16.complements!!!!!!!!!

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 Refers to the ability of these proteins to
complement i.e augment the effects of other
components of the immune system e.g. Antibody.
 Consists of a series of inactive precursor proteins
that are activated which then activate the next
protein in the sequence.
 Each precursor is cleaved into two or more
components.
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 Cell lysis ; such as bacteria, allografts, and
tumour cells.
 Inflammatory responses i.e. generation of
mediators that paticipatein inflammation and
attract neutrophils.
 Opsonization; enhancement of phagocytosis.
This is usually trigger by the major
component of the complement system.
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 Triggers inflammation.
 Chemo-tactically attracts phagocytes to infection
sites.
 Promotes the attachment of antigens to phagocytes.
 Causes lysis of gram-negative bacteria and human
cells displaying foreign epitopes.
 Plays a role in the activation of naive b lymphocytes.
 Removes harmful immune complexes from the body.

 There are more than 30 components.
 They are named/ numbered according to
how they were discovered.
 These components include;
 C1, C2, C3, C4, C5, C6, C7, C8, C9.
 Factor B, Factor D, Factor H, Factor I’
 Properdin, C1 inhibitor, C4 binding protein, S
protein.

 Several complement components are
proenzymes, which must be cleaved to form
active enzymes.
 The critical step in the complement
activation is the cleavage of C3 components
by complement derived enzyme C3
convertase.
 The cleavage of C3 can be activated by 3
routes namely;

 There are 3 pathways involved;
 Classical pathways
 Lectin pathway
 Alternate pathway

 Also known as the usual pathway
 Antigen-antibody in the presence of
complements destroy the invading organism.
 Considered to be part of the specific immune
response as it requires the antibody for its
initiation.
 The classical pathway recquires the IgM and IgG
antibody for its activation.
 The other antibodies cant initiate classical
pathway.

 Binding of C1 to the antigen-antibody
complex;
 the antigen-antibody complex is formed when
the epitope of the antigen binds to the fab
component of the IgM OR IgG.
 The fc component of the antibody binds to the
C1q complement to activate it.
 The C1 complement has 3 subunits C1q, C1r and
C1s

 Cleavage of C4 by C1
 The enzyme C1 activates two complements; C4
and C2.
 Enzyme C1 cleaves C4 into C4a and C4b .
 The C4b bind adjacent proteins and
carbohydrates on the surface of the antigen.

 Cleavage of C2 and formation of C3
convertase.
 C2 binds to the C4b and the enzyme C1
subsequently cleaves C2 into C2a and C2b.
 The classical complement pathway is now
activated.
 The C4bC2a functions as a C3 convertase that
can enzymatically cleave hundreds of molecules
of C3 into C3a and C3b.

 Cleavage of C3 by C3 convertase enzyme.
 The C4b2a functions as a C3 convertase enzyme.
 Cleaves hundreds of molecules of C3 into C3a and
C3b.
 C3b and to a lesser extent, C4b, attaches antigens to
phagocytes for opsonization.
 A portion of the C3b binds to proteins and
polysaccharides on the surface of microbes, another
to the CR1 receptors of phagocytes, b-lymphocytes
and dendritic cells. This leads to improved
phagocytosis.

 C3a can promote inflammatory responses
that enable body defend cells and defence
chemicals to leave the blood and enter the
tissues.

 Formation of C5 convertase enzyme
 Some molecules of C3b bind to the C4b2a, to
form C4b2a3b.
 This functions as C5 converting enzyme.
 Cleaves C5 into C5a and C5b.
 C5b binds to the cell surface.
 C5a diffuses away but before doing so has the
some biological functions.

 Formation of the membrane attack complex
 The C5b complex is quite labile and has about 2 mins
to bind to C6 to form a C5b6 complex
 The C5b6 complex binds C7 and C8 to form a C5b678
complex.
 Upto 19 molecules of C9 can be added to one C5b678
complex.
 They assemble to form a pore some 100A in diameter.
 This is usually what is meant by membrane attack
complement (MAC) .

 Lysis due to osmotic imbalance.
 The pores formed by the MAC are large enough to
allow the passage of ions, small molecules and
water but too small to allow passage of proteins.
 There is therefore influx of water and loss of ion
balance which leads to lysis by ‘bursting’ of the
cell.

 Also known as mannose binding lectin pathway.
 Independent of antibodies in its activation.
 Lectins are proteins that recognise and bind to specific
carbohydrates targets.
 Very similar to the classical pathway.
 Mannan binding protein (MBP) is structurally similar to
C1q.
 Instead of antibody binding to antigen on a pathogen, MBP
which is always present in the serum, binds to mannose
residues on the surface of pathogens such as certain
salmonella, listeria and neisseria strains

 Two more lectin pathway proteins called MASP1
and MASP2 now bind to the MBP.
 This forms an enzyme similar to C1 of the
classical complement pathway that is able to
cleave C4 and C2 to form C4b2a(C3 convertase).
 The C3 convertase enzymatically cleaves
hundreds of C3 into C3a and C3b.
 The rest of the sequence is the same as for the
classical pathway,

 Also like the lectin pathway does not depend
on the presence of antibodies.
 The C1, C4 and C2 complements are not
involved in activation of the alternative
pathway.
 This pathway uses different components to
generate the C3 and C5 convertase enzymes.

