COMPLEMENT SYSTEM: THE CLASSICAL PATHWAY Flashcards by RHEMA ENCARNACION

Complements were discovered in the 1890s by who?

Jules Bordet

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a heat-labile component of normal plasma that augmented the
opsonization and killing of bacteria by antibodies

COMPLEMENTS

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composed of more than 30 different plasma proteins

COMPLEMENTS

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produced mainly by the liver

COMPLEMENTS

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Inactive in the absence of infection

COMPLEMENTS

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heat-labile serum component

COMPLEMENT

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Can lyses bacteria (activity is destroyed (inactivated) by heating serum at 56
degrees C for 30 minutes)

COMPLEMENT

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Can opsonize bacteria for enhanced phagocytosis; it can recruit and
activate various cells including polymorphonuclear cells (PMNs) and
macrophages

COMPLEMENT

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Can participate in regulation of antibody responses and it can aid in the
clearance of immune complexes and apoptotic cells

COMPLEMENT

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Can participate in regulation of antibody responses and it can aid in the
clearance of immune complexes and apoptotic cells

COMPLEMENT

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Can participate in regulation of antibody responses and it can aid in the
clearance of immune complexes and apoptotic cells

COMPLEMENT

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have detrimental effects for the host; it contributes to inflammation and
tissue damage and it can trigger anaphylaxis

COMPLEMENT

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comprises over 20 different serum proteins

COMPLEMENT

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produced by a variety of cells including, hepatocytes, macrophages and
gut epithelial cells

COMPLEMENT

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Some complement proteins bind to immunoglobulins or to membrane
components of cells.

COMPLEMENT

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Others are PROENZYMES that, when activated, cleave one or more other
complement proteins

COMPLEMENT

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Upon cleavage some of the complement proteins yield fragments that
ACTIVATE cells, INCREASE VASCULAR PERMEABILITY or OPSONIZE BACTERIA

COMPLEMENT

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named in the order of their discovery

PROTEINS OF THE CLASSICAL
PATHWAY

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Whaat is the Reaction sequence in the classical pathway:

C1, C4, C2, C3, C5, C6, C7,
C8, and C9

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▪Products of cleavage reactions are designated by adding a

lowercase
letter as a suffix

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: designated by the suffix b

larger fragment

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enzymatically active fragment

larger fragment

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How is the larger fragment of C2 written

C2a

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are not cleavage products of C1 but are distinct
proteins that together comprise C1

C1q, C1r, and C1s

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Binding to anitgen antibody complexes and pathogen surfaces

C1q

Binding to carbohydrates structures such as mannose or GicNAc on microbial surfaces

- MBL - Ficolins - C1q - Properdin (factor P)

Activating enzymes

- C1r - C1s - C2a - Bb - D - MASP-2

Membrane-binding proteins and opsonins

C4b C3b

Peptide mediators of inflammation

- C5a - C4a - C3a

Membrane attack proteins

- C5b - C6 - C7 - C8 - C9

Complement receptors

- CR1 - CR2 - CR3 - CR4 - CRIg

Complement regulatory proteins

- C1 INH - C4BP - CR1 - MCP - DAF - H - I - P - CD59

What are the 4 pathways of complement activation?

- the classical pathway - the lectin pathway - the alternative pathway - the membrane attack (or lytic) pathway

These pathways lead to the ACTIVATION OF C5 CONVERTASE

classical and alternative

These pathways result in the production of C5b

classical and alternative pathways

This is essential for the activation of the membrane attack pathway

production of C5b

THE CLASSICAL PATHWAY IS INITIATED BY ACTIVATION OF WHAT?

C1 COMPLEX

This pathway is IS HOMOLOGOUS TO THE LECTIN PATHWAY

CLASSICAL PATHWAY

Classical pathway uses a pathogen sensor known as the

C1 complex, or C1

C1 interacts with 2 things

1. directly with some pathogens 2. Interact with antibodies

acts as the pathogen sensor; recognition function

C1q

serine proteases

C1r and C1s

initially in their inactive form

C1r and C1s

closely related to MASP-2

C1r and C1s:

interact non- covalently, forming C1r:C1s pairs

C1r and C1s

two or more of C1 interact with a what

ligand,

this causes a conformational change in the C1r:C1s complex

two or more of C1 interact with a ligand

a multi-subunit protein containing three different proteins (C1q, C1r and C1s

C1:

bind to the Fc region of IgG and IgM antibody molecules that have interacted with antigen

does not occur to antibodies that have not complexed with antigen

C1:

C1 binding requires

calcium and magnesium ions

binding of C1 to antibody is via what

via C1q

This must cross link at least two antibody molecules before it is firmly fixed.

C1q

The result of the activation of C1r which in turn activates

C1s

is an enzyme that cleaves C4 into two fragments C4a and C4b

activated “C1qrs”

CAN ATTACH ITSELF TO THE SURFACE OF PATHOGENS IN SEVERAL DIFFERENT WAYS.

C1Q

C1Q CAN ATTACH ITSELF TO THE SURFACE OF PATHOGENS BY

- by binding directly to surface components on some bacteria - through binding to C-reactive protein - binding to the constant regions of anti bodies that have bound pathogens via their antigen-binding sites

C1q binds directly to surface components on some bacteria like

certain proteins of bacterial cell walls, polyanionic structures eg. lipoteichoic acid on Gram (+)

an acute-phase protein in human plasma that binds to phosphocholine residues in bacterial surface molecules such as pneumococcal C polysaccharide—hence the name Creactive protein

C-reactive protein

What are the constant regions of anti bodies

Fc regions

is composed of six identical subunits with globular heads and long collagen-like tails, and it has been described as looking like “a bunch of tulips

C1q

is composed of six identical subunits with globular heads and long collagen-like tails, and it has been described as looking like “a bunch of tulips

C1q

” The tails combine to bind to two molecules each of C1r and C1s, forming the C1 complex C1q:C1r2:C1s2.

C1q

The heads of C1q can bind to the ...

1. constant regions of immunoglobulin molecules 2. directly to the pathogen surface

The C1 complex is similar in overall structure to the

MBL– MASP complex

The C1 complex is similar in overall structure to the MBL– MASP complex, and has an identical function, cleaving C4 and C2 to form the

C3 convertase C4b2a .

also cleaves C2 into C2a and C2b

Activated “C1qrs”

binds to the membrane in association with C4b

C2a

is released into the microenvironment

C2b

is released into the microenvironment

C2b

The resulting C4bC2a complex is what convertase

a C3 CONVERTASE

cleaves C3 into C3a and C3b

C3 CONVERTASE

C4b fragment binds to the

membrane

C4a fragment is released into the

microenvironment

C3 activation is the generation of

C5 convertase

binds to the membrane in association with C4b and C2a

C3b

C3a is released into the microenvironment | true or false

true

The resulting C4bC2aC3b is what convertase

C5 CONVERTASE

It is the end of the classical pathway

generation of C5 convertase