03 Complement System

Complement System

major INNATE defense system

• Protect against infections (MAIN)

• Regulate inflammatory processes

• Remove damaged or altered cells

• Send "danger" signals to the body

• Regulate adaptive immune responses.

• Clearance of immune complexes

• Angiogenesis

• Mobilization of stem cells

• Tissue regeneration

• Lipid metabolism.

activated;

C3b;

terminal complement complex;

Complement System

First, the complement system must be ___________.

Second, a key protein called ___________ must be generated.

Third, a ________________________ is assembled through an amplification pathway.

Once activated, the complement system generates multiple effector molecules

Alternative Pathway

Lectin Pathway

Classical Pathway

Complement System Pathway

MICROBIAL CARBOHYDRATES (PAMPS)

Lectin Pathway and Alternative Pathway are

Activated directly by

ANTIBODIES

Classical Pathway

Activated when ____________ bind to the surface of an organism and thus works only in association with adaptive immune responses

5% to 10%

Complement components account for about ____________ of the proteins in blood serum

C3, C6, C8, and B;

C2, C3, C4, C5, B, D, P, and I;

C6 and C7

Complement PROTEINS

• Liver:

• Macrophages:

• Neutrophil granules:

Alternative Pathway

triggered when microbial cell walls interact with complement components in the bloodstream

C3;

C3;

C3 thioester;

The most important complement protein is called _________

_______ possesses a highly reactive thioester side chain, that, when activated, binds to the surface of microbes and marks them for destruction by immune cells.

The activation of the _____________ must be carefully regulated to ensure that it does not bind to normal tissues.

To prevent such accidents, the thioester group in unactivated C3 is hidden inside the folded molecule.

C3a and C3b.;

C3b irreversibly

In healthy normal animals, C3 breaks down slowly but spontaneously into two fragments called ___________

This opens up the C3b molecule to expose the thioester group.

The thioester then generates a carbonyl group that binds the _____________ to carbohydrates and proteins on nearby cell surfaces.

factor H;

factor I; iC3b and C3c

iC3b;

C3dg

The breakdown of C3 also exposes binding sites for a protein called __________

When factor H binds to these sites, a protease called __________ degrades the C3b, blocking further activity and generating two fragments, __________

________ binds receptors found on circulating leukocytes.

Leukocytes are then stimulated to engulf pathogens and activate inflammatory cells.

___________ is the final breakdown product of C3

It targets pathogens to surface receptors on B cells and so promotes antibody production.

C3b;

SIALIC ACID;

SIALIC ACID

In a healthy individual: factors H and I destroy ______ as fast as it is generated.

When factor H interacts with normal cells, glycoproteins rich in ________________ and other neutral or anionic polysaccharides enhance its binding to C3b, factor I is activated, and the C3b is destroyed.

BACTERIAL CELL WALLS LACK ________________

bind;

inactivated;

persists

factor B.;

C3bB

When C3b is deposited on bacterial cell wall:

• factor H cannot ____

• factor I is ________

• bound C3b therefore _______

• The opening of C3b on an activating surface exposes a binding site for another complement protein called

• As a result, a complex called _________ is formed

factor D;

C3bBb

The bound factor B is then cleaved by a protease called ______________, releasing a soluble fragment called Ba and leaving C3bBb attached to the bacteria.

Factor D can only act on factor B after it has bound to C3b but not before (substrate modulation)

The bound _________ is a protease whose preferred substrate is C3. (It is therefore called the alternative C3 convertase)

: It can act on C3 to generate more C3b

factor P (or properdin);

C3bBbP

C3bBb is, however, very unstable, with a half-life of only 5 minutes.

If another protein, called ___________, binds to the complex, it forms

___________ with a half-life of 30 minutes.

Since C3b thus serves to generate more C3bBbP, the net effect of all this is that a positive loop is generated where increasing amounts of C3b are produced and irreversibly bound to the surface of the invading organism.

80% to 90%

Despite its name, the alternative complement pathway accounts for ___________ of all complement activated even if initially triggered by the classical or lectin pathway.

