Download Lecture 2: Innate Immunity

Lecture 2: Innate Immunity
Questions to Consider
 How can the immune system detect invasion by
pathogens and alert the immune systemimmunological triage?
 Can the immune system use pathogen profiling as
a quick and dirty way to differentiate pathogens
from self-antigens
Pathogen Profiling
Sensitivity.
vs.
Specificity
Immune System Design
 How can the immune system detect invasion by pathogens
and alert the immune system?
 Can the immune system use pathogen profiling as a quick
and dirty way to differentiate pathogens from self-antigens?
 How does the immune system contain pathogens?
 How are immune cells directed to sites of infection?
Initiation of an Inflammatory Response
 Clinical Manifestations
• pain-increased vascular
diameter
• redness and heatincreased blood flow and
decreased blood flow
velocity
• swelling- increased
vascular permeability
Initiation of an Inflammatory Response
 Causes
•
•
•
Response to bacterial replication
Response to tissue damage
Response to macrophage mediator
release
Goals of the Inflammatory Response
 Prevent the initial
establishment of infection
 Prevent spread of infection
from invasion site
 Recruit effector cells for
assistance
 Alert and mobilize B cells
and T cells
The Innate Immune Response is the Layered Front Line
of the Host Defense System Using Pattern Recognition
B and T cells Reside in Lymphoid Tissues
Thought Experiment
 Which limb of the immune system would you rather
give up?
 Innate
 Adaptive
Far More Rapid Progression of Bacterial Infection in Mice
Lacking the Innate Immune Response Than in Mice
Lacking the Adaptive Immune Response
The Innate Immune System Uses Different
Receptors From the Adaptive Immune System
The Innate Immune System Uses Multiple Fixed
Barriers to Prevent Infection
Infection is Initiated By Bacterial Adherence
and Penetration of the Epithelial Barrier
Persistent Local Infection of Tissues
Induces Adaptive Immunity
Phagocytic Cells Express Receptors That Specifically
Bind Pathogen-derived Moieties Which Can Induce
Cellular Activation and Differentiation
Bacterial Derived Factor
Cellular Receptor
Glucan
Glucan receptor
Mannose
Mannose receptor
Lipopolysaccharide (LPS)
CD14/Toll-like receptor
(TLR)-4
Toll- An Important
Immune Molecule In Flies
 Toll, discovered in 1996, is
a drosophila developmental
gene
 When this gene was
knocked out, the fruit flies
succumbed to massive
fungal infection
 This indicated Toll encoded
an important immune
molecule
Phagocytic Cells Express Receptors That Specifically
Bind Pathogen-derived Moieties Which Can Induce
Cellular Activation and Differentiation
Bacterial Derived
Factor
Cellular Receptor
Lipopolysaccharide
(LPS)
CD14/Toll-like
receptor
(TLR)-4
Mannose
Mannose receptor
Glucan
Glucan receptor
Lipopolysaccharide Binds to CD14 Which Interacts
With TLR-4 Inducing Translocation of NFkB
Toll-like Receptors Recognize Unique
Pathogen-associated Molecular Patterns (PAMP)
Gram positive bacteria
ssRNA (HIV)
Seminars in Immunology 2004;16:3-9
Gram
negative
bacteria
Role of TLR in HIV Infection
Langerhans’ cells Provide a Link Between
the Innate and Adaptive Immune Systems
 Immature dendritic cells that are present in the skin
 After activation, they migrate to the lymph nodes and
transport skin-derived antigens
 In the lymph nodes, they become activated dendritic cells
and activate antigen specific lymphocytes
 These cells are one way the innate immune system
activates the adaptive immune response
LPS Interacts With TLR-4 Expressed by Langerhans’ Cells
and Induces Their Migration to Lymph Nodes and
Differentiation Into Antigen Presenting Dendritic Cells
Binding of LPS to
CD14/TLR-4
Migration into
Lymph Nodes
Differentiation Into
Dendritic Cells
IL-6 Produced by Monocytes Activated by
Bacterial Components Stimulates the Liver to
Produce Factors That Bind to PAMPs
Monocytes Activated by Bacterial Components
Secrete Cytokines Including TNF-That
Amplify the Immune Response
Appropriate Amounts of TNF- Contain Infection
but Too Much TNF- May Cause Shock And Death
Appropriate Amounts of TNF- Contain Infection
but Too Much TNF- May Cause Shock And Death
How Can Effector Cells be
Recruited to Sites of Infection?
 Local site that is infected
•
Requires expression of focused signals that can recruit specific
cells needed to contain infection
 Effector cells
•
Need capacity to recognize these signals so that they can
migrate from the circulation into the inflammatory site
A Broad Range of Chemokines Selectively Induce
the Migration of Different Inflammatory Cells
CXC Motif Chemokines
CC Motif Chemokines
Adhesion Molecules Expressed by Epithelial Cells Bind to
Other Adhesion Molecules Expressed by Inflammatory Cells
Adhesion Molecules Expressed by Epithelial
Cells Bind to Other Adhesion Molecules
Expressed by Inflammatory Cells
Expression of ICAM-1 and ICAM-2 by Endothelial Cells
Recruits Phagocytes Expressing Mac-1 and LFA-1
Weak Adhesion Molecule Interaction Mediates
Cellular Rolling Along the Walls of Blood Vessels
Infected Tissues Produce IL-8 and Express Adhesion
Molecules to Recruit Phagocytes Into Infected Tissues
•Infected tissues
Produce IL-8 and
express ICAM-1
•IL-8 induces LFA-1
expression by
phagocytes
•LFA-1 binds to
ICAM-1 and mediates
phagocyte entry into
interstitial tissues
Host-derived ICAM-1 Incorporated Into
the HIV Membrane Enhances Infectivity
Questions to Consider
 How can the immune system detect invasion by pathogens
and alert the immune system?
 Can the immune system use pathogen profiling as a quick
and dirty way to differentiate pathogens from self-antigens?
 How does the immune system contain pathogens?
 How are immune cells directed to sites of infection?