COMPLEMENT SYSTEM EDEN cdhkjyuuy 2019.pdf

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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 as Ag –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
DerivedfromexperimentsperformedbyJules
Bordetshortlyafterthediscoveryofantibodies
Hedemonstratedthatiffreshserumcontainingan
antibacterialantibodieswasaddedtobacteriaat
37⁰C,thebacteriawerelysed.
However,iftheserumwasheatedat56⁰Cor
more,itlostitslyticcapacity.

7. The complement system
ThelosswasNOTduetodecayofantibodies
activitybecauseantibodiesareheatstable.
Heconcludedthattheserumcontainedanother
heat–labilecomponentthatassistedor
complementedthelyticfunctionofantibodies.
Thiscomponentwaslatergiventhename
complement.

8. The complement system
Becomeseffectivewhenactivated
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.
Thecomplementcascademaybeactivated
byoneofthethreepathways.
Thealternativepathway.
Theclassicalpathway.
Thelectinpathway.

10. The complement cascade.
Thecomplementpathwaysareactivated
differentlybutallofthemresultinthe
generationofenzymecomplexesthat
cleavethemostabundantcomplement
proteinC3.

11. Activation of pathways.
Alternativepathway.
Bacterialendotoxins(LPS),yeastcells,cobra
venom
Classicpathway.
Ag–Abrxn
Lectinpathway
•Mannoseresiduesonbacterialcellwalls
•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
Mannanbindinglectins(MBL)alsoknownasmannose
bindinglectins(MBL)bindtothesurfaceofbacteria
bearingmannan(polymerofasugarmannose)(e.g
Salmonella,Neisseria,Candidaalbicans)
MBLisanacutephaseproteinproducedin
inflammatoryresponses&bindtothesurface
ofpathogens.

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.
Inaddition,productsofComplement
facilitatestheactivationofB-lymphocytes
andtheproductionofantibodies.

18. The role of Complement system
in host defense.
Opsonization and phagocytosis.
C3borC4bcoatmicrobehencephagocytosis
Stimulationofinflammatoryresponses
•C5a,C4aandC3ainduceinflammationby
activatingmastcellsandneutrophils.
Complement-mediatedcytolysismediatedbythe
Membraneattackcomplex(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.(Staphspp).

23. Evasion of complements by
microorganisms
Expressingsialicacidwhichcaninhibit
alternativepathwaybyrecruitingfactorH
whichdisplacesC3bfromBb.

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 .