Transcript Document

Innate Immunity
Review on your own:
Clathrin-mediated endocytosis
Endomembrane transport system
Also review slides on innate immunity
in previous ppt
Note about the alternative pathway of
Complement: You are not responsible
for knowing the specific steps that are
unique to this pathway.
Self-Test
Questions:
A: both
B1: all
B2-3: 1 - 6, 9
B4: 1 - 4
B5: 1 - 5
B6: 1
Innate Immunity
1
What is inflammation?
An Innate response involves
cellular & physiological elements
Localized-- infection or wounding can trigger
Capillary vasodilation – redness (erythrema)
Capillary vasopermeation – swelling (edema)
Cell influx
‘Vasoactive molecules’ released by WBC
Inflammation around a wound
© Copyright 2003, Georgetown University
Systemic -- infection only
Fever
Increase in WBC
Changes in serum proteins
(e.g., Acute phase proteins)
Diagnostic for infection
Excessive inflammation causes immunopathogies
Innate Immunity
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“Danger signals”
activate innate cells
Some Danger Signals
(See Table 3-1 & Table 7-3)
“Danger signals” = PAMPs
“Pathogen-associated molecular patterns”
-- molecules of pathogens or wounding
-- general structure/widespread occurrence
PAMPS bind to Receptors called PRRs
“Pattern Recognition Receptor”
Viral dsRNA
Viral ssRNA
Bacterial LPS, flagellin, pilin
Bacteral and fungal cell wall components
Microbial polysaccharides
Reactive oxygen molecules
H202, OH-, O2Certain cellular molecules
-- e.g., “Toll-like receptors” (TLR)
-- other types also
Very important to DC activation
-- upregulates MHC expression
-- allows T-cell activation
Innate Immunity
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Danger signals
trigger a variety
of defensive
measures
Cells can enter an
“antiviral state”
Signaling other cells
Signaling the immune
system
Tick and Sick 8
4
Viruses can evade
cellular defense
mechanisms
. . . A few examples
Tick and Sick - 8
5
Macrophage killing mechanisms
External
-- mediator secretion
Internal: requires phagocytosis
-- Receptor mediated, or not
-- Antibody Fc receptors, PRR, etc.
O2 dependent vs independent
-- “respiratory burst”
-- enzymes
Innate Immunity
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Neutrophil granule contents
Neutrophil mechanisms
-- rapid responders
Degranulation & phagocytosis
Extracellular Traps
-- Chromatin & antimicrobial enzymes
Antimicrobial enzymes
• defensins
• lysozyme
• etc.
Acid hydrolases
• proteases, etc.
Myeloperoxidase
-- produces HOCl
& much more
Images from Brinkman et al. 2004 Science 333:1532
Innate Immunity
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Effectors of Mast cells and Eosinophils
Target parasites
Degranulation and secretion
-- releases mediators of anaphylaxis
• Histamine
• Seratonin
• Prostaglandins
• etc
Effects:
Sneezing
Cramping
Tearing
Scratching
Etc
Also cause allergies
Innate Immunity
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The Acute Phase Response,
Black bile, & Medieval bleeding
Acute Phase Response
--Systemic inflammatory response
Rouleaux
Fever, Changes in “Acute Phase Proteins”
e.g., CRP, Complement proteins,
plasminogen, fibrinogen, etc
Fibrinogen causes RBCs to stick together
form Rouleaux (“Ru-Lo”)
= “Black bile”
Fast sedimentation rate
Was bled to cure illness
Innate Immunity
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What is complement?
What are the 4 principal functions of complement?
Innate Immunity
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Complement involves a “proteolytic activation cascade”
C1 activates C4, which activates C2 … to C9
What are the 3 pathways of initiation?
Classical (acquired)
-- initiated by Ab bound to AG
C3
Alternative (innate)
-- does not involve Ab binding
Lectin (innate)
-- activated by mannose-binding lectin
Innate Immunity
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The Classical Pathway involves 3 stages
Initiation begins with C1 binding
to Ab bound to Ag
Bind to Fc part of Ab
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Activated C1 triggers
activationof C4 and then C2
-- to form C3 Convertase
C3 convertase activates C3
-- which acts as an opsonin
and becomes part of
C5 convertase
Activation of C3 is an important ‘amplification’ step
Innate Immunity
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C5b triggers formation of the Membrane Attack Complex
MAC is most effective against
Gram-negative bacteria
Nucleated cells
Enveloped viruses
Innate Immunity
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The Alternative Pathway
C3 spontaneously fragments into C3a and C3b
-- which can bind to AGs
-- pathogens and Immune complexes
Binding to other protein “factors”
creates alternative C3 & C5 Convertases
-- leading to MAC formation
Lectin pathway is initiated
by Mannose-Binding Lectin
-- binds to bacterial glycoproteins
Creates C1-like activator
-- activates C4, C2, etc
McGraw-Hill
Complement Activation
Innate Immunity
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How is Complement regulated?
1) Lability of protein fragments
-- rapid, spontaneous inactivation
2) Sialic acid in glycoproteins
-- inactivates C3b on body cells
3) Regulatory proteins
-- e.g., C1 inhibitor
(see table 3-3)
Hereditary Angioedema
Complement receptors
mediate other functions
-- immune complex clearing
-- chemotaxis
-- opsonization
Innate Immunity
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How does C3b cause
opsonization by
phagocytic cells?
Roles for both Fc and
Complement receptors
C3b is primary opsonin
binds to CR1 receptor
Coating of viruses blocks
receptors and enhances
opsonization
Innate Immunity
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RBCs and CR1 play major role
in immune complex clearance
Immune complexes generate C3b
-- via classical or alternative pathways
Transport to spleen & liver
Phagocytosis
Deficiencies in complement-mediated
IM-complex clearing are major cause of
Systemic Lupus Erythromatosus (SLE)
Innate Immunity
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