Midterm #3: Complement System Flashcards Preview

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Flashcards in Midterm #3: Complement System Deck (12):
1

Complement System relationship to Immune System

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

2

Complement factors can be proteolytically cleaved

  • A (small)
  • B (large)

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3

Initiation and 3 Main outcomes of Complement system

  • 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

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4

Antibody Structure

  • 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)

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5

The Classical Complement Pathway

  • 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

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6

The Lectin Pathway

  • 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

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7

Activation of C3: The Central Step

  • 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 

8

Alternative Complement Pathway

  • 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 

9

C5 Activation and the Membrane Attack Complex

  • ​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

10

The Complete Complement Cascade 

  • 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

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11

Control of the Complement System 

  • 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

12

Complement Disorders 

  • 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