Transcript Lecture 7 Host Defense Against Infection

Microbiology 532: Immunology
Dennis E. Lopatin, Ph.D.
Dept. of Biologic and Materials Sciences
4209 Dental Building
Office Hours by Appointment
Phone: 647-3912
Electronic mail: [email protected]
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Lecture 1
Immunology
Introduction & Innate immunity
Why Does a Dentist Need to
Understand Immunology?
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Many of the oral diseases have an immune component
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Periodontal disease
Caries
Sjögren’s Syndrome
Current and future therapeutics affect the immune
system and oral health
Systemic and Oral diseases are interrelated
Cooperation with other health care professional requires a
common language
What is immunity?
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“Protection” from infection, tumors, etc.
Innate immunity is always available
Adaptive immunity distinguishes “self” from
“non-self” and involves immune system
“education”
Responses that may result in host tissue
damage
Two types of immunity
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Innate immunity (not antigen-specific)
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Anatomical barriers
Mechanical
Biochemical
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Non-specific (eg. Low pH in stomach)
Receptor-driven (eg. PAMP-recognition)
Adaptive immunity (antigen-specific)
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Receptor-driven
Pre-existing clones programmed to make a specific
immune response (humoral/cellular)
Antigen
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A substance (antigen) that is capable of
reacting with the products of a specific immune
response, e.g., antibody or specific sensitized Tlymphocytes.
A “self” component may be considered an
antigen even though one does not generally
make immune responses against those
components.
Characteristics of Adaptive Immunity
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Immune response is highly specific for the antigen that triggered
it.
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Receptors on surface of immune cells have same specificity as the
antibody/effector activity that will be generated
Exposure to antigen creates an immunologic “memory.”
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Due to clonal expansion and creation of a large pool of cells committed to
that antigen
Subsequent exposure to the same antigen results in a rapid and vigorous
response
Components of the immune
system
platelets
Cells eosinophil
involved
neutrophil
in
immunity
basophil
megakaryocyte
T Lymphocyte
Pluripotent
hematopoietic
stem cell
B Lymphocyte
common
myeloid
progenitor
common
lymphoid
progenitor
plasma cell
mast cell
Natural
Killer cell
monocyte
macrophage
Blood
Where is that stuff?
Serum or
Plasma
Leukocytes,
Platelets and RBC
Serum Proteins
Mononuclear
Cells
•Immunoglobulins
•Complement
•Clotting factors
•Many others
•Lymphocytes
(T cells, B cells
& NK cells)
•Monocytes
Polymorphonuclear
leukocytes (or
Granulocytes)
•Neutrophils
•Eosinophils
•Basophils
Lymphoid Organs
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Primary or central lymphoid organs
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bone marrow and thymus
where lymphocytes are generated
Secondary or peripheral lymphoid organs
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where adaptive immune responses are initiated
Distribution of Lymphoid Tissues
Response to Initial Infection
Stages of Response to Infection
Course
of Typical
Acute
Infection
Innate Host Defense Mechanisms
 Anatomic
Factors
 Mechanical Factors
 Biochemical Factors
Skin
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Stratified and cornified epithelium provides a
mechanical barrier
Indigenous microbiota competes with pathogens
Acid pH inhibits growth of disease producing
bacteria
Bactericidal long chain fatty acids in sebaceous
gland secretions
Respiratory Tract
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Upper Respiratory Tract
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Lower Respiratory Tract
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Nasal hairs induce turbulence
Mucous secretions trap particles
Mucous stream to the base of tongue where material is swallowed
Nasal secretions contain antimicrobial substances
Upper respiratory tract contains large resident flora
Particles trapped on mucous membranes of bronchi and bronchioles
Beating action of cilia causes mucociliary stream to flow up into the
pharynx where it is swallowed
90% of particles removed this way. Only smallest particles (<10µ in
diameter) reach alveoli
Alveoli
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Alveolar macrophage rapidly phagocytize small particles
Alimentary Tract
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General defense mechanisms
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Stomach
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Generally sterile due to low pH
Small Intestine
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Mucous secretions
Integrity of of mucosal epithelium
Peristaltic motions of the gut propel contents downward
Secretory antibody and phagocytic cells
Upper portion contains few bacteria
As distal end of ilieum is reached flora increases
Colon
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Enormous numbers of microorganisms
50-60% of fecal dry weight is bacteria
Genitourinary Tract
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Male
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No bacteria above urethrovesicular junction
Frequent flushing action of urine
Bactericidal substances from prostatic fluid
pH of urine
Bladder mucosal cells may be phagocytic
Urinary sIgA
Female (Vagina)
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Large microbial population (lactobacilli)
Microorganisms produce low pH due to breakdown of glycogen
produced by mucosal cells
Eye
Flushing action of tears which drain through
the lacrimal duct and deposit bacteria in
nasopharynx
 Tears contain a high concentration of
