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INTRODUCTION TO IMMUNOLOGYINTRODUCTION TO IMMUNOLOGY
ImmunologyImmunology
Biochemical study of body defenses againstBiochemical study of body defenses against
parasites and microbes (bacteria, virus, fungiparasites and microbes (bacteria, virus, fungi
and parasites).and parasites).
Immunology important inImmunology important in Biomedical, clinical, dentistry, pharmacy andBiomedical, clinical, dentistry, pharmacy and
basic sciencesbasic sciences
Evolutionary trends from innate to adaptiveEvolutionary trends from innate to adaptive
immunityimmunity
Immunodiagnostics in the treatment andImmunodiagnostics in the treatment and
management of patients including underlyingmanagement of patients including underlying
mechanisms in the disease process.mechanisms in the disease process.
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Importance contImportance cont
Clinical transplantation offers life savingClinical transplantation offers life savingbenefits in diseased organs or tissuesbenefits in diseased organs or tissues Immunotherapeutic vaccines in theImmunotherapeutic vaccines in the
control of many diseases (viral andcontrol of many diseases (viral and
bacterial infections)bacterial infections) Anthropological studies to determineAnthropological studies to determine
migration patternsmigration patterns
Paternity identity and criminalPaternity identity and criminalidentification (employment of DNA andidentification (employment of DNA and
HLA profiles)HLA profiles)
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Historical PerspectivesHistorical Perspectives
First studies (1796) by Edward JennerFirst studies (1796) by Edward Jenner
Showed body could respond to foreignShowed body could respond to foreign
substances and generate the ability to defendsubstances and generate the ability to defend
itself in subsequent infections.itself in subsequent infections.
Exposure to cowpox led to resistance againstExposure to cowpox led to resistance against
smallpox.smallpox.
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Scientist(s) Contribution
Edward Jenner (1749 1823) Experimented with cowpox leading to small pox vaccine in
1796
Lowis Pasteur (1822) Introduced vaccine with the first attenuated virus vaccine.
Pasteur (1881 1885) Germ theory led to production of attenuated vaccines
against anthrax, cholera and rabies.
Ilya Metchnikoff (1845 1916) Proposed cellular theory of immunity involving
phagocytosis of wondering cells (1884).
Paul Ehrlich (1854 1915 Believed humoral immunity involving antibodies and notcells.
Wright and Douglas (1903) Demonstrated enhancement of phagocytosis by serum
opsonins indicating a linkage between humoral and cellular
immunity.
Von Behring (1854-1917) and
Kitasato (1870)
First described diphtheria antitoxin (antibody) (1890).
Robert Koch (1843-1910) Described delayed hypersensitivity reaction to tuberculin
(Kochs phenomenon).
Buchner (1893) Described a heat labile serum factor (complement)
Bordet (1895) Demonstrated bacteriolysis of Cholera vibrio by antibodyand complement.
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Ehrlich (1897) Proposed receptor theory of antibody synthesis and
first described neutrophils and eosinophils.
Landsteiner (1900) Discovered human ABO blood groups system
Von Pirquet (1874-1929) Described serum sickness
Fleming (1922) Identified lysozymes
Tiselius and Kobet (1938) Demonstrated that antibody activity resided in thegamma globulin portion of serum proteins.
Paul Ehrlich (1892) Showed maternal transfer of species specific
immunity to infant through milk.
Calmette Guerrin (1920) Developed avirulent BCG vaccine.
Colonel Ogden Bruton
(1952)
Found agammaglobulinaema in a male child.
Glick and Change (1956) Observed that antibody production in chickens
dependent on the presence of the Bursa of Fabricius
in birds
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Henson (1739-1774) Described lymphocytes and were stained and
studied by Paul Ehrlich (1879).
Holmes et al (1966) Described phagocytic defect, chronic granulomatowdisease, in children.
Doherty and Zinkernagel
(1974)Demonstrated that T cell recognition of antigen was
self MHC restricted (1996).
