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T4 Complement System

The document outlines the complement system, including its components, activation pathways, regulation, and biological consequences. It discusses the three activation pathways (classical, lectin, alternative), how they converge on C3 cleavage and generate C3/C5 convertases. Complement activation leads to opsonization, anaphylatoxin production, cell lysis, and enhances immune responses. The system is tightly regulated to prevent damage to host cells. Deficiencies increase risk of infection or autoimmune disease.

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กฤติน วนิจวรางกุล
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41 views

T4 Complement System

The document outlines the complement system, including its components, activation pathways, regulation, and biological consequences. It discusses the three activation pathways (classical, lectin, alternative), how they converge on C3 cleavage and generate C3/C5 convertases. Complement activation leads to opsonization, anaphylatoxin production, cell lysis, and enhances immune responses. The system is tightly regulated to prevent damage to host cells. Deficiencies increase risk of infection or autoimmune disease.

Uploaded by

กฤติน วนิจวรางกุล
Copyright
© © All Rights Reserved
Available Formats
Download as PDF, TXT or read online on Scribd
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Lecture outline

 The Functions of Complement


 The Complement Components
 Complement Activation
 Regulation of the Complement System
 Biological Consequences of Complement
Activation
 Complement Deficiencies
Introduction
Complement – A series of serum and
membrane expressed proteins involved in
the effector role of the immune response
to pathogens
Made up of approximately 30 circulating
and membrane-bound proteins.
Synthesized in the liver and by cells
involved in the inflammatory response.
Key role in defense against many
foreign invaders.
Most important functions are:
 Production of opsonin
 Production of anaphylatoxins
 Direct killing of organisms
 Enhancing antigen-specific immune
response
 Maintaining homeostasis
Complement Activation
Pathways
Involves a “cascade” of successive
components.
Enhances a small initiating signal.
Components are cleaved into activated
fragments.
Fragments induce intense inflammatory
responses to eliminate infectious agents.
Pathways of the complement activation
• Distinct recognition events for each pathway
– Classical - C-reactive protein
– Lectin – Mannose-binding lectin (MBL)
– Alternative – serum factors B, D, and P
COMPLEMENT PATHWAY
The molecules involved in complement system
The Classical Pathway
Antigen-Antibody complexes are main
activators of this pathway.
Activated by the formation of soluble Ag-
Ab complexes or binding of Ab (IgM or
IgG) to Ag on a target cell.
C-reactive protein binds to the surface of
many bacteria and are also activators.
Component Protein Complex C1
ACTIVATION OF
CLASSICAL
COMPLEMENT
PATHWAY
 Pentameric IgM molecules bind to antigens on bacterial surface
and adopt ‘stable’ form.
 IgG molecules binds to Antigens on bacterial surface also.
Activation Effectiveness
IgM is more effective at activating complement than
IgG
C1q binds to the CH2 domain of Ig and requires at
least two adjacent Fc regions
Activation of the Thiol-Ester bond and covalent
attachment to antigen

C1q binds to one IgM molecule C1q binds to at least two IgG molecules
The Lectin Pathway
• Antibody-independent pathway
• Activated by mannose-binding lectin to mannose
residues on foreign surface
• Binding activates MASP-1 and MASP-2 that cleave
and activate C4 and C2
• Cleaved C4 and C2 generate C3 convertase
• Converges with the classical pathway at activation
of C3
Mannose-binding Lectin
Pathway
The Alternative Pathway

• Does not require Ag-Ab complex


formation
• Initiated by foreign cell surface proteins
• Produces active C3 and C5 convertase
• Active C3 is generated spontaneously
• Host cells regulate the progression
Alternative Pathway
“C3” the central molecule of
Complement cascades
Activation of C3
• Cleavage of C3 is a critical step in all
three pathways.
• C3 convertases split C3 into two
fragments:
C3a---smaller, fluid-phase
anaphylatoxin
C3b---larger, continues the
sequential activation of
successive components
Activities of activated C3

• C3a promotes inflammation


• C3b fixation to surfaces leads to
opsonization
• C3b fixation leads to immune complex
clearance
• Generation of the C5 Convertase activity
Activation of C5

• Cleavage of C5 produces two fragments:


C5a---released into the fluid phase,
potent anaphylatoxin
C5b---binds to the cell surface,
nucleus for binding the terminal
complement components
C3 and C5 convertases of each pathway
The Terminal Sequence
• Terminal components of the complement
cascade:
C5b, C6, C7, C8, and C9
• Components are common to all pathways

• Bind to each other and form a MAC

• Results in cell lysis


Formation of the membrane attack
complex (MAC)
Summary of complement activation pathway

https://cjasn.asnjournals.org/content/early/2015/01/08/CJN.06230614/tab-figures-data?versioned=true
Regulation of Complement Activity

• Regulators may:
–dissociate the convertase
–cleave the complement component
that is left on the cell surface
–Act as a cofactor for this cleavage
Why doesn’t complement attack our
own tissues?
Inhibiting the classical pathway
C4BP exclusively regulates the
classical pathway
Factor H exclusively regulates the
alternative pathway
Biological Activities of Complement

Production of Opsonins
Production of Anaphylatoxins
Lysis of Cells
Enhancing B Cell Response to Antigens
Controlling the Formation and Clearance
of Immune Complexes
Removing Dead and Dying Cells
Responses to Viruses
Biological Activities
of Complement

Killed

Alive Killed
The roles of C3b
and antibody in opsonization
Enhancing B Cell Responses to Antigens
 B lymphocytes express a receptor for a
protein of the complement system that
provides signals for the activation of these
cells
 Activation of complement by microbes
leads to the binding of a complement
breakdown product, C3d, to the microbes.
The B cell simultaneously recognizes a
microbial antigen (by the immunoglobulin
receptor) and bound C3d (by the CR2
receptor). CR2 is attached to a complex of
proteins (CD19, CD81) that are involved in
delivering activating signals to the B cell.
Removal of Immune Complexes
Removal of Necrotic cells and
Subcellular Membranes
Responses to Viruses

Alternative
pathway

Classical
pathway
Complement Deficiencies

SLE – C1, C4, or C2 deficiencies

Membranoproliferative
Glomerulonephritis – C3 deficiency, rare

Properdin and factor B and D defects


Complement deficiency and disease
C3 deficiency – severe, recurrent life-
threatening infections with encapsulated
microbes
C1 inhibitor deficiency – hereditary
angioneurotic edema
C1, C2, C4 deficiency – autoimmune
disease
DAF deficiency – paroxysmal nocturnal
hemogloblinuria (PHN); RBC hemolysis
Complement Deficiencies
Detection of complementary deficiency
by ELISA
• Complement concentration in plasma reflects
activity of the immune system
– Activated complement components are
unstable and extensive formation of
immune complexes may deplete
complement faster than it can be replaced
by the liver.
• Complement Fixation Assay
– Detects immune complexes
References
1. Janeway, CA Jr; Travers P; Walport M; et al. (2001). "The
complement system and innate immunity". Immunobiology:
The Immune System in Health and Disease. New York:
Garland Science. Retrieved 25 February 2013.
2. Abbas AK, Lichtman AH, Pillai S (2010). Cellular and
Molecular Immunology (6th ed.). Elsevier. pp. 272–
288. ISBN 978-1-4160-3123-9.

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