Lecture 2: Innate Immunity

Questions to Consider

How can the immune system detect invasion by pathogens and alert the immune system- immunological 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 heat-

increased 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)

ssRNA (HIV)Gram positive bacteriaGram

negativebacteria

Seminars in Immunology 2004;16:3-9

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 toCD14/TLR-4

Migration intoLymph Nodes

Differentiation IntoDendritic 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?