Susumu Tonegawa (1976) Discovered that single immunoglobulin proteinswere encoded by separate rearranging genes (1987).
Kohler and Milstein (1975) Discovered the principle for production of
monoclonal antibodies
Porter (1950s and 1960s) Showed immunoglobulins were composed of two
heavy and two light chains covalently bonded (1950).
Max Theiler (1938) Contributed to development of yellow fever vaccine
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BRANCHES OF IMMUNOLOGYBRANCHES OF IMMUNOLOGY
Basic ImmunologyBasic Immunology
Immunochemistry(PhysiochemicalImmunochemistry(Physiochemical
Properties)Properties)
Cellular (Cells) and MolecularCellular (Cells) and Molecular
(Molecules) Immunology(Molecules) Immunology
Clinical Immunology: Immunodeficiency;Clinical Immunology: Immunodeficiency;
Allergic and Hypersensitivity; AutoimmuneAllergic and Hypersensitivity; Autoimmune
Diseases; Reproductive Immunology;Diseases; Reproductive Immunology;
Immunohaematology; Tumour ImmunologyImmunohaematology; Tumour Immunology
and ClinicalTransplantationand ClinicalTransplantation
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Classification of Immune ResponsesClassification of Immune ResponsesBody defence mechanismsBody defence mechanisms
Innate and adaptive immunity.Innate and adaptive immunity.
Humoral responses involveHumoral responses involve
Soluble components includingSoluble components including
immunoglobulins (antibodies) andimmunoglobulins (antibodies) and
complement proteinscomplement proteins
Cellular (cells) responsesCellular (cells) responses
Lymphocytes, macrophages andLymphocytes, macrophages and
natural killer (NK) cells (principalnatural killer (NK) cells (principal
components)components)
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Outstanding FeaturesOutstanding Features
Adaptive immunityAdaptive immunity Recognition, narrow specificity andRecognition, narrow specificity and
memory.memory.
Innate immunityInnate immunity Constituted by inborn defenseConstituted by inborn defense
mechanismsmechanisms
Broad specificity, no memoryBroad specificity, no memory
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Characteristic Features of Immunity
Innate Immunity Adaptive Immunity
Inborn pattern recognition receptors
(PRRs) recognize pathogens
Randomly generated receptors
recognize pathogens
PRRs possess a broad specificity for
various Pathogen Associated
Molecular Patterns (PAMP)
Receptors specific for particular
epitopes : B cell receptor (BCR) and T
cell receptor (TCR)
Response immediate Response slow (3 - 5days) because of
immune system stimulation
No memory of prior exposure
Memory of prior exposure exists
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Innate MediatorsInnate Mediators
Innate immune responses involve severalInnate immune responses involve several
determinants (factors)determinants (factors)
Genetics, anatomical barriers, bacterialGenetics, anatomical barriers, bacterial
antagonismsantagonisms
Pattern-recognition receptors (PRR)Pattern-recognition receptors (PRR)
Nonspecific defense chemicalsNonspecific defense chemicals
Inflammation and fever.Inflammation and fever.
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Innate mediators contInnate mediators cont
Phagocytic cellsPhagocytic cells Neutrophils, monocytes and macrophagesNeutrophils, monocytes and macrophages
Basophils, mast cells and eosinophils releaseBasophils, mast cells and eosinophils release
inflammatory mediators.inflammatory mediators.
Soluble factorsSoluble factors Alternative pathway of complement activationAlternative pathway of complement activation
Provides defense against gram-negative bacteriaProvides defense against gram-negative bacteria
Interferons inhibit viral replication and activateInterferons inhibit viral replication and activate
inflammatory cells.inflammatory cells.
