4. Complement System
补体系统
MAC
1. Introduction
• Complement was discovered at the
end of the 19th century as a heat-labile
component of normal plasma that
augments the opsonization and killing
of bacteria by antibodies.
• Although first discovered as an effector
arm of the antibody response, complement
can also be activated early in infection in
the absence of antibodies.
• Complement, C
Complement: History
Discovered in 1894 by
Dr. Jules Bordet.
It represents lytic activity
of fresh serum.
Its lytic activity destroyed
when heated at 56℃ for
30 min.
Antibodies are heat stable.
What is Complement?
• Complement is a system of proteins that
interact with pathogens to mark them for
destruction by phagocytes and induce a series
of inflammatory responses that help to fight
infection.
• Complement is a group of plasma and cell
membrane proteins that form the principal
effective arm of the humoral immune system.
General Functions of Complement
Proteins of the complement
system (nomenclature)
• C1(q,r,s), 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)
• C1 inhibitor (C1-INH, serpin), C4-binding protein
(C4-BP), decay accelerating factor (DAF),
Complement receptor 1 (CR1), protein-S
(vitronectin)
Activation product of complement proteins
(nomenclature)
• Activated component are usually overlined: e.g. C1qrs.
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)
2. Pathways of Complement
Activation
Three pathways of complement activation are:
1. Classical pathway 经典途径 humoral immunity
2. Alternative pathway 旁路途径 innate immunity
3. Lectin pathway 凝集素途径 innate immunity
Abbas AK et al
Chapter 12 p293
1. Classical Pathway
Molecular structure of C1
C5a stimulates inflammation
Cell-associated C5 convertase cleaves C5 and
generates C5b,which becomes bound to the
convertase. C6 and C7 bind sequentially, and
C5b,6,7 complex becomes directly inserted into
the lipid bilayer of plasma membrane, followed
by stable insertion of C8. Up to 15 C9 molecules
may then polymerize around the complex to
form MAC.
Membrane Attack Complex(MAC)
2. Alternative
pathway
• IgM is the most efficient activator, but unbound
IgM in plasma does not activate complement.
• Question:
What physiological advantages and problems
can you see in a system with a positive feedback
loop (i.e. where the presence of C3b leads to the
production of an enzyme C3bBb that generates
more C3b)?
3. Lectin pathway
C4
C4a + C4b
MBL
+
+ serine protease
Mannose residues
of pathogens
MASP
C2
+
C4b2a
C3 convertase
C2a + C2b
Lectin pathway is triggered by a plasma protein called
mannose-binding lectin(MBL),which recognizes
terminal mannose residues on microbial glycoproteins
and glycolipids. Then, go on to activate the classical
pathway.
MASP: MBL-associated serine protease
MBL-associated serine proteases(MASP)
Late steps of activation
Structure of MAC in cell membrane
Products of C3 cleavage
Adjuvant
Binding of complement
receptor 2 (CR2) to
complement fragments
(C3d) deposited on the
surface of a pathogen
cross-links the B-cell coreceptor complex with
the B-cell receptor. This
causes them to cluster
together on the B-cell
surface.
3. Receptors for Complement Proteins
4. Regulation of complement activation
4.1 Self-Regulation of Complements
4.2 Functions of Regulators
Regulation of Classical Pathway
Regulation of Alternative Pathway
• Assembly of the components of C3 and C5
convertases is inhibited by the binding of
regulatory proteins to C3b and C4b deposited
on cell surfaces.
• C3bBb complex cleaves more C3, leading to
amplification of alternative pathway.
In the presence of cell membrane-bound cofactors
(MCP) or complement receptor 1(CR1), Factor I
cleaves C3b on cell surface, leading to inactivate
C3b(iC3b). Factor H also serves as cofactors for
Factor I-mediated cleavage of C3b.
Regulation of Formation of the MAC
5. Functions of complement system
• Stimulation of Inflammatory Responses
• Opsonization and Phagocytosis
• Complement-Mediated Cytolysis
• Other Functions,
C5a enhances the phagocytosis of opsonized pathogens
Anti-C5a therapy is a double-edged sword. Tell me why.
Complement is central to the development
of inflammatory reactions
Complement plays important roles
in adaptive immunity
C5a is chemotactic for macrophages
and polymorphs
• Binding of C3a and C5a to the receptors on
macrophages causes cell activation:
— increasing adhesive properties;
— triggering extravasation; and
— priming phagocytes to release
proinflammatory molecules and inflammatory
cytokines.
C3a and C5a activate mast cells
and basophils
• Binding to the receptors on mast cells triggers
massive release of histamine and cytokines.
Mast cell
6. Complement Deficiency
―Porcine Factor H deficiency
Immunology Seminar
1. 全体参加
2. 题目自选，例如：
NK cells, friend or foe?
Macrophage what I know
Antibody: Its two sides of coin
3. 评比：冠军：15分，亚军：13分，
季军：11分。其他人6-10分。
4. 初赛有各班自行组织。每个题目文章的长度在3000字
左右。
5. 总决赛在6月的第一个星期六。每个班由5人参加，每
人报告15分钟，用PPT格式(双语，鼓励使用英语)。
Thank You!
Next lecture:
Section 6 Cytokines