. cell lysis

2. opsonization of the Ag

3. mediate inflammation

4. removal of immune complexes
Is complement innate or aquired?
Innate (even though it uses Abs, it does so NON-specifically)
What causes cell lysis?
MAC (membrane attack complex; C5b-C9)
How does complement mediate inflammation?
C’ products bind to complement receptors on various cells (mast cells, basophils, and neutrophils), resulting in release of histamine and other inflammatory mediators
How and when was complement discovered?
1890s

observed that fresh, immune sera was capable of lysing live bacteria
Will heating serum to 56C for 30 minutes destroyed the lytic capacity? The antibodies?


What happens whne fresh, NON-immune serum is added to the heated serum?
--lytic capacity destroyed when heated.
--antibodies NOT destroyed

--addition of fresh, non-immune serum restored the lytic action
Which fraction does the Ab belong to? The complementary component (compement)?
--heat stabile fraction (antibody)
--heat labile fraction (“complementary” component)
now called complement
What is the major effector of the humoral immune response?
complement cascade
Where are most of the 30 complement cascade proteins made?
in the liver; some in the WBCs
Usually which is larger a or b? Which one will diffuse from the site? Which will bind to the target?

What is the exception?
smaller fragment is designated as “a”

larger fragment is designated as “b”

usually, the smaller (a)fragment diffuses from site and is important in stimulating inflammation

usually, the larger (b)fragment stays in the local area and may bind to target cell
How is an enzymatically ACTIVE molecule indicated?
has a bar over top
How does the end result differ among the three major pathways of complement?
They don't. The end result is the same, just a different way of getting there for each
What is the classical pathway dependent on?

How is the classical pathway activated?

Which Abs are most important?
--Ag Ab interaction

--activated by the interaction of C1 with the Fc region of antibodies

--IgG (not IgG4) and IgM
Where does C1 act?
Fc regions of Abs IgG and IgM
How many IgMs are needed to activate the classical pathway? IgGs? Why is this?
need only ONE IgM (pentameric) and at least 2 IgGs (monomeric)

NOTE: Actually need more like 1000 IgGs b/c of probability that the 2 will be close enough together
What happens upon Ag binding?
the conformation of Fc changes to expose regions where C1 binds
What makes up C1?
a complex of proteins: C1q, C1r, and C1s

(r and s subunits are in dimers; C1qr2s2)
Where does C1q bind? What happens as a result?
CH2 domain of Ig

upon binding, C1r activates C1s
What does C1s activate?
C1s then activates C4 and C2
How is C4b2a formed? What is another name for C4b2a?
C4b2a is formed after lysis of C4 and C2. C4b and C2a bind together forming C4b2a AKA C3 convertase
What does C3 convertase do? What complex results from this action?
cleaves C3

forms C4b2a3b AKA c5 convertase
What does C3a do?
important inflammatory mediator

anaphylatoxin – cause degranulation of mast cell/basophil
What does C5 convertase do? What do these products do?
C5 convertase cleaves C5

C5a diffuses away (anaphylatoxin)

C5b binds to target cell
C5b binds C6, C7, C8 and C9
What happens when C5b binds C6, C7, C8 and C9?
This is the membrane attack complex.

displaces membrane lipids to form a pore by which ions and molecules can go through

causes lysis--holes in the cell suface
Does the alternative pathway require Abs?
Nope!
What is the alternative pathway CRITICAL for?
opsonization function of C’

The alternative pathway “calls” in macrophages, B cells, etc
those that can bind C’ proteins via complement receptors
What is the alternative pathway activated by?
cell surface components that are foreign to the host

eg. bacterial LPS, cell wall components, etc
Which complement protein is most important to the alternative pathway?
C3 because it can spontaneously be split into C3a and C3b

C3b will then bind the foreign Ag in order to begin the alternative pathway
Besides the Ag what else does C3b bind?
Factor B on the Ag
What activates C3b-Factor B to release Ba and Bb?
Factor D
What is C3bBb's job? What stabilizes C3bBb?
C3 convertase (like in classical pathway)

Properdine
What makes C5 convertase?

