Complement system

“the activity of blood serum that completes the action of antibody.”
By...
Pawan Kumar
Hemant Joshi
Velentina
Ashna Prakash

Begins in 1890,
Jules Bordet at the Institute Pasteur in Paris
showed that sheep antiserum to the bacterium Vibrio cholerae
caused lysis of the bacteria and that heating the antiserum
destroyed its bacteriolytic activity.
the ability to lyse the bacteria was restored to the heated serum
by adding fresh serum that contained no antibodies directed against
the bacterium and was unable to kill the bacterium by itself.
Bacteriolytic activity requires two different substances
1).The specific antibacterial antibodies, which survive the heating process
2).Heat-sensitive component responsible for the lytic activity.

 Major effectors in both innate and acquired
immunity.
 Lysis (of cells, bacteria and viruses)
 Opsonization
 Activation of inflammatory response
 Clearance of immune complexes
 After initial activation, various complement
components interacts and acts as a cascade;
and carry out various functions.

Serum Complement proteins leads
in the lysis of the killed cell
material,
Exposed cell material is triggered
to phagocytosis by the cascade of
complement system.

Foreign Material like bacteria and
viruses are triggered to
phagocytosis by the attachment
of complement system.

Immune complexes like
Antigen-Antibody complexes
are cleared by the
complement component
attachment to it.

 Proteins and glycoproteins compose the complement system.
Synthesized mainly in liver hepatocytes. Also produced by blood
monocytes, tissue macrophages and epithelial cells of the GI and
genitourinary tracts.
Constitute 5% of the serum globulin fraction.
Designated by numerals (C1-C9), by letter symbols (e.g. factor D), or
by trivial names.
Most circulate in the serum in functionally inactive forms as
proenzymes, or zymogens.
Peptide fragments formed by activation of a component are denoted by
small letters.
Smaller fragment designated as “a” , larger fragment designated by
“b”(e.g. C3a, C3b). C2 is an exception; C2a is the larger cleavage
fragment.
Larger fragment bind to the target site. Smaller fragments initiate
inflammatory responses.
Complement fragments interact with one another to form functional
complexes.

Classical: Initiated by formation of an Ag-Ab complex.
Alternative: Antibody-independent part of innate immunity
initiated by foreign cell surfaces.
Lectin: Initiated by host proteins binding microbial surfaces.

CLASSICAL PATHWAY
 Classical was discovered first (but actually evolved
later).
 Initiated by:
-formation of a soluble Ag-Ab complex or
-binding of antibody to antigen on a target such
a bacterial cell.
 Only certain antibodies can activate this
pathway (IgM and certain classes of IgG).

• Initial stage of activation involves C1, C2, C3 and
C4. (named in order of their discovery)
• Formation of Ag- Ab complex induces
conformational changes in Fc region of IgM
molecule, exposing binding site for C1.
• C1- macromolecular complex consists C1q and
two molecules each of C1r and C1s (C1qr2s2).
• C1 complex is stabilized by calcium ions.

Hydrolysis of C3 by C3 convertase C4b2a (a) Native
C3. (b) Activated C3 showing site of cleavage by C4b2a
resulting in production of the C3a and C3b fragments.
(c) A labile internal thioester bond in C3 is activated as C3b is
formed, allowing the C3b fragment to bind to free hydroxyl or
amino groups (R) on a cell membrane. Bound C3b exhibits
various biological activities, including binding of C5 and
binding to C3b receptors on phagocytic cells.

ALTERNATIVE PATHWAY
 Does not need Ag- Ab complex for initiation.
 A component of innate immunity (as no Ab required)
 Four components: C3, factor B, factor D, properdin.
 Triggering substances may be pathogens or
Nonpathogens; bacterial cell wall components, fungi,
viruses, parasites immune complexes, RBCs, polymers.

LECTIN PATWAY
 Lectins are proteins that recognize and binds to
specific carbohydrate targets.
 Lectin activating complement binds to mannose
residues.
 Same as classical pathway but does not depend on
Ab for its activation.
Activated by binding of MBL (mannose-binding lectin) to
mannose residues on the surface of microorganisms.

MBL is an acute phase protein produced by liver in
inflammatory responses.
 Acts like C1q
Once MBL binds to target cell, 2 serine
proteases (MASP-1, MASP-2) bind to it.
 Active complex formed causes cleavage and
activation of C4 and C2.
MASP-1 and 2 similar to C1r and C1s.

MEMBRANE- ATTACK COMPLEX
• C5b, C6, C7, C8 and C9 forms membrane attack
Complex (MAC).
• MAC forms a large channel through the membrane,
enabling ions and small molecules to diffuse freely.
• C5 convertase, cleaves C5 which comprises of two
protein chains, alpha and beta.
• C5 binds C3b component of convertase, amino
terminus of alpha chain is cleaved, generating C5a
and C5b fragment.

