The document discusses the crosstalk between the complement system and other immune systems. It outlines how the complement system interacts and regulates toll-like receptors, B cell and T cell immunity, tissue factor production, and lipid metabolism. Some key points are that complement pathways regulate TLR-induced cytokine production in macrophages and dendritic cells. Complement components like C3a and C5a are also essential for optimal CD4+ T cell and antibody responses. The complement system also activates coagulation and promotes processes like bone remodeling, tissue repair, and adipocyte lipid clearance through receptors on various cell types.

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