1. BIOLOGY 151 LECTURE 11
The Complement
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Sunday, March 13, 2011
2. WHAT YOU NEED TO KNOW
RECALL: Functions &
Components of the
Complement
Activation and Regulation
of the Complement
Cascade
Biological Consequences
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3. RECALL... PARUNGAO-BALOLONG 2011
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4. Complement...
Paul Erlich (1890s)
describe how cells respond to a range of different
threats
proposed that cells produce more of these side
chains, which eventually break off, circulate in the
blood stream and attach to toxic products
released by bacteria (ANTIBODIES)
Jules Bordet (1900s)
experiments revealed how antibodies need to
recruit special allies in order to destroy specific
bacteria
wasn’t sealed by antibodies alone (partner up with
a substance that is routinely present in the blood
= COMPLEMENT) PARUNGAO-BALOLONG 2011
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7. FUNCTIONS AND COMPONENTS
OF THE COMPLEMENT
Synthesized mainly by
liver hepatocytes (blood
monocytes, tissue
macrophages, epithelial
cells of GI &GU tracts)
Most circulate in the
serum in functionally
inactive forms as
proenzymes (zymogens)
ACTIVATION:
trigger inflammation activate naïve B-
larger fragments: bind lymphocytes
to the target near the attract phagocytes
site of activation remove immune
opsonize antigens complexes
smaller fragments:
local inflammation cause cell lysis PARUNGAO-BALOLONG 2011
Sunday, March 13, 2011
9. STRUCTURE OF
C1q
http://student.ccbcmd.edu/
courses/bio141/lecguide/
unit4/innate/c1act.html
assembly of C1 during
classical pathway
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10. SCHEMATIC DIAGRAM OF INTERMEDIATES IN THE
CLASSICAL PATHWAY OF COMPLEMENT ACTIVATION
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11. SCHEMATIC DIAGRAM OF INTERMEDIATES IN THE
CLASSICAL PATHWAY OF COMPLEMENT ACTIVATION
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12. SCHEMATIC DIAGRAM OF INTERMEDIATES IN THE
CLASSICAL PATHWAY OF COMPLEMENT ACTIVATION
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13. CLASSICAL PATHWAY
http://student.ccbcmd.edu/courses/bio141/lecguide/unit4/innate/
c1act.html
assembly of C1 during classical pathway
http://student.ccbcmd.edu/courses/bio141/lecguide/unit4/innate/
c3case.html
assembly of C3 convertase
http://student.ccbcmd.edu/courses/bio141/lecguide/unit4/innate/
c5case.html
cleavage of C3 and assembly of C5 convertase
Sunday, March 13, 2011
18. ALTERNATIVE PATHWAY (PROPERDIN PATHWAY)
a primitive defense system, a bypass
mechanism that does not require C1,
C4, and C2 interaction (does not
depend on antibody for its activation)
Activation
immunologically (e.g., by IgA and
some IgG)
non immunologically (e.g., by
certain microbial cell surfaces,
complex polysaccharides, and
bacterial lipopolysaccharides)
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19. COMPONENTS: ALTERNATIVE PATHWAY
(PROPERDIN PATHWAY)
C3: The initial recognition event
necessary for alternative pathway
activation is the presence of C3,
specifically C3b, which is probably
continuously generated in small
amounts in the circulation
Factor B (C3 proactivator)
C3b interacts with factor B, to form
C3bB, which is a magnesium ion-
dependent complex
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20. COMPONENTS: ALTERNATIVE PATHWAY
(PROPERDIN PATHWAY)
Factor D (C3 proactivator
convertase)
The complex C3bB is susceptible
to enzymatic cleavage by factor D,
into two fragments, Ba and Bb
(Ba fragment is released)
An active site is exposed in the Bb
fragment, which remains bound
to C3b, forming the C3bBb
(amplification C3 convertase)
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21. COMPONENTS: ALTERNATIVE PATHWAY
(PROPERDIN PATHWAY)
Factor D
When stabilized by the binding of
properdin (P), which slows the
dissociation of Bb, the C3bBb complex
becomes a C3 convertase that cleaves C3
and generates more C3b
C3b then fixes to the activator surface so
that more factor B binding sites are
exposed
As more C3b is generated, the complex
expands and becomes a C5 convertase
(cleaving C5 into C5a and C5b and
initiating the membrane attack
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pathway)
Sunday, March 13, 2011
23. PARUNGAO-BALOLONG 2011
The mannose-binding lectin pathway
does not depend on antibody for its MBL, like C1q, is a two- to six-headed
activation; originates with host proteins molecule that forms a complex with two
(MBL) binding microbial surfaces protease zymogens (MASP-1 and
MASP-2)
MBL, an acute phase protein, binds to
mannose residues, and to certain other
sugars on many pathogens
