CLS 306 Lecture 3 part 2

what is complement in the immune system?  

series of >50 soluble and cell bound proteins of the innate immune system that interact to enhance host defense mechanisms against foreign cells

where are most plasma complement proteins made?

liver

which complement components are exceptions to liver synthesis?

• C1 components: produced by intestinal epithelial cells

• Factor D: produced in adipose tissue

Which WBCs are additional sources of early complement components?

C1, C2, C3, C4

In what form are most complement proteins found in plasma?

As zymogens (inactive precursors)

How are complement zymogens activated?

they are converted to active enzymes in a very precise order

major functions of complement components?

• lyse foreign cells

• act as opsonins (enhance phagocytosis) 

• clear immune complexes 

• increase vascular permeability 

• recruit monocytes and neutrophils to area of Ag concentration 

• trigger secretion of immunoregulatory molecules that amplify immune response

What is opsonization by complement?

Complement acts as opsonins that coat pathogens, making them easier for phagocytes to recognize and ingest

How does complement affect blood vessels?

Increases vascular permeability

Which cells are recruited by complement to sites of antigen concentration?

Monocytes and neutrophils

What are the three pathways of complement system activation?

Classical pathway

Lectin pathway

Alternative pathway

Can more than one complement activation pathway be triggered at the same time?

Yes, multiple pathways can be activated simultaneously

What is the common end product of complement activation?

Lysis of the invading cell

what are the stages of the classical pathways?

• Recognition unit

• Activation unit

• Membrane Attack Complex (MAC)

What is the recognition unit of the classical complement pathway?

C1 binds to ag-ab complexes or other substances to initiate the pathway

Which complement components are activated after C1 binding in the recognition unit?

C4 and C2, forming C4b2a (C3 convertase)

What is the activation unit in the classical pathway?

C3 is activated, producing fragments that combine with C4b2a to form C5 convertase (C4b2a3b)

What happens after C5 convertase formation in the classical pathway?

Successive activation of C5-C9 occurs, forming the Membrane Attack Complex (MAC)

What is the structure of the Membrane Attack Complex (MAC)?

C5b6789

What is the ultimate effect of the MAC?

cell lysis

Which antibodies can initiate the classical pathway when bound to antigen?

IgG

IgM

Besides antibodies, what plasma protein can initiate the classical pathway when bound to a ligand?

C-reactive protein

Name some pathogens that can directly initiate the classical pathway

Certain viruses

mycoplasmas

gram-negative bacteria (ex: E. coli)

some protozoa

What is the first complement component to bind in the classical pathway?

C1

What are the three subunits of C1?

C1q, C1r, and C1s

How many globular heads of C1q must bind to antibody to initiate the classical pathway?

at least two 

Which Ab classes can activate the classical complement pathway?

IgG or IgM (when bound to antigen)

• these must be bound to ag in order for complement (C1q) to bind

How close must two IgG molecules be to activate complement?

Within 30–40 nm of each other

Rank the IgG subclasses in their effectiveness at activating complement.

IgG3 > IgG1 > IgG2

How many IgM molecules are needed to activate complement? Why?

Only 1, because IgM is a pentamer that can bind two adjacent antigenic determinants to initiate cascade 

Which antibody classes cannot activate complement?

IgG4

IgA

IgE

What does C1q recognize on antibodies to initiate complement activation?

The Fc region of two adjacent antibodies

What happens to zymogens C1r and C1s when C1q binds?

• converted into active enyzmes

• C1r undergoes autoactivation and then activates C1s

  • cleaves thioester bond on C1s which activates it 

What substrates does activated C1s act on?

C4 and C2

• limited specificity 

what is the recognition unit of classical pathway?

C1 complex

• C1q, C1r, C1s 

what is the activation unit of classical pathway?

c4b2a → c4b2a3b

what is MAC of classical pathway?

c5b → c5b6789

c1s cleaves ___ to create ___ ,and it cleaves ___ to create ___

C1s cleaves C4 to create C4a and C4b, and it cleaves c2 to create C2a and C2b

C4a and C4b combined to form what? this is called what?

• C4b2a

• called C3 convertase 

C3 convertase cleaves ___ to ___ which is bound to ___ to form ___ known as ____

C3 convertase cleaves C3 to C3a and C3b which is bound to C4b2a to form C4b2a3b known as C5 convertase 

C5 convertase cleaves ___ to ____

C5 to C5a and C5b

which complement is released into circulation?

which binds?

• “a” is released into circulation

• “b” is bound