THE COMPLEMENT SYSTEM

 

THE COMPLEMENT SYSTEM

Class III region

¢  Between class I and II regions is class III –contain genes coding for complement components

¢  Complement is a protein cascade composed of more than 40 proteins including factors

¢  Components are made from the liver, though some local production at sites of inflammation maybe undertaken by macrophages

Complement has 3 pathways

¢  Alternative pathway

¢  Classical pathway

¢  Lectin pathway

¢  Membrane attack pathway/common pathway

¢  The majority of complement proteins are soluble,  some are membrane bound

¢  The soluble proteins circulate in an inactive state, and each must be activated sequentially for the reaction to proceed

¢  Each activated molecules can catalyze the conversion  of several molecules of the next component in the sequence, this leads to amplification

Complement activation

¢  In complement activation, classical and alternative pathways converge for the terminal complement sequence which provides most of the biological activity

¢  The final common pathway may be activated via classical or alternative routes,

¢  which are initiated by antibody –antigen complex or bacterium respectively.

 

CLASSICAL PATHWAY

¢  Its activated by an interaction  between  antigen and antibody to form an immune complex

¢  The formation of the antibody-antigen complex provokes a conformational change in the antibody molecule that discloses a site for binding of the C1

¢  C1 is a multimeric compound composed of 6 molecules of C1q, two each of C1s and C1r

¢  C1q is composed of a triple helical structure and a globular head resembling a tulip.

¢  When antibody binds to 2 or more heads of c1q, c1r is cleaved to give an active molecule cir, which cleaves c1s.

¢  C1s extends the activation process by cleaving  the next complement component C4 to  give C4b, which continues the reaction process, and C4a

¢  Cleavage of C to C4b reveals an internal thioester bond, which can be inactivated by binding water molecules unless it can form covalent bonds with cell surface proteins or carbohydrates

¢  if covalent bonds form, c4b becomes relatively stable and binds to C2

¢  C2 is also cleaved by c1s to form the complex C4b2a, (classical pathway C3 convertase)

¢  Cleavage  of c3, results in 2 fragments. C3a and C3b (displays binding site that allows the molecule to bind to membrane close to.

¢  The proximity of c3b and c4b2a leads to generation of the last enzyme of classical pathway C4b2a3b the (c5 convertase)



LECTIN PATHWAY

¢  The lectin pathway is homologous to the classical pathway,

¢  This pathway is activated by  mannose-binding lectin (MBL) - to mannose residues on the pathogen surface,

¢  MBL  activates  the serine proteases to form the MBL-associated serine proteases, MASP-1, and MASP-2 (very similar to C1r and C1s, respectively),

¢  which can then split C4 into C4a and C4b and C2 into C2a and C2b. C4b and C2a then bind together to form the C3-convertase, as in the classical pathway

 

ALTERNATIVE PATHWAY

¢  c3 generates c3b, c3Bb and C3bBb which cleaves c3. the activation is accelerated if the active enzymes are stabilized on bacterial walls or if more c3b is produced from classical pathway

¢  the alternative pathway c5 convertase C3bBb3b is generated

 

¢  the complex C3bBb3b analogues to c4b2b3b in  c5 convertase which initiates the membrane attack sequence.

MEMBRANE ATTACK COMPLEX

¢  Cleavage of C5 by c5 convertase gives c5a  and c5b  which binds to C6 and induces it to express a reactive site for C7

¢  The C5b67  binds to membrane.

¢  C567 has high-affinity receptor for c8.

¢  C8 has 3 domains (α, β and γ) of inserts γ into the membrane, anchoring the c5b678 complex

¢  C5b678 binds and polymerize c9- forming the MAC.

¢  As many12-15 C9 molecules may cluster around one c5b678 complex, inserting into and transversing the membrane bilayer

¢  Holes are made in the membrane and a sufficient number are created death results trough osmotic lysis.



REGULATION OF COMPLEMENT SYSTEM

 

¢  C1-inhibitor blocks the enzymatic function of Activated c1 by combining with it a virtually irreversible stoichiometric complex

¢  Factor I –  an enzyme that degrades c3b,

¢  factor I restrains activation of c4b(classical pathway) by destroying it.

¢  factor H – binds c3b and accelerates  destruction of factor I

¢  protein s and SP-40,40 (circulating proteins)Both are able to bind C5b67 complex to form inactive moiety, preventing membrane insertion and formation of Mac.

¢  Carboxypeptidase N (circulating enzyme), it cleaves the carboxy- terminal arginine from c3a, c4a. c5a and resulting molecules are inactivated

¢  Membrane attack complex inhibitory factor (MACIF), interferes with the MAC    insertion, thus preventing cell lysis.

¢  Decay accelerating factor (DAF)- compete for C4b,thus inhibiting formation of the classical pathway c3 convertase

¢   complement receptors  (CR)

—  found on the cells of the immune system

—  Have restricted distribution

—  CR-1 to CR-4, bind breakdown products of c3

—  CR-1 is involved in regulation of classical pathway by binding to c4b

—  CR-1 enhances the action of factor I

 

BIOLOGICAL ACTIVITIES GENERATED BY COMPLEMENT ACTIVATION

a)   Opsonisation – proteins with opsonic activity coat bacteria or other pathogens and facilitate their removal.

C3b accounts for most of the complement opsonic activity,

once organisms are coated with c3b, then CRs 1, 3 and 4 on neutrophils can result in more efficient engulfment

b)   Cell recruitment and activation – c4a, c3a and c5a are anaphylatoxins- mast cells and basophils are activated through specific receptors c5a and c3a are chemotactic, ability to attract cells e.g. neutrophils

c)    Cell lysis – complete complement activation on cell surface lead to cell lysis  of bacteria

d)   Removal of immune complexes –ab-ag complexes increase during infection or inflammation episodes. These are harmful because they can be deposited in vessels wall and incite/induce complement activation

 Covalent binding of c3b to antibody in a complex inhibit lattice formation and maintains solubility. In addition c3b-coated complexes attach to cells CR-1, a phenomenon, immune adherence

Erythrocytes (main cells involved) express over 85% of circulating CR-1, they act as a buffer, constantly restoring the no. of complexes to an acceptably low level

once bound (Ag-Ab-C3b) immune complexes are transported on cells to the liver and spleen by erythrocytes, where they are released and taken up by resident macrophages

 

C-reactive protein (CRP) –its produced in the liver and binds phosphorycholine moieties (bacterial cell wall). when bound to cell wall, CRP activate complement through classical pathway , independent of antibody

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