Lectin Pathway

involves the use of soluble pattern-recognition molecules that recognize microbial carbohydrates. These lectins bind to microbes and then activate proteases that activate complement

Mannose-binding lectin (MBL)

Can attach to bacteria, fungi, parasitic protozoa, and viruses

Binds to mannose or N-acetylglucosamine on microbial cell walls.

It does not bind to mammalian glycoproteins.

Once bound, MBL activates a serum protease called MASP-2 (MBL-associated serine protease)

MBL-associated serine protease

MASP-2

C4;

C4b2;

C4b2b

Activated MASP-2

Acts on the complement component _____, splitting it into C4a and C4b.

This exposes a thioester group on the C4b that generates a reactive carbonyl group that covalently attaches the C4b to the microbial surface.

Another complement component, C2, then binds to C4b to form a complex, _______. The bound C2 is then cleaved by MASP-2 to generate ________.

C3

Cell-bound C4b2

Protease that splits ______ to generate C3a and C3b and exposes the thioester group on the C3b.

C3b

The activation of _______ by C4b2b is a major step because each C4b2b complex can generate as many as 200 C3b molecules.

The microbe-bound C3b then binds C5 and cleaves it to C5a and C5b.

MBL-MASP-2 pathway

Classical Pathway

triggered by clusters of antibody molecules on the surface of a foreign organism. May occur as late as 7 to 10 days after infection.

Fc regions.

When antibody molecules bind an antigen they expose active sites on their ____________

C1

the first component of the classical complement pathway

Consists of three proteins (C1q, C1r, C1s) bound together by calcium.

C1q

looks like a six-stranded whip when viewed by electron microscopy

• Two molecules of C1r and two of C1s form a structure located between the C1q strands

• Activated when at least two of its strands bind to complement-activating sites on clustered antibody molecules.

• Binding to antibodies causes a conformational change in C1q that is transmitted to C1r.

• As a result, C1r exposes an active proteolytic site that acts on C1s to convert that molecule to an active enzyme.

Classical Pathway

Ig-M (Single)

Ig-G (Paired)

are needed to activate C1.

Escherichia coli and Klebsiella pneumoniae;

C-reactive protein (CRP)

C1 may also be activated directly by some viruses, or by bacteria such as _______________

It can also be activated by cell surface-bound pentraxins such as _____________

C1s;

C4b2;

C2a;

C4b2b.

C4b2b

Classical Pathway

Activated ________ cleaves C4 into C4a and C4b.

C2 then binds to C4b to form _________.

Activated C1s then splits the bound C2, generating a small peptide fragment _______ and active __________

Active _________ is a potent protease that cleaves C3 and is therefore called classical C3 convertase. C3b generated in this way binds and activates C5.

C1s cannot act on soluble C2; the C2 must first be bound to C4b before it can be cleaved (substrate modulation)

C3bBb;

C5a;

C5b67;

C5b67

Once C5 binds to C3b, substrate modulation occurs, and the C5 can be cleaved by ________.

The convertases cleave C5 (195 kDa) into a small fragment called ________, leaving a large fragment C5b attached to the C3b.

This cleavage also exposes a site on C5b that can bind two new proteins, C6 and C7, to form ________.

The ________ complex can then insert into the microbial cell membrane.

Amplification Pathway

All surface-bound C3 convertases, regardless of their origin, can induce the next step in complement activation, the amplification pathway

C5b67;

terminal complement complex (TCC)

Once inserted in the surface of an organism, the complex binds a molecule of C8.

C9 molecules then aggregate with the C5b678 complex to form a tubular structure called the _______________, also called the membrane attack complex (MAC).

C3a and C5a (anaphylatoxins)

degranulate mast cells and stimulate platelets to release the vasoactive molecules histamine and serotonin

powerful chemoattractants for neutrophils and macrophages.

they increase vascular permeability, causing lysosomal enzyme release from neutrophils and thromboxane release from macrophages

E. coli,

Pseudomonas aeruginosa,

Enterococcus faecalis, and

Streptococcus pyogenes

C3a is an efficient killer of __________