VMED 5172 - The Complement System

inflammation

The complement system is a group of soluble factors that can sense PAMPs on microbes and contribute to ______________________, attaching in concert with the immune cells (sentinel cells, recruitment)

Complement

What are the soluble proteins present in the blood or other body fluids that "complement" the bactericidal activity of the immune sera (antibodies)?

heat-labile

Complement proteins are considered a _____________ substance in the blood as they can be degraded at higher temperatures (~50 degrees)

liver

The complement system is composed of more than 30 different plasma proteins mainly produced by the __________, but also some innate immune cells (neutrophils)

Zymogens

Many complement components are produced as _____________________________ - enzymes synthesized in their inactive form

- Presence of pathogens

- Presence of antibody bound to pathogens

- Presence of dying cells, such as those at sites of ischemic injury

What are some of the causes of complement activation (causes biochemical alteration to activate the protein)?

proteolytic

Complement activation occurs via a cascade of ________________ events (degradation)

classical

Most complement proteins are named by the letter C followed by number, with C standing for the __________________ pathway (ex. C2, C3, C4)

- Small "a" fragments (C3a, C4a and C5a)

- Big "b" fragments (C3b, C4b and C5b)

What are the two pieces that early components of the complement cascade are broken into?

C2 - C2a is the large subunit

What is the exception for the a/b rule for the small and big subunits?

Binding - can bind microbes!

What does the b of the big subunits stand for?

proteases

B subunits are often ________________ and cleave/activate the next component in the sequence

Anaphylatoxin = potent chemoattractants and activators - Cause smooth muscle contraction, vasodilation, histamine release from mast cells, and enhance vascular permeability

What does the a of the small units stand for and what do they cause?

• Classical pathway

• Lectin pathway

• Alternative pathway

What are the 3 pathways by which the complement system can be activated?

differ

While the beginning steps of the complement pathways ___________, the ending steps are the same

a

Producing _______ fragments in any pathway results in recruitment and activation of immune cells

b

Producing ________ fragments in any pathway results in coating the microbes and phagocytosis

Hole

Inducing microbial lysis in any pathway always results in forming a ______________ in the microbe plasma membrane

adaptive

The classical pathway is referred to as an ________________, as it requires antibodies (Ag-Ab) to bind to the microbe (**only pathway that needs antibodies)

C1 complex (C1qC1rC1S)

What complex binds the antibodies when the classical pathway is activated?

microbial

In the lectin pathways, the mannose-binding lectin (MBL) complex (MBL+MASP 1,2) binds to carbohydrates on _________________ structures (can just recognize pathogens w/o antibodies)

classical, lectin

The _____________ and __________________ pathways only differ in their first step (C1 activated by antibodies or MBL recognizing pathogens)

alternative

The _____________________ pathway follows the spontaneous hydrolysis and activation of the complement component C3, which can bind to microbial surfaces OR just degrades if there are no bacteria present

Classical & Lectin - C4b2a

Alternative - C3bBb

What are the enzymes formed by each pathway to breakdown C3 (first step in the final steps common to all pathways)?

C5b

What complement component interacts with additional complement proteins to form a membrane- attack complex (MAC) and killing pathogens?

shape

When an antibody finds a microbe, it binds it and alters its ______________

classical

In the ________________ pathway, C1 can only be activated if it binds to an altered antibody attached to a microbe

efficient

The more antibody units there are, the more _________________ activation of C1 will be (why IgM (pentamer) is more efficient than IgG (monomer))

C4b2a

What is the C3 convertase of the classical pathway?

C3

____________ is the most critical component for all pathways

C3b

After C3 is cleaved by the C3 convertase (C4b2a), _________ comes back and joins the C4b2a complex bound to the microbe's surface

C5

The C4b2a3b is a __________ convertase that cleaves and activates it

mediators

The a subunits (not for C2) that are not used in the complex float away to become ______________ of inflammation (chemokines, cytokines)

binds

Once the C4b2a3b complex (C5 convertase) cleaves C5, the C5a subunit floats away to become a mediator of inflammation and the C5b subunit ______________ the microbe surface

C6, C7, C8, and multiple C9

What complement components bind the C5b subunit stuck to the microbial surface?

Membrane Attack Complex (MAC)

What does the C5b6789 complex form?

Forms a pore and pokes a hole in the microbe

What does the MAC do to the microbe?

IgM - more antibody units

Which is more efficient for activating C1 in the classical pathway: IgM or IgG?

C4b2a

What is the C3 convertase of the classical pathway?

classical

The _____________________ pathway is an important method by which the adaptive immune response enhances the innate immune reaction

C4b2a3b

What is the C5 convertase of the classical pathway?

