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: lopatin@umich.edu
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Readings in text are beneficial
I expect you to read the relevant chapters in Nester.
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Think, rather than memorize
Test questions are based on concepts
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Lecture 1
Immunology
Introduction & Innate immunity
Why Does a Dentist Need to
Understand Immunology?
Many of the oral diseases have an immune component
Periodontal disease
Caries
Sjgrens 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?
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
Innate immunity (not antigen-specific)
Anatomical barriers
Mechanical
Biochemical
Non-specific (eg. Low pH in stomach)
Receptor-driven (eg. PAMP-recognition)
Adaptive immunity (antigen-specific)
Receptor-driven
Pre-existing clones programmed to make a specific
immune response (humoral/cellular)
Antigen
A substance (antigen) that is capable of
reacting with the products of a specific immune
response, e.g., antibody or specific sensitized
T-lymphocytes.
A self component may be considered an
antigen even though one does not generally
make immune responses against those
components.
Characteristics of Adaptive Immunity
Immune response is highly specific for the antigen that triggered
it.
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.
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
Cells
involved
in
immunity
platelets
megakaryocyte
eosinophil
neutrophil
basophil
mast cell
common
myeloid
progenitor

monocyte
macrophage
Natural
Killer cell

plasma cell
B Lymphocyte
T Lymphocyte

common
lymphoid
progenitor

Pluripotent
hematopoietic
stem cell
Blood
Serum or
Plasma
Leukocytes,
Platelets and RBC
Serum Proteins
Mononuclear
Cells
Polymorphonuclear
leukocytes (or
Granulocytes)
Immunoglobulins
Complement
Clotting factors
Many others
Neutrophils
Eosinophils
Basophils
Lymphocytes
(T cells, B cells
& NK cells)
Monocytes
Where is that stuff?
Lymphoid Organs
Primary or central lymphoid organs
bone marrow and thymus
where lymphocytes are generated
Secondary or peripheral lymphoid organs
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
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
Upper Respiratory Tract
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
Lower Respiratory Tract
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 (<10 in
diameter) reach alveoli
Alveoli
Alveolar macrophage rapidly phagocytize small particles
Alimentary Tract
General defense mechanisms
Mucous secretions
Integrity of of mucosal epithelium
Peristaltic motions of the gut propel contents downward
Secretory antibody and phagocytic cells
Stomach
Generally sterile due to low pH
Small Intestine
Upper portion contains few bacteria
As distal end of ilieum is reached flora increases
Colon
Enormous numbers of microorganisms
50-60% of fecal dry weight is bacteria
Genitourinary Tract
Male
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)
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
Receptors
Almost all of biology occurs because recognition
Enzymatic action
Interactions between cells (cooperation/activation)
Communication between cells
Innate and adaptive immunity requires it
Innate Immune Recognition
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
Lipopolysaccharides
Peptidoglycans
Certain nucleotide sequences unique to bacteria
Other bacterial components
Endogenous Signals Induced by PAMPs
Mediate inflammatory cytokines
Antigen-presenting cells recognize PAMPs
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
Four hundred peptides described to date
Defensins (3- 5-kD, four families in eukaryotes)
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
Three pathways now known
Classical
Alternative
Lectin or MBL pathway (binding to mannose-
containing carbohydrates)
Host cells have complement regulatory proteins
on their surface that protect them from
spontaneous activation of C3 molecules
Inflammatory Mediators in Innate Immunity
Cytokines secreted by phagocytes in response to infection
include:
IL-1
activates vascular endothelium and lymphocytes
Increases adhesiveness of leukocytes
IL-6
Induces B-cell terminal maturation into Ig-producing plasma cells
IL-8
Induces expression of b2 integrin adhesion molecules on neutrophils, leading
to neutrophil migration to infection site
IL-12
Activates NK cells and induces Th1-cell differentiation
IL-18
TNF-a
Activates vascular endothelium and increases vascular permeability, leading to
accumulation of Ig and complement in infected tissues
Other Mediators and Molecules
Phagocytes
Toxic oxygen radicals
Peroxides
Nitric oxide (NO)
Lipid mediators of inflammation
Prostaglandins
LTB4
Platelet activating factor
Complement component C5a
Stimulates mast cells to release histamine, serotonin and LTB4
IL-1, IL-6 and TNF-a
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
Phagocytes
Neutrophils
Moncyte/macrophage
Eosinophils (to a lesser extent)
NK cells (large granular lymphocytes)
Antibody-dependent cell-mediated cytotoxicity (ADCC)
Have two major functions
Lysis of target cells
Production of cytokines (IFN-g and TNF-a)
Act against intracellular pathogens
Herpesviruses
Leishmania
Listeria monocytogenes
Act against protozoa
Toxoplasma
Trypanasoma
Immune Cells and Innate Immunity (contd)
g/d T cells
Two types of T cell receptors
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
One group found in lymphoid tissues
One group located in paracellular space between epithelial cells
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
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
Chemotaxis, complement activation, inflammation
TNF-a secreted by mast cells results in neutrophil influx into infected site

Summary of Innate Immunity
External and mechanical barriers
Receptors for pathogen motifs
Soluble antimicrobial proteins
Pattern of cytokines produced influences
adaptive response