Immunity

THE COMPLEMENT SYSTEM OBJECTIVES: When you finish this section, you should be able to: 1. Describe the effects of complement activation. 2. Outline the Classical, Mannan-Binding (MB) Lectin and Alternative pathways of complement activation, including their activators. 3. Discuss the major regulatory points in complement activation and the consequences of deficiencies in complement or complement regulators. 4. Discuss the functions of the various complement receptors.
5. Discribe the biologic activities of complement and identify the components involved.

Complement: History

Discovered in 1894 by Bordet It represents lytic activity of fresh serum Its lytic activity destroyed when heated at 56C for 30 min

Complement functions

Host benefit: opsonization to enhance phagocytosis phagocyte attraction and activation lysis of bacteria and infected cells clearance of immune complexes clearance of apoptotic cells Host detriment: Inflammation, anaphylaxis

Proteins of the complementsystem (nomenclature)

C1(qrs), C2, C3, C4, C5, C6, C7, C8, C9 factors B, D, H and I, properdin (P) mannose binding lectin (MBL), MBL associated serine proteases (MASP-1 MASP-2)


C-activation: alteration of C proteins such that they interact with the next component C-fixation: utilization of C by Ag-Ab complexes Convertase/esterase: altered C-protein which acts as a proteolytic enzyme for another C-component
Definitions

Activation product of complement proteins (nomenclature)

When enzymatically cleaved, the larger moiety, binds to the activation complex or membrane and the smaller peptide is released in the microenvironment
Letter “b” is usually added to the larger, membrane-binding, peptide and “a” to the smaller peptide (e.g., C3b/C3a, C4b/C4a, C5b/C5a), EXCEPT C2 (the larger, membrane-binding moiety is C2a; the smaller one is C2b)


Pathways of complement activation
CLASSICAL PATHWAY
ALTERNATIVE PATHWAY
activation of C5
LYTIC ATTACK PATHWAY
antibody dependent
LECTIN PATHWAY
antibody independent
Activation of C3 and generation of C5 convertase

Components of the Classical Pathway

C4
C2
C3
C1 complex

Ca++
C1r
C1s
C1q

Ca++

C1r
C1s
C1q

C4
C4a
b
Classical Pathway Generation of C3-convertase

Classical Pathway Generation of C3-convertase

C4b
Mg++
C4a
Ca++
C1r
C1s
C1q

C2
C2a
a
C2
b
_____ C4b2a is C3 convertase

Classical Pathway Generation of C5-convertase

C4b
Mg++
C4a
Ca++
C1r
C1s
C1q

C2a
C2
b
C3

C3a
b
________ C4b2a3b is C5 convertase; it leads into the Membrane Attack Pathway

Opsonization and phagocytosis

* Biological Activities of Classical Pathway Components

Component
Biological Activity
C2a
Prokinin; cleaved by plasmin to yield kinin, which results in edema
C3a
Anaphylotoxin; can activate basophils and mast cells to degranulate resulting in increased vascular permeability and contraction of smooth muscle cells, which may lead to anaphylaxis
C3b
Opsonin Activation of phagocytic cells
C4a
Anaphylaotoxin
C4b
Opsonin

* Control of Classical Pathway Components

Component
Regulation
All
C1-inhibitor (C1-INH); dissociates C1r and C1s from C1q
C3a
C3a-inactivator (C3a-INA; Carboxypeptidase B)
C3b
Factors H and I; Factor H facilitates the degradation of C3b by Factor I
C4a
C3a-INH

Generation of C5 convertase leads to the activation of the Lytic pathway

Lytic pathway

Components of the lytic pathway

C6
C 9
C8
C7
C5

Lytic pathwayC5-activation

C3b
C2
b
C4b
C5
b
C5a


Lytic pathway:insertion of lytic complex into cell membrane
C5
b

C6
C7
C8

C 9
C 9
C 9
C 9
C 9
C 9
C 9
C 9
C 9

C1-inhibitor deficiency:hereditary angioedema

Components of mannose-binding lectin pathway
C4
MBL
C2
MASP1
MASP2

Mannose-binding lectin pathway

C4
MBL
C4b
C4a
C4b
C2
C2a
C2a
C2b
_____ C4b2a is C3 convertase; it will lead to the generation of C5 convertase
MASP1
MASP2


