The complement system consists of 20 proteins that complement the effects of antibodies in the immune system. It plays an important role in innate immunity through lysing cells, generating mediators, and opsonization. The three complement pathways - classical, lectin, and alternative - are activated and converge on C3b, which opsonizes bacteria and generates the membrane attack complex. Complement is tightly regulated to prevent damage to host cells. Deficiencies or dysregulation of complement components can increase susceptibility to infection or cause diseases like hereditary angioedema or hemolytic uremic syndrome.

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.