complement 2016
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8/17/2019 Complement 2016
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Complement system
8/17/2019 Complement 2016
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The complement : Facts
“The activity of blood serum that completes the action of antibody”
Lyses cells, bacteria, and viruses
Opsonization promotes phagocytosis
Removes immune complexes from circulation (Immune clearance)
and deposits them in spleen/liver
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Complement is activated in many ways
Classical Pathway: begins with Ag-Ab complex
Alternative Pathway: foreign cell-surface constituents initiated
Lectin Pathway: activated by mannose-binding lectin (MBL) to microbes
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Classical Pathway Begins with Ag-Ab Binding
Bacterial surface Ag-Ab binding
Binding of C1q to IgM
C1qr 2s2 is stabilized by Ca++
C1 molecule
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Antibody conformation and complement
IgM C1q binding sites are unexposed(‘planar’ configuration)
IgM Exposes 3 C1q binding sites
(‘staple’ configuration)
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C1s hydrolyzes C4b and C2a to form
C4b2a complex (called C3 convertase)
C4b C2a
( )
Formation of C3 Convertase
C1q binds to Ag-bound Ig
Activated C1r activates C1s
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Hydrolysis of C3 by C3 Convertase (C4b2a)
In C3 convertase, C4b stabilizes and 2a hydrolyzes C3 into C3b and C3a
formation of labileThioester bond
Binding to free-OH or -NH2 groups onmembrane
C 3 C o n v e r t a s e
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C4b2a3b makes C5 convertase which cleaves C5 into C5b and C5a
i nf l a
mm a t or y
r e s p on s e s
inflammatory
responsesOpsonization
Formation of C5 Convertase
inflammatory
responses
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Initiated by bacterial cell wall
C3, factor B, factor D, and properdin (factor P)mediate this pathway
Ba
( C 3 b B b s t a
b i l i z e r )
M g + +
©
C3bBb (C3 convertage) amplifies C3b response
C3bBb3b acts like a C5 convertase
Alternative Pathway also activates C5 convertase
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Lectin pathway also activates C5 convertase
MBL
(Mannose-binding lectin)
- acute phase protein similar to C1q
- induced during inflammation
- binds mannose, NAG, D-glucose,L-fucose pattern on microbes
C4b2a3b acts like a C5 convertase
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C5b67 undergo a hydrophilic-
amphiphilic structural transition
↓
C8 induces a 10Å pore that can lyseRBCs
↓
C9 (perforin-like molecule) binding &polymerization completes MAC (70-100 Å)
Formation of C5b6789 (MAC)
A tubular functional pore (70 – 100 Å)
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MAC formation on target cell surface
Complement lesionson RBC membrane
Poly-C9 complex(in v i t ro )
~100 Ȃ
Bi l i l Eff t M di t d b C l t
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Inflammatory responses
Biological Effects Mediated by Complement
C3a, C4a, C5a (anaphylatoxins)
Bind complement receptors (mast cells and basophils), inducedegranulation and release of histamine
C3a, C5a, and C5b67
Induce smooth-muscle contraction, vascular permeability, extravasation,and chemo attraction
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Opsonization
Biological Effects Mediated by Complement
C3b and C4b are opsonins
Bi l i l Eff t M di t d b C l t
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Immune clearance phenomenon
Biological Effects Mediated by Complement
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Regulations of complement
R l t f C l t A ti ti (RCA)
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Regulators of Complement Activation (RCA)
Complement deficienc and disease
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Complement deficiency and disease
@ SLE : No clearance of circulating immune complexes activate leukocytesthrough FcR to produce local inflammation
# renal deposition of immune complexes
Complement Deficiency
C3 and Factor B
C3b-inactivator, C6 and C8
Deficiencies of early C
components C1, C4, C2
C1-inhibitor
Diseases
Severe bacterial infections
Severe Neisseria infections
Systemic lupus erythematosus@ (SLE),
glomerulonephritis# and polymyositis
(inflammation in muscles)
Hereditary angioedema (inflammation of
dermis)
C3 depletion due to unregulated C3
convertase, increased infections withpyrogenic bacteria
Factor I, H deficiency
S i b l t i k t id l t tt k
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Some microbes play trick to avoid complement attack
Group A Streptococcal strains inhibits C3
M+ wild type
S i b l t i k t id l t tt k
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Salmonel la enterica Short types of LPS or lipo-oligosaccharide (LOS) binds to serum amyloid P
component (SAP) to affect complement pathway
Some microbes play trick to avoid complement attack
S i b l t i k t id l t tt k
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Some microbes play trick to avoid complement attack
Salmonel la typhimurium Resistant strain
Microbial evasion of complement
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Microbial evasion of complement
Gram negative bacteria
Gram positive bacteria
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Q???
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