microbiology 532: immunology dennis e. lopatin, ph.d. dept. of biologic and materials sciences 4209...
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Microbiology 532: Microbiology 532: ImmunologyImmunology
Dennis E. Lopatin, Ph.D.Dennis E. Lopatin, Ph.D.Dept. of Biologic and Materials SciencesDept. of Biologic and Materials Sciences
4209 Dental Building4209 Dental Building
Office Hours by AppointmentOffice Hours by Appointment
Phone: 647-3912 Phone: 647-3912
Electronic mail: [email protected] mail: [email protected]
Helpful HintsHelpful Hints Readings in text are beneficialReadings in text are beneficial I I expectexpect you to read the relevant chapters in you to read the relevant chapters in
Nester.Nester. Understanding the Understanding the conceptsconcepts is not optional is not optional ThinkThink, rather than memorize, rather than memorize Test questions are based on Test questions are based on conceptsconcepts Ask questionsAsk questions Don’t wait until the last minute to studyDon’t wait until the last minute to study Check the websiteCheck the website
Lecture 1Lecture 1ImmunologyImmunology
Introduction & Innate immunityIntroduction & Innate immunity
Why Does a Dentist Need to Why Does a Dentist Need to Understand Immunology?Understand Immunology?
Many of the oral diseases have an immune Many of the oral diseases have an immune componentcomponent Periodontal diseasePeriodontal disease CariesCaries Sjögren’s SyndromeSjögren’s Syndrome
Current and future therapeutics affect the immune Current and future therapeutics affect the immune system and oral healthsystem and oral health
Systemic and Oral diseases are interrelatedSystemic and Oral diseases are interrelated Cooperation with other health care professional Cooperation with other health care professional
requires a common languagerequires a common language
What is immunity?What is immunity?
““Protection” from infection, tumors, Protection” from infection, tumors, etc.etc.
Innate immunity is always availableInnate immunity is always available Adaptive immunity distinguishes “self” Adaptive immunity distinguishes “self”
from “non-self” and involves immune from “non-self” and involves immune system “education”system “education”
Responses that may result in host Responses that may result in host tissue damagetissue damage
Two types of immunityTwo types of immunity Innate immunity (not antigen-specific)Innate immunity (not antigen-specific)
Anatomical barriersAnatomical barriers MechanicalMechanical BiochemicalBiochemical
Non-specific (eg. Low pH in stomach)Non-specific (eg. Low pH in stomach) Receptor-driven (eg. PAMP-recognition)Receptor-driven (eg. PAMP-recognition)
Adaptive immunity (antigen-specific)Adaptive immunity (antigen-specific) Receptor-drivenReceptor-driven Pre-existing clones programmed to make a Pre-existing clones programmed to make a
specific immune response (humoral/cellular)specific immune response (humoral/cellular)
AntigenAntigen
A substance (antigen) that is capable of A substance (antigen) that is capable of reactingreacting with the products of a specific with the products of a specific immune response, e.g., antibody or immune response, e.g., antibody or specific sensitized T-lymphocytes.specific sensitized T-lymphocytes.
A “self” component may be considered an A “self” component may be considered an antigen even though one does not antigen even though one does not generally make immune responses generally make immune responses against those components.against those components.
Characteristics of Adaptive Characteristics of Adaptive ImmunityImmunity
Immune response is highly specific for the antigen that Immune response is highly specific for the antigen that triggered it.triggered it. Receptors on surface of immune cells have same specificity as the Receptors on surface of immune cells have same specificity as the
antibody/effector activity that will be generatedantibody/effector activity that will be generated Exposure to antigen creates an immunologic “memory.”Exposure to antigen creates an immunologic “memory.”
