Complement Pathways

Question 1

What are complements?

Answer 1

Circulating and cell membrane proteins that form part of the innate immune system

Question 2

What is the function of complement proteins?

Answer 2

Help the innate system
Promote inflammatory and immune responses

Question 3

What are the 3 complement activation pathways?

Answer 3

• Classical
• Lectin
• Alternative

Question 4

Why are there 3 pathways?

Answer 4

Redundancy in case 1 fails

Question 5

How does the classical pathway act?

Answer 5

Antigen-antibody complexes —> complement activation

Question 6

What are the 3 consequences of complement activation?

Answer 6

• Inflammatory cell recruitment
• Opsonization
• Pathogen killing

Question 7

How is the classical complement pathway activated?

Answer 7

• C1 (complement component) binds to antigen-antibody complex via its C1q recognition region

Question 8

How is the lectin pathway activated?

Answer 8

Mannan-binding lectin (MLB) binds to terminal polysaccharide on surface of microbe

-Not found on mammalian cell surfaces

Question 9

How is the alternative pathway activated?

Answer 9

Deposition of complement component C3b on pathogen surface

Question 10

At which complement component do the 3 different pathways converge?

Answer 10

C3

Question 11

What is the relationship between the complement and immune system?

Answer 11

Bridge between the adaptive and immune system

Classical complement responds to the adaptive immune system (Ig production —> antigen-antibody complexes)
- Effector mechanism

Question 12

What antibodies are involved in the classical pathway?

Answer 12

IgM or IgG
- Bind with antigen —> antibody-antigen complex
- Complex binds to C1q (subunit of C1)

Question 13

What is C1q?

Answer 13

One of 3 proteins making up C1 protein complex - binding domain

Question 14

What is the region that C1q binds to on the antibody called?

Answer 14

Fc region
The “pole” of the “Y” on antibodies

Question 15

What Ig is most effective at activating C1?

Answer 15

IgM

Question 16

What Ig cannot activate the complement system?

Answer 16

IgG4

Question 17

What becomes active when a complex binds to C1q?

Answer 17

C1s and C1r proteases are activated

Question 18

What does C1s esterase cleave?

Answer 18

C4 –> C4b & C4a –> C2 –> C2a & C2b

Question 19

What happens in the classical pathway to form C3 convertase?

Answer 19

C4b complexes with C2a on the Ab-Ag membrane –> C4bC2a (aka classical pathway C3 convertase)

Question 20

What is distinct about the MBL pathway?

Answer 20

Specific for pathogens that have mannose residues on their surface?

Question 21

What are the steps of the MBL pathway?

Answer 21

• MBL similar to C1q
• MBL binding with mannose –> MASP-2 (protease) to cleave C4 and C2 –> C4bC2a on pathogen surface –> C3 convertase

Question 22

How is MBL similar to the classical pathway?

Answer 22

MBL = C1q
MASP2 = C1s esterase

Question 23

What are some substances that can trigger the alternative pathway?

Answer 23

• Endotoxins
• Necrotic cells
• Some microorganisms
• Aggregated Ig molecules

Question 24

What are the steps in the alternative pathway?

Answer 24

C3b deposition on particle surface –> factor B (serum protein) combining with C3b –> C3bB –> factor D cleaves B –> Ba
Ba released into fluid phase
Bb associated with C3bBb
C3bBb –> C3 convertase and stabilized on cell surface with properdin

Question 25

What is a common product of all 3 complement pathways?

Answer 25

C3 convertase

Question 26

What parts make up C3 convertase in the classical and lectin pathways?

Answer 26

C4b and C2a = C4bC2a

Question 27

What parts make up C3 convertase in the alternative pathway?

Answer 27

C3b and Bb = C3bBb

Question 28

Which C3 fragment after cleavage is released into the fluid phase?

Answer 28

C3a

Question 29

Which C3 fragment after cleavage binds to the cell surface?

Answer 29

C3b

Question 30

What does properdin (factor P) do?

Answer 30

Stabilizes C3bBb to cell surface --> rapid cleaving of C3 molecules --> C3b buildup on pathogen surface --> alternative pathway amplification loop

Question 31

What doe C5 convertase consist of?

Answer 31

C4b, C2a, and C3b = C3 convertase + C3b

Question 32

What C5 fragment after cleavage is released into the fluid phase?

Answer 32

C5a

Question 33

What C5 fragment after cleavage binds to the cell surface?

Answer 33

C5b

Question 34

What are the main activities of the complement system?

Answer 34

- Opsonin production - Anaphylatoxins that add inflammation - Direct lysis of microbes

Question 35

How does the complement system carry out opsonization?

Answer 35

C3b binding marks antigens for immune cell recognition Cells of the innate immune system have complement receptors (CRs) that bind to C3b

Question 36

What cells is CR1 found on?

Answer 36

Phagocytic cells

Question 37

What cells is CR3 found on?

Answer 37

- Monocytes - Granulocytes - NK cells

Question 38

What cells is CR4 found on?

Answer 38

- Myeloid cells - others

Question 39

What complement proteins are involved in opsonization?

Answer 39

C3b and C4b

Question 40

What is an anaphylatoxin?

Answer 40

- Bind to receptor on mast cell —> rxn similar to allergic hypersensitivity rxn

Question 41

List the anaphylatoxin complement proteins (3)

Answer 41

C3a C4a C5a

Question 42

What is triggered by anaphylatoxin binding to its cell receptor?

Answer 42

Histamine and other mediator release Increases smooth muscle contraction More vascular permeability and fluid accumulation in tissue

Question 43

What anaphylatoxin is also chemoattractant?

Answer 43

- C5a attracts neutrophils

Question 44

These 3 complement proteins bind in sequence to C5b to form membrane attack complex

Answer 44

C6 binds to C5b C7 binds to C6 C8 binds to C7

Question 45

What is the consequence of a membrane attack complex forming?

Answer 45

Essential for cell lysis Allows water to enter the cell —> lysis

Question 46

Where are complement proteins made?

Answer 46

Mainly made in the liver

Question 47

What acts on the liver to induce synthesis of acute phase proteins?

Answer 47

IL-6

Question 48

This protein interacts with C1q to trigger the classical pathway in the absence of antibody

Answer 48

CRP

Question 49

What does CRP bind to —> phagocytosis?

Answer 49

Phosphorylcholine on liposaccharides in microbial cell walls

Question 50

What does an immune complex consist of?

Answer 50

Ab-Ag

Question 51

What cell transports immune complexes to the liver and spleen?

Answer 51

RBCs

Question 52

On what receptor does the immune complex bind to be carried to the liver and spleen?

Answer 52

CR1

Question 53

What is a consequence of not clearing immune complexes from circulation?

Answer 53

IC deposit on vessel —> acute inflammation and immune pathology

Question 54

What complement receptor is associated with acute inflammation?

Answer 54

CR5a

Question 55

What cells is CR5a found on?

Answer 55

Causes inflammatory response Smooth muscle cells Endothelial cells Mast cells Basophils Enhances chemotasix - Phagocytes

Question 56

This receptor has similar distribution to CR5a

Answer 56

CR3a — binds C3a (anaphylatoxin)

Question 57

What 3 steps can regulation occur in the complement pathway?

Answer 57

Initiation and activation Amplification Membrane attack complex

Question 58

How does C1 inhibitor work?

Answer 58

Binds activated C1r and C1s, removes them from C1q - Controls activation and initiation

Question 59

How is **C4-binding protein** involved in complement regulation?

Answer 59

Controls amplification Dissociates C3 convertase subunits in classical pathway Cofactor for Factor I-mediated cleavage of C4b

Question 60

How is Factor I involved in complement regulation?

Answer 60

Controls amplification - Cleaves C3b and C4b

Question 61

How is Factor II involved in complement regulation?

Answer 61

Controls amplification Dissociated C3 convertase in alternative pathway cofactor for Factor I mediated cleavage of C3b

Question 62

What can C1 inhibitor deficiency cause?

Answer 62

Angioedema

Question 63

Would C4 levels be expected to be high or low in C1 inhibitor deficiency?

Answer 63

Low R/t spontaneous C4 activation and consumption

Question 64

What is decay accelerating factor?

Answer 64

CD55 — Controls amplification Membrane protein Dissociates C3 convertase subunits

Question 65

What pathways are impacted if there is a defect in CD55 (decay accelerating factor)?

Answer 65

All 3 pathways since it impacts C3 convertase (convergence point for all 3 pathways)

Question 66

What does CD59 do?

Answer 66

Membrane protein that regulates membrane attack complex - Acts by blocking C9 binding and forming of MAC

Question 67

What is a consequence of CD55 and CD59 deficiencies?

Answer 67

Cells more susceptible to lysis