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24. PARUNGAO-BALOLONG 2011
The mannose-binding lectin pathway
When the MBL complex binds to a The MBL pathway is of importance
pathogen surface, MASP-2 is in innate host defense mechanisms
activated to cleave C4 and C2 in early childhood
A C3 convertase is formed from C2a
bound to C4b
Sunday, March 13, 2011
25. The three complement pathways converge at the membrane-
attack complex
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33. Scanning electron
micrographs of E. coli
showing (a) intact cells
and (b, c) cells killed by
complement-mediated
lysis
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35. The
complement
system
neutralizes
viral infectivity
Electron
micrographs of
negatively
stained
preparations of
EB virus
formation of larger viral aggregates - blocking attachment to susceptible
reduce the net number of infectious host cells - facilitate binding of the
viral particles viral particle to cells
a coating of Ab and/or complement possessing Fc or CR1 - lysing most
to the surface of a viral particle enveloped viruses
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36. REGULATION
Inclusion of highly labile components A series of regulatory proteins
that undergo spontaneous inactivation (regulators of complement activation
if they are not stabilized by reaction [RCA] gene cluster - chromosome 1 in
with other components humans)
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39. REGULATION: RECEPTORS
Many of the biological activities of the complement system depend on the
binding of complement fragments to complement receptors, which are
expressed by various cells
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40. ROLE OF COMPLEMENT IN
B CELL ACTIVATION
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41. COMPLEMENT & DISEASES
Complement deficiencies
genetic deficiencies in classical pathway components (C1q, C1r, C4,
C2 and C3)
deficiencies in components of the alternative pathway (properdin,
factor D, C3)
deficiencies in the terminal complement components (C5, C6, C7, C8,
C9, Neisseria bacteria)
deficiencies in complement regulatory proteins (abnormal
complement activation)
deficiencies in complement receptors (CR3 & CR4 – inadequate
adherence of neutrophils to endothelium at tissue sites of infection)
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42. COMPLEMENT & DISEASES
Pathologic effects of a normal complement system
The immune complexes produced in autoimmune
diseases may bind to vascular endothelium and kidney
glomeruli and activate complement (MAC generation)
It initiates the acute inflammatory responses that destroy
the vessel walls or glomeruli and lead to thrombosis,
ischemic damage to tissues, and scarring
Some of the late complement proteins may activate
prothrombinases in the circulation that initiate
thrombosis
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44. What is the rate-limiting step
in the complement cascade?
C4. The liver can produce a finite
amount of C4
In rare cases, when an angioedema
attack is treated with large
amounts of FFP, symptoms may
worsen because of a temporary C4
depletion
Sunday, March 13, 2011
45. WRAPPING UP!!!
The complement system comprises a group of serum
proteins, many of which exist in inactive forms
Complement activation occurs by the classical,
alternative, or lectin pathways, each of which is
initiated differently
The three pathways converge in a common sequence
of events that leads to generation of a molecular
complex that causes cell lysis
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46. WRAPPING UP!!!
The classical pathway is initiated by antibody binding
to a cell target; reactions of IgM and certain IgG subclasses
activate this pathway
Activation of the alternative and lectin pathways is
antibody- independent. These pathways are initiated by
reaction of complement proteins with surface molecules of
microorganisms
In addition to its key role in cell lysis, the complement
system mediates opsonization of bacteria, activation of
inflammation, and clearance of immune complexes
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47. WRAPPING UP!!!
Interactions of complement proteins and protein fragments
with receptors on cells of the immune system control both
innate and acquired immune responses
Because of its ability to damage the host organism, the
complement system requires complex passive and active
regulatory mechanisms
Clinical consequences of inherited complement deficiencies
range from increases in susceptibility to infection to
tissue damage caused by immune complexes
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48. NEXT MEETING:
CELL-MEDIATED
EFFECTOR RESPONSE
Sunday, March 13, 2011