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Complement System

The complement system is an essential part of the immune system, consisting of proteins that enhance immune responses against infections. It plays key roles in opsonization, inflammation, cell lysis, and the clearance of immune complexes, and can be activated through three pathways: classical, alternative, and mannose-binding lectin. Deficiencies in complement components can lead to severe infections and autoimmune diseases.

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5 views

Complement System

The complement system is an essential part of the immune system, consisting of proteins that enhance immune responses against infections. It plays key roles in opsonization, inflammation, cell lysis, and the clearance of immune complexes, and can be activated through three pathways: classical, alternative, and mannose-binding lectin. Deficiencies in complement components can lead to severe infections and autoimmune diseases.

Uploaded by

maybeyouknowwho365
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© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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Complement System

UNIT VI
• The complement system is a crucial part of
the immune system, playing a key role in
defence against infections.

• It consists of a complex set of proteins that


work together to enhance the immune
response.
History and Definition
• Complement was discovered by Jules Bordet as a heat-labile component
of normal plasma that causes the opsonization and killing of bacteria.
• Named as Alexins (in Greek, means ‘to ward off’)
• Paul Ehrlich – “complement”
• Part of immune system
• Consists of series of proteins

• 1. The ‘Theory of Metchnikoff’- Phagocytes (phagocytic theory )


• 2. Buchner and colleagues (1891) – Alexins (heat labile factor in blood)
(Humoral Theory)
• 3. Jules Bordet - a heat-labile lytic factor (alexin) and a heat-stable factor
(sensitizer)
• 4. Paul Ehrlich – “complement”

Zymogens: Inactive precursor stage of complement proteins


• The complement system, also known as complement cascade,
is a part of the immune system that enhances (complements)
the ability of antibodies and phagocytic cells to
clear microbes and damaged cells from an organism, promote
inflammation, and attack the pathogen's cell membrane.
Functions of Complement System
• Lysis
• Opsonization
• Triggers cell function
• Immune clearance
• Opsonization: C3b coats pathogens, making it easier for phagocytes (such
as macrophages and neutrophils) to recognize and engulf them.

• Inflammation: Complement activation results in the release of


inflammatory mediators, contributing to the recruitment and activation of
immune cells.

• Cell Lysis: The membrane attack complex (MAC) formed by the


complement system can puncture the cell membranes of certain
pathogens, leading to their destruction.

• Clearance of Immune Complexes: The complement system helps in the


removal of immune complexes formed during the immune response.

• Enhancement of Adaptive Immunity: Complement fragments can


enhance the adaptive immune response by promoting the activation of B
cells and the production of antibodies.
Components of complement system
Pathways of activation
• There are three known pathways for
complement activation:
• Classical,
• Alternative and
• Lectin pathway.
Classical Pathway
• The classical pathway of complement activation was proposed by
Jules Bordet and Octave Gengou in 1895.

• The classical pathway is initiated by IgM or IgG antigen/antibody


complexes binding to C1q (first protein of the cascade) leading to
activation of C1r, which in turn trigger C1s.

• This in turn activates the serine proteases that lead to cleaving of


C4 and C2, leading to formation of C4b2a (C3 convertase), which
in turn cleaves C3 into C3a and C3b.

• While C3a acts as a recruiter of inflammatory cells


(anaphylatoxin), C3b binds to the C4b2a complex to form C5
convertase (C4b2a3b).

• The C5 convertase initiates the formation of the Membrane


Attack Complex (MAC), that inserts into membrane creating
functional pores in bacterial membranes leading to its lysis.
Classical Pathway

C4b2a

The classical pathway can also be activated by other danger signals like C-reactive
protein, viral proteins, polyanions, apoptotic cells and amyloid, thus providing evidence
that classical pathway could be activated independent of antibodies
Alternative pathway
• The alternative pathway of complement activation was actually proposed
by Michael M. Frank and Baruj Benacerraf in 1955.

• They identified a distinct pathway of complement activation that could be


triggered independently of the classical pathway.

• This alternative pathway was later confirmed and further elucidated by


other researchers, including Michael Pillemer.

• Michael Pillemer and his colleagues made significant contributions to the


understanding of the alternative pathway in the 1960s and 1970s.

• They identified and characterized key components and reactions involved


in the alternative pathway, such as the properdin protein and the
alternative pathway C3 convertase.
Alternative pathway –
‘the amplification loop’
• Pillemer et al. ‘Properdin
• pathway’
This pathway involves various factors, B, D, H & I.

• Which interact with each other, and with C3b, to form a C3


convertase, C3bBb, that can activate more C3, hence the pathway
is sometimes called ‘the amplification loop’.

• Activation of the loop is promoted in the presence of bacterial


and fungal cell walls, but is inhibited by molecules on the surface
of normal mammalian cells.

• The alternative pathway is not so much an activation pathway, as


it is a failure to regulate the low level continuous formation of a
soluble C3 convertase.

• The internal thioester bond of C3 is highly reactive and undergoes


spontaneous hydrolysis resulting in a molecule known as C3
(H2O) which resembles C3b.
Alternative pathway - ‘the amplification loop’

Factors B and D
Mannose-binding Lectin Pathway
• MBL (mannose-binding lectin)/MASP (MBL-associated serine protease) pathway.

• The Mannose-binding lectin (MBL) pathway was actually proposed by Dr. Roy A.
Mariuzza and Dr. W. Henry Boom in 1990. Dr. Teizo Fujita, on the other hand, made
significant contributions to the study of complement activation pathways.

• This pathway was characterized by using proteins isolated from rabbit liver and
serum, but its function remained unclear initially.

• Two forms of MBL (MBL-A and -C) are present in rodents compared to a single form
in the humans.

• Studies linking the deficiency of MBL protein to immunodeficiencies in children led


to its recognition as an important activator of the complement system.

• The initiating molecules for this pathway are collectins (MBL and ficolin), which are
multimeric lectin complexes.
• The binding of collectins (MBL and ficolin) to specific
carbohydrate patterns uncommon in the host, leading to
activation of the pathway through enzymatic activity of MASP
(Mannose-binding lectin Associated Serine Protease).

• There are structural similarities shared between MBL and C1


complexes (MBL- with C1q associated serine proteases, MASP-1
and MASP-2 with C1r and C1s, respectively), leading to the belief
that complement activation by MBL and C1 complexes are similar.

• MASP-2 cleaves C4 and C2 to form C3 convertase, while MASP-1


may cleave C3 directly bypassing the C4b2a complex, albeit at a
very slow rate.

• Another serine protease, MASP-3 was shown to down-regulate


the C4 and C2 cleaving activity of MASP-2.
Mannose-binding Lectin Pathway
Conclusion
Deficiency in complement system
Complement Deficiency Disease

C3 and Factor B Severe bacterial infections

C3b, C6 and C8 Severe Neisseria infections

Deficiencies of early C components Systemic lupus erythematosus


C1, C4, C2. (SLE), glomerulonephritis and
polymyositis

C1-inhibitor Hereditary angioedema

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