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Complement System

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Sohail Ahmed
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21 views26 pages

Complement System

Uploaded by

Sohail Ahmed
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
Available Formats
Download as PPT, PDF, TXT or read online on Scribd
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COMPLEMENT

SYSTEM
WHAT IS COMPLEMENT SYSTEM

• Complement system is a part of the immune system


called the innate immune system that is not adaptable
and does not change over the course of an individual's
lifetime.
• However, it can be recruited and brought into action by
the adaptive immune system.
OVERVIEW

• The complement system is part of the innate immune


system.
• It is named “complement system” because it was first
identified as a heat-labile component of serum that
“complemented” antibodies in the killing of bacteria
• It is now known that it consists of over 30 proteins and
contributes 3 g/L to overall serum protein quantities
Function of Complement
• After initial activation, the various complement components interact, in a
highly regulated cascade, to carry out a number of basic function.

1. Lysis of cells, bacteria and viruses.

2. Opsonization, which promots phagocytosis of perticulate antigens

3. Binding to specific complement receptors on cells of the immune system,


triggering specific cell function, inflammation, and secretion of
immunoregulatory molecules
Components of Complement

The soluble proteins and glycoproteins that constitute complement system


are synthesize mainly by liver hepatocytes, although significant amount are
produced by blood monocytes, tissue macrophages and epithelial cells of GI
tract.
• Components are designated by munerals(C1-C9), by latter symbols (factor
D),
• Peptide fragments formed by activation of a component are denoted by
small letters. In most cases, the smaller fragment resulting from cleavage of
a component is designated “a” and the larger fragment designated “b” (e.g.,
C3a, C3b; note that C2 is an exception: C2a is the larger cleavage fragment).
• The larger fragments bind to the target near the site of activation, and the
smaller fragments diffuse from the site and can initiate localized
inflammatory responses by binding to specific receptors. The complement
fragments interact with one another to form functional complexes. Those
complexes that have enzymatic activity are designated by a bar over the
number or symbol (e.g., C4b2a, C3bBb).
Complement Activation
CLASSICAL PATHWAY

•Begins with antibody binding to a cell (antigen) surface and ends with the
lysis of the cell

•The proteins in this pathway are named C1-C9 (the order they were
discovered and not the order of the reaction)

•When complement is activated it is split into two parts


– a – smaller of the two
– b – larger part and usually the active part (except with factor 2)
•Three steps in this pathway-
– ACTIVATION
– AMPLIFICATION
– ATTACK
CLASSICAL PATHWAY

• ACTIVATION
– C1q portion of C1 attaches to the Fc portion of an
antibody
– Only IgG and IgM can activate complement
– Once activated C1s is eventually cleaved which activates
C4 and C2
– C4b & C2a come together to form the C4b2a
which is the C3 convertase
– C3 convertase activates C3 to C3a and C3b
CLASSICAL PATHWAY

• ACTIVATION
– C3a binds to receptors on basophils and mast cells triggering
them to release there vasoactive compounds (enhances
vasodilation and vasopermeability)
– C3a is called an anaphylatoxin
– C3b serves as an opsonin which facilitates immune complex
clearance
CLASSICAL PATHWAY

• AMPLIFICATION
– Each C1s creates many C4b and C2a fragments
– Each C4bC2a creates many C3b (activated C3)
– Each C3b goes on to create many Membrane Attack
Complexes
– Example
• 1 C1S makes 100 C4bC2a
• 100 C4bC2b makes 10,000 C3b
• 10,000 C3b makes 1,000,000 MAC (membrane attack
complex)
CLASSICAL PATHWAY

• ATTACK
– Most C3b serves an opsonin function
– Some C3b binds to C4bC2a to form the C5 convertase
C4bC2aC3b
– C5 convertase cleaves C5 leading to the formation of the
Membrane attack Complex (C5-C6-C7-C8-C9)
– The MAC “punches holes” in cell walls resulting in lysis
ALTERNATIVE PATHWAY

• Requires no specific recognition of antigen in order to cause


activation
• Usually activated by bacterial products like endotoxins

ACTIVATION
– Spontaneous conversion from C3 to C3a and C3b occurs
in body
ALTERNATIVE PATHWAY

• AMPLIFICATION
– Factor B binds to C3b
– Factor B is then cleaved by factor D into Ba and Bb
– C3bBb remains which acts as a C3 convertase (C3
 C3a and C3b)
– C3bBbC3b is formed which acts as a C5 convertase
ALTERNATIVE PATHWAY

• ATTACK
– C5 is cleaved to C5a and C5b
– C5b then starts the assembly of the Membrane Attack
Complex

C5a
C5
C5b
LECTIN PATHWAY

• Lectins are proteins that recognize and bind to specific


carbohydrate targets.

• The lectin pathway, like the alternative pathway, does not


depend on antibody for its activation.

• The lectin pathway is activated by the binding of mannose-


binding lectin (MBL) to mannose residues on glycoproteins or
carbohydrates on the surface of microorganisms including
certain Salmonella, Listeria, and Neisseria strains
• MBL is an acute phase protein produced in inflammatory
responses.
LECTIN PATHWAY
• MBL function in the complement pathway is similar to that of C1q, which
it resembles in structure.

• After MBL binds to the surface of a cell or pathogen, MBL- associated


serine proteases,MASP-1 and MASP-2, bind to MBL.

• The active complex formed by this association causes cleavage and


activation of C4 and C2.

• The MASP-1 and -2 proteins have structural similarity to C1r and C1s and
mimic their activities.

• This means of activating the C2–C4 components to form a C5 convertase


without need for specific antibody binding represents an important innate
defense mechanism comparable to the alternative pathway,but utilizing the
elements of the classical pathway except for the C1 proteins.
LECTIN BINDING COMPLEMENT
PATHWAY
MBP C2
C4 C3

C5
C4b

C4a

Bacteria
LECTIN BINDING COMPLEMENT PATHWAY

MBP C2
C4 C3

C5
C4b
C2a
C4a

C2b
Bacteria
LECTIN BINDING COMPLEMENT PATHWAY

MBP C2
C4 C3

C5
C4b
C2b
C3b C4a

C2a
Bacteria C3a
LECTIN BINDING COMPLEMENT PATHWAY

MBP C2
C4 C3

C5
C4b
C2b
C3b C4a
C5b
C2a
Bacteria C3a
C5a
LECTIN BINDING COMPLEMENT PATHWAY

MBP

C4b C6
C2b
C3b C7
C5b C8
Bacteria C6
C9
C7
C8
C9 C9
C9 C9
C9
C9
Complement Deficiencies
Role of Complement in Disease

The complement system plays a critical role in


inflammation and defense against some bacterial
infections.
Complement may also be activated during
reactions against incompatible blood transfusions, and
during the damaging immune responses that
accompany autoimmune disease.
Deficiencies of individual complement components or inhibitors
of the
system can lead to a variety of diseases , which
gives some indication of their role in protection against
disease
Complement Deficiencies

Diseases associated with complement deficiencies

Complement Deficiency Disease

C3 and Factor B Severe bacterial infections

C3b, C6 and C8 Severe Neisseria infections

Deficiencies of early C Systemic lupus erythematosus (SLE),


components C1, C4, C2. glomerulonephritis

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