5 : THE COMPLEMENT SYSTEM

Jules Bordet

He observed that the sheep antiserum to the bacterium Vibrio cholera caused lysis of the bacteria

was awarded the Nobel prize in 1919 for his role in elucidating the nature of complement

Paul Ehrlich

he coined the term complement system

Sheep antiserum + V.cholera

Lysis of bacteria

Sheep antiserum + V.cholera + heat

no lysis of bacteria

Soluble

they are present in the circulation

Cell-bound

they are bound to the surface of the cells in the immune systems

Complement activation

described as a cascade or sequence because numerous proteins of the complement system are sequentially activated

Activation

refers to the conversion of several latent proteins to an enzymatic form

Proteolysis

causing activation of complement proteins

Proteolytic cleavage

proteins are cleaved to become activated, resulting in complement fragments

Soluble proteins

are found in the serum

freely floating as zymogens

responsible for lysis of microbial cells

Cell-bound proteins

found in plasma

attached to the surface of normal cells

control or inhibit activity of zymogens to prevent lysis of own cells by the complement system

Acute phase proteins

are proteins that increases in number during inflammation

Hepatocyte

produces the vast majority of complement components

C1q

produced in the intestinal epithelial cells

Factor D

produced in the adipocytes

Properdin and C7

produced in monocytes and macrophages

Nonspecific

do not discriminate antigens

Specific

directed to a certain antigen

Classical pathway

affects acquired immune system

Alternative pathway

affects innate immune system

Mannose-binding lectin pathway

affects innate immune system

C4b

C4 is cleaved and produces C4a and C4b

C3a and C3b

C3 undergoes proteolysis. What are the fragments produced?

C3a

Which is considered the smaller fragment?

In a highly regulated manner

the complement proteins are activated in what manner?

C1→C4→C2→C3→C5→C6→C7→C8→C9

Order of sequence of activation

Lectin pathway

activated by binding MBL to mannose residues on glycoproteins or carbohydrates on the surface of microorganisms

Recognition phase

stage/phase 1

comprised of C1 complex

Activation unit

stage/phase 2

comprised of C4, C2, C3 unit

Complement fixation

the activation of the classical pathway is initiated when the first complement component, C1, binds to antibodies bound to a bacterial cell surface

C1

a molecular complex of 740,000 D

consists of three subunits: C1q, C1r, and C1s, which are stabilized by calcium

C1q subunit

part that binds to antibody molecules, the C1r and C1s subunits generate enzyme activity to begin the cascade

comprised of polypeptides namely a, b, and c

particular component of C1 that binds to the antibody that is bound to the surface of the antigen

C1q stalk

composed of six strands that form six globular heads with a collagen like tail portion

Staple configuration

pentameric IgM bound to an antigen

assumes when it is bound to an antigen

Planar configuration

circulating IgM

free floating

Catalytic / proteolytic domain

causes activation of the next complement protein to be activated

Interaction domain

interacts with other complement proteins

facilitates interaction with C1q with each other

C1r subunit

beta globulin

proteolytic zymogen in its native state

tends to self-associate to form a dimer

C1s subunit

alpha globulin

proteolytic zymogen

develops an esterase activity once bound to C1r

C4

second-most-abundant complement protein

1st amplification process in the complement system

a glycoprotein consists of three polypeptide chains joined by disulfide bonds

Anaphylatoxin

small molecule that binds to receptor present on mast cells and basophils which induces degranulation

C2

activated by C4b

single-chain glycoprotein

closely associated with the gene for factor B on chromosome 6 in the major histocompatibility complex

C3

major constituent of the complement system

the most abundant complement protein in the serum

C3 cleavage

considered as a major amplification process because its the most abundant thus produces hundredths and thousands of these fragments of C3

Potassium

the major cation inside the cell

Sodium

major cation outside the cell

C5b6789

Complete membrane attack complex

C1q

binds to FC region of IgM and IgG

C1r

actiavates C1s

C1

C4

part of C3 convertase

C2

binds to C4b

forms C3 convertase

C3

key intermediate in all pathways

C5

initiates membrane attack complex

C6

binds to C5b in MAC

C7

binds to C5bC6 in MAC

C8

starts pore formation on membrane

C9

polymerizes to cause cell lysis

Factor B

binds to C3b to form C3 convertase

Factor D

cleaves factor B

Properin

stabilizes C3bBb-C3 convertase

MBL

binds to mannose

MASP-2

cleaves C4 and C2

Alternative pathway

is a complement activation pathway in which it is activated only when there is exposure to cell surface constituents

part of innate or natural immunity

Properdin pathway

former term of Alternative pathway

Pillemer thought properdin was the one that initiated the cascade

C4b2a

the C3 convertase of the classical pathway

C3bBb

the C3 convertase of the alternative pathway

Properdin

stabilizes the alternative pathway C3 convertase

Forms a complex called C3bBbp

Lectin

complement proteins that bind to a carbohydrate

Mannose

a carbohydrate at the surface of microogranisms

Mannose-Binding Lectin

an acute phase protein which binds to mannose residues on glycoproteins or carbohydrates on the surface of microorganisms

structurally similar to C1q

C1 inhibitor

inhibits activation at the first stages of both the classical and lectin pathways

inactivates C1 by binding to the active sites of C1r and C1s

also inactivates MASP-2 by binding to the MBL-MASP complex

C4b-binding protein

inhibits further formation of C3 convertase in the classical and lectin pathway because it is capable of combining with either fluid-phase or bound C4b

Complement receptor type 1

also known as CD35

inhibits further formation of C3 convertase in the classical and lectin pathway

acts as a receptor on platelets and red blood cells

Membrane cofactor protein

CD46

inhibits further formation of C3 convertase in the classical and lectin pathway

Decay accelerating factor

CD55

capable of dissociating both classical and alternative pathway C3 convertases

S protein

also known as vitronectin

soluble control protein that acts at a deeper level of complement activation

Membrane Inhibitor of Reactive lysis

CD59

block formation of the membrane attack complex

binds to C8 and prevent insertion of C9 into host cell membranes

Homologous Restriction Factor

prevent formation of the MAC on the surface of autologous cells

Anaphylatoxin

small peptide that causes increased vascular permeability, contraction of smooth muscle, and release of histamine from basophils and mast cells

C3a, C4a, C5a

Chemotaxin

cells are directed to the source of antigen concentration

Opsonization

facilitates phagocytosis and clearance of foreign substances

one of the key functions of the complement system

CH50

measure overall C’ activity of classical pathway

AH50

measure overall C’ activity of alternative pathway

CH50 Hemolytic Assay

will identify those patients with a total or severe deficiency in any one of the complement proteins

Radial immunodiffusion

based on precipitation of immune complexes in agar gels

Serum proteins are added to wells cut into antibody-containing agar gels

can be used to measure any complement component that is normally present

Nephelometry

technique in which light scatter, occurring as a result of contact with a non-soluble, is measured