Download 12 Complement system BA

THE COMPLEMENT SYSTEM
The complement system
• The complement system is a set of plasma proteins that
act in a cascade to attack and kill extracellular
pathogens.
• Approximately 30 components:
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activating molecules
complement receptors
regulator factors
membrane proteins wich inhibit the lysis of host cells
• Most of the complement proteins and glycoproteins are
produced in the liver in an inactive form (zymogen).
Activation is induced by proteolitic cleavage.
Amplification of the complement cascade
inactive
precursors
limited
proteolysis
enzyme
activating surface
Activating surface needed!
Pathways of complement activation
Cellular and Molecular Immunology, 7th ed., 2014 Elservier
INITIATION OF THE CLASSICAL PATHWAY
The C1 complex
Collagen „legs”
Gobular „heads”
C1 is always present in serum but it can operate only on an activating surface
Low affinity binding to the Fc region of antibody  conformational change  activation
Multiple interaction with immune complexes
C-reactive protein also activates the classical pathway
At least two molecules of IgG bound to pathogens
or soluble antigens are required to activate
the complement cascade
Different isotypes of antibodies activate the
complement system differently
Binding of IgM to antigen on a pathogen’s surface
initiates the classical pathway of
complement activation
INITIATION OF THE LECTIN PATHWAY
Glycosylation of proteins is different in various species
Prokaryotic cells
Eukaryotic cells
Mannose
Glucoseamine
Mannose
Galactose
Neuraminic acid
(sialic acid)
Mannose-binding lectin and ficolin bind
mannose and N-acetylglucosamin,
respectively
Cellular and Molecular Immunology, 7th ed., 2014 Elservier
The activated MBL complex cleaves C4 and C2 to
produce C4b and C2a, which associate to form
the classical C3 convertase
INITIATION OF THE ALTERNATIVE PATHWAY
C3, the central component of the complement
system
Strong covalent binding
(3 900 000 000 000 000 molecules/ml)
Formation and action of the soluble C3 convertase
that initiates the alternative pathway of
complement activation
Alternative pathway is
instantly inactivated on
eukariotic cell surfaces
(in the presence of sialic
acid molecules)
C3b can derive
from classical or the
lectin pathway too
Cellular and Molecular Immunology, 7th ed., 2014 Elservier
The early steps of complement activation by
the alternative, classical, and lectin pathways
Complement receptors on phagocytes
trigger the uptake and breakdown of
C3b-coated pathogens
C3a and C5a contribute to local inflammatory responses
The membrane-attack complex (MAC) assembles
to generate a pore in the lipid bilayer membrane
Membrane attack complex (MAC)
SUMMARY
Complement receptors
Cellular and Molecular Immunology, 7th ed., 2014 Elservier
REGULATION OF THE COMPLEMENT SYSTEM
C1 inhibitor (C1INH) binds to C1r and C1s and
dissociates them from C1q
C1 inhibitor (C1INH) permanently inhibits C1r and C1s
Formation and stability of the alternative C3 convertase
on cell surfaces is determined by complement
control proteins
Factor H inhibits binding of only Bb to C3b
and is thus a regulator of the alternative but
not the classical pathway
DAF: decay-accelerating factor
MCP: membrane cofactor protein
DAF and MCP also disrupt C3 convertase
C4b2a
C4-binding protein (C4BP) can also serve as cofactor
for factor I–mediated inhibition of C3 convertase
CD59 prevents assembly of the membrane attack
complex on human cells
Regulation of complement system
Factor I
C1Inh
DAF C4BP CR1 MCP
LECTIN PATHWAY
CD59
Properdin
DAF
positive feedback
Fact-H CR1 MCP
Factor I
membrane protein
soluble molecule
Deficiencies of complement system – cascade molecules
Deficiencies of regulatory molecules, receptors