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

C1r
C1s
C1q



C1r
C1s
C1q

C4
C4a
b
Classical Pathway Generation of C3-convertase

Classical Pathway Generation of C3-convertase

C4b
C4a
C1r
C1s
C1q

C2
C2b
a
C2
a
_____ C4b2a is C3 convertase

Classical Pathway Generation of C5-convertase

C4b
C4a
C1r
C1s
C1q

C2b
C2
a
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(or b)
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
C3b
Factors H and I; Factor H facilitates the degradation of C3b by Factor I
C4a
C3a-INH

C1-inhibitor deficiency:hereditary angioedema

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
a
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

Components of mannose-binding lectin pathway

C4
MBL
C2
MASP1
MASP2

Mannose-binding lectin pathway

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