 Formation of C3 convertase.
 C3b is a highly labile protein which is continually
undergoing hydrolysis to produce C3b and C3a.
 Some of the C3b bind to body’s own cells where
its inactivated by surface regulatory proteins.
 Some binds to the surface of pathogens which
unfortunately does not posses surface regulatory
proteins.
 Factor B then combines with the cell bound C3b
to form C3bB.

 The factor B bound to the C3b is then cleaved by
another alternative pathway protein, factor D to yield
Bb and Ba.
 Ba diffuses away but Bb remained bound to C3b to
form C3bBb which is equivalent to the C4b2a of the
classical pathway.
 The C3bBb (C3 convertase enzyme) formed is
stabilised by another alternative pathway protein
called properdin to form C3bBbP that functions as a
C3 convertase capable of enzymatically hundreds of
molecules of C3 into C3b and C3a.
 This provides a powerful amplication loop.

 Formation of C5 convertase
 Some of the C3b subsequently binds to some of
the C3bBb to form C3bBb3b which is a C5
convertase equivalent to C4b2a3b in the classical
pathway.
 C3bBb3b cleaves C5 into C5a and C5b
components.
 The later stages of the complement pathway
involving formation of the MAC proceed in
exactly same way as for the classical pathway.

 The complement cascade irrespective of how its
activated generate a number of molecules that
have a variety of biological activities.
I. Cell lysis; this is mediated by the C5-9 forming
the MAC as earlier discussed.
I. Opsonization; promoting the attachment of
antigens to phagocytes.
C3b and to a lesser extent C4b can function as
opsonins.
phagocyte, B- lymphocytes and dendritic cells all
have receptors for C3b on their surfaces called
complement receptor type 1(CR1)

III. Chemotaxis; many complements components
produced by the splitting of inactive precursors
have chemotactic activity and therefore plays a
role in recruiting cells to the site of inflammatory
response. The most active is C5a which is
chemotactic for neutrophils, monocytes and to a
lesser extent, eosinophils. C3a is also chemotactic
for eosinophils.
IV. Triggering inflammation; C5a is the most potent
complement protein triggering inflammation
 It causes neutrophils to release toxic oxygen radicals for
extracellular killing.
 It also serves as chemo attractants for phagocytes.
 It enhances diapedesis of leucocytes.
 It induces fever
 Causes mast cells to release vasodilators such as histamine

 To a lesser extent, C3a and C4a also promote
inflammation.
V. Clearance of immune complexes; C3b and to
a lesser extent, C4b help to remove harmful
immune complexes from the body. The C3b
and C4b attach the immune complexes to
CR1 receptors on erythrocytes. The
erythrocytes then deliver the complexes to
fixed macrophages within the spleen and
liver for destruction.
VI. Activation of B lymphocytes; serving as a
second signal for activating naive B-
lymphocytes.

 The importance of regulating the
complement system cant be over-emphasised
due to its amplification and potentially
tissue-damaging properties.
 This is achieved in 2 ways;
 Regulating the amount of complement activity.
 Regulating the site of complement activity.

 Regulation of C3 convertase. Various proteins
either inhibit the assemblage of C3 convertase or
accelerate it dissociation.
 Regulators of C3 convertase assembly;
 complement receptor 1 (CR1), membrane co-factor
protein (MCP) and C4b binding protein, are able o bind
C4b and stop it binding to C2a, thereby inhibiting the
formation of C4b2a. Another regulatory protein, factor 1
then cleaves C4b, resulting in irreversible inhibition of
C4b2a assembly.
 CR1, MCP and a soluble protein, factor H, are able to
bind C3b and stop it associating with factor B to form
the alternate C3 convertase, C3bBb. Factor 1 then
cleaves the C3b, irreversibly inhibiting assembly of
C3bBb.

 Factors causing decay of C3 convertase
 A membrane protein, decay accelerating factor, causes
dissociation of C2a from C4b or C4b or C3b from Bb,
inhibiting the classical and alternate C3 convertase
respectively. Factor 1 then cleaves the membrane-
bound C4b or C3b, making the inactivation
irreversible.

 Regulation of the membrane attack complex
(MAC); a soluble protein called S-protein
(vitronectin) binds the C5b-7 complex and
stops it inserting into the cell membrane. A
cell surface protein, CD59, inhibits MAC
formation on the cell surface by blocking the
binding of C8 and C9 to the C5b-7 complex.

 Deficiency of C5-C8 and MBL
 Enhances susceptibility to Neisseria infections.
 Deficiency of C3
 Severe recurrent pyogenic and respiratory tract
infections.
 Inherited deficiency of C1 esterase inhibitors
 Angioedema’
 Acquired deficiency of Decay accelerating
factor.
 Paroxysmal nocturnal haemoglobinuria.

16.complements!!!!!!!!!

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16.complements!!!!!!!!!