The document discusses the complement system, a complex group of proteins involved in the immune response, classified into several components (C1-C9) that act through three main pathways: classical, alternative, and lectin. It details the activation mechanisms, roles in host defense, and the importance of regulation to prevent damage to healthy cells. Additionally, it addresses how pathogens evade the complement system and clinical implications of complement deficiencies.

1. MIM 2525
COMPONENT COMPLEMENT SYSTEM

2. The complement system
Nomenclature of Complement Components
 Complement components are designated as C1 to
C9
 Products of reactions are designated asAg –Ab –
C e.g.Ag-Ab-C1423
 Components , which acquire enzymatic or
biological activity, are indicated by a bar over the
component e.g. C1 is the enzymatically-activated
form of C1

3. The complement system
 Fragments of complement cleaved during the
reaction are indicated by lower case letter, e.g.
C3a, C3b
 Inactivated forms of complement components are
indicated by a suffix‘i’ e.g. C3i

4. The complement system
 Complex group of proteins present in normal
humans and animals consisting approximately of 5
to 10 % of human serum proteins.
 it’s an integral part of the body’s immune system
that has the ability to
- lyse red blood cells (haemolytic activity)
- destroy Gram negative bacteria ( bacteriolytic
activity )

5. - kill Gram positive bacteria without lysis
(bactericidal activity)
- inactivate viruses ( virus neutralization)
- damage tumour cells
Ag – Ab complexes absorb it non specifically and
mediate a number of immunological and biological
activities

6. The complement system
 Derived from experiments performed by Jules
Bordet shortly after the discovery of antibodies
 He demonstrated that if fresh serum containing an
antibacterial antibodies was added to bacteria at
37⁰C , the bacteria were lysed.
 However, if the serum was heated at 56⁰C or
more, it lost its lytic capacity.

7. The complement system
 The loss was NOT due to decay of antibodies
activity because antibodies are heat stable.
 He concluded that the serum contained another
heat–labile component that assisted or
complemented the lytic function of antibodies.
 This component was later given the name
complement.

8. The complement system
 Becomes effective when activated
 Out of the more than 20 proteins, 11 proteins are
mostly involved in the reactions, B (serine protease),
C1 to C9 and D (D - adipsin, serine protease)

9. The complement cascade.
 The complement cascade may be activated
by one of the three pathways.
The alternative pathway.
The classical pathway.
The lectin pathway.

10. The complement cascade.
 The complement pathways are activated
differently but all of them result in the
generation of enzyme complexes that
cleave the most abundant complement
protein C3.

11. Activation of pathways.
Alternative pathway.
 Bacterial endotoxins(LPS), yeast cells, cobra
venom
Classic pathway.
 Ag – Ab rxn
Lectin pathway
• Mannose residues on bacterial cell walls
• Neisseria, Candida, Salmonella

12. Alternative pathway
 Cell surface substances such as bacterial
lipopolysaccharides (endotoxin), teichoic acid
from g+ bacteria , fungal cell walls and viral
envelopes can activate the complement system
without antibody complexes .
 The pathway starts from C 3 which undergoes
spontaneous hydrolysis that yields C3a and C3b.
 C3b binds to foreign surface antigens & to Factor B

13. Alternative pathway
 Binding of C3b exposes a site on Factor B that acts as a
substrate for Factor D.
 Factor D cleaves the C3b –bound Factor B releasing a small
fragment (Ba) and generates C3bBb.
 This complex has C3 convertase activity. ( this complex is stabilized
by binding to properdin )

14. The classical pathway
 Antigen - antibody complexes activate CI to form protease
which cleaves C2 and C4 to form C4b , C2a complex, (C3
covertase.)
 This complex cleaves C3 molecules into C3a and C3b
fragments.
 C3a is an anaphylatoxin and C3b forms a complex
with C4b , C2a producing a new enzyme called C5
convertase (C4b ,C2a ,C3b) that cleaves C5 into C5a
and C5b.

15. The lectin pathway
 Mannan binding lectins (MBL) also known as mannose
binding lectins (MBL) bind to the surface of bacteria
bearing mannan (polymer of a sugar mannose) (e.g
Salmonella, Neisseria, Candida albicans)
 MBL is an acute phase protein produced in
inflammatory responses & bind to the surface
of pathogens .

16. The lectin pathway
 This activates MBL - associated serine proteases
(MASP-1 & 2 ) similar to ( C1r and C1s) , that
BIND TO :
MBL & the complex formed cleaves C4 & C2.
 This means of activating C2 –C4 to form C5- covertase
without specific antibody represents an important
innate defense mechanism .

17. The role of different complement
components in immunity.
 In addition, products of Complement
facilitates the activation of B-lymphocytes
and the production of antibodies.

18. The role of Complement system
in host defense.
Opsonization and phagocytosis.
 C3b or C4b coat microbe hence phagocytosis
Stimulation of inflammatory responses
• C5a, C4a and C3a induce inflammation by
activating mast cells and neutrophils.
Complement- mediated cytolysis mediated by the
Membrane attack complex (MAC).

19. The role of Complement system
in host defense
In neutrophils,C5a stimulates
 Motility,
 Firm adhesion to endothelial cells.
 Respiratory burst and production of reactive oxygen
intermediates.
 C5a may act directly on vascular endothelial
cells and induce increased vascular permeability and
expression of p- selectin which promotes neutrophil
binding.
 C5a is the most important mediator of mast
cell degranulation

20. Regulation of Complement
 Regulation is needed because spontaneous and
continuous generation of complements can
damage normal cells and tissues.
 Regulation is mediated by cells and membrane
proteins.
 Inhibiting the formation of C3 convertase
 Breaking down and inactivating C3 and C5
convertases.
 Inhibiting the formation of MAC.

21. Evasion of complement by
microorganisms
 Pathogens have evolved diverse mechanisms for
evading the complement system.
 Expressing thick cell walls or capsules to avoid MAC
e.g. gram positive bacteria and fungi.
 Recruiting host complement regulatory proteins.
 Expressing sialic acid which can inhibit alternative
pathway by recruiting factor H which displaces C3b
from Bb.

22. Evasion of complement by
microorganisms
 Plasma protein called C1 inhibitor (C1 INH)
inhibit the formation of MAC
 Synthesizing proteins which are antagonist of the
C5a.(Staph spp).

23. Evasion of complements by
microorganisms
Expressing sialic acid which can inhibit
alternative pathway by recruiting factor H
which displaces C3b from Bb.

24. Evasion of complement by
microorganisms
 Scavenging sialic acid from the host and
enzymatically transfering the sugar to their cell
surfaces.
 Synthesizing proteins which are antagonists of the
C5a.(Staph spp).

25. Clinical Aspects
 In miss- matched blood transfusion reactions
complement is activated to cause haemolysis and large
amounts of anaphylatoxins and membrane attack
complexes are generated.
 Immune complexes bind complement and its levels are low
in immune- complex diseases e.g. acute
glomerulonephritis, systemic lupus erythematosus (SLE).
 Patients with genetic deficiencies of complement
suffer from immune-complex diseases & recurrent
infections by pyogenic bacteria .