What will C5b do?
C3bBb3b

C5b will bind to the Ag surface and then MAC
Summarize the alternative pathway.
1. C3 - spontaneous hydrolysis
2. C3b binding to foreign surface

3. C3b + Factor B + Factor D
= C3bBb (Ba diffuses)

4. C3bBb + Properdine – stabilizes
= cleaves more C3

5. C3bBb3b cleaves C5

6. MAC
Name the initiators of the alternative pathway for the following:

Gram - bacteria

Gram + bacteria

Fungal/Yeast cell
LPS from Gram - bacteria

teichoic acid from Gram + bacteria

fungal/yeast cell wall (zymosan)
Name some more initiators.
some viruses and viral-infected cells

Trypanosoma (and some other parasites)

human IgG, IgA, and IgE in complexes

cobra venom factor

anionic polymers (dextran sulfate)

pure carbohydrates (agarose, inulin)
What is the name of the third complement pathway?
MBP (mannan binding protein) or lectin pathway
What is a lectin?
proteins that bind carbohydrates
What are some of the collectins of the respiratory and digestive systems?

What domains do the collectins have? What does each do?
surfactants, mannan binding protein

1. lectin binding domain (to bind microbe) and

2. a collagen domain (interact with cells = opsonin)

3. C’ activating portion as well
After activation, what does MBP acts like?

What is the rest of the pathway like in comparison to the classical pathway?
MBP acts like C1 and activates C2 and C4.

rest of pathway similar to classical pathway
Which proteins are responsible for opsonization?
C3b and C4b – bind to antigens AND to C’ receptors on host defense cells

increase phagocytic cell recognition/destruction of Ag
Which proteins are most important for inflammation (anaphylatoxins)?

Which is strongest?

What do they do?
C3a, C4a, and C5a

C5a is most potent of the three

degranulation of mast cells, basophils, eosinophils

extravasation of WBCs

release of neutrophils from bone marrow

increased expression of C’ receptors on neutrophils
What does receptor CR1 bind?

What cells have this receptor and why is it important?
Binds C3b and C4b on:

erythrocytes

neurtophils

monocytes

lymphocytes

important in transport and opsonization of immune complexes

RBCs bind immune complexes (containing C3b or C4b) and carry them to the liver and spleen where macrophages can “grab” the complexes for destruction

RBC goes back into circulation
What does the CR2 bind to?

What important function does this receptor serve?
C3d, iC3b of B cells

uptake of immune complexes and B cell activation

important in memory B cell activation (binds B cell co-receptor)
What does CR3 bind to?

What function does the CR3 receptor serve?

What is the relationship to T helper response?
monocytes, neutrophils, NK cells

uptake of immune complexes

opsoniation funciton (iC3b)

binding can REGULATE CYTOKINE PRODUCTION (IL-12 and IFNg from Macrophate…determine Th1 vs Th2 response)
Why must complement activation be regulated?
because of strong biological activity of C’ activation
bystander cells can be lysed if C5b binds

many active components breakdown spontaneously if not attached to next component in cascade
Which step is the most important level of control?
C3 step in ALL three pathways
What is Factor I?

Where does it act?

Which pathway is it involved with?
Factor I cleaves C3 into inactive components (first iC3b, then C3d)
these remain attached to cell surface
only happens on host cells (so microbes can still be killed)

Involved in ALL three pathways
What is Factor H?

Which pathway is it involved with?

How does it work?
Factor H – inhibits alternative pathway (binds C3b and prevents association with Factor B)
What is the S protein?

How does it work?

What is S protein often associated with?
--S protein – binds C5b67 if released by target cell

--help prevent bystander cell lysis

--often associated with bacteria
What do gram negative bacteria with long chain polysaccharides to LPS do?
prevent insertion of MAC

strains of E coli and salmonella
What do Gram – bacterial with certain outermembrane proteins do?
MAC interacts with outermembrane protein and not cell membrane (strains of Neisseria gonorrhea)
What do bacteria that produce elastase do?
Ex. Pseudomonas aeruginosa

inactivates anaphylatoxins
What does the thick peptidoglycan layer of Gram + bacteria prevent?
MAC does not get into cell membrane
What does the gram + capsule provide a barrier against?

What happens as a result?
barrier between C3b deposited on cell membrane and CR1 on phagocytic cell


--decreases opsonization
--in order to lyse encapsulated bacteria, usually need C3b and Abs
When microbes produce proteins that mimic complement protein what effect does this usually have?

Give some ex.
usually inhibitory

ex. Vaccinia virus, HSV, EBV, Trypanosoma cruzi, Candida albicans, etc.