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

Innate Immunity

Jeffrey K. Actor, Ph.D.

MSB 2.214, 500-5344

Lecture Objectives:

Introduce innate immune defense mechanisms.

Review cell types involved in innate immune

responses, and their role in inflammation.

Define ADCC, Chemokines, and Pattern-Recognition

Receptors.

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 molecules

frequently encountered on invading pathogens
allows defensive measures until specific immune
response is generated

4 Categories of Innate Immunity

Anatomic.

Physiologic.

Phagocytic and Endocytic.

Inflammatory.

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.

Physiologic Barrier

Includes temperature, low pH, chemical mediators.

Organisms can not multiply in elevated temperature.

Lysozymes degrade bacterial membranes.

Complement components in serum attack bacterial

membranes.
Low stomach pH discourages organism growth.
Lactoferrin inhibits bacterial growth.

Anatomic/Physiologic
(Secreted Substances)

Defensins: natural anti-microbial peptides

Phagocytic and Endocytic Barrier

Blood monocytes, tissue macrophages and neutrophils

phagocytose and kill microorganisms via complex
digestion mechanisms.
Bacteria ingested into phagocytic vesicles.
Phagosomes fuse with lysosomes.
Lysosomal enzymes digest captured organisms.
Interferons ( and ) inhibit viral expansion.

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

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).

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.

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).

Chemical Mediators of Inflammation

Kinin -> Fibrinolytic

Clotting
Complement

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.

Arachidonic Acid Metabolites: Inflammatory Role

Cells of the Innate Immune Response

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 oxygen
dependent or independent
pathways.

Neutrophils (contd)
Chemoattractants (eg. Interleukin-8 [IL-8], complement C5a)
trigger adhesion and subsequent diapedesis.
Neutrophil interaction with antibody and complement allow
increased 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 the

process of suppuration consists of innumerable neutrophils
(some dead and dying) and tissue debris.

Bactericidal Agents in Phagocytes

Neutrophil Transendothelial Migration

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

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 neutrophils
extra time to interact with adhesion molecules

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.

Mononuclear Cells and Macrophages

Monocytes and macrophages ingest and destroy bacteria
Multiple factors prepare particulate for engulfment and
targeting for destruction
opsonins comprised of complement components.

Phagocytes bear several different receptors that recognize

microbial components
induce phagocytosis
Pattern Recognition Receptors

Phagosome:Lysosome fusion
enzymatic degredation
NO mediated events
low pH
See Case #26: Chronic
Granulomatous Disease

Macrophages
After activation, these cells secrete interferons, lysosyme and
other immunoregulators of immune response. Released
molecules (cytokines) work on a local and on a systemic level.

What are Cytokines????

Cytokines from macrophages link Innate immunity (nonspecific)

with Adaptive immunity (specific).

Cytokines
Small molecular weight glycopeptides
Made by a variety of cells
Each cytokine has multiple activities [plieotropic],
dependent upon cell target, concentration, and
presence of other cytokines
Cytokines can facilitate innate immune function
and assist in activation of inflammatory responses
Often referred to as Interleukins

Selected Cytokines and their functions.

IL-8

Oh so simple..
Remember: I mentioned that each cytokine has multiple
activities [plieotropic] and is dependent upon cell target,
concentration, and presence of other cytokines. Actions can get
complicated very quickly.

NK Cells and ADCC

Kill infected or tumor self cells in the absence of
antigen-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 Mediated
Cytotoxicity (ADCC).

ADCC
Mediate ADCC using receptors for the constant portion of
an 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 killer
cells (Type II hypersensitivity).

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 two
cysteine residues.

Chemokine receptors are integral membrane proteins

having seven membrane-spanning helices.

Properties of Selected Chemokines

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 and
Macrophages,
Endothelium and
Epithelium

Chemoattractant for Eosinophils

CXCL8
(IL-8)

Monocytes and
Macrophages,
Fibroblasts, Endothelial
cells

Chemoattractant for Neutrophils

See syllabus appendix for more complete list of chemokines, their

source, and their biological function.

Complement

Complement
Direct Cytolysis of foreign organisms
An enyzmatic cascade: forms a pore channel in the lipid
bilayer, causing osmotic lysis of the cell.

Opsonization of foreign organisms

Coating organism enhances phagocytosis and targeted
destruction.

Directed leukocyte migration

Proteolytic degradation of complement components results
in leukocyte chemotaxis.

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.

Pattern Recognition Receptors

Receptors are referred to as Pattern-Recognition
Receptors (PRRs).
Engagement of PRRs leads to triggering of signal
pathways that promote inflammation.
-Complement receptors: target cell wall components
-Mannose-binding lectins: target mannose microbial carbohydrates
in bacterial cell membranes
-LPS-binding proteins: target bacterial lipopolysaccharide

-Toll-like receptors: multiple targets

-Scavenger receptors: targets phosphatidylserine and lipoproteins

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.

They recognize various pattern motifs, and control subsequent
signal transduction pathways.

Nature Reviews Immunology 1; 135-145 (2001); TOLL-LIKE RECEPTORS AND INNATE IMMUNITY

See Appendix for full list of receptors and ligands.

 Recognition of
pathogen via TLRs
activates and matures
Dendritic Cells and
macrophages (APCs).
APCs process antigen
and present to nave
T cells.
Presentation is
accompanied by
secretion of specific
cytokines to control
development of
phenotypic T cell
responses.

Toll-Like Receptors: The Complex Explanation

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

Component

Effectors

Anatomic and
physiologic
barriers

Skin and mucous membranes

Physical barriers to limit
Temperature, acidic pH, Lactic
entry, spread, and
acid, Chemical mediators
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 and

lactoferrin

Mediation of response

Leukotrienes and
prostaglandins

Vasodilation and increased

vascular permeability

Polymorphonuclear cells
Neutrophils, eosinophils
Basophils, mast cells

Phagocytosis and
intracellular destruction of
microorganisms

Phagocytic-endocytic cells
Monocytes and macrophages
Dendritic cells

Presentation of foreign
antigen to lymphocytes

Cellular
components

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

Function

Geha and Notarangelo Correlates

15. Chediak-Higashi Syndrome
25. Neutropenia
26. Chronic Granulomatous Disease *
27. Leukocyte Adhesion Deficiency *
* Posted online

Innate -> Adaptive Summary

Immune responses of the innate immune system provide natural immunity and
first 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 an
influx 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 control
bacterial 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.

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

Complement
Direct Cytolysis of foreign organisms
Antibodies recognize pathogens.
Complement interacts with antibodies.
An enyzmatic cascade occurs to initiate development of a
membrane attack complex forming a pore channel in the
lipid bilayer, causing osmotic lysis of the cell.

Opsonization of foreign organisms

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

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 venules
permeability; activates phospholipase A2
Phospholipases then feed into the Arachadonic Acid Pathway.