Inmunidad Innata Actor

7/26/2019 Inmunidad Innata Actor

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Reminder:

Review the Histology lectures* about

Cells and Organs of the Immune System

Review posted review on Blackboard. Also found at:http://www.uth.tmc.edu/pathology/medic/immunology/Immuno/ReviewInfoImmuneOrgans.2012.pdf

*Info from Histology lectures is testable material


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Innate Immunity

Jeffrey K. Actor, Ph.D.

MSB 2.214, 500-5344


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Lecture Objectives:

Introduce innate immune defense mechanisms.

Review cell types involved in innate immuneresponses, and their role in inflammation.

Define ADCC, Chemokines, and Pattern-Recognition

Receptors.


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What Constitutes Innate Immunity?

The innate immune system:

present from birth present prior to onset of infection

constitutes non-specific mechanisms of defense

Innate components recognize classes of moleculesfrequently encountered on invading pathogens

allows defensive measures until specific immune

response is generated


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4 Categories of Innate Immunity

Anatomic.

Physiologic.

Phagocytic and Endocytic.

Inflammatory.


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Anatomic Barrier

Skin

thin outer epidermis, thicker underlying dermis impedes entry of foreign material

Sebaceous glands produce sebum, comprised of lactic acid and fatty

acids

reduces skin pH, inhibits organism growth.

Mucous membranes covered by cilia

traps organisms, propels them out of the body.


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Physiologic Barrier

Includes temperature, low pH, chemical mediators.

Organisms can not multiply in elevated temperature.

Lysozymes degrade bacterial membranes.

Complement components in serum attack bacterialmembranes.

Low stomach pH discourages organism growth.

Lactoferrin inhibits bacterial growth.


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Anatomic/Physiologic

(Secreted Substances)

Defensins: natural anti-microbial peptides


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Phagocytic and Endocytic Barrier

Blood monocytes, tissue macrophages and neutrophils

phagocytose and kill microorganisms via complexdigestion mechanisms.

Bacteria ingested into phagocytic vesicles.

Phagosomes fuse with lysosomes. Lysosomal enzymes digest captured organisms.

Interferons ( and ) inhibit viral expansion.


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Inflammatory Barrier

Rubor et Tumor cum Calore et Dolore

2000 years ago Celcus defined 4 cardinal signs of acute inflammation

Inflammation through injury

Inflammation through infection


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Rubor et Tumor cum Calore et Dolore

Redness (rubor)

Inflamed tissue appears red due to dilatation of small blood vessels

within the damaged area.

Swelling (tumor)

Extravascular fluid accumulation as part of the fluid exudate

(edema).

Physical mass of inflammatory cell migration into area.

Heat (calor)

Vascular dilation and increased blood flow (hyperaemia).

Chemical mediators lead to systemic fever. Pain (dolor)

Stretching/distortion of tissues by inflammatory edema, pus

pressure.

Via chemical mediators (bradykinin, prostaglandins, serotonin).


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Beneficial Effects of Fluid Exudate

(Vascular Permeability)

Dilution of toxins.

Entry of antibodies.

Lysis of microorganisms (complement).

Assisted phagocytosis (opsonisation).

Neutralization of toxins.

Fibrin formation.

Impede movement/trap micro-organisms; facilitate

phagocytosis. Delivery of nutrients and oxygen.

Stimulation of immune response.

Drainage of fluid exudate/antigens into lymphatics.


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Harmful Effects of Fluid Exudate

Release of lysosomal enzymes by inflammatory cells.

Digestion/destruction of normal tissues by enzymes. Swelling.

Obstruction of ducts, lymphatics.

Leads to ischaemic damage (vascular constriction by

pressure).


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Chemical Mediators of Inflammation

Kinin -> Fibrinolytic

Clotting

Complement


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Critical Molecules in Injury

Many of the clotting factors and kininogens lead to

production of vasoactive peptides. Some activate

phospholipases.

Phospholipases then feed into the Arachidonic Acid Pathway.


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Arachidonic Acid Metabolites: Inflammatory Role


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Cells of the Innate Immune Response


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Neutrophils

The neutrophil's main role is in inflammation.

First cells to arrive at the site of inflammation.

Neutrophils are attracted to tissue by chemotactic

factors.

Complement proteins and clotting proteins.

actively phagocytic in tissue

kill microorganisms by oxygendependent or independent

pathways.


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Neutrophils (contd)

Chemoattractants (eg. Interleukin-8 [IL-8], complement C5a)trigger adhesion and subsequent diapedesis.

Neutrophil interaction with antibody and complement allowincreased phagocytosis of invading organisms.

Activation of neutrophils leads to:

respiratory burst

production of reactive oxygen and nitrogen intermediates

release of primary and secondary granules

proteases, phospholipases, elastases and collagenases.