lysozyme (effective against gram positive
microorganisms
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Receptors
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Almost all of biology occurs because recognition
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Enzymatic action
Interactions between cells (cooperation/activation)
Communication between cells
Innate and adaptive immunity requires it
Innate Immune Recognition
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All multi-cellular organisms are able to recognize
and eliminate pathogens
Despite their extreme heterogeneity, pathogens
share highly conserved molecules, called
“pathogen-associated molecular patterns”
(PAMPs)
Host cells do not share PAMPs with pathogens
PAMPs are recognized by innate immune
recognition receptors called pattern-recognition
molecules/receptors (PRMs/PRRs)
Typical PAMPs
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Lipopolysaccharides
Peptidoglycans
Certain nucleotide sequences unique to bacteria
Other bacterial components
Endogenous Signals Induced by PAMPs
Mediate inflammatory cytokines
 Antigen-presenting cells recognize PAMPs
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Same APC processes pathogens into specific
pathogen-derived antigens and presents them with
MHC encoded receptors to T-cells
T-cell responds only when presented with both
signals
Different Effector Cytokines in Response to Different
Pathogens (Th1 vs. Th2)
Antimicrobial Peptides/Defensins
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Four hundred peptides described to date
Defensins (3- 5-kD, four families in eukaryotes)
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a-defensins (neutrophils and intestinal Paneth cells)
b-defensins (epithelial cells)
Insect defensins
Plant defensins
Defensins appear to act by binding to outer membrane
of bacteria, resulting in increased membrane
permeability.
May also play a role in inflammation and wound repair
Complement System
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Three pathways now known
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Classical
Alternative
Lectin or MBL pathway (binding to mannosecontaining carbohydrates)
Host cells have complement regulatory proteins
on their surface that protect them from
spontaneous activation of C3 molecules
Inflammatory Mediators in Innate Immunity
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Cytokines secreted by phagocytes in response to infection
include:
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IL-1
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IL-6
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Induces expression of b2 integrin adhesion molecules on neutrophils, leading
to neutrophil migration to infection site
IL-12
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Induces B-cell terminal maturation into Ig-producing plasma cells
IL-8
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activates vascular endothelium and lymphocytes
Increases adhesiveness of leukocytes
Activates NK cells and induces Th1-cell differentiation
IL-18
TNF-a
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Activates vascular endothelium and increases vascular permeability, leading to
accumulation of Ig and complement in infected tissues
Other Mediators and Molecules
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Phagocytes
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Toxic oxygen radicals
Peroxides
Nitric oxide (NO)
Lipid mediators of inflammation
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Complement component C5a
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Stimulates mast cells to release histamine, serotonin and LTB4
IL-1, IL-6 and TNF-a
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Prostaglandins
LTB4
Platelet activating factor
Induce acute-phase response in liver
Induce fever
IL-1 and IL-18 signaling pathways activate NF-kB, important in
innate immunity
Immune Cells and Innate Immunity
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Phagocytes
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Neutrophils
Moncyte/macrophage
Eosinophils (to a lesser extent)
NK cells
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Antibody-dependent cell-mediated cytotoxicity (ADCC)
Have two major functions
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Lysis of target cells
Production of cytokines (IFN-g and TNF-a)
Act against intracellular pathogens
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(large granular lymphocytes)
Herpesviruses
Leishmania
Listeria monocytogenes
Act against protozoa
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Toxoplasma
Trypanasoma
Immune Cells and Innate Immunity (cont’d)
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g/d T cells
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Two types of T cell receptors
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One composed of a and b chains (basic T cell antigen receptor)
One composed of g and d chains (minor population of T cells)
Two groups of g/d T cells
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One group found in lymphoid tissues
One group located in paracellular space between epithelial cells
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Recognizes unprocessed target antigen in absence of APC help
B-1 cells (minor fraction of B cells, do not require T-cell help)
Mast cells
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Located in serosa, under epithelial surfaces and adjacent to blood
vessels, nerves and glands
Capable of phagocytosis
Process and present antigen using MHC class I or II receptors
LPS can directly induce release of mast cell mediators
Complement (C3a and C5a) induce mast cells to release mediators
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Chemotaxis, complement activation, inflammation
TNF-a secreted by mast cells results in neutrophil influx into infected site
Summary of Innate Immunity
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External and mechanical barriers
Receptors for pathogen motifs
Soluble antimicrobial proteins
Pattern of cytokines produced influences
adaptive response