• C5b – binds to the surface of target cell, providing
the binding site for subsequent components of
MAC.
• C6 binds to C5b and stabilizes its activity.
• C5b6 binds to C7.
• Complex undergoes a hydrophobic-amphiphilic
structural transition, exposing hydrophobic regions,
exposing sites for membrane phospholipids.

•C8 binds to membrane bound C5b67 and undergoes
a hydrophobic-amphiphilic transition, exposing a
hydrophobic region, which interacts with plasma
membrane.
• C5b678 complex creates a pore leading to the lysis
of red blood cells.
• Finally, C9 binds to C5b678 leading to its
polymerization.
• Ions and small molecules can diffuse freely, hence
cell is unable to maintain its osmotic stability and is
killed by an influx of water and loss of electrolytes.

Regulation of complement
system
Passive
mechanism
Active
mechanism
Regulation
of
complement
system

Passive mechanism
Inclusion of highly labile components
that undergo spontaneous inactivation if
they are not stabilized with other
components. For example, the C3
convertase activity generated in the
alternative pathway has an active half
life of only 5 minutes unless stabilized
by reaction with properdin.

Anaphylatoxin inactivator
This regulatory protein are soluble in
nature and affecting the effector
function of complement system by
inactivating the activity of C3a and C5a
by carboxypeptidase N-catalyzed
removal of C-terminal arginine.

 Amplifies humoral response Destroys invading bacteria and viruses
(lysis by MAC).
Other components or products participate in
 Inflammatory response.
 Opsonization of antigen (enhances phagocytosis).
 Virus neutralization.
 Clearance of immune complexes.

Many of the biological activities depends upon the binding of
complement fragments to complement receptors…
Which are expressed by various cell….

 Complement system is quite effective in lysing Gram-negative
bacteria,
 Some Gram-negative and most Gram-positive bacteria have
mechanisms for evading complemented mediated damage.

Anaphylatoxins- C3a, C4a, C5a
 Bind to receptors on mast cell, blood basophils and induce
degranulation with release of Histamine and other activator
mediator.
 Induce smooth muscle contraction and induced capillary
dilation; fluid influx)
 Play a role in blood cell chemotaxis

 Serum protease Carboxypeptidase N regulate anaphylatoxins
activity
 Which cleaves an Arg residue from C-terminus of the molecule and
form des-Arg complex.
 The des-Arg form of C3a is completely inactive, where as
 C5a retains a fraction of both its chemotactic activity and its ability to
cause smooth muscle contraction.
 C3a and C5a each can induce monocytes and neutrophils to adhere
to vascular endothelial
cell.
 C5a is most potent in mediating
these processes, effective in
Picomolar quantities.
 C3a is the major opsonin of
complement system.
 C3b targets the antigen directly
to the phagocyte, enhancing
the initiation of antigen
processing and accelerating
specific antibody production.

Some viruses activate alternative or lectin pathway where as Antibody-
mediated (classical) pathway is more common.
Eg. Retroviruses, Epstein-Barr virus, Newcastle disease virus and
rubella virus.
Viral aggregates:
C3a component facilitate aggregate formation as little as 2 antibody
molecule per virion, which reduce the net number of infectious viral
particles.
Eg: Polyoma virus.

1) Interference with the binding of complement to Ag-
Ab complex. Eg: Herpesvirus, which synthesizes viral
proteins that have Fc receptor properties.
2) Mimicry of mammalian complement regulators.
Eg: Vac-cinia virus, that produce a protein which binds C3b and
C4b and interfering with its activity.
3) Incorporation of cellular complement regulators in
the virion. Eg: HLTV-1(Human Leukemia Virus) incorporate
significance level of sialic acid in its viral envelope, masking its
property as mammalian cell.

Mostly seen in people with Autoimmune
disease
Systemic Lupus Erythematosus (SLE)
Produce large amount of immune
complexes, and suffer from tissue
damage.
Erythrocytes plays an important role in
binding C3b-coated immune complexes
and carrying them to spleen and liver.
In SLE patients, deficiencies in C1, C2
and C4 contribute to reduce level of
C3bon immune complexes and inhibit
their clearance.

 Immune Complex Disease:
Early components of classical pathway (C1, C4, C2) deficiency, result
in absence of C3b, which is needed for solubilization
 Early components of Alternative pathway (factor-D and properdin)
deficiency appear to be associated with Neisseria infection.
 MBL deficiency results in serious pyogenic infection in neonates
and children.
 C3 deficiencies (can’t activate C5 and form MAC)
 C4 deficiencies lead to higher level of autoimmune disease.
 C9 deficiencies results in no clinical symptoms.
 C1Inh deficiency is an autosomal dominant condition called
hereditary angioedema, which manifests clinically as localized
edema of the tissue, often cause trauma.
Complement Deficiency

Complement system

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