Midterm #3: Complement System

Question 1

Complement System relationship to Immune System

Answer 1

• Part of innate immunity but closely related to adaptive immune system

Question 2

Complement factors can be proteolytically cleaved

Answer 2

• A (small)
• B (large)

Question 3

Initiation and 3 Main outcomes of Complement system

Answer 3

• Initations: antibodies bound to antigen, or binding complement factor to pathogen surface
• 3 Major Outcomes:
  
  • 1: Inflammation: Complement stimulate basophil and mast cell degranulation. C5a is also a chemokine, attracting cells of the immune system to the site of infection
  • 2: Opsonisation: Complement factor 3b coats foreign organsims, which stimulates phagocytosis by WBC.
  • 3: Pathogen Lysis: Complement C5b initate steps to create MAC
• Also plays role in solubuilizing and removing immune complexes

Question 4

Antibody Structure

Answer 4

• IgG have 2 heavy and 2 light chains, each with variable and constant domains
• Antigen binding sites (aka complementarity determining regions) are located on variable region of light and heavy chain
• Fc region composed of constant domain of heavy chain and binding site for immune cell receptors and complement factors
• Therapeutic antibodies may consist of entire IgG (cetuximab), isolated Fab fragments (ranibizumab), or single-chain variable fragments (scFv e.g. pexelizumab)

Question 5

The Classical Complement Pathway

Answer 5

• aka the antibody dependent complement pathway
• Triggered by C1 binding to Fc region
  
  • activates it
• Cleaves C2 into C2a and C2b and C4 into C4a and C4b
• C4a stimulates an inflammation response
  
  • it is an anaphylatoxin
• C4b and C2b form a complex C4b2b that is also called C3 convertase

Question 6

The Lectin Pathway

Answer 6

• Pathogens recognized by their pathogen-derived carbohydrates
• Recognized by mannann-binding lectin (MBL)
  
  • pattern recognition receptor
• MBL:carb compex recruits MBL-associated serine proteases (MASPs) related to C1 complex
• MASP activate C4 and C2 resulting in C4b2b complex and C4a anaphylatoxin

Question 7

Activation of C3: The Central Step

Answer 7

• C4b2b bind C3 and cleaves it to C3a and C3b
• C3a is small chemokine that stimulate chemotaxis of phagocytes
  
  • also anaphylatoxin stimulating degranulation by basophils and mast cells
• C3b remains associated with pathogen and can act as opsonin

Question 8

Alternative Complement Pathway

Answer 8

• AKA intrinsic complement pathway
• Constituively active
• C3 has low levels of autoproteolytic activity, so small amounts of C3b are present
• When C3b binds pathogen, recruits factor B and factor P to form C3bBb complex (alternative C3 convertase)
• C3bBb can cleave C3 to C3a and C3b
• Feedback activation/positive feedback
  
  • Enables rapid immune response to pathogens even if the adaptive immune system has not yet mounted an antibody response
  • It greatly amplifies the effects of the classical complement pathway and lectin patway

Question 9

C5 Activation and the Membrane Attack Complex

Answer 9

• ​C3b protease that can activate C5 into C5a and C5b
• C5a is an anaphylatoxin and chemokine
• C5b recruits other complement factors (C6, C7, C8 , C9) to form a pore in the bacterial membrane called the membrane attack complex
• cell lysis and death in antibody independent manner
• MAC in host cell inhibited by CD59
  
  • ​certain viruses incorporate this into envelops to protects themselves

Question 10

The Complete Complement Cascade

Answer 10

• 3 Routes to Stimulate:
  
  • Recognition of antibody:antigen complexes by C1 binding to Fc region of the Ab
  • Recognition of pathogen-derived carbohydrates by MBL
  • C3b binding to pathogen surfaces in the alternative pathway
• 3 Outcomes:
  
  • Chemokine and anaphylatoxin activity to stimulate inflammation and recruitment of immune system cells
  • opsoinazation to enhance phagocytosis
  • MAC

Question 11

Control of the Complement System

Answer 11

• Factors H and I in the plasma inactivate C3b in solution but not those bound to pathogen
• C3b bound to a bacterial cell is maintained in an active state by Factor P
• Complement is also closely linked to coagulation, adaptive immunity, wound repair and other biologically important pathways

Question 12

Complement Disorders

Answer 12

• Factor P deficiency and recurrent bacterial infections
• Deficiencies in classical pathway linked to systemic lupus erythematosus (SLE)
  
  • thought to result from defect in clearance of immune complexes
• Overactivation of complement system could cause inflammatory diseases
  
  • complement inhibitors like pexelizumab (C5 inhibitor) are under active investigation