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1. Presented by:
Sivasankar. P
Cross talk of complement with other
immune system

2. Introduction
 Innate immune system
 Immune surveillance system
 Homeostasis of body
 Three pathways
Functions:
 Opsonization
 Removal of immune complex
 Clearance of apoptotic cells
 Membrane attack complex
 chemotaxis

3. Contd…

4. Other functions
 Synapse maturation
 Angiogenesis
 Mobilization of haematopoietic progenitor cell
 Tissue repair
 Lipid metabolism
 Release of hormones from pituitary gland

5. Crosstalk with other system
 Toll like receptors
 B cell immunity
 T cell immunity
 Regulation of Treg cells
 Blood clotting system
 Kinin system

6. Interaction betweenTLR and complement
 Shapes the innate response, synergistic or antagonistic
 Synergistic: TNF, IL-1β and IL-6 in vitro and in vivo through C3aR,
and especially C5aR signaling (Zhang et al.,2007)
 In the apparent absence of c5a genetic ablation of C5aR inhibits TLR2-
induced cytokine production in DCs, suggesting that C5aR has a C5a-
independent effect on TLR2 signaling

7. Complement regulates production
of TLR induced IL-12
Macrophage
c3a
R
c5a
R
TLR-4
IL-12 production inhibited
Dentritic cell
?
• C5aR essentil for
TLR2 induced
cytokine production
in dentritic cell

8. Contd…
 C3aR--, c5aR-- mice failed to produce T cell immunity
 Underlying mechanism not clear
 c5aR is TLR modulatory receptor
 Porphromonas gingivalis (TLR2) impairs NO2 dependent killing in
macrophage (C5aR-TLR2 crosstalk)
 CR3 facilitates TLR2, TLR4 induced signalling

9. B cell immunity
 Complement is essential for B cell immunity (Pepys, 1974).
 C1q and C4 as well as CD21/CD35 essential for elimination of self
reactive B cells (Carroll, 2004)
 CR2 mediates antigen independent signal– survival of B cell in
germinal center
 CR2+CD19+CD81 has strong co stimulatory effect on B cell
 B cell can act as source of C5

10. Contd…
 Memory B cells can produce C5 suggesting that B cells may serve as a
local source of C5 in secondary lymphoid tissues (Ottonello et al.,
1999)
 CR1, CR2 on follicular dentritic cell essential for uptake of antigen
,Contributes B cell memory maintenance
 CR1, CR2 on B cell essential for production of Ag specific Ab
 C3a suppresses B cell polyclonal respone
 C5a essential for migration of naive & memory B cell
 C5aR downregulates threshold value of Fc gamma receptor
 Complement plays accessory role in induction of immune response
 C3dg opsonized antigen natural adjuvant
 Deficiency of c2 c3 c4 markedly impairs antibody response
 Formation of memory B cell also complement dependent process

11. T cell immunity
 CR1 CR2 essentail for production of antibody and T cell response
 Blocking CR1 CR2 impaired Ab , intact T cell response
 CR1 CR2 deficient mice  intact T cell response but pathogen
specific T cell response was absent
 C3ar deficient dentritic cell failed to produce cd4 T cell response
 DAF & CD46 essential for T cell response
 CD46 promotes formation of T reg cell
 M protein of stp. Pyogenes bnds CD46
 Complement and T cell response depend on environment
 In astma early sensitization phase C5ar signalling protects lung
 In inflammatory phase c5ar signalling Th2 response

12. Contd…
 IL 12 family cytokine suppressed in macrophage in response to
TLR 2/4
 IL12, IL23, IL27
 L.major binds TLR4
 CR3, CD46, gC1qR downregulates IL12
 CR3,- hepatitis C
 CD46-measles
 gC1qR- P.gingivalis

13. Contd…
 DAF(CD55) deficient mice suffer from vigorous T cell activation
characterized by hypersecretion of IFN- gamma and IL-2 in response to
Ag recall (Liu et al., 2005)
 C5a is necessary to mount an appropriate antiviral CD8+ T cell response
to control acute influenza virus infection (Kim et al., 2004).
 C3a, essential in CD4+ T cell immunity . In a murine model of allergic
asthma, C3aR−/− mice exhibited decreased Th2 responses including
reduced IL-4 production from pulmonary cells (Drouin et al., 2002).

14. Role of complement in bone
 Deficiency C1q – increases risk of fracture
 Deficiency of CD59,C5,C9, C5aR-- decreases risk of fracture (Liang et
al,2011)
 Anaphylotoxins induces release of IL-1, IL-6 from osteoblast
 Essential for osteoclast formation (Tu et al.,2010)
 Involved in PGs sythesis for remodelling of bone

15. Complement and coagulation
 Complement activates coagulation vice versa
 Why coagulation needed?
 C5a induces tissue factor, PA-I & inhibits fibrinolysis
 MASP-2 favours formation of thrombin which cleaves C5
 Certain pathogen countercts procoagulatory mechanism
complement coagulation
FactorXIICleaves
C1
Activates classical
pathway

16. Contd…
 C3a in pituitary gland (Francis et al,2003)
 C3a,C3aR involved in neural crest formation in early embryogenesis
 Remodelling of synaptic connections

17. Complement in tissue repair
 Complement removes dead cells
 Induces release of growth factor
 C3a,C5a – vascular growth factor
 Induces IL-6, TNF –promotes hepatocyte growth
 C3aR--,C5aR--, C3-- mice showed impaired regeneration

18. C5L2 in lipid metbolism
Adipocyt
e
C3
fB
fD
More turn
over of
alternative
pathway C3a
Adipocyte
1.Lipid clearance
2.Glucose upatke
3.TG synthesis
C5L2
Intake of
lipid &Insulin

19. Conclusion
 Complement regulates the TLR induced immunity & signalling
 Complement favours coagulation
 Essential in remodelling of bone
 Essential in B & T cell immunity
 Favours lipid metabolism

20. THANK YOU