7 - Complement Flashcards
Complement
Define
- *System** or Cascade of
- *Plasma Proteins** produced mainly by the LIVER
Acts to complement actions of AB’s in:
destruction of bacteria // ridding body of foreign antigens
Can cause:
local leakiness in BV –> swelling / pain / loss of fxn / inflammation
Regulation is KEY
What ACTIVATES the Complement?
Variety of Stimuli:
Immunoglobulins // Lipid A
Ploynucleotides // C-Reactive Protein
Viruses / Polysaccharides / lipopolysaccharides
- *Complement System**
- *Acts on What?**
Acts on:
- *BIOMEMBRANES** leading to:
- *Cytolysis**
Production of MEDIATORS of Inflammatory response
Assistance in Particle OPSONIZATION + CLEARANCE
Three Complement Pathways
Classical = Cl –> Ig
Lectin = MBL –> Mannose Residues
Alternative = C3b –> deposits on pathogen surface
Classical Pathway
Can also be activated by:
Soluble Ab-Ag Complexes, not just membrane bound antigens
Antigen-Antibody Complexing:
Either:
2 Adjacent IgG** Molecules OR **1 IgM Molecule
VVVVV
Induces binding of the C1 molecule through the C1q
VVVV
C1q attaches to the:
CH2 domain of IgG or CH3 domain of IgM
VVVV
C1r is activated –> cleaves C1s
VVVV
C1 converts into an enzyme whose substrates are C4 + C2
Classical Pathway Photo
Soluble Ab-Ag Complexes can ALSO activate Classical Pathway
NOT just Membrane-bound antigens
Terminal Phase
of the Complement Cascade
- *MAC**
- *Membrane Attack Complex**
Bound C5b protein recruits:
C6 / C7 / C8 / C9
VVV
Multiple C9 units form a Multimer –> extends ACROSS Lipid Bilayer
VVVV
Forms a PORE that can pass water & ions
VVVV
Pathogen cell SWELLS & LYSIS
- *Lectin Pathway
- differences from Classical Pathway***
Cell-Surface Protein recognizes & BINDS:
SUGARS or OLIGOSACCHARIDES
generally to help mediate Cell-Cell interactions
unlike the CLASSICAL pathway, does NOT start with
AB recognition of a pathogen
Instead it imploys:
MBL = Mannose Binding Lectin
to recognize pathogens
VVV
Binds Terminal Mannose (Mannan) Residues of
Oligosaccharades on surfaces of Bacteria
Ficolin
LECTIN PATHWAY
Plasma Proteins that are SIMILAR to MBL in structure
Bind to different species of Bacteria
N-acetylglucosamine, lipoteichoic acid
Coating them = OPSONIZATION
then causing:
Complement Proteins to Attack
Lectin Pathway
INITIATION PHASE
MBL circulates bloodstream, in complex with MASPs
(Mannose-Associated Serine Proteases)
Which resembles the C1 component of the classical pathway
MASP-2 cleaves C4 / C2 –> forming C4B2a
analogous classical
VVVVV
Converges with the Classical Pathway
VVVV
Cleavage of C3 / C5 –> MAC formation
The 3 Different COMPLEMENT INITIATORS
Classical = IgM
Lectin = Mannose
Ficolin = NAG / Lipoteichoic Acid
ALL HAVE:
Serine Protease Activity
Alternative Pathway
Complement INITIATION
Small amounts of C3b are formed SPONTANEOUSLY in circulation
@ a low rate
They recognize a variety of foreign substances = Initiation Phase
Serum protein factor B binds to –> C3b
VVVV
is then cleaved to Bb, by c3 convertase
VVVV
C5 is cleaved & C5b is bound
VVVV
MAC FORMATION
(Convergence w/ classical & lectin paths)
Review of Each Complement Pathway
REGULATION
Of Complement
Host needs to conserve complement components
despite activation, need to have a RESERVE agaisnt other pathogens
Some cleavage products can strongly activate inflammation
and damage the host
- *Dysregulation of complement** is involved in several Immune diseases:
- *RA** / Macular Degeneration
REGULATION
of the Classical Pathway
C1 Esterase Inhibitor = C1INH
VVVV
Binds to C1r & C1s –> PREVENTING complement activation
Several diff. proteins cause dissociation of C4b2a & STOP cascade:
C4BP // DAF // CR1/CD35 // MCP
Factor 1 cleaves C4b after C2a leaves
which HALTS the cascade
Regulation of the
ALTERNATIVE PATHWAY
FACTOR H
Binds to C3bBb complex –> displaces Bb
Factor 1
causes celavage of C3b –> STOPS pathway
Mammalian cells carry SIALIC ACID on their surface,
promoting binding of Factor H so that the complement cascade STOPS ATTACK on mammalian cells
Bacterial cells LACK sialic acid, so factor B –> binds to C3b
leading to complement attack
3 Major FUNCTIONS
of Complement
Opsonization
Anaphylatoxin Production
Cell Lysis
OTHER Activities
Of Complement
Enhancement of B-Cell Responses
REMOVAL of Immune Complexes
REMOVAL of Necrotic Cells + Subcellular Membranes
Responses to Viruses
Opsonization
1 of 3 Major Fxns of Complement
C3b + iC3b + C4b
VVVV
NEUTROPHIL + MACROPHAGE
CR1 CR3 CR4
VVVV
ENHANCED UPTAKE of PATHOGEN
Anaphylatoxin Production
1 of 3 Major Fxns of Complement
C5a + C3a + C4a
are produced by complement
VVVV
Smooth Muscle Contraction
+
Mast Cell DEGRANULATION-release of Vasoactive substances
Plasma Exudation
VVV
Active Neutrophil + Macrophage
