Immunology: Complement System

___ is the central step in all complement pathways. _________ form a complex called C5 convertase. This cleaves C5 and forms _________.

*C3* is the *central step in all complement pathways.* *C4bC2aC3b* form a complex called C5 convertase. This cleaves C5 and forms C5> C5a + C5b.

___ blocks C9 binding and *prevents the formation of MAC.*

*C59* blocks C9 binding and *prevents the formation of MAC.*

C1INH (C1 inhibitor) deficiency leads to:

*angioedema (hereditary and acquired), uncontrolled activation of C*.

C1 Complex:

-*C1q+C1s+C1r*. -*C1q has globular heads that bind to IgG and IgM by the Fc region*. -Binding needs: two molecules of IgG + One molecule of IgM. -Ionic and hydrophobic bonds. -*Conformation leads to release of C1s*.

Classical Pathway:

-9 Individual Proteins -C1, C2, C3, C4, C5, C6, C7, C8, C9

How does the complement system induce inflammation?

-Anaphylatoxin: C3a,C4a,C5a. -Pro-inflammation: -Strongly chemotactic for neutrophils and inflammatory cells. -Degranulate mast cells to release inflammation mediator, including histamine. -Vasodilation. -Induce expression of adhesion molecules to increase extravasation. -Enhance production of inflammation mediators.

How does the complement system clear immune complexes?

-Antigen-Antibody complexes get very large. -Complement binds to complex. -Activate complement cascade. -Complex binds to complement receptor, CR3 on phagocytotic cells. -Enhanced phagocytosis and destruction of Ag:Ab complexes.

Complement-mediated cytolysis:

-Binding of C3b to microbe, activation of late components of complement. *-Formation of membrane attack complex (MAC).* -Osmotic lysis of microbe.

How does the complement system induce phagocytosis?

-Binding of complement components C3b or inactivated C3b, (iC3b) and C4. -Complement receptors (CR1-complement receptor 1, CR3, CR4,) *expressed on natural killer cells, granulocytes, etc..* -*Facilitate phagocytosis by opsonization.*

Regulation of the *classical pathway*:

-C1 S activity inhibited by C1 receptor (C1 INH). -C4bC2a dissociated by C4 binding protein. -Decay accelerating factor blocks formation of C3 convertase.

Alternate Pathway:

-C3 hydrolyzed to C3b on bacteria and yeast. -C3b binds to activator surface form nucleus to complement cascade. *-C3b binds Factor B and forms C3bFactorB complex.* -Factor D cleaves Factor B when it is bound to C3B. *-Forms C3bBb=C3 convertase.* -*Properdine* binds to form a *more stable complex C3bBbP*. -C3bBb and C3bBbP cleave more C3 to C3b so more C3 becomes available. -Amplfication loop. -*C3b binds to C3bBb and forms C3bBbC3b that cleaves C5. C5>C5a+C5b*. -*C5b initiates the formation of Membrane attack complex*.

C1s:

-Cleaves C4 and C2. -C4>C4a+C4b. -C2>C2a+C2b. -*C4bC2a form complex on membrane= C3 Convertase. -C3 Converstase cleaves C3.* -C3>C3a+C3b. -*C3b is the key molecule.*

What are the differences and similarities of the complement pathways?

-Difference: unique proteins and enzymes for the 1st. -Similarities: *results are the same.*

Regulation of *Alternate Pathway*:

-Factor H dissociation of C3 convertase (displaces Bb from C3bBb). -Factor I and membrane co-factor protein (co-factor I) cleave and inactivate C3b to iC3B. -Decay accelerating factor dissociates C3bBb.

C5b:

-Initiates the formation of *Membrane attack complex (MAC)*. -C5b forms nucleus for formation of Mac. -C6 binds to C5b. -C7 binds to C5bC6. -C8 binds to C5C6C7. -*C5bC6C7C8 complex serves as a receptor for C9. -C9 polymerizes into poly-C9 tube. -Insert into membrane. -Ions escape, water enters, osmotic cell lysis.*

Functions of Complement system:

-Kill micro-organism, *lysis* (cells, bacteria, virus, yeasts). -Induce *inflammation*. -Increase *phagocytosis by opsonization*. -Clearance of insoluable immune complexes.

Lectin (protein that bind to carbohydrates) Pathway:

-Mannose-binding lectin (MBL) binds carbohydrate on the surface of bacteria. -MBL associated serine proteases (MASP) cleaves C4 and -C4: C4> C4a + C4a. C2: C2> C2a + C2a. -C4bC2a: (C3 convertase) form complex on membrane. -Rest is similar to the classical pathway. -*C5b initiates the formation of Membrane attack complex (MAC)*.

Individuals deficienct in complement components C1, C4, C4 develop:

-Systemic lupus erthematous (SLE). -*Impaired ability to clear immune complexes.*

Activation Pathways:

1. Classical Pathway: initiated by *antigen-antibody complex.* 2. Alternate Pathway: activated by *cell wall of bacteria and yeast.* 3. Lectin Pathway: initiated by *lectins that bind Mannose* [MBL].

Steps to complement activation:

1. Recognition. 2. Enzyme activation. 3. Expression of biological activity.

C3 convertase cleaves ______ of copies of C3.

C3 convertase *cleaves hundreds of copies of C3.*

Deficiency in alternative pathway:

Increase susceptibility to *recurrent infection with pyogenic bacteria.*

Serum ______________ inactivates anaphylatoxins C3a, C5a, C4a.

Serum *carboxypeptidase* inactivates anaphylatoxins C3a, C5a, C4a.

Complement System:

system comprising of many circulating and membrane-fixed proteins.