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Genetic DeterminantsGenetic DeterminantsIr genesIr genes Determine susceptibility or resistanceDetermine susceptibility or resistance
and clinical expression of variousand clinical expression of various
infectionsinfections
HLA genetic markersHLA genetic markers Linked to susceptibility rather thanLinked to susceptibility rather than
resistance to particular diseasesresistance to particular diseases
(autoimmune diseases)(autoimmune diseases)
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Genetic Factors in MalariaGenetic Factors in MalariaInnate protection associated withInnate protection associated with
Negative Duffy (a-b) blood groupsNegative Duffy (a-b) blood groups (Plasmodium(Plasmodiumvivax)vivax) Sickle cell trait A/SSickle cell trait A/S Plasmodium parasite infected erythrocytesPlasmodium parasite infected erythrocytes
highly susceptible to toxic oxygen intermediateshighly susceptible to toxic oxygen intermediatesor radicals.or radicals. Intracellular development ofIntracellular development ofP.falciparumP.falciparum in G-in G-
6-PO4 dehydrogenase deficient erythrocytes6-PO4 dehydrogenase deficient erythrocytesinhibited or retarded.inhibited or retarded.
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Physical BarriersPhysical BarriersSkin providesSkin provides
Intact outer horny layer mechanicalIntact outer horny layer mechanicalbarrier against most pathogens and theirbarrier against most pathogens and theirproductsproducts
Protective interface between internalProtective interface between internal
organs and the environment.organs and the environment.Dermis contains lymphocytes, mast cellsDermis contains lymphocytes, mast cells
and tissue macrophagesand tissue macrophages
Epidermis equipped withEpidermis equipped withimmunocompetent cells (Langerhans,immunocompetent cells (Langerhans,keratinocytes, epithelial cells, dendritickeratinocytes, epithelial cells, dendriticcells and epidermal T lymphocytes)cells and epidermal T lymphocytes)
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Physical Barriers ContPhysical Barriers ContMucous, air-blood barriers and cilia lining theMucous, air-blood barriers and cilia lining the
respiratory tractrespiratory tract Prevent adherence onto this portal entry byPrevent adherence onto this portal entry by
infectious agents.infectious agents. High viscosity mucous and beating cilia (upperHigh viscosity mucous and beating cilia (upper
and lower respiratory tracts)and lower respiratory tracts) Trap and expel inhaled micro-organisms andTrap and expel inhaled micro-organisms and
noxious agents through mucociliary systemnoxious agents through mucociliary system
mediated (mucociliary elevation)mediated (mucociliary elevation) Mucous gels are inherently sticky and the layerMucous gels are inherently sticky and the layer
provides a barrier to parasite establishmentprovides a barrier to parasite establishmentlike intestinal worms.like intestinal worms.
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GIT barriersGIT barriers
Epithelium of the mouth and tongueEpithelium of the mouth and tongueprotected by antimicrobial peptidesprotected by antimicrobial peptides
Stomach protected by pepsin digestedStomach protected by pepsin digested
antimicrobial peptides and by low pH ofantimicrobial peptides and by low pH of
gastric juicegastric juice
Colon supports commensals prevented fromColon supports commensals prevented from
invasion of its lining by antimicrobialinvasion of its lining by antimicrobial
peptides.peptides.
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Physical Barriers ContPhysical Barriers Cont
Human large intestine (colon) containsHuman large intestine (colon) containsenormous populations of commensalenormous populations of commensal
bacteria with several benefitsbacteria with several benefits
Synthesize vitaminsSynthesize vitamins Digest polysaccharides without humanDigest polysaccharides without human
enzymesenzymes
Prime adaptive immunity.Prime adaptive immunity.
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Physical Barriers To Infection
Barrier site (first line of defense) Activity
Skin sweat
Flushing, organic acids
Skin and GI tract natural fauna
(commensals)
Compete for niches
GI tract
Peristalsis, low pH, bile acid,
flushing, antibacterial peptides
Lung tracheal cilia
Mucociliary elevation
Nasopharynx, mucus and saliva, eye tears
Flushing, lysozymes
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RecognitonRecognitonInnate immunity recognizes a few highlyInnate immunity recognizes a few highly
conserved structures present in many differentconserved structures present in many differentmicroorganisms (pathogen associatedmicroorganisms (pathogen associatedmolecular patterns, PAMPs) egmolecular patterns, PAMPs) eg
Lipolysaccharide (LPS) or endotoxin fromLipolysaccharide (LPS) or endotoxin fromgram-negative bacteria cell wallgram-negative bacteria cell wall
Peptidoglycan, lipotechoic acids from gram-Peptidoglycan, lipotechoic acids from gram-positive cell wall, the sugar mannose (commonpositive cell wall, the sugar mannose (commonmicrobial glycolipids and glycoproteins)microbial glycolipids and glycoproteins)
Bacterial DNA, N-formylmethionine found inBacterial DNA, N-formylmethionine found in
bacterial proteinsbacterial proteins Double stranded RNA from viruses andDouble stranded RNA from viruses and
glucans from fungal cell walls.glucans from fungal cell walls.
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Toll-like ReceptorsToll-like Receptors Pattern-recognition receptors (PRRs) recognizePattern-recognition receptors (PRRs) recognize
common PAMPs of microorganisms.common PAMPs of microorganisms.Macrophages, dendritic cells and epithelial cellsMacrophages, dendritic cells and epithelial cells
expressexpress Transmembrane receptors that recognizeTransmembrane receptors that recognize
different types of PAMPs designated Toll-likedifferent types of PAMPs designated Toll-likereceptors (TLRs) egreceptors (TLRs) eg TLR-2 that binds to peptidoglycan of gram-TLR-2 that binds to peptidoglycan of gram-
positive bacteria (streptococci andpositive bacteria (streptococci andstaphylococci);staphylococci);
TLR-3 binds to ds RNA of virusesTLR-3 binds to ds RNA of viruses TLR-4 binds to LPS (endotoxin) of gram TLR-4 binds to LPS (endotoxin) of gram
negative bacteria (negative bacteria (SalmonellaSalmonella andandE.coliE.coli).).
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TLRs and FunctionsTLRs and FunctionsBinding of gram-positive bacteria to TLR-2 andBinding of gram-positive bacteria to TLR-2 and
gram-negative bacteria to TLR-4gram-negative bacteria to TLR-4
Enhances phagocytosis and fusion of theEnhances phagocytosis and fusion of thephagosomes with lysosomes. TLR-5 bindsphagosomes with lysosomes. TLR-5 bindsto flagellin of motile bacteria (to flagellin of motile bacteria (ListeriaListeria).).
TLR-7 and TLR-8 bind to single stranded RNTLR-7 and TLR-8 bind to single stranded RNA(ssRNA) genomes of various viruses (influenza,(ssRNA) genomes of various viruses (influenza,
measles and mumps).measles and mumps).
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Opsonization and PhagocytosisOpsonization and PhagocytosisOpsonization involves opsoninsOpsonization involves opsonins
Fibronectin (cold insoluble globulin)Fibronectin (cold insoluble globulin) Specific IgG antibodies (Fc-fragment),Specific IgG antibodies (Fc-fragment), C3b and iC3b, C3 products that facilitateC3b and iC3b, C3 products that facilitate
adherence of pathogens and membraneadherence of pathogens and membraneperturbation.perturbation.
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Phagocytosis processPhagocytosis processInvolveInvolve Formation of phagosome, fusion of phagosomeFormation of phagosome, fusion of phagosome
with lysosome and signal transduction leadingwith lysosome and signal transduction leadingto stimulation of calcium intracellular influx.to stimulation of calcium intracellular influx.
Activation of protein kinase C andActivation of protein kinase C andphospholipase occurs by diacylglycerolphospholipase occurs by diacylglycerolreleasing acid hydrolases and proteolyticreleasing acid hydrolases and proteolyticenzymes.enzymes.
Secondary granules contain lactoferrin,Secondary granules contain lactoferrin,gelatinase; complement receptors (CR1 andgelatinase; complement receptors (CR1 andCR3) and cytochrome B558 responsible forCR3) and cytochrome B558 responsible forintracellular killing machineryintracellular killing machinery
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Events in Phagocytosis involve (1) organism (bacterium) attaches to pseudopodia (long membrane evaginations) leading to (2) ingestion occurs forming
phagosome that (3) fuses with lysosome releasing lysosomal enzymes into phagosome and (4) digestion of ingested organism leading to (5) release of
products from the cell.
Source;http://www.whfreeman.com/COH1/phagocytosis.htm
http://www.whfreeman.com/COH1/phagocytosis.htmhttp://www.whfreeman.com/COH1/phagocytosis.htmhttp://www.whfreeman.com/COH1/phagocytosis.htm -
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Antimicrobial PeptidesAntimicrobial PeptidesAntimicrobial peptides include defensins andAntimicrobial peptides include defensins and
cathelicidinscathelicidins Protect against bacteria and other pathogens.Protect against bacteria and other pathogens.
DefensinsDefensins Secreted by epithelial cells (skin, GIT,Secreted by epithelial cells (skin, GIT,
genitourinary tract and nasal passages and lungs)genitourinary tract and nasal passages and lungs)or by recruited leukocytes (neutrophils).or by recruited leukocytes (neutrophils). Punch lethal holes facilitated by their positivePunch lethal holes facilitated by their positive
charges in penetrating the bacterial membranes.charges in penetrating the bacterial membranes.
CathelicidinsCathelicidins Secreted by epithelial and neutrophils withSecreted by epithelial and neutrophils withsecondary alpha helix structures.secondary alpha helix structures.
Synergistically with defensins confer protectionSynergistically with defensins confer protectionagainst microbes.against microbes.
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Microbicidal MechanismsMicrobicidal MechanismsMicrobicidal mechanisms associated withMicrobicidal mechanisms associated with
Assembly of NADPH oxidaseAssembly of NADPH oxidase Upregulation of cytochrome B558 inUpregulation of cytochrome B558 in
the activated neutrophils leading tothe activated neutrophils leading to
production of ROI (superoxides,production of ROI (superoxides,hydrogen peroxide)hydrogen peroxide)
Formation of chlorinated derivativesFormation of chlorinated derivatives
from hydrogen peroxide reaction withfrom hydrogen peroxide reaction withchlorides generating hypochloric acid,chlorides generating hypochloric acid,
a microbicidal agent.a microbicidal agent.
i A i i i
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Macrophage Derived Factors and Activities
Products Activity
Metabolites:
Reactive oxygen intermediates (ROI)
Reactive nitrogen intermediates (RNI)Eicosanoids, prostaglandins leukotrienes
Platelet activating factor
Inflammation and intracellular killing
Inflammation and intracellular killingRegulation of inflammation
Recruitment and activation of platelets.
Cytokines:
IL-1, TNF-, IL-6
IFN-IL-10
IL-12, IL-18
TGF-
Inflammation
Th1 activationTh1 suppression, Th2 activation
Activation of NK and T cells
Inflammation, tissue repair
Adhesion molecules:
Fibronectin
Thrombospondin
Opsonisation
Adhesion, phagocytosis
Complement:
C3b, C4b and C2b
Opsonisation
Enzymes:
Lysozyme
Collagenase, elactase
Degrades bacterial cell walls
Matrix catabolism
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Natural Killer (NK) CellsNatural Killer (NK) Cells Large granular lymphocytesLarge granular lymphocytes Posses CD16, CD56, CD 94, lectin-likePosses CD16, CD56, CD 94, lectin-like
and Ig-like receptors.and Ig-like receptors. Provide early MHC independentProvide early MHC independent
defence against intracellular infectionsdefence against intracellular infections(herpex group viruses,(herpex group viruses, LeishmaniaLeishmania andandListeria)Listeria)..
Activated by IFN-Activated by IFN- and IFN-and IFN- ininresponse to double stranded RNAresponse to double stranded RNAviruses.viruses.
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InflammationInflammation
Represents generalized response to infectionRepresents generalized response to infectionor tissue damageor tissue damage Designed to localize invadingDesigned to localize invading
microorganisms and arrest the spread ofmicroorganisms and arrest the spread of
the infectionsthe infections
Characterized by 4 symptoms: Heat,Characterized by 4 symptoms: Heat, PainPain
RednessRedness SwellingSwelling
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Inflammation contInflammation contMast cells initiate inflammation mediatedMast cells initiate inflammation mediated
by granules exocytosed when gram-by granules exocytosed when gram-negative bacteria derived LPS bindnegative bacteria derived LPS bindTLRs.TLRs.
Released histamine responsible forReleased histamine responsible for
redness and swelling associated withredness and swelling associated withinflammation.inflammation. Tumour necrosis factor-alpha (TNF-Tumour necrosis factor-alpha (TNF-))
and chemotactic cytokines secreted byand chemotactic cytokines secreted by
stimulated mast cells.stimulated mast cells.
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Inflammation contInflammation contReactive oxygen species and nitric oxideReactive oxygen species and nitric oxide
produced by activated phagocytesproduced by activated phagocytes
Toxic to microorganisms and may alsoToxic to microorganisms and may also
lead to tissue injury.lead to tissue injury. Macrophages and monocytes main sourceMacrophages and monocytes main source
of interleukin-1 (IL-1) causing fever.of interleukin-1 (IL-1) causing fever. Arachidonic acid derivatives (leukotrienesArachidonic acid derivatives (leukotrienes
and prostaglandins) potent mediators ofand prostaglandins) potent mediators ofinflammationinflammation
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Inflammatory responseInflammatory responseLyses of blood cells and releaseLyses of blood cells and release Bradykinin and prostaglandin cause theBradykinin and prostaglandin cause the
pain associated with inflammationpain associated with inflammation Lysosomal enzymes from damaged whiteLysosomal enzymes from damaged white
blood cellsblood cells Serotonin from plateletsSerotonin from platelets Prostaglandins from damaged cellProstaglandins from damaged cell
membranesmembranes
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Acute phase proteinsAcute phase proteins
Acute phase responesAcute phase respones Leads to elevated production of protectiveLeads to elevated production of protective
acute phase proteins by greater than 100acute phase proteins by greater than 100
fold (C-reactive proteins, serum amyloid Afold (C-reactive proteins, serum amyloid Aprotein and protein and 22
macroglobulin).macroglobulin).
Acute phase proteins mediate restoration ofAcute phase proteins mediate restoration of
tissue integrity by restricting damage to thetissue integrity by restricting damage to theinjured site.injured site.
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Summary of Innate DeterminantsSummary of Innate Determinants Genetics: Ir and HLA genesGenetics: Ir and HLA genes Anatomical (physical barriers): skin,Anatomical (physical barriers): skin,
mucociliary elevation, cough reflex, waxmucociliary elevation, cough reflex, wax Antagonism: commensal bacteriaAntagonism: commensal bacteria Soluble factors/chemicals: alternativeSoluble factors/chemicals: alternative
complement proteins, IFNs, cytokines,complement proteins, IFNs, cytokines,
lysozymes, lactoferrin, antimicrobiallysozymes, lactoferrin, antimicrobial
peptides, acidspeptides, acids Cells: phagocytes, granulocytes, NK cellsCells: phagocytes, granulocytes, NK cells
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Summary contSummary contInflammation and feverInflammation and fever PMNL recruitment and activationPMNL recruitment and activation Bradykinins and prostaglandinsBradykinins and prostaglandins HistaminesHistamines
Lysosomal enzymesLysosomal enzymes Serotonin from plateletsSerotonin from platelets Reactive oxygen intermediatesReactive oxygen intermediates Cytokines (IL-1, TNF)Cytokines (IL-1, TNF) Acute phase proteinsAcute phase proteins
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Activation of Adaptive ImmunityActivation of Adaptive ImmunityInnate immunity may trigger adaptive immuneInnate immunity may trigger adaptive immune
responses thruresponses thru Antigen processing and presentation byAntigen processing and presentation by
macrophages and dendritic cellsmacrophages and dendritic cells Induction of costimulatory molecules (CD80/86)Induction of costimulatory molecules (CD80/86)
by interaction with PAMPs and TLRs, CD28by interaction with PAMPs and TLRs, CD28binding and full T cell activation.binding and full T cell activation. PAMPs (LPS) bind to TLR on B cells enhancingPAMPs (LPS) bind to TLR on B cells enhancing
their response to antigen.their response to antigen.
Several adjuvants contain PAMPs thusSeveral adjuvants contain PAMPs thusaugmenting further adaptive response toaugmenting further adaptive response to
vaccines.vaccines.
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Heat shock proteins (HSP)Heat shock proteins (HSP)
HSP lHSP linked to activation of adaptiveinked to activation of adaptiveimmunity.immunity.
Family of substances produced when cellsFamily of substances produced when cells
and various infectious agents are exposed toand various infectious agents are exposed toelevated temperatures.elevated temperatures.
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Immune System ComponentsImmune System ComponentsMajor histocompatibility complex (MHC) systemMajor histocompatibility complex (MHC) system Chromosome, gene, haplotype, and polymorphismChromosome, gene, haplotype, and polymorphism
and super gene family molecules.and super gene family molecules.
Humoral immunity consists ofHumoral immunity consists of B-lymphocytes, bone marrow, stem cells, plasmaB-lymphocytes, bone marrow, stem cells, plasma
cells, immunoglobulins (Igs) IgG, IgM, IgA, IgEcells, immunoglobulins (Igs) IgG, IgM, IgA, IgEand IgD classes, class switching, antibody,and IgD classes, class switching, antibody,gammaglobulins and complement system proteins.gammaglobulins and complement system proteins.
Cell mediated immunity comprisesCell mediated immunity comprises
Lymphocytes(CD1,CD2, CD3, CD4, CD8),Lymphocytes(CD1,CD2, CD3, CD4, CD8),monocytes-macrophages, NK cells and cytokinesmonocytes-macrophages, NK cells and cytokines
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Concepts and PrinciplesConcepts and PrinciplesAntigenicity and immunogenicity requireAntigenicity and immunogenicity require
definition ofdefinition of Antigen, immunogen, hapten, carrier,Antigen, immunogen, hapten, carrier,
mitogen, alloantigen and an adjuvant.mitogen, alloantigen and an adjuvant.
Antigen-antibody reactions involve theAntigen-antibody reactions involve the
understanding ofunderstanding of Immune complex (IC), epitope, agretope,Immune complex (IC), epitope, agretope,
affinity, avidity, cross-reactivity,affinity, avidity, cross-reactivity,precipitation reactions and agglutinationprecipitation reactions and agglutination
reactions.reactions.
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AntigensAntigensSubstance which induce and react with immuneSubstance which induce and react with immune
responses (B or T or B+T)responses (B or T or B+T) ProteinsProteins Glycoproteins and lipoproteinsGlycoproteins and lipoproteins Synthetic peptidesSynthetic peptides Alloantigens (transmembrane proteins)Alloantigens (transmembrane proteins) Nucleoproteins, hormones, drugs, metalsNucleoproteins, hormones, drugs, metals Polysaccharides and glycolipidsPolysaccharides and glycolipids
Pathogen (microbial) components and vaccinesPathogen (microbial) components and vaccines
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Microbial derived antigensMicrobial derived antigensEntire cell (virus, bacteria and tumourEntire cell (virus, bacteria and tumour
cells), parasite surface coat (protozoa) orcells), parasite surface coat (protozoa) orproducts (toxins).products (toxins).
Conserved proteins major antigens in infectionConserved proteins major antigens in infection
Aldolase (target of human antibodyAldolase (target of human antibodyresponse againstresponse againstP. falciparum)P. falciparum) Myosin (antigen inMyosin (antigen in S. mansoniS. mansoni)) Superoxide dismutase (Superoxide dismutase (M. lepraeM. leprae) and) and
cyclophilin (cyclophilin (E. granulosusE. granulosus).).
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Sperm antigensSperm antigensSperm surface antigenic determinants and theSperm