Components of thealternative pathway
C3
B
D
P


B
D
b
C3b
C3-activationthe amplification loop
C3
C3a
b


C3a
B
D
Bb
C3b
C3
b
C3-activationthe amplification loop
C3b
C3a
b



C3a
C3a
Bb
C3b
C3b
C3
Bb
B
D
b
b
C3a
C3-activationthe amplification loop
C3b

C3a
C3a
Bb
C3b
Bb
Bb
C3a
C3-activationthe amplification loop
C3b
C3b


C3b stabilization andC5 activation
C3b
C3b finds an activator (protector) membrane
C3
C3a
b
B
D
b
P
This is stable C5 convertase of the alternative pathway

C5-convertase of the two pathways

C3b
Bb
C3b
C5-convertase of the Alternative Pathway
C4b
C2b
C3b
C5-convertase of the Classical and lectin Pathways
Properdin


Generation of C5 convertase leads to the activation of the Lytic pathway
Lytic pathway

Components of the lytic pathway

C6
C 9
C8
C7
C5

Lytic pathwayC5-activation

C3b
C2
b
C4b
C5
b
C5a


Lytic pathwayassembly of the lytic complex
C5
b

C6
C7

Lytic pathway:insertion of lytic complex into cell membrane

C5
b

C6
C7
C8

C 9
C 9
C 9
C 9
C 9
C 9
C 9
C 9
C 9

Biological effects of C5a

Product
Biological Effects
Regulation
Biological properties of C-activation products
C2a (prokinin)
edema
C1-INH
C3a (anaphylatoxin)
mast cell degranulation; enhanced vascular permeability; anaphylaxis
carboxy-peptidase- B (C3-INA)

Product

Biological Effects
Regulation
Biological properties of C-activation products
as C3, but less potent
(C3-INA)
C4a (anaphylatoxin)
opsonization; phagocytosis
C4b (opsonin)
C3b (opsonin)
opsonization; phagocyte activation
factors H & I

Product

Biological Effects
Regulation
Biological properties of C-activation products
anaphylactic as C3, but much more potent; attracts & activates PMN causes neutrophil aggregation .
C5a (chemotactic factor)
carboxy-peptidase-B (C3-INA)


CLASSICAL PATHWAY1. INHIBITION OF PROTEOLYTIC ACTIVITY OF C1•C1 inhibitor (C1INH), a serine protease inhibitor, binds to and inactivates C1r, C1s.ѓ Most of the C1 in blood is bound to C1 INH to prevent spontaneous complement activation. Binding of C1q to Ag-Ab complex releases C1 from C1 INH inhibition

C1Inh

C1qrs breakdown
C1r
C1s
C1q

C1r
C1s


* Complement Deficiencies and DiseaseClassical Pathway
Pathway Component
Disease
Mechanism
C1INH
Hereditary Angioedema
Overproduction of C2a (prokinin)
C1, C2, C4
Predisposition to SLE
Opsonization of immune complexes by complement ,if deficiency results in increased precipitation in tissues and inflammation

* Complement Deficiencies and DiseaseLectin Pathway

Pathway Component
Disease
MBL
Susceptibility to bacterial infections in infants or immunosuppressed

* Complement Deficiencies and DiseaseAlternative Pathway

Pathway/Component
Disease
Mechanism
Factors B or D
Susceptibility to pyogenic (pus-forming) bacterial infections
Lack of sufficient opsonization of bacteria
C3
Susceptibility to bacterial infections & SLE
Lack of opsonization and inability to utilize the membrane attack pathway
C5, C6, C7 C8, or C9
Susceptibility to Gram-negative infections
Inability to attack the outer membrane of Gram-negative bacteria

* Complement Deficiencies and DiseaseAlternative Pathway cont.

Pathway Component
Disease
Mechanism
Properdin (X-linked)
Susceptibility meningococcal meningitis
Lack of opsonization of bacteria
Factors H or I
C3 deficiency and susceptibility to bacterial infections & SLE
Uncontrolled activation of C3 via alternative pathway resulting in depletion of C3


Massive complement activation -DICGram negative septicemiaHemorrhagic fever Platelets have Receptors for C3b