complement system done
TRANSCRIPT
COMPLEMENT SYSTEM
DR. MALEEHA ASLAM
Complement system (nomenclature)
• Protective cascading system- composed of 25 proteins
• Can be activated via Classical and Alternate pathways
• Culminates in three useful results– phagocytosis, lysis and inflammation
• Classical pathway C1- C9= C1(qrs), C2, C3, C4, C5, C6, C7, C8, C9
• Alternate pathway = factors B, D, and IF, properdin (P)
• C3b inactivator, anaphylotoxin inhibitors
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 microenvironmentLetter “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)
Activated component are usually over-lined: e.g. C1qrs
GENERAL PROPERTIES OF COMPLEMENT SYSTEM
• PRESENT IN NORMAL SERA• DOES NOT INCREASE ON IMMUNIZATION• DESTROYED AT 56oC IN 30 MINUTES• NOT A SINGLE SUBSTANCE- COMPLEX• IN CLASSICAL PATHWAY- 9 PROTEINS COMPLEX• IN ALTERNATE PATHWAY- 13 PROTEINS
COMPLEX• IgM, IgG-1,2,3 REACT WITH COMPLEMENT• ACTIVATION BY ANTIGEN ANTIBODY COMPLEX• ACTIVATION BY POLYSAC/ ENZYMES –
ALTERNATE PATHWAY• INACTIVATORS AND INHIBITORS PRESENT IN
SERUM
COMPLEMENT FUNCTIONS
• Host benefit:– opsonization to enhance
phagocytosis– phagocyte attraction and activation– lysis of bacteria and infected cells– regulation of antibody responses– clearance of immune complexes– clearance of apoptotic cells
• Host detriment:– Inflammation, anaphylaxis
Pathways of complement activation
CLASSICALPATHWAY
ALTERNATIVEPATHWAY
activationof C5
LYTIC ATTACKPATHWAY
antibodydependent
LECTINPATHWAY
antibodyindependent
Activation of C3 andgeneration of C5 convertase
CLASSICAL PATHWAY
3 GROUPS
• RECOGNITION UNIT
CI( C1q, C1r, C1s)
•ACTIVATION COMPLEX
C4,C2,C3
•MEMBRANE ATTACK COM
C5,C6,C7,C8,C9
ALTERNATE PATHWAY
IMPORTANT PROTEINS
•FACTOR B- C3 PROACTIVATOR
•FACTOR D- C3 PROACTIVATOR
CONVERTASE – SPLIT FACTOR B
Ba & Bb •FACTOR P- PROPERDIN
Activation of Complement
THE CLASSICAL AND ALTERNATE PATHWAYS
Components of the Classical Pathway
C4C2 C3
C1 complex
Ca++
C1r C1s
C1q
Ca++
C1r C1s
C1q
C4
C4a
b
Classical Pathway Generation of C3-
convertase
Generation of C3-convertase
C4b
Mg++
C4a
Ca++
C1r C1s
C1q
C2
C2ba
C2a
_____
C4b2a is C3 convertase
Classical Pathway Generation of C5-convertase
C4b
Mg++
C4a
Ca++
C1r C1s
C1q
C2b
C2a
C3
C3a
b
________
C4b2a3b is C5 convertase; it leads into the Membrane
Attack Pathway
ALTERNATE PATHWAY
Components of thealternative pathway
C3 B
D
P
Spontaneous C3 activation
C3
H2O
i B
D
Generation of C3 convertase
C3iBb complex has a very short half life
b C3
C3a
b
B
D
bC3b
If spontaneously-generated C3b is not degraded
C3-activationthe amplification
loop
C3C3a b
C3a
C3a BbC3b
C3bC3 BbB
D
bb
C3a
C3-activationthe amplification
loop
C3b
C3a
C3a BbC3b
BbBbC3b
C3a
C3-activationthe amplification
loop
C3bC3b
Control of spontaneousC3 activation via DAF
C3b
DAF prevents
the binding of
factor B to C3b
B
Autologous cell membrane
DA
F
CR1
Control of spontaneousC3 activation via DAF
DAF dislodges
C3b-bound
factor Bb
B bb C3b
Autologous cell membrane
DA
F
CR1
B b
C3b stabilization andC5 activation
C3b
C3b finds an activator (protector) membrane
C3
C3a
bB
D
b
PThis is stable C5 convertase
of the alternative pathway
C5-convertase of the two pathways
C3b Bb C3b
C5-convertase of the Alternative Pathway
C4b C2a C3b
