INNATE IMMUNITY: THE INDUCED RESPONSES
April 6, 2009
11:00-12:00
THE INDUCED RESPONSE A.K.A INFLAMMATION
EFFECT
Rubor (red)
CAUSE
Tumor (swollen)
Calor,doler (hot and painful)
Dilation of capillaries
Reduced blood flow
Increased permeability
SOLUBLE MEDIATORS AND INDUCED INNATE IMMUNITY
Cytokines
IL-6, IL-1, TNFa, IL-12, Type I Interferons
Chemokines
IL-8
PRODUCTS OF ACTIVATED MACROPHAGES
CYTOKINES ACT BOTH LOCALLY AND SYSTEMICALLY
THE ROLES OF CYTOKINES AND CHEMOKINES
Local Effects:
Alterations in vascular endothelium:
TNFa, IL-1
Influx of neutrophils and lymphocytes:
IL-8
Activation of Lymphocytes:
IL-1, IL-6 ( antibody secretion),
IL-12 (T cells and NK cells)
Systemic Effects
Fever
IL-1, IL-6, TNFa
Shock
TNFa
Acute Phase Response
IL-6
NON-CYTOKINE MEDIATORS OF INFLAMMATION
Macrophage products:
plasminogen activator, phospholipases,
prostagandins, oxygen radicals, leukotrienes
PAF
COMPLEMENT
Promotes vascular leakage
Stimulates mast cell degranulation
TNFa—A KEY CYTOKINE IN LOCAL INFLAMMATORY RESPONSES
Signaling via CD14/TLR-4 activates NFkB and promotes transcription
of “proinflammatory” cytokines such as TNFa
TNFa has multiple effects on endothelium: increase ICAM,
stimulates production of proteins that increase clotting and
promote vascular leakage
SEPTIC SHOCK
The systemic effects of TNFa lead to cachexia
Both gram negative and gram positive bacteria cause septic shock,
but the mediators are different.
INFLAMMATION RECRUITS CELLS TO THE SITE
Vessel dilation affects blood flow
TNFa/leukotrienes increases expression of adhesion molecules
(selectins)
ROLLING, ROLLING, ROLLING..THE FIRST STEP IN EXTRAVASATION
Interaction between S-Le and selectins is weak causing rolling vs sticking
EXTRAVASATION OF NEUTROPHILS
Tight binding: mediated by LFA (integrin) which is activated by IL-8
and LFA which is increased by TNFa
Migration is directed by chemokines (IL-8)
Neutrophils eat and die leaving behind pus
NEUTROPHILS: A SHORT-LIVED, POTENT PHAGOCYTE
Figure 8-20
Neutrophils and macrophages
use similar mechanisms
to recognize and phagocytize
pathogens
Neutrophils take up a wider
range of particles than mf
Attack with a variety of degradative
enzymes and anti-microbial peptides
(defensins)
Oxidases generate toxic oxygen
radicals
MACROPHAGE PRODUCED CYTOKINES EFFECT MULTIPLE
CELLS AND TISSUES
Enhance both innate and adaptive immune response
Cause Fever
Induce the Acute Phase Response
THREE BENEFITS OF FEVER
Increased temperature decreases the rate of pathogen replication
At higher temperatures, human cells become resistant to TNFa
Antigen processing and presentation is increased (degradation
of proteins to peptides and association with MHC proteins)
THE ACUTE PHASE RESPONSE
3 PROTEINS
(C-reactive protein, fibrinogen,
Mannose binding protein)
2 EFFECTS
(opsonization and
Complement fixation)
THE INNATE IMMUNE RESPONSE TO VIRUSES
VIRUS INFECTED CELLS PRODUCE TYPE I INTERFERONS
ds RNA stimulates
IFN production
and produce IFNg
Oligoadenylate synthetase
degrades viral RNA
Activation of
Adaptive Immunity
CELL MEDIATED RESPONSE TO VIRUS---NK CELLS
RECOGNITION BY NK CELLS: TO KILL OR NOT KILL
Healthy cells express MHC class I which interacts with an NK cell receptor
issuing a “don’t kill” signal that counteracts the “kill signal”
Viruses decrease MHC class I expression so there is no “don’t kill” signal
Viruses stimulate production of type I IFNs which increase MHC class I on
neighboring healthy cells
KIRs
Two types of KIR
CD94 and NKG2A recognize
“non-classical” class I, HLA-E
KIR2DL and KIR3DL recognize
classical class I, HLA-B,C
Different individuals have different HLAs…a problem in transplantation
CYTOKINE REGULATION OF CELLULAR RESPONSE TO VIRUS
TIMING OF INNATE AND ADAPTIVE IMMUNE RESPONSE TO VIRUS
Figure 8-28