Pus, a yellowish white opaque creamy matter produced by theprocess of suppuration consists of innumerable neutrophils(some dead and dying) and tissue debris.


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Bactericidal Agents in Phagocytes


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Neutrophil Transendothelial Migration

Reversible binding, activation, adherence, and movement between endothelial cells.


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Erythrocyte Sedimentation Rate

(ESR = sed rate)

During infection, elevated ESR

Increased protein

Interaction with charge on RBCs

Causes stacking

Rouleaux formation

Stacking of RBC in vascular beds gives neutrophilsextra time to interact with adhesion molecules


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Loss of any factor that impairs neutrophil function

would make individual susceptible to bacterial infection!

See case study #27: Leukocyte Adhesion Deficiency

Missing expression of integrin LFA-1, beta chain.


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Mononuclear Cells and Macrophages Monocytes and macrophages ingest and destroy bacteria

Multiple factors prepare particulate for engulfment andtargeting for destruction

opsonins comprised of complement components.

Phagocytes bear several different receptors that recognizemicrobial components

induce phagocytosis

Pattern Recognition Receptors


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Phagosome:Lysosome fusion

enzymatic degredation NO mediated events

low pH

See Case #26: ChronicGranulomatous Disease


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Macrophages

After activation, these cells secrete interferons, lysosyme andother immunoregulators of immune response. Released

molecules (cytokines) work on a local and on a systemic level.

Cytokines from macrophages link Innate immunity (nonspecific)

with Adaptive immunity (specific).

What are Cytokines????


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Cytokines

Small molecular weight glycopeptides Made by a variety of cells

Each cytokine has multiple activities [plieotropic],

dependent upon cell target, concentration, andpresence of other cytokines

Cytokines can facilitate innate immune function

and assist in activation of inflammatory responses Often referred to as Interleukins


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Selected Cytokines and their functions.


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IL-8


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Oh so simple..

Remember: I mentioned that each cytokine has multipleactivities [plieotropic] and is dependent upon cell target,

concentration, and presence of other cytokines. Actions can get

complicated very quickly.


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NK Cells and ADCC

Kill infected or tumor self cells in the absence ofantigen-specific receptors.

Therefore, NK cell killing is considered nonspecific.

NK cells can function to actively lyse target cells in a

process know as: Antibody-Dependent, Cell MediatedCytotoxicity (ADCC).


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ADCC

Mediate ADCC using receptors for the constant portion ofan antibody. CD16

Recognize antibody coated target release lytic enzymes that damage target cell membranes .

They also cause death by inducing apoptosis in the target.

Antibody-Dependent, Cell

Mediated Cytotoxicity: target

cells coated with antibody are

destroyed by specialized killercells (Type II hypersensitivity).


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Chemokines

Small polypeptides acting via G-protein coupled receptors.

All chemokines related in amino acid sequence.

Grouped into two distinct categories:

CC chemokines have two adjacent cysteine residues(hence the name "CC").

CXC chemokines have an amino acid between twocysteine residues.

Chemokine receptors are integral membrane proteins

having seven membrane-spanning helices.


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Chemokine Major Cell Source Cell Type Attracted

CCL2

(MCP-1)

Monocytes and

Macrophages,

Fibroblasts

Chemoattractant for monocytes

CCL3(MIP-1)

Monocytes, T cells,Fibrobalsts, Mast cells

Chemoattractant for neutrophilic granulocytes

CCL5

(Rantes)T cells, Endothelium

Chemoattractant for Eosinophils and Basophils,

Monocytes and Dendritic cells, and T cells

CCL11

(Eotaxin)

Monocytes andMacrophages,

Endothelium and

Epithelium

Chemoattractant for Eosinophils

CXCL8(IL-8)

Monocytes and

Macrophages,Fibroblasts, Endothelial

cells

Chemoattractant for Neutrophils

Properties of Selected Chemokines

See syllabus appendix for more complete list of chemokines, their

source, and their biological function.


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Complement


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Complement

Direct Cytolysis of foreign organisms

Opsonization of foreign organisms

An enyzmatic cascade: forms a pore channel in the lipid

bilayer, causing osmotic lysis of the cell.

Coating organism enhances phagocytosis and targeteddestruction.

Directed leukocyte migration

Proteolytic degradation of complement components results

in leukocyte chemotaxis.


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The innate immune system is a universal and

ancient form of host defense against infection.

Question: How does innate immunity

(nonspecific) directly recognize invading

micro-organisms to trigger a host defense

response?

Receptors of the innate immune system recognize broad

structural motifs highly conserved within microbial species.


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Pattern Recognition Receptors

Receptors are referred to as Pattern-RecognitionReceptors (PRRs).

Engagement of PRRs leads to triggering of signalpathways that promote inflammation.