C5-convertase of the Classical and lectin
Pathways
Generation of C5 convertase leads to the activation of the
Lytic pathway
Lytic pathway
Components of the lytic pathway
C6
C9
C8
C7C5
Lytic pathwayC5-activation
C3b C2 aC4b
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
C7C8
C9
C9
C9
C9C9
C9 C
9C9
C9
Products and their Control FactorsFragment Activity Effect Control Factor (s)
C2a Prokinin, accumulation of fluids Edema C1-INHIBITOR
C3a
Basophil and mast cells degranulation; enhanced vascular permeability, smooth muscle contraction
Anaphylaxis C3a-INACTIVATOR
C3b Opsonin, phagocyte activation Phagocytosis Factors H and I
C4a
Basophil and mast cells degranulation; enhanced vascular permeability, smooth muscle contraction
Anaphylaxis(least potent)
C3a-INACTIVATOR
C4b Opsonin Phagocytosis C4-BP and Factor I
C5a
Basophil and mast cells degranulation; enhanced vascular permeability, smooth muscle contraction
Anaphylaxis(most potent)
C3a-INACTIVATORChemotaxis, stimulation of respiratory burst, activation of phagocytes, stimulation of inflammatory cytokines
Inflammation
C5bC6C7Chemotaxis Inflammation
Protein S (vitronectin)Attaches to other membranes
Biological Activities of Classical Pathway ComponentsComponent Biological ActivityC2b Prokinin; cleaved by plasmin to yield
kinin, which results in edemaC3a 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 OpsoninActivation of phagocytic cells
C4a AnaphylaotoxinC4b Opsonin
Product Biological Effects Regulation
Biological properties of C-activation products
anaphylactic as C3, but much more potent;attracts & activates PMN causes neutrophil aggregation, stimulation of oxidative metabolism and leukotriene release
C5a (chemotactic factor)
carboxy-peptidase-B (C3-INA)
C5b67 protein-Schemotaxis, attaches to other membranes
Biological effects of C5a
Control of Classical Pathway Components
Component RegulationAll C1-inhibitor (C1-INH); dissociates C1r
and C1s from C1qC3a C3a-inactivator (C3a-INA;
Carboxypeptidase B)C3b Factors H and I; Factor H facilitates the
degradation of C3b by Factor IC4a C3a-INHC4b C4 binding protein (C4-BP) and Factor I;
C4-BP facilitates degradation of C4b by Factor I; C4-BP also prevents the association of C2a with C4b thus blocking formation of C3 convertase
Complement deficiencies and diseasePathway/Component Disease Mechanism
Classical Pathway
C1INH Hereditary angioedema Overproduction of C2b (prokinin)
C1, C2, C4 Predisposition to SLE
Opsonization of immune complexes help keep them soluble, deficiency results in increased precipitation in tissues and inflammation
Alternative Pathway
Factors B or D Susceptibility to pyogenic (pus-forming) bacterial infections
Lack of sufficient opsonization of bacteria
C3 Susceptibility to bacterial infectionsLack of opsonization and inability to
utilize the membrane attack pathway
C5, C6, C7 C8, and C9 Susceptibility to Gram-negative infections
Inability to attack the outer membrane of Gram-negative bacteria
Properdin (X-linked) Susceptibility meningococcal meningitis Lack of opsonization of bacteria
Factors H or I C3 deficiency and susceptibility to bacterial infections
Uncontrolled activation of C3 via alternative pathway resulting in depletion of C3
C1-inhibitor deficiency:hereditary angioedema