Jan. 24th (Exam 1) Flashcards by Benton Schaefer

What are the three ways that immediate barriers are able to do their jobs?

Mechanical
Chemical
Microbiological (normal microbiota)

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What are some examples of mechanical immediate barriers?

(Skin, Gut, Lungs, ENT)

they all contain tight junctions that join cells

Skin/Gut - there is a longitudinal flow of air or fluid
Lungs - there is movement of mucus by cilia
ENT - tears/nasal cillia

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What are some examples of chemical barriers (Skin, Gut, Lungs, ENT)?

Skin - fatty acids and antimicrobial peptides
Gut - low pH, antimicrobial enzymes, and antimicrobial peptides
Lungs - pulmonary surfactant, antimicrobial peptides
ENT - antimicrobial enzymes in tears and saliva, and antimicrobial peptides

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What happens if the pathogen is not eliminated via the immediate innate immune response?

We proceed to the induced innate immune response.

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What is the complement system?

Where are the proteins that are involved made?

The complement system is a collection of soluble proteins that are found in the blood, lymph, and extracellular fluid.

We learned that they will mark pathogens in order to attack them or alert effector cells.

They are made all the time in the liver.

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There are around 30 different types of proteins involved in the complement system and many of them are zymogens.

What is a zymogen?

This is a enzyme that is the precursor to the active form.

It must be activated by something before it can perform its function.

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Why would it be advantageous to have zymogens for complement proteins?

Why can’t we just make them when there is an infection?

Because we don’t want it on all the time.

Takes much too long.

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Think about the chart that shows the various things that can happen when the complement system is activated.

What are those two main things and what is involved in each?

Altered membranes

bacterial cell lysis
opsonization

Inflammation

mast cells degranulate
neutrophil chemotaxis

THESE SHOULD ALL LEAD TO PATHOGEN DESTRUCTION

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What are some other activities that complement activation can impact? (four things)

Immune Regulation
Angiogenesis
Removal of apoptotic cells
Blood coagulation

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What are the three different pathways for complement activation?

Alternative Pathway
Lectin Pathway
Classical Pathway

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What do all three pathways of complement activation in common?

What do they converge on?

All three pathways of activation will converge on C3 which gets cleaved into C3a and C3b.

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Explain the Alternative Pathway to Complement Activation.

Is it the 1st, 2nd or 3rd to act?

The pathogen surface creates a local environment conducive to complement activation.

It is the first to act.

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Explain the Lectin Pathway to Complement Activation.

Is it the 1st, 2nd, or 3rd to act?

Lectin, which binds mannose, will bind to the pathogen surface.

It is the second to act.

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Explain the Classical Pathway to Complement Activation.

Is it the 1st, 2nd, or 3rd to act?

C-reactive protein or antibody will bind to specific a specific antigen on the pathogen surface.

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What generally activates the complement system?

What does a lack of C3 impart?

Infections generally activate the complement system.

Severe infections can result from having a lack of C3

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How does the C3 Zymogen get activated?

What are the products?

It gets cleaved into:

What does C3a do generally?

What is an example of what it could do?

It is what we call a chemoattractant / ANAPHYLATOXIN

Recruit phagocytes.

What does C3b do generally?

What is an example of what it could do?

It works in complement fixation.

Could tag a bacterium for destruction.

What does the cleavage of C3 expose in its, once hydrophobic, interior?

It exposes a thioester group.

Thioester is a central carbon double bound to an oxygen a sulfur and R group

Once the thioester bond present on C3b is exposed, what may happen to the electrophilic bond?

Attacked by the nucleophile of water creating a soluble C3b
Attacked by either -OH or R-NH2, binding it to the surface of the pathogen.

Which of the two types of nucleophilic attack will create the most inactive version of C3b?

Attack by water

What is a thiol group?

-SH

functional group

What is an ester linkage?

How is it made?

It is when two groups, an alcohol and an acid, react to release water and form an ester bond.

What is a nucleophile?

A nucleophile is an electron rich species that donates an electron pair to form a bond, typically attacking electrophiles or electron-deficient centers.

Can water be a nuceophile?

Yes!

Explain the process of C3 becoming iC3Bb. What does iC3Bb do?

C3 has its thioester group exposed by either force of movement or by C3 convertase and becomes iC3 when water attacks the electrophilic thioester. Factor B then binds to iC3, but is inactive. Only when the serine protease Factor D cleaves the bound Factor B into Ba and Bb (Ba breaks off). What we are left with is called iC3Bb (C3 convertase) C3 Convertase is a protease that cleaves and activates C3 into C3b and C3a

What is the downside of iC3Bb (C3 Convertase) ?

It is not bound by anything and can easily diffuse away.

What is the alternative C3 Convertase? Explain how bound C3b can become this, and how this is different than the hydrolysis activation of C3 convertase.

It is called C3bBb Convertase Factor B binds to bound C3b, and then Factor D serine protease will cleave the bound Factor B into Bb and Ba. Ba and Factor D dissociate and now the bound C3bBb can act as a convertase to cleave C3 into C3a and C3b.

Explain how the pathogen bound C3b (that will become C3bBb convertase) is a positive feedback loop.

As each C3bBb is activated and starts acting as a convertase, more and more C3 will be cleaved and more and more will become bound and have the potential to become convertases themselves.

What is the stabilizer of C3bBb? How does it do this? Does this increase or decrease complement activation?

This is a protein called Properdin. It does this by preventing degradation. This increases the complement activation, because it allows the bound convertase to keep working on cleaving C3

What are the roles of Factor H and Factor I in complement activation/inactivation?

When C3b is bound on a pathogens surface, Factor H comes along and binds to the C3b portion, changing the shape of C3 slightly allowing for Factor I to bind and cleave C3b, leaving iC3b.

What type of enzyme is Factor I? What mechanisms of action does it use?

It is a hydrolase It uses a serine residue to attack the peptide bond and break it.

What is DAF and what does it do? How does it do this?

DAF is known as Decay Accelerating Factor DAF can disrupt the C3bBb alternative convertase on the surface of human cells. DAF will bind to the human cell bound C3bBb convertase and will flex the protein so that Bb disassociates and the enzyme is dysfunctional.

What is MCP and what does it do? How does it do this?

MCP is known as membrane cofactor protein. It has a similar function to DAF where it will disrupt the alternative convertase C3bBb on the surface of human cells. It does this by first binding the complex of Bb and C3b, disassociating the two, and promoting the binding of Factor I, which subsequently binds and cleaves a piece of C3b making it officially iC3b