-Complement receptors: target cell wall components

-Mannose-binding lectins: target mannose microbial carbohydratesin bacterial cell membranes

-LPS-binding proteins: target bacterial lipopolysaccharide

-Toll-like receptors: multiple targets-Scavenger receptors: targets phosphatidylserine and lipoproteins


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Toll-Like Receptors: The Simplified Explanation

A way for innate cells to influence development of

adaptive immune function.

11+ Toll like receptors and ligands have been identified


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11+ Toll-like receptors and ligands have been identified.

They recognize various pattern motifs, and control subsequent

signal transduction pathways.

Nature Reviews Immunology 1; 135-145 (2001); TOLL-LIKE RECEPTORS AND INNATE IMMUNITYSee Appendix for full list of receptors and ligands.

Recognition of


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Recognition of

pathogen via TLRs

activates and maturesDendritic Cells and

macrophages (APCs).

APCs process antigenand present to nave

T cells.

Presentation isaccompanied by

secretion of specific

cytokines to control

development of

phenotypic T cell

responses.

T ll Lik R t Th C l E l ti


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Toll-Like Receptors: The Complex Explanation

A l h t f i t t ff t d f ti


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Component Effectors Function

Anatomic and

physiologic

barriers

Skin and mucous membranes

Temperature, acidic pH, Lactic

acid, Chemical mediators

Physical barriers to limit

entry, spread, and

replication of pathogens

Inflammatory

mediators

Complement Direct lysis of pathogen or

infected cells

Cytokines and interferons Activation of other immune

components

Lysozymes Bacterial cell wall destruction

Acute-phase proteins andlactoferrin

Mediation of response

Leukotrienes and

prostaglandins

Vasodilation and increased

vascular permeabili ty

Cellular

components

Polymorphonuclear cells

Neutrophils, eosinophilsBasophils, mast cells

Phagocytosis and

intracellular destruction ofmicroorganisms

Phagocyt ic-endocytic cells

Monocytes and macrophages

Dendritic cells

Presentation of foreign

antigen to lymphocytes

A general summary chart of innate components, effectors and function:

Table 1.1. Consult . Elseviers Integrated Immunology and Microbiology. 2007.


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Geha and Notarangelo Correlates

15. Chediak-Higashi Syndrome

25. Neutropenia26. Chronic Granulomatous Disease *

27. Leukocyte Adhesion Deficiency *

* Posted online

Innate > Adaptive Summary


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Innate -> Adaptive Summary

Immune responses of the innate immune system provide natural immunity andfirst line of defense against microorganisms via phagocytosis and intracellular

killing, recruitment of other inflammatory cells, and presentation of antigens.

Innate defense barriers include (1) anatomic barriers, (2) physiologic barriers, (3)

Phagocytic barriers, and (4) inflammatory barriers. Tissue damage causes aninflux of inflammatory cells through chemotaxis, activation, margination and

diapedesis.

Neutrophils are usually the first cell type to arrive at the site of tissue damage.

Activation leads to respiratory bursts and release of granules to controlbacterial growth. Mononuclear cells and macrophages engulf organisms via

multiple mechanisms, leading to destruction within intracellular phagosomes.

Chemokines and cytokines are critical for activation of innate immune functions.

Defects may lead to severe clinical complications.

Pattern Recognition Receptors present on innate immune system cells assist in the

recognition of bacteria and virions. Recognition by PRRs leads to activation of

multiple facets of cellular response.

Signals from innate immune response drive maturation of T cell responses.

Selected Cytokines and their functions


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Selected Cytokines and their functions.

More Selected Cytokines and their functions


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More Selected Cytokines and their functions.

See syllabus appendix for more complete list of mediators, their

source, and their biological function.

Chemokines: Receptors and Associated Ligands


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Chemokines: Receptors and Associated Ligands

Complement


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Complement

Direct Cytolysis of foreign organisms

Opsonization of foreign organisms

Antibodies recognize pathogens.

Complement interacts with antibodies.

An enyzmatic cascade occurs to initiate development of amembrane attack complex forming a pore channel in the

lipid bilayer, causing osmotic lysis of the cell.

Complement components bind to pathogens.

Bound components interact with complement receptors on

the surface of macrophages, monocytes, and neutrophils.

Enhances phagocytosis and targeted organism destruction.

Activation and directed leukocyte migration Proteolytic degradation of complement components results

in leukocyte chemotactic anaphylatoxin.



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Hageman factor: Clotting and Complement activation

Thrombin: Clotting

Protease (34 kD) that acts on fibrinogen to produce fibrin

Kallikrein: Vascular reactions and Pain mediation

Plasma serine proteases; acts on kininogens to produce kinins

Plasmin: Management of Blood Clotting

Digestion of fibrin in blood clots

Bradykinin: Vasoactive nonapeptide

Potent vasodilator to increase post capillary venulespermeability; activates phospholipase A2

Phospholipases then feed into the Arachadonic Acid Pathway.

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Inmunidad Innata Actor