Chapter 4 Complement system I'Concept and composition of the complement system II'Activation of comp

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Chapter 4 Complement system   I.Concept and
composition of the complement system
II.Activation of complement system
III.regulation of complement activity
IV.Biologic activity of complements
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I.Concept and composition of the complement
system 1.Definition Complements are a group of
globulins which possess enzymatic property and
exist in blood and other body fluids attending
specific and non-specific immune reponse.
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2.Composition 1) Intrinsic components
C1C9,factor B ,factor D, MBL,Serine protease
2) Regulatory proteins factor P,C1 inhibitor,C4
binding protein, factor I,MCP,DAF, factor H,C8
binding protein, et al. 3) Complement receptors
CR1CR5,C3aR,C2aR,C4aR,et al.
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II.Activation of complement system 1.Classical
pathway 1) Triggering substance ------immune
complex 2)  participant components     
C1(C1q,C1r,C1s),C2,C3,C4,C5,C6,C7,C8,C9 3)
Process
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3) Process (1)   Recognition step Binding of
C1 to Ag-AbBinding of C1q to Ag-Ab complexes
results in autocatalysis of C1r.   The altered
C1r cleaves C1s and this cleaved C1s becomes an
enzyme (C4-C2 convertase) capable of cleaving
both C4 and C2             
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(2)   Activation step generation of C3
convertase   ----Activated C1s enzymatically
cleaves C4  into C4a and C4b. ----Activated C1s
enzymatically cleaves C2  into C2a and C2b.
----C4b2b complex binding to the membrane, is
known as C3 convertase . generation of C5
convertase     ----C3 convertase cleaves C3 into
C3a and C3b.      -----C3b binds to the membrane
to form C4b2b3b complex.     -----C4b2b3b
complex functions as C5 convertase .
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3)  Effect step C5 convertase cleaves C5 into
C5a and C5b. C5b binds the membrane. C5b binds
C6 and  C7 to yield a hydrophobic C5b67 complex
which attaches quickly to the cell membrane. 
 C8 binds to this complex and causes the
insertion of several C9 molecules.C5b6789 complex
is known as MAC which  leads to formation of a
hole in the membrane resulting in cell lysis.
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2. Alternative pathway 1) Triggering substance
-----LPS,aggregated Ig (IgG4,IgA),et al. 2)
participant components -----C3,C5C9, factor B,
factor D, factor P. 3) Process
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3) Process (1)   preparation stageSpontaneous
activation of C3 ----C3 is hydrolyzed slowly  by
some protease in body fluid.----Factor B which
is binded to C3b and is cleaved by Factor D to
produce C3bBb.----C3bBb complex (C3 convertase)
cleaves native C3 into C3a and C3b .----C3b or
C3bBb, in fluid phase, is very short lived unless
it finds a suitable  stabilizing membrane or
molecule (C3 activator).
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(2)   activation stageStabilization of C3
convertase ------- Certain bacteria or their
products (lipid polysaccharides, etc.), provide a
protected (activator) surface for C3b and
C3bBb.Morover, binding of another protein,factor
P, further stabilizes this complex. Generation
of C5 convertase -------- Stabilized C3
convertase cleaves more C3 and produces C3bnBb
complex , the C5 convertase which cleaves C5 into
C5a and C5b.                                      
        
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3) effect stage     Generation of MAC (membrane
attack complex)    which leads to cell lysis.
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While these pathways of C3 activation are
initiated by different mechanisms, they are
analogous to each other and both can lead to
membrane lysis.
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3.MBL pathway 1) This pathway is initiated by
acute phase response.  2) participant components
     MBL,serine protease,C2,C4,C3,C5,C6,C7,C8,
C9 3)Process     (1)binding stage
Mannan-binding lectin (MBL) binds  mannose of
bacteria and interacts with serine protease
resulting in MBL-associated serine protease
(MASP).       MASP is analogous to C1 and leads
to cleaving of C4 and C2.    (2) Activation
stage    (3) effect stage
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II.regulation of complement activation 1.self
regulation Spontaneous decay of complement
components C3b,C4b,C5b C3 convertase
(C4b2b,C3bBb),C5 convertase (C4b2b3b,C3bnBb) .
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2. Effect of regulative factors (1)  regulation
of C1activation   C1 inhibitor -----binds to
C1r and C1s and prevent further activation of C4
and C2
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(2) Regulation of C3 convertase formation
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  a.  I factor --------enzymatically
inactivates C3b and C4b,prevents formation of C3
convertase  
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b.  DAF -----binds to C4b and C3b, prevent
formation of C3   convertase
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  c. Factor P -----binds to C3bBb and
stabilizes it. d.H factor ---binds to C3b and
promotes inactivation of C3b (3) regulation of
MACC8 bp ------interfers with binding of C9 and
C8, prevents formation of MAC CD59--------interfe
rs with binding of C5b6 complex and C7,C8, and
prevents formation of MAC
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IV.Biologic activity of complements 1.Cell lysis
Complement activation by classical pathway,MBL
pathway or alternative pathway leads to the
formation of MAC.MAC mediates lysis of target
cell. 2. Opsonization C3b and C4b in the
surface of microorganisms attach to C-receptor
(CR1) on phagocytic cells and promote
phagocytosis.
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3. Elimination of immune complex Ag-Ab-C3b
complex can adhere to the C3bR which exists on
the surface of RBC or platelet .This facilitates
phagocytosis of inmmune complex by phagocytes.
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4.mediating Inflammation response C3a,C4a,C5a
Anaphylatoxins C4a, C3a and C5a (in increasing
order of activity) are all Anaphylatoxins which
cause basophil/mast cell degranulation resulting
in dilatation of blood vessels and contraction of
smooth muscles. Chemotactic factors  C3a,C5a
and  (C5b67) are chemotactic. They are able to
attract neutrophils and phagocytes to the
location of inflammation response.
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5. Regulation of immunity Help APC to present Ag
Promote the proliferation and differentiation of
B cell. In summary the complement system takes
part in both the specific and non specific
resistance and generates a number of products of
biological and pathophysiologic significance .