the complement system, cytokines, the innate immune system, immunology, body defence mechanisms, complement proteins,

2. Complement
• The complement system consists of about
20 proteins in normal human serum
• They are synthesized mainly by the liver
• Complement is heat labile i.e. it is
inactivated at 56o
C for 30 minutes
• Immunoglobulins are not inactivated at this
temperature

3. Main Functions of Complement
• Lysis of cell
– Bacteria
• Generation of mediators
– Participation in inflammation and attract
neutrophils
• Opsonization
– Enhancement of phagocytosis

4. Antibody receptor
binding
Effector Mechanisms Against Extracellular Pathogens
OPSONISATION
OPSONISATION Phagocytosis
Bacteria in extracellular space
Ab
+

5. Effector Mechanisms Against Extracellular Pathogens
COMPLEMENT Activation
Bacteria in plasma
Ab &
COMPLEMENT
+
Phagocytosis
binding
Complement &
Fc receptor
Lysis
Opsonisation

6. Complement Activation
• Several complement components are pro-
enzymes and required cleavage to form
active enzymes
• Activation of complement is initiated either
by antigen-antibody complexes or by non-
immunologic molecules such as endotoxin

7. Complement Activation
• Pathways of activation
– Classic Pathway
– The Lectin Pathway
– The Alternative Pathway
• Lectin and alternative pathways are
activated with the first encounter with
bacteria since the antibody required to
trigger classic pathway is not present

8. • Classic Pathway
– Antigen-antibody complexes activate C1 to form
protease which cleaves C2 and C4 to form C4b,C2b
complex
• The Lectin Pathway
– Mannan-binding lectin (MBL) binds mannan present
on the surface of bacteria and cleaves C2 and C4 to
activate classic pathway without the help of an
antibody
• Alternative Pathway
– Cell surface substances such as bacterial
lipoploysaccharides (endotoxin), fungal cell walls and
viral envelopes can activate complement system
directly by cleaving C3 into C3a and C3b

9. Complement
Activation
Cascade

10. Generation of C5 convertase
leads to the activation of the
Lytic pathway
Lytic pathway

11. Components of the lytic pathway
C6
C
9
C8
C7
C5

12. Lytic pathway
C5-activation
C3b
C2 a
C4b
C5 b
C5a

13. Lytic pathway
assembly of the lytic complex
C5 b
C6
C7

14. Lytic pathway:
insertion of lytic complex into cell membrane
C5 b
C6
C7
C8
C
9
C
9
C
9
C
9C
9
C
9 C
9
C
9
C
9

15. C9 complex Complement-induced lesions on the
membrane of a red blood cell
Kuby J et al., Immunology 2003

16. Complement functions
• Host benefit:
– Opsonization to enhance phagocytosis (C3b)
– Phagocyte attraction and activation (C5a and
C5,6,7)
– Lysis of bacteria and infected cells
– Regulation of antibody responses
– Clearance of immune complexes
– Clearance of apoptotic cells
• Host detriment:
– Inflammation
– Anaphylaxis – mast cell degranulation (C3a, C4a,
C5a)

17. Regulation of Complement System
• Antigen-antibody reaction is necessary for
complement activation.
• C1 inhibitor
• Human cells are protected from lysis by
membrane attack complex by “decay accelerating
factor” (DAF)
– DAF de-stabilizes C3 and C5 convertase to prevent the
formation of membrane attack complex

18. Hereditary
Angioedema
Immune complex
disease
Recurrent bacterial
infections
Recurrent Neisserial
Infections
Clinical Syndromes Associated with Deficiencies
of Complement Components
C1 Inhibitor

19. Cytokines

20. Cytokines
• Facts
– They are low molecular weight proteins
– They are involved in immunity and
inflammation where they regulate the amplitude
and duration of inflammation
– They are extremely potent
– They are produced transiently (short duration of
action)

21. Cytokines
– They act with cell surface receptors specific for
each cytokine group
– Individual cytokines have multiple overlapping
cell regulatory actions and interact in the form of a
network
• Synergistic and antagonistic actions

22. Pleiotropic
Redundant
Synergistic
Antagonistic
-
Cytokines : Mode of Action

23. General Properties of Cytokines
• Cytokines induce their effects in three ways
– Autocrine effect: ie, they act on the same cell that
produces the cytokine eg, IL-2
– Paracrine effect: that effect other cells in the
vicinity eg, IL-7 in the bone marrow act on B cells
progenitors
– Endocrine effect: they affect many cells
systemically eg, IL-1 and TNF- which produce
acute-phase response during inflammation

24. Autocrine
Paracrine
Endocrine
General Properties of Cytokines
Mode of Action
Close proximity
Distant cells

25. Working Classification of Cytokines
• Cytokines that mediate natural immunity
– Interleukin-1 (IL-1), tumor necrosis factor alpha
(TNF), interferons and IL-6
• Cytokines that regulate lymphocyte growth,
activation and differentiation
– IL-2, IL-4, IL-5, IL-12, IL-15 and transforming
growth factor- (TGF- )

26. Working Classification of Cytokines
• Cytokines that activate inflammatory cells
– IFN-, TNF, lymphotoxin (TNF-) and
migratory inhibitory factor
• Cytokines that affect leukocyte movements
also called “chemokines”
– IL-8, Macrophage Inflammatory Protein
(MIP), Macrophage Chemotactic Protein
(MCP) etc.

27. Working Classification of Cytokines
• Cytokines that stimulate hematopoiesis
– Stimulate the production of blood cells by acting
on hematopoietic progenitor cells.
– The members of this family are called “colony-
stimulating factors” (CSFs) eg, granulocyte-
monocyte colony stimulating factor (GM-CSF),
granulocyte-colony stimulating factor (G-CSF)

28. Cytokine Actions
IL-1 Activates T cells to produce IL-2
IL-2 Stimulates both helper and cytotoxic T cells
IL-4 and IL-5 They promote growth and differentiation of B cells respectively
IL-6 Stimulates B cell differentiation, induces fever
IL-8 Attracts neutrophils
IL-10 Inhibits the development of Th-1 by decreasing production of IF
IL-12 Promotes the development of Th-1 cells
IL-13 Mediates allergic inflammation in asthma
Transforming Growth
Fctor beta (TGF-)
Anti-cytokine – inhibits growth and activities of T cells
Promotes synthesis of collagen (wound healing)
Chemokines Attract neutrophils and macrophages
Tumor Necrosis Factor
(TNF)
Promotes neutrophil phagocytosis and killing, mediates
extravascular migration of inflammatory cells
Interferones (INF) Block viral replication, Class switching of IgGs

29. Disease Cytokines
Bacterial Septic Shock High TNF serum levels
Lymphoid and Myeloid
Cancers
High levels of IL-6
T cell leukemia is associated
with HTLV-1 retrovirus
Low levels of IL-2
Cytokines and Disease

30. Cytokine Related Therapies
• Soluble form of IL-1 receptor inhibits Th
cell activation – prolongs graft survival in
heart transplantation
• IL-2 conjugated with toxin diminishes
rejection of kidney and heart transplants
• Lymphokine activated killer cells in tumor
therapy
• Antibody to IL-4 reduces IgE production

31. Cytokine Network
• Targets

32. Thank you