Transcript Complement and Cytokines.ppt

Complement and
Cytokines
Immunology Unit
Department of Pathology
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 56oC for 30 minutes
• Immunoglobulins are not inactivated at this
temperature
Main Functions of Complement
• Lysis of cell
– Bacteria
• Generation of mediators
– Participation in inflammation and attract
neutrophils
• Opsonization
– Enhancement of phagocytosis
Effector Mechanisms Against Extracellular Pathogens
OPSONISATION
Bacteria in extracellular space
+
Ab
OPSONISATION
Antibody receptor
binding
Phagocytosis
Effector Mechanisms Against Extracellular Pathogens
COMPLEMENT Activation
Bacteria in plasma
Lysis
+
Ab &
COMPLEMENT
Opsonisation
Complement &
Fc receptor
binding
Phagocytosis
Complement Activation
• Several complement components are proenzymes and required cleavage to form
active enzymes
• Activation of complement is initiated either
by antigen-antibody complexes or by nonimmunologic molecules such as endotoxin
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
• 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
Complement
Activation
Cascade
Lytic pathway
Generation of C5 convertase
leads to the activation of the
Lytic pathway
Components of the lytic pathway
C7
C6
C
9
Lytic pathway
C5-activation
b
C4b
C3b
Lytic pathway
assembly of the lytic complex
C6
C7
b
Lytic pathway:
insertion of lytic complex into cell membrane
C6
C7
CC C C
C9 9 9 9C
9C C C9
9 9 9
b
C9 complex
Complement-induced lesions on the
membrane of a red blood cell
Kuby J et al., Immunology 2003
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)
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
Clinical Syndromes Associated with Deficiencies
of Complement Components
Hereditary
Angioedema
C1 Inhibitor
Immune complex
disease
Recurrent bacterial
infections
Recurrent Neisserial
Infections
Cytokines
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)
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
Cytokines : Mode of Action
Pleiotropic
Redundant
Synergistic
Antagonistic
-
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
General Properties of Cytokines
Mode of Action
Autocrine
Paracrine
Close proximity
Endocrine
Distant cells
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- )
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.
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 “colonystimulating factors” (CSFs) eg, granulocytemonocyte colony stimulating factor (GM-CSF),
granulocyte-colony stimulating factor (G-CSF)
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
Cytokines and Disease
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
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
Cytokine Network
• Targets
Thank you