Download Reminder: Review the Histology lectures* about Cells and Organs of

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 (cont’d)
• 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 naïve
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 . Elsevier’s 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….