K6 - Innate Immunity2

Innate immunityEvy Sulistyoningrum

Immune system protects body against pathogen

External barriers prevent microorganism entry to the body

Immune system performs immune response resulted in immunity

Classification◦ Innate immune response◦ Adaptive immune response

Introduction

Innate immunity◦ Immediate◦ Short protection◦ Non specific◦ Elimination: phagocytosis & killing

activity◦ Cells: granulocyt, macrophage, NK cell

(natural killer)◦ Humoral: complement

Innate immunity vs adaptive immunity

Adaptive immunity◦ Induced immune response◦ Long term protection◦ Memory◦ Specific◦ Cells: lymphocyte (B and T)◦ Humoral: antibody

Innate immunity vs adaptive immunity

Non-Specific or natural Immune system Immediate response (0-4 hours) Function: provide the initial defense

against infections:◦Prevent infections ◦Eliminate microbes : depends on the

presence of cells that recognize and kill pathogens and foreign materials directly

Innate Immune System

Consists of: ◦ Cellular

Phagocytes NK cell

◦ Humoral Acute phase protein Complement

◦ Other Immune responses: Fever Response Inflammatory Response, Interferon Response

Innate Immune System

Stages of response to infection

Epithelial barriers Phagocytes:

◦ Recognition of foreign particle◦ Rapid destruction of an infectious organism

phagocytic cells Localized protective response

(inflammation) Cytokine reactions Extracellular killing

How innate immunity works?

Intact epithelial form physical barriers Produces peptides that have antimicrobial

properties◦ Defensins (epithel/paneth cell, neutrophil, NK

cells, Tcytotoxic,) direct toxicity to microbes◦ Cathelicidins (neutrophil, skin, GI mucosal cells,

respiratory mucosal cells) direct toxicity Intraepithelial T lymphocytes, B-1

lymphocytes Mast cell in lamina propria

Epithelial barriers

Epithelial barriers

Function: identify, ingest, destroy microbes Members:

◦ Granulocytes◦ Macrophages◦ DC

Steps:◦ Recruitment to sites of infection◦ Recognition of pathogens◦ Ingestion of microbes◦ Destruction

Other: produce cytokine

Phagocytes

Chemokine as a chemo-attractant Selectin

◦ P-selectin & E-selectin: express by endothelial cells

◦ L-selectin: express by leucocytes ◦ Selectin-selectin receptor affinity is low rolling

Integrin stabilize adhesion of leucocyte to endothelium

Cytoskeleton alter the shape of cells Extracellular matrix

Molecules involved

Phagocyte migration to infection site

Recruitment to sites of infection

The innate immune system distinguishes infectious microbes from self cells by recognizing molecular structures which expressed by microbes

Pathogen has non-self structures : Pathogen-Associated Molecular Patterns (PAMPs)

Part of the innate immune cells which bind to PAMPs known as Pattern-recognition receptors

Recognition

PAMPS-PRR interaction

PAMPS in pathogens PRR in phagocytes

Certain sugar residue Certain sugar residue

Anionic polymers Broad spectrum of

ligands LPS (in gram negative

bacteria)

Mannose binding lectin

Macrophage mannose receptor

Scavenger receptor Toll-like receptor

(TLRs)

Activate phagocyte Release of cytokine & chemokine Inflammatory process

Phagocytic receptor : stimulate ingestion of pathogen

Chemotactic receptor : binds to special peptide on bacteria

Reactions mediated by PRR-PAMPs

Activation of macrophages

Phagocytosis

O2 dependent degradation (ROS) O2-independent degradation (ex: NO) Opsonins: protein that coat pathogen easy

to be ingested◦ Antibodies◦ Complements◦ Lectins

Other mechanism

Killing mechanism

Mechanism of cell killing

CRP Mannose binding protein Serum amyloid P component α1 acid glycoprotein, etc

Opsonization Inhibits bacterial protease Increase complement function

Acute phase protein

Substance that interfere with viral replication

14 class of IFN Infected cell secretes IFN to the

extracelullar fluid bind to uninfected cell cordon of uninfected cell around site of infection inhibits viral reproduction between cells

Interferon Response

Some mediator resets thermal setpoints in the hypothalamus induce heat formation fever

Mediator = pyrogen Can be endogenous ( PG, IL-1) or

exogenous (bacterial toxin, etc)

Fever Response

Inflamare: to set on fire Complex biological response of vascular &

tissues to harmful stimuli Objection:

◦to remove the injurious stimuli◦initiate the healing process for the tissue

Terminology:◦ Organ + -itis

Inflammation

Deliver additional effectors molecule and cells to sites of infection augment killing of invading microorganism

Induce blood clotting physical barrier to the spread of infection in blood stream

Promote the repair of injured tissue

Role of inflammation

Steps of inflammation

Clinical sign

Inflammatory process

Increase in vascular diameter increase local blood flow increase the metabolic rate heat and redness

Changing of blood vessels ininflammatory response

1

Endothelial cells lining the blood vessels are activated to express cell-adhesion molecules promote binding of circulating leukocytes

Changing of blood vessels ininflammatory response

2

Increase in vascular permeability exit of fluid and protein from blood accumulate in the tissue swelling and pain

Changing of blood vessels ininflammatory response

3

Clotting in microvessels in the site of infection prevents the spread of pathogen via the blood

Changing of blood vessels ininflammatory response

4

Macrophage activation by pathogen lead to cytokine; chemokine release & local mediators

Various cytokine can lead to fever & interferon response

Various chemokine attract other cell to come to site of infection

Local mediators make blood vessels dilate & increase vascular permeability redness & heat

Step 1

Leukocyte in blood circulation has receptor for chemokine come to blood vessel near the site of infection

Blood vessel express cell adhesion molecule bind leucocyte◦ Margination ◦ Rolling adhesion◦ Tight adhesion◦ Diapedesis ◦ Migration

Step 2

Leucocyte migration/extravasation together with fluid & protein increase interstitial volume swelling

Accumulation can activate free nerve endings pain

Inflammatory mediators can also induce pain sensation

More accumulation loss of function

Step 3

Summary of inflammation

Lymphocytes derived from lymphoid progenitor.

Circulate in the blood Contain cytolytic granules Important in the defense from certain

lymphoid tumor cell lines and from virally infected cells.

Innate immune response Act without prior activation

NK cells are:

NK cell

NK cells' activity is increased when they are exposed to:IFN-αIFNβIL-12

NK cell has 2 receptors: killing receptors & inhibiting receptors allow NK cells to kill infected cells, while sparring uninfected cells.

Activation of NK cell is regulated by a balance between signal from activating receptor and inhibitory receptors

Activating receptor recognize ◦ stressed cell◦ Virus infected cell◦ Malignant cell

Inhibitory receptor recognize:◦ Normal cell that expressed MHC class I

NK cells

Activation of NK cells results in:release of cytotoxic granule contentsproduction of the cytokines IFN-γ and TNF-α

NK cells are activated through Killer Activating Receptors (KARs). Ex: NKp46, NKp30, NKp44

Each of these receptors contain a (+) charge in their transmembrane domain associated with adaptor to internalize external signals stimulates granule release

Figure 1 – Moretta A., et al. “Surface Receptors Delivering Opposite Signals Regulate the Function of Human NK Cells.” Seminars in Immunology. Vol 12, 2000:

pg. 129-138.

Structures of various KARs, including their associations with adaptor molecules.

Perforin or cytolysin can insert into cell target’s membrane

Polymerize form transmembrane pore Release of granzymes through

transmembrane pore Granzymes consists of serine protease

activate apoptosis reaction cell target death

NK cell contain Fas Ligand bind with receptor (Fas) apoptosis

Killing mechanism…

NK cell killing

NK cell doesn’t kill normal cell

Infected cells can inhibit the synthesis of all proteins decreases the amount of MHC-I produced.

Viruses can also selectively prevent the export of MHC-I molecule number of MHC class I molecules on the cell surface is decreased

Decreased MHC-I expression decrease in the number of KIR/MHC-I interactions reduces inhibition signaling killing activity of NK cell

Virus-infected and tumor cells are able to alter MHC-I expression.

Macrophage produces cytokine IL-12 activates NK cell

NK cell produces cytokine IFN-γ activates macrophage

NK cell interaction with macrophages

Complement : heat-labile component of normal plasma that augments the opsonization and killing of bacteria by antibodies.

Complement= the ability to assist or complement the antimicrobial activity of antibodies

The complement system may be activated by microbes in the absence of antibody as part of innate immune response to infection, and by antibodies attached to microbes

Complement system

Complement system

Summary of innate immunity

Activity of innate immune system

Signal needed to induce adaptive immune response:◦ Antigen : presented by APC◦ Molecules induced by innate response ◦ Cytokine signal

Adjuvants : substances that need to be administered to elicit maximal immune response

Innate immunity stimulates adaptive immune response

Thank you…