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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.
Critical Molecules in Injury
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Critical Molecules in Injury
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.