Due to clonal expansion and creation of a large pool of cells Due to clonal expansion and creation of a large pool of cells committed to that antigencommitted to that antigen
Subsequent exposure to the same antigen results in a rapid and Subsequent exposure to the same antigen results in a rapid and vigorous responsevigorous response
Components of the Components of the immune systemimmune system
Cells Cells involved involved
in in immunityimmunity
platelets platelets
megakaryocyte megakaryocyte eosinophil eosinophil
neutrophil neutrophil
basophil basophil
mast cell mast cell
common common myeloid myeloid progenitor progenitor
monocyte monocyte
macrophage macrophage
NaturalNaturalKiller cellKiller cell
plasma cell plasma cell
B LymphocyteB Lymphocyte
T LymphocyteT Lymphocyte
common common lymphoid lymphoid progenitor progenitor
Pluripotent Pluripotent hematopoietichematopoieticstem cellstem cell
BloodBloodBloodBloodSerum or Serum or PlasmaPlasma
Leukocytes, Leukocytes, Platelets and RBCPlatelets and RBC
Serum ProteinsSerum ProteinsSerum ProteinsSerum Proteins Mononuclear Mononuclear CellsCells
Mononuclear Mononuclear CellsCells
Polymorphonuclear Polymorphonuclear leukocytes (or leukocytes (or Granulocytes)Granulocytes)
Polymorphonuclear Polymorphonuclear leukocytes (or leukocytes (or Granulocytes)Granulocytes)
•ImmunoglobulinsImmunoglobulins•ComplementComplement•Clotting factorsClotting factors•Many othersMany others
•ImmunoglobulinsImmunoglobulins•ComplementComplement•Clotting factorsClotting factors•Many othersMany others
•NeutrophilsNeutrophils•EosinophilsEosinophils•BasophilsBasophils
•NeutrophilsNeutrophils•EosinophilsEosinophils•BasophilsBasophils
•Lymphocytes Lymphocytes (T cells, B cells (T cells, B cells & NK cells)& NK cells)•MonocytesMonocytes
•Lymphocytes Lymphocytes (T cells, B cells (T cells, B cells & NK cells)& NK cells)•MonocytesMonocytes
Where is that stuff?Where is that stuff?
Lymphoid OrgansLymphoid Organs
Primary or central lymphoid organsPrimary or central lymphoid organs bone marrow and thymusbone marrow and thymus where lymphocytes are generatedwhere lymphocytes are generated
Secondary or peripheral lymphoid organsSecondary or peripheral lymphoid organs where adaptive immune responses are where adaptive immune responses are
initiatedinitiated
Distribution of Lymphoid TissuesDistribution of Lymphoid Tissues
Response to Initial Infection Response to Initial Infection
Stages of Response to InfectionStages of Response to Infection
Course Course of Typical of Typical
Acute Acute InfectionInfection
Innate Host Defense MechanismsInnate Host Defense Mechanisms
Anatomic FactorsAnatomic Factors Mechanical FactorsMechanical Factors Biochemical FactorsBiochemical Factors
SkinSkin
Stratified and cornified epithelium provides a Stratified and cornified epithelium provides a mechanical barriermechanical barrier
Indigenous microbiota competes with pathogensIndigenous microbiota competes with pathogens Acid pH inhibits growth of disease producing Acid pH inhibits growth of disease producing
bacteriabacteria Bactericidal long chain fatty acids in sebaceous Bactericidal long chain fatty acids in sebaceous
gland secretionsgland secretions
Respiratory TractRespiratory Tract Upper Respiratory TractUpper Respiratory Tract
Nasal hairs induce turbulenceNasal hairs induce turbulence Mucous secretions trap particlesMucous secretions trap particles Mucous stream to the base of tongue where material is swallowedMucous stream to the base of tongue where material is swallowed Nasal secretions contain antimicrobial substancesNasal secretions contain antimicrobial substances Upper respiratory tract contains large resident floraUpper respiratory tract contains large resident flora
Lower Respiratory TractLower Respiratory Tract Particles trapped on mucous membranes of bronchi and bronchiolesParticles trapped on mucous membranes of bronchi and bronchioles Beating action of cilia causes mucociliary stream to flow up into the pharynx Beating action of cilia causes mucociliary stream to flow up into the pharynx
where it is swallowedwhere it is swallowed 90% of particles removed this way. Only smallest particles (<10µ in 90% of particles removed this way. Only smallest particles (<10µ in
diameter) reach alveolidiameter) reach alveoli
AlveoliAlveoli Alveolar macrophage rapidly phagocytize small particlesAlveolar macrophage rapidly phagocytize small particles
Alimentary TractAlimentary Tract General defense mechanismsGeneral defense mechanisms
Mucous secretionsMucous secretions Integrity of of mucosal epitheliumIntegrity of of mucosal epithelium Peristaltic motions of the gut propel contents downwardPeristaltic motions of the gut propel contents downward Secretory antibody and phagocytic cellsSecretory antibody and phagocytic cells
StomachStomach Generally sterile due to low pHGenerally sterile due to low pH
Small IntestineSmall Intestine Upper portion contains few bacteriaUpper portion contains few bacteria As distal end of ilieum is reached flora increasesAs distal end of ilieum is reached flora increases
ColonColon Enormous numbers of microorganismsEnormous numbers of microorganisms 50-60% of fecal dry weight is bacteria50-60% of fecal dry weight is bacteria
Genitourinary TractGenitourinary Tract MaleMale
No bacteria above urethrovesicular junctionNo bacteria above urethrovesicular junction Frequent flushing action of urineFrequent flushing action of urine Bactericidal substances from prostatic fluidBactericidal substances from prostatic fluid pH of urinepH of urine Bladder mucosal cells may be phagocyticBladder mucosal cells may be phagocytic Urinary sIgAUrinary sIgA
Female (Vagina)Female (Vagina) Large microbial population (lactobacilli)Large microbial population (lactobacilli) Microorganisms produce low pH due to breakdown of glycogen produced by Microorganisms produce low pH due to breakdown of glycogen produced by
mucosal cellsmucosal cells
EyeEye
Flushing action of tears which drain through the Flushing action of tears which drain through the lacrimal duct and deposit bacteria in nasopharynxlacrimal duct and deposit bacteria in nasopharynx
Tears contain a high concentration of lysozyme Tears contain a high concentration of lysozyme (effective against gram positive microorganisms(effective against gram positive microorganisms
ReceptorsReceptors
Almost all of biology occurs because Almost all of biology occurs because recognitionrecognition Enzymatic actionEnzymatic action Interactions between cells Interactions between cells
(cooperation/activation)(cooperation/activation) Communication between cellsCommunication between cells
Innate and adaptive immunity requires itInnate and adaptive immunity requires it
Innate Immune RecognitionInnate Immune Recognition All multi-cellular organisms are able to All multi-cellular organisms are able to
recognize and eliminate pathogensrecognize and eliminate pathogens Despite their extreme heterogeneity, Despite their extreme heterogeneity,
pathogens share highly conserved molecules, pathogens share highly conserved molecules, called “pathogen-associated molecular called “pathogen-associated molecular patterns” (patterns” (PAMPsPAMPs))
Host cells do not share PAMPs with pathogensHost cells do not share PAMPs with pathogens PAMPs are recognized by innate immune PAMPs are recognized by innate immune
recognition receptors called pattern-recognition receptors called pattern-recognition molecules/receptors (recognition molecules/receptors (PRMs/PRRsPRMs/PRRs))
Typical PAMPsTypical PAMPs
LipopolysaccharidesLipopolysaccharides PeptidoglycansPeptidoglycans Certain nucleotide sequences unique to Certain nucleotide sequences unique to
bacteriabacteria Other bacterial componentsOther bacterial components
Endogenous Signals Induced by PAMPsEndogenous Signals Induced by PAMPs
Mediate inflammatory cytokinesMediate inflammatory cytokines Antigen-presenting cells recognize Antigen-presenting cells recognize
PAMPsPAMPs Same APC processes pathogens into specific Same APC processes pathogens into specific
pathogen-derived antigens and presents them pathogen-derived antigens and presents them with MHC encoded receptors to T-cellswith MHC encoded receptors to T-cells
T-cell responds only when presented with both T-cell responds only when presented with both signalssignals
Different Effector Cytokines in Response to Different Different Effector Cytokines in Response to Different Pathogens (Th1 vs. Th2)Pathogens (Th1 vs. Th2)
Antimicrobial Antimicrobial Peptides/DefensinsPeptides/Defensins
Four hundred peptides described to dateFour hundred peptides described to date Defensins (3- 5-kD, four families in eukaryotes)Defensins (3- 5-kD, four families in eukaryotes)
-defensins (neutrophils and intestinal Paneth cells)-defensins (neutrophils and intestinal Paneth cells) -defensins (epithelial cells)-defensins (epithelial cells) Insect defensinsInsect defensins Plant defensinsPlant defensins
Defensins appear to act by binding to outer Defensins appear to act by binding to outer membrane of bacteria, resulting in increased membrane of bacteria, resulting in increased membrane permeability.membrane permeability.
May also play a role in inflammation and wound May also play a role in inflammation and wound repairrepair
Complement SystemComplement System
Three pathways now knownThree pathways now known ClassicalClassical AlternativeAlternative Lectin or MBL pathway (binding to mannose-Lectin or MBL pathway (binding to mannose-
containing carbohydrates)containing carbohydrates) Host cells have complement regulatory Host cells have complement regulatory
proteins on their surface that protect them proteins on their surface that protect them from spontaneous activation of C3 moleculesfrom spontaneous activation of C3 molecules
Inflammatory Mediators in Innate Inflammatory Mediators in Innate ImmunityImmunity
Cytokines secreted by phagocytes in response to Cytokines secreted by phagocytes in response to infection include:infection include: IL-1 IL-1
activates vascular endothelium and lymphocytesactivates vascular endothelium and lymphocytes Increases adhesiveness of leukocytesIncreases adhesiveness of leukocytes
IL-6IL-6 Induces B-cell terminal maturation into Ig-producing plasma cellsInduces B-cell terminal maturation into Ig-producing plasma cells
IL-8IL-8 Induces expression of b2 integrin adhesion molecules on Induces expression of b2 integrin adhesion molecules on
neutrophils, leading to neutrophil migration to infection siteneutrophils, leading to neutrophil migration to infection site IL-12IL-12
Activates NK cells and induces Th1-cell differentiationActivates NK cells and induces Th1-cell differentiation IL-18IL-18 TNF-TNF-
Activates vascular endothelium and increases vascular permeability, Activates vascular endothelium and increases vascular permeability, leading to accumulation of Ig and complement in infected tissuesleading to accumulation of Ig and complement in infected tissues
Other Mediators and MoleculesOther Mediators and Molecules
PhagocytesPhagocytes Toxic oxygen radicalsToxic oxygen radicals PeroxidesPeroxides Nitric oxide (NO)Nitric oxide (NO) Lipid mediators of inflammationLipid mediators of inflammation
ProstaglandinsProstaglandins LTB4LTB4 Platelet activating factorPlatelet activating factor
Complement component C5aComplement component C5a Stimulates mast cells to release histamine, serotonin and LTB4Stimulates mast cells to release histamine, serotonin and LTB4
IL-1, IL-6 and TNF-IL-1, IL-6 and TNF- Induce acute-phase response in liverInduce acute-phase response in liver Induce feverInduce fever
IL-1 and IL-18 signaling pathways activate NF-IL-1 and IL-18 signaling pathways activate NF-B, important in B, important in innate immunityinnate immunity
Immune Cells and Innate ImmunityImmune Cells and Innate Immunity
PhagocytesPhagocytes NeutrophilsNeutrophils Moncyte/macrophageMoncyte/macrophage Eosinophils (to a lesser extent)Eosinophils (to a lesser extent)
NK cells NK cells (large granular lymphocytes)(large granular lymphocytes) Antibody-dependent cell-mediated cytotoxicity Antibody-dependent cell-mediated cytotoxicity
(ADCC)(ADCC) Have two major functionsHave two major functions
Lysis of target cellsLysis of target cells Production of cytokines (IFN-Production of cytokines (IFN- and TNF- and TNF-))
Act against intracellular pathogensAct against intracellular pathogens HerpesvirusesHerpesviruses LeishmaniaLeishmania Listeria monocytogenesListeria monocytogenes
Act against protozoaAct against protozoa ToxoplasmaToxoplasma TrypanasomaTrypanasoma
Immune Cells and Innate Immunity (cont’d)Immune Cells and Innate Immunity (cont’d)
// T cells T cells Two types of T cell receptorsTwo types of T cell receptors
One composed of One composed of and and chains (basic T cell antigen receptor) chains (basic T cell antigen receptor) One composed of One composed of and and chains (minor population of T cells) chains (minor population of T cells)
Two groups of Two groups of // T cells T cells One group found in lymphoid tissuesOne group found in lymphoid tissues One group located in paracellular space between epithelial cellsOne group located in paracellular space between epithelial cells
Recognizes unprocessed target antigen in absence of APC helpRecognizes unprocessed target antigen in absence of APC help B-1 cells (minor fraction of B cells, do not require T-cell help)B-1 cells (minor fraction of B cells, do not require T-cell help) Mast cellsMast cells
Located in serosa, under epithelial surfaces and adjacent to Located in serosa, under epithelial surfaces and adjacent to blood vessels, nerves and glandsblood vessels, nerves and glands
Capable of phagocytosisCapable of phagocytosis Process and present antigen using MHC class I or II receptorsProcess and present antigen using MHC class I or II receptors LPS can directly induce release of mast cell mediatorsLPS can directly induce release of mast cell mediators Complement (C3a and C5a) induce mast cells to release Complement (C3a and C5a) induce mast cells to release
mediatorsmediators Chemotaxis, complement activation, inflammationChemotaxis, complement activation, inflammation TNF-TNF- secreted by mast cells results in neutrophil influx into infected secreted by mast cells results in neutrophil influx into infected
sitesite
Summary of Innate ImmunitySummary of Innate Immunity
External and mechanical barriersExternal and mechanical barriers Receptors for pathogen motifsReceptors for pathogen motifs Soluble antimicrobial proteinsSoluble antimicrobial proteins Pattern of cytokines produced Pattern of cytokines produced
influences adaptive responseinfluences adaptive response