complement system from Robbin

1. BY DR.NASEER

2.  Complement system consist of 20 proteins in
normal human serum. Complements refers to
ability of these proteins to complements the effects
of other components of immune system(antibody).
 It is an important component of innate host
defense.
 Main effects of complements are :
 1) Lysis of cells(bacteria and other cells)
 2) Generation of mediators
 3) Opsonisation

3.  Complements are proenzyme must be cleaved to form
active enzyme.
 Complements are activated through three pathways:
 1) Classic pathway
 2) Lectin pathway
 3) Alternative pathway
 In lectin and alternative pathways are more important, as
the antibody required to trigger the classic pathway is not
present.

4.  Lectin pathway and alternative pathways are participants,
initiate arm of immune system.
 All three pathways lead to production of C3b which is the
central molecule of complement system.
 C3b has two important functions:
 1) It combines with other complement components to
generate C5 convertase that leads to cleave complement
5 into 5a and 5b. 5b combines with rest of component to
form 5b to 9 called membrane attack complex(MAC).
 2) It opsonizes bacteria and make it attractive for
phagocytization by macrophages and neutrophils.

6.  First formation of antigen-antibody complexes which
activate C1 to form proteases to cleave C2 and C4 to
form C4b,2b (which is C3 convertase) which cleave C3
molecule into 3a and 3b.
 3a is anaphylatoxin.
 3b forms a complex with C4b, 2b producing C5
convertase ( C4b,2b,3b) which cleaves C5 to form C5a
and C5b.

7.  C5a is anaphylatoxin and chemotactic factor.
 C5b binds to C6 and C7 to form complex that interact
with C8 and C9 to produce (C5b,6,7,8,9) membrane
attack complex, which causes cytolysis.
 Note:- “b” fragment continues in the main pathway
whereas “a” fragment is split off and has other activities.

8.  Mann binding lectin (MBL), aslo known as Manmose
binding protein binds to surfaces of microbes bearing
Mann
( polymer of sugar mannose).
 This activate proteases that cleave C2 and C4
components of complements and classic pathway.
 Note:- This process by pass the antibody requiring step,
so this is protective early in infection before antibody is
formed.

9.  Many unrelated cell surface substances e.g bacterial
polysaccharide, endotoxin, fungal cell wall and viral
envelops can initiate the process by binding C3H2O and
factor B.
 The complex is cleaved by protease factor “D” produces
C3bBb , this acts as C3 convertase to generate more 3b.

11.  First regulatory step in classic pathway is at the level of
antibody, when antigen binds to antibody a
confirmational shift occur and the C1 component can
bind and initiate the cascade.
 Several proteins regulate the complement system.
 1) C1 inhibitor is an important regulator of classic
pathway, it inactivate the protease activity of C1
(activation of classic pathway by generation of sufficient
C1 to overwhelm the inhibitor).

12.  2) Regulation of alternative pathway is mediated by
binding of Factor H to 3b and cleavage of this, by
Factor 1a proteases, this reduces amount of C5
convertase available .
 The alternative pathway can proceed past this
regulatory point if sufficient 3b attaches to cell
membrane.
 Attachment of 3b to cell membrane protect it from
degradation by Factor H and I .
 Another component that enhance the activation of
alternative pathway is propodine which protects 3b
and stabilize the C3 convertase.

13.  3) Protection of human cells from lysis by membrane
attack complex of complement is mediated by “Decay
Accelerating Factor” (DAF, CD55) a glycoprotein located
on the surface of human cells.
 DAF acts by binding to C3b and C4b and limiting the
formation of C3 convertase and C5 convertase. This
prevents the formation of membrane attack complex.

14.  OPSONISATION: Bacteria and viruses are phagocytized
much better in the presence of 3b. There are 3b receptors
on the surface of phagocytes(Macrophages and
neutrophil polys).
 CHEMOTAXIS: C5a and C567 complex attract
neutrophils, they migrate specially towards C5a. C5a also
enhances the adhesiveness of neutrophils to
endothelium.
 In addition C5a activate the lipoxygenase pathway of
Arachadonic acid metabolism in neutrophils and
monocytes causing for the release of inflammatory
mediators.

15. ANAPHYLATOXIN:
 C3a, C4a, C5a – cause degranulation of mast cells
and release of histamine leading to increased
vascular permeability and smooth muscles
contraction of bronchioles leading to bronchospasm.
 Anaphylatoxin can also bind directly to smooth
muscle cells of bronchioles and cause
bronchospasm.
 C5a is the most potent of these anaphylatoxin.
 Anaphylaxis caused by these complement component
is less common than Anaphylaxis caused by Type 1 (
Ig E mediated hypersensitivity)

16.  CYTOLYSIS:
 Insertion of C5b,6,7,8,9 complex into cell membrane
leads to killing or lysis of many types of cells including
erythrocytes - bacteria and tumour cells.
 Cytolysis occurs not through enzymes it occurs by
insertion of MAC, which results in disruption of
membrane and the entry of water and electrolytes into
cell.
ENHANCEMENT OF ANTIBODY PRODUCTION:
 The binding of C3b to its receptor on the surface of
activated B cell greatly enhances antibody production
than the B cells activated by antigen alone.

17.  Clinical Importance:
 The patient who are deficient in 3b produce significantly
less antibody.
 So low concentration of antibody and amount of 3b
significantly impairs host defence resulting in multiple
severe pyogenic infection.
 Clinical aspects of Complement:
 1. Inherited deficiency of some complement components
especially C5-8 greatly enhance the deficiency of MBL
(Mannon binding lectin) – Predispose to severe NEISSERIA
INFECTION.

18.  Deficiency of C3 leads to severe recurrent pyogenic sinus
and respiratory tract infection.
 2) Inherited deficiency of C1 inhibitors results in hereditary
angioedema.
 When C1 inhibitor is reduced there is over production of C1
esterase leads to increase in anaphylatoxin which causes
increase capillary permeability and oedema.
4) Transfusion mismatches:
 When Type A blood is given by mistake to a person of type
B blood:
 1) Antibody to “A” antigen in recipient binds to the “A”
antigen on donor red cells.

19.  2) Complement is activated.
 3) and large amount of anaphylatoxin and MAC are
generated.
 4) Anaphylatoxin cause shock and MAC cause red cell
hemolysis.
 Decay accelerating factor (DAF) and CD59 are linked to
plasma membrane by glycophospholidyl inositol (GPI)
anchor.
 DAF prevent formation of C3 convertase and CD59
inhibits formation of MAC.

20.  An acquired deficiency of the enzyme DAF x CD59
leads to excessive compliment activation and lysis
of red cells in the disease called paroxysmal
nocturnal haemoglobinurea(PNH).
Immune complexes binds complements:
 Complements levels are low in immune complex
diseases (e.g acute glomerulonephritis, systemic
lupus erythematosis).
 Binding complement attracts polymorphnuclear
leucocytes which release enzymes that damage
tissue.

21.  Complement Factor H is circulating glycoprotein that
inhibits the alternative pathway of complement activation
by promoting the cleavage and destruction of 3b and
turnover of the C3 convertase.
 Inherited defect in Factor ”H” and other regulatory
proteins that interact with Factor H cause “Hemolytic
uremic syndrome” , in which complements deposits in
glomerular vessels leading to endothelial damage and
formation of platelet rich thrombi.
 Polymorphism in Factor H gene also been linked to age
related molecular degeneration.