The complement
system
Immunity
Natural/innate/nonspecific
Humoral: type I IFN (IFN-lysozyme,
Complement proteins
Cellular: phagocytes (neutrofil,
makrofag), NK cells
Adaptive/acquired/specific
Humoral: B lymphocytes (B cells: B1, B2)
Abs: IgM, IgG, IgA, IgE, IgD
Cellular: T lymphocytes: T cells:
CD4+ Th (Th1, Th2, Th17), CD8+CTL (cytolytic
T lymphocytes), Tregs (Tr1, Th3)
Complement proteins
Serum anti-cholera + Vibrio cholerae
lysis
Heated (56o, 30 minutes) serum anti-
cholera + V. cholerae no lysis
Heated (56o, 30 minutes) serum anti-
cholera passively transferred:
immunity
Immune and Non-immune
(normal) serum
Immune serum
Heat-labile component: Complement
Heat-stable component: Antibodies
(Abs)
Non-immune serum
Heat-labile component: Complement
Complement system
Consists of serum-and cell surface
proteins
C proteins are plasma proteins, normally
inactive
Activation of complement proteins produces
products mediate effector function of the C
Major effector mechanisms of humoral
immunity
An important effector mechanisms of
innate immunity
Complement activation
Classical pathway
Initiated by binding of C1 to CH2 domains
of IgG, and CH3 domains of IgM
A mechanism of humoral immunity
Alternative pathway
Activated on microbial cell surface; no
Abs required
Effector mechanism of innate immunity
Complement activation
(contnd)
Lectin pathway
Triggered by the binding of plasma MBL
to mannose residues of microbial
proteins & polysaccharides
Effector mechanism of innate immunity
Figure 2-18
C activation: General features
Sequential proteolysis of proteins to
generate proteolytic enzymes
Enzymatic activity/cascade reactions
Its products become attached to microbial
cell surfaces, or to Abs bound to
microbes/other antigens
The sites of their biologic functions
Inhibited by regulatory proteins that are
present on normal host cells, but absent
from microbes
C activation: General features
(contnd)
Inhibited
by regulatory proteins that
are present on normal host cells, but
absent from microbes
Adaptation of normal cells to minimize
C-mediated damage
Component of C proteins
C1q, MW 400 kDa
C1r, 95 kDa
C1s, 85 kDa
C1q: polymer of 6 identical subunits
C1q activation
Bindingof C1q subunit with specific
receptor of Fc At least 2 molecules
of IgG are required, while IgG4, IgA &
IgE have no receptor
Activated C1q C1r C1s C4
Figure 2-21
Figure 2-22
C4 activation
C4
Glycoprotein, MW 180 kDa
Synthesized by macrophages
Activated C4 + C1s C2
Activated C2 C4 2 (C3 convertase)
C3 activation
C3
globulin; MW 180 kDa
Secreted (pro-C3) by macrophages
C3 + C4 2 C3a and C3b (small & large
fragments, respectively)
Amplification step, where C3b attach to
the membrane of target cell
C3b + C4 2 C4 2 3 (C5 convertase)
Figure 2-27
C5 9 activation
C5 + C 4 2 3 C5a, C5b
C5b + C6, C7 C5 6 7
C8, C9 + C 5 6 7 attach to the cell
membrane, forming a trans-membrane
channelimbalance in osmotic
pressure water influx cell swelling,
increased membrane permeability to
macromolecules CELL LYSIS
Figure 2-30
Biological functions of C
proteins
End-products
Cell lysis, membrane attack complex
(MAC) formation
By-products
Biological effect of proteolytic fragments
Anaphylatoxins: C3a, C4a, C5a inflammatory
mediators
C3b, iC3b have receptor on phagocytes
(neutrophils, macrophages) opsonization
Studies on cellular immune
responses
Macrophages
Phagocytic activities
Phagocytosis
ROI secretion, NO
secretion
NK cells (Ghufron et al.,
2007)
(Courtesy of Dr. Wijayanti)
NK cell activities
IL-2 receptor (CD122)
expression
FACS,
IFN- production ELISA
Target (YAC-1) cell lysis
Mouse/Rat models
Infected with Listeria.
monocytogenes
Figure 2-34
Figure 2-35