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5-Complement System

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5 views23 pages

5-Complement System

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finalgame91
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Lecture 5: The Complement System

Click toPresenter:
edit Master subtitle style
Dr. Abdulaziz Almutairi

IMMC
Objectives

▪ Describe the nature of the complement components


▪ Describe the classical and the alternate pathways
▪ Describe the biological consequences of complement activation
▪ List the antibodies that are effective in activating Complement
Introduction
▪ Complement:
▪ A group of serum and cell membrane proteins that interact with one
another and with other molecules of innate and adaptive immunity to carry
out key effector functions leading to pathogen recognition and elimination.
▪ Circulate as an inactive precursors
▪ Synthesize:
▪ Primarily in the liver, also monocytes, macrophages, and epithelial cells.
▪ Function:
▪ Clearing pathogens, dying cells, and form immune complexes.
▪ They can kills pathogen directly or indirectly (induce phagocytosis).
Immune Components:
Complement Components
White Blood Cells:

Soluble and membrane-bound (B cells)


Complement System
▪ Most of complements are soluble but some of them are membrane bound and widely
distributed in body fluids and tissues.

▪ Activation:
▪ The site of complement activation is usually the surface of pathogens.
▪ Complement activation result in an enzymatic cascade that is highly regulated.
▪ Once a complement is activated, it cleaves its substrate to its active enzymatic form,
this in turn will cleave and activate the next complement in the pathway and so on.

▪ Pathways:
▪ Classical Pathway
▪ Mannan-binding (lectin) Pathway
▪ Alternative Pathway
Complement Pathways

▪ Pathways:
▪ Classical:
▪ Triggered by antibody-antigen complexes.
▪ Mannan-binding lectin pathway:
▪ Triggered by spontaneous hydrolysis of C3.
▪ Alternative:
▪ Triggered by mannose-binding lectin (MBL) recognition of microbial carbohydrates.
Complement Pathways
pathogen

Classical Pathway surface

▪ Is usually activated by antigen: antibody complexes.


▪ Binding and Initiation: Triggered by the binding of the C1 complex
(C1q + C1s + C1r) to the pathogen surface or antigen-antibody
complex.
▪ C1q binds directly to the pathogen or to the Fc region of antibodies, causing
conformational changes.

▪ Cleavage and Activation: The binding activates C1r, which then


cleaves C1s to its active form.
▪ Active C1s cleaves C4 and C2, forming C4b and C2a.

▪ C3 Convertase Formation and Function: C4b and C2a together


form C3 convertase (C4b2a).
▪ Cleavage of C3, producing C3b that opsonizes pathogens and C3a that
induces inflammation.
inactive

active

C1

active

C1s C4b and C2a combine


C4 C4a + C4b
inactive active active to form C4b2a
C1s
C2
inactive
C2a
active
+ C2b
active

C4b2a
C3
inactive
C3a
active
+ C3b
active

C4b2a is a C3 convertase
pathogen
surface

Mannan-binding Lectin Pathway

▪ Binding and Initiation: Triggered by mannose-binding lectin


(MBL) binding to mannose residues on pathogen surfaces.
▪ Complex Formation: MBL associates with zymogens MASP-1
and MASP-2.
▪ Cleavage and Activation: MBL-pathogen binding activates
MASP-2, which cleaves C4 and C2.
▪ C3 Convertase Formation: Cleavage produces C2a and C4b,
which together form the C3 convertase.
▪ C3 Convertase Function: Cleaves C3 into C3b, which coats
pathogens, and C3a, which induces inflammation.
Alternative Pathway

▪ Initiation: Begins with the spontaneous hydrolysis of


C3 into C3(H2O).
▪ Factor B Binding: C3(H2O) binds to factor B, making
it susceptible to cleavage.
▪ Activation of Factor D: Factor D cleaves factor B into
Ba and Bb fragments.
▪ Formation of C3 Convertase: Bb binds to C3(H2O) to
form the C3(H2O)Bb complex, a C3 convertase.
▪ Cleavage of C3: C3 convertase cleaves additional C3
molecules, producing C3b for pathogen coating and
C3a to induce inflammation.
▪ Formation of C3bBb: C3b binds factor B, which is cleaved by
factor D into Bb and Ba, forming another C3 convertase,
C3bBb, which continues to act on C3. C3 convertase
C4b2a and C3bBb
are C3 convertases
but if you add another
C3b then:
C4b2a3b and C3b2Bb are
C5 convertases

C5 convertase
C5 C5a + C5b
Membrane Attack Complex
(MAC)
▪ C5 Convertases: Enzyme complexes that cleave C5, leading to the formation of the
membrane attack complex (MAC).
▪ Components: C5b, C6, C7, C8, and C9.
▪ Function: Forms a pore in the cell membrane of pathogens, leading to cell lysis.
▪ Regulation: Controlled activation to prevent damage to host cells.

Kuby Immunology (8th ed)


Membrane Attack Complex
(MAC)

Kuby Immunology (8th ed)


The Main Functions of Complement System

▪ 1. Opsonization by coating the pathogens and enhancing


phagocytosis.

▪ 2. Direct killing of certain bacteria by the membrane attack


complex (MAC) which creates pores in the bacteria cell
membrane.

▪ 3. Inducing inflammation by recruiting phagocyte to the site of


infection.
Opsonization

C3b
CR1

Opsonisation: Coat bacteria to facilitate their removal


C3b accounts for most of the complement opsonic activity
Direct Killing: Formation of MAC
Complement Mediated Inflammation

▪ The small fragments (C3a, C4a, C5a)


induce inflammation.
▪ They are also called anaphylatoxins.
▪ Anaphylactic shock can be caused
by systemic distribution of
anaphylatoxins and mast cell
degranulation.
IgM and IgG Antibodies Activate Complements

▪ Both IgM & IgG can activates


complement cascade.
Antibodies and Their Functional Activities

ADCC

* Opsonin in 50% of Caucasians (appropriate Fc receptor)


Clinical Relevance
▪ Autoimmune Diseases:
▪ Role: Dysregulation of the complement system contributes to autoimmune disorders such as Systemic
Lupus Erythematosus (SLE).
▪ Infectious Diseases:
▪ Protection: The complement system plays a critical role in defending against bacterial infections by
enhancing phagocytosis and directly lysing pathogens.
▪ Therapeutic Interventions:
▪ Targeting Complement Activity: Development of drugs that inhibit or modulate the activity of specific
complement components to treat conditions like age-related macular degeneration, hereditary angioedema,
and paroxysmal nocturnal hemoglobinuria.
▪ Complement and Transplantation:
▪ Graft Rejection: Complement activation is a key factor in transplant rejection. Understanding
complement pathways helps in designing strategies to prevent organ rejection.
Thank you

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