Big

________ fragments (all "b"s except for C2a) activate the next component in the classical pathway

Microbial lysis and death

What is the end results of big fragment cascade and development of MAC in the classical pathway?

opsonins

Complement fragments can also be potent ______________ (especially C3b and C5b) - help enhance phagocytosis of macrophages

- Recruit cells (much like chemokines)

- Activate inflammatory cells (Especially neutrophils, mast cells and endothelium)

- Increase vascular permeability

What are the functions of the small fragments (anaphylatoxins) in the classical pathway (esp. C3a, C5a)?

- Mannose binding lectin (MBL) - binds carbs on microbes

- MASP2 - protease bound bound by MBL

What are the first two factors of the lectin complement pathway that differ from the classical (rest is the same)?

MASP2 activates C2 and C4 (much like C1 in classical) and from there are the same steps

What does the MASP2 do after binding to MBL in the lectin pathway?

antibody

The lectin complement pathway does not require a ______________ like the classical

The C3 component normally spontaneously "self-activates" to C3b at a low frequency

How can there be a alternative pathway to the classical pathway (how is it different)?

endogenous inhibitor proteins

What keeps the spontaneous C3 activation under control and deactivates free C3b?

microbe

The endogenous inhibitor proteins cannot deactivate C3b if it is already bound to a _______________________

- Binds factor B (now C3bB)

- Binds factor D (now C3bBb)

- Activates more C3 and C5

What must occur to the bound C3b to continue the pathway?

C3bBb

What is the C3 convertase of the alternative pathway?

C3b2Bb

What is the C5 convertase of the alternative pathway?

D

In the alternative pathway, Factor ______ is circulated as an active enzyme rather than a zymogen

Properdin (factor P)

What is released by neutrophils to stabilize C3bBb (C3 convertase of alternative pathway)?

first

The alternative pathway can work on _____________ exposure and also does not require antibodies

- Lysis of microbes via membrane attack complex (MAC)

- Opsonization of microbes: fragments can bind to bacteria and increase phagocytosis

- Opsonization of immune complexes: target them for disposal

- Recruit inflammatory cells

- Activate inflammatory cells

What are the overall functions of the complement?

- Inhibitory factors in serum and on cell surfaces

- Individual components susceptible to proteolytic degradation

- Cascade is stabilized on microbial surfaces

What are some of the mechanisms used to regulate the complement system?

DAF, MCP, CR1

To regulate the complement, Host factors compete with factor B for binding to C3b = what are some of these factors?

Factor H

What is a plasma protein that binds C3b (inactivates it)?

Factor I

What is a protein that cleaves C3b into an inactive iC3b?

C1INH

Active C1 is inactivated by ____________________

- Critical in all 3 pathways

- Opsonin (C3b)

- Anaphylotoxin (C3a)

Why does C3 deficiency have the greatest impact?

Brittany Spaniel

What breed of dog has been reported to have a C3 deficiency?

- decreased IgG

- More susceptible to sepsis, pneumonia, pyometra and wound infections

- Also suffer from increased immune complex deposition

What are the signs of C3 deficiency in individuals that have homozygous gene for deficiency?

Clinically unaffected

What are the signs of C3 deficiency in individuals that have heterozygous genes for deficiency?

Factor H deficiency

Deficiency of what factor in homozygously affected individuals causes them to suffer uncontrolled activation of the alternative complement causing damage to the patient's cells (esp. in tissues with very fine capillary networks, kidneys)?

MBL or MASP-2

__________________ deficient individuals are susceptible to more respiratory infections during early childhood

Factor P

_______________ deficient patients are susceptible to infection with Neisseria meningitidis (meningitis)

The patient's serum is unable to assist in antibody-mediated lysis

A child presents with a history of multiple bacterial infections. You suspect a complement deficiency, specifically C3. You test each individual component of the immune system to see if its function is intact. If you are correct, you will find that which of the following is true?

- The patient's macrophages are unable to phagocytize

- The patient's B cells are unable to produce antibodies.

- The patient's DCs are unable to present antigens.

- The patient's serum is unable to assist in antibody-mediated lysis

C3

Activation of the alternative pathway involves?

- C1

- C3

- C2

- C4

Antibodies

The classical pathway of complement is primarily activated by?

- Microbial surfaces

- Cytokines

- Antibodies

- C3

- All of the above

C3a and C3b

What are two products of C3 convertase?

- C2a and C2b

- C4a and C4b

- C3a and C3b

- C5a and C5b

It cleaves C5 into C5a and C5b

What does the C5 convertase do?

- It binds C6, C7, C8, and C9 to form the MAC complex

- It cleaves C5 into C5a and C5b.

- It opsonizes bacteria.

- It cleaves factor B.

C3bBb

Complement component C3 is cleaved by?

- C3b

- C3bBb

- Factor B

- Factor D

- Factor P

C5a

A complement component which is strongly chemotactic for neutrophils is:

- C9

- C5a

- C3b

- C5b

C1

The initial complement component that is bound by complement-fixing antibodies is:

- C1

- MBL

- C3b

- iC3b