MLSP 5511 Complement

What is Complement?

Heat-labile serine protease enzymes that enhance antibody destruction of foreign cells

Where are Complement Components Made?

Most in liver, however:

-C1 made in intestinal epithelial cells

-Factor D made in adipose tissue

-macrophages & monocytes can make C1, C2, C3 & C4

What are the 3 Pathways of Complement Activation?

Classical, Alternative, Lectin

What Immunoglobulins Activates Complement Most Efficiently?

IgG3, followed by IgG1 and IgG2

-IgM can also activate complement, but needs 10 molecules to activate

What are the Steps to Classical Pathway of Complement Activation?

1) C1q binds to antibody Fc region of IgM or 2 IgG molecules

2) C1r activates C1s

3) C1s splits C4 into C4a and C4b

4) C4b splits C2 into C2a and C2b

5) C4b and C2a bind to make C4b2a (C3 convertase)

6) C4b2a splits C3 into C3a and C3b

7) MAC (described in different flashcard)

What is C3b's Functions?

-Opsonizes antigen surfaces

-1/2 life of 60 milliseconds

-Binds to C3b receptors on macrophages

What are the Steps to Alternate Pathway of Complement Activation?

1) C3 spontaneously hydrolyzed to make C3(H2O) [similar to C3b]

2) C3(H2O) binds to Serine Protease Factor B and makes C3(H2O)B

3) Factor D cleaves the bound Factor B to make Ba and Bb [Requires Mg2+]

4) C3(H2O)Bb is formed [same as C3 convertase C4b2a]

5) C3(H2O)Bb splits C3 and creates C3(H2O)BbC3b [unstable]

6) C3(H2O)BbC3b binds to Properdin and makes C3(H2O)BbC3bP [same as C5 convertase C4b2a3b]

7) MAC (described in different flashcard)

What are the Steps to Lectin Pathway of Complement Activation?

1) Mannose Binding Lectin (MBL) binds to mannose on microorganism, activating MASP-1 & MASP-2

2) MASP-1 & MASP-2 cleave C4 into C4a & C4b

3) C4b splits C2 into C2a & C2b

4) C4b and C2a bind to make the C3 convertase C4b2a

5) MAC (described in different flashcard)

What are the Steps in the Membrane Attack Complex (MAC)?

1) C3b combines with C4b2a to make the C5 convertase C4b2a3b

2) C4b2a3b splits C5 into C5a and C5b

3) C5b binds to antigen/bacterial surface

4) C6, C7, C8 and C9 bind to antigen/bacterial surface, causing cell lysis

What is the Activation Stage of Complement?

Initiation of cascading enzyme events

-C1q binding to antibody Fc region (Classical)

-C3 hydrolyzed into C3a and C3b (Alternative)

-MBL binding to mannose (Lectin)

What is the Amplification Stage of Complement?

Development of C3 and C5 convertases

What is the Effector Phase of Complement?

Development of Membrane Attack Complex and leading to inflammation and opsonization

-Releases anaphylatoxins (histamine) when C3a and C5a bind to mast cells and basophils, also causing edema

What Does Complement Receptor 1 Do?

Binds C3b and C4b, helps to clear immune complexes, enhances phagocytosis and antigen processing

-Found on RBCs, WBCs and some antigen-presenting cells

What does Complement Receptor 2 Do?

Binds the breakdown products of C3, helps bind antigens to B cell surfaces and enhances antigen processing

-Found on B cells

What does Complement Receptor 3 and 4 Do?

Binds the breakdown products of C3 on WBCs, enhances phagocytosis and helps stimulate accessory cells

What Does C1 Inhibitor Do?

-Inactivates C1 and C3b (Classical)

-Inactivates MASP-2 (Lectin)

What Does Decay Accelerating Factor, CR1 and C4 Binding Protein Do?

Manages C3 convertases

-C4b2a (Classical & Lectin)

-C3(H2O)Bb (Alternate)

What Does Factor H Do?

Binds to C3b, which prevents the binding of Factor B and accelerates dissociation of C3b(H2O)Bb

What Does Factor I Do?

Inactivates C3b and C4b

What Does Protectin Do?

Found on host cells that prevents the attachment of MAC

What Does Complement S Protein Do?

Binds fluid phase C5b67

What Does Carboxypeptidase Do?

Removes C-terminal arginine residues and manages anaphylactic reactions

What is the Most Common Complement Deficiency?

C2 Deficiency (1 in 20,000)

-Recurrent strep and staph infections

What is a Common Complement Deficiency in Children?

Mannose-Binding Lectin (MBL) Deficiency

-Pneumonia, sepsis and meningococcus common

What Symptoms Describe C5-C8 Deficiencies?

Increased systemic Neisseria infections

What is the Most Serious Complement Deficiency?

C3 Deficiency

-C3 is key mediator in all 3 complement activation pathways

What Symptoms Describe C1 Inhibitor Deficiency?

Excessive cleavage of C4 and C2, which results in increased edema and vascular permeability

-Affects mucosal surfaces and extremities

What Symptoms Describe Decay-Accelerating Factor (DAF) Deficiency?

Causes chronic anemia in RBCs

What Symptoms Describe C5-C9 Deficiencies?

High risk of meningococcal disease

How do Microbes Defend Against Complement?

-Microbe binds to Fc, preventing activation of C1q

-Pseudomonas makes elastase that degrades C1q

-Streptococcal M binds C4BP and Factor H

-Trypanosoma and Schistosoma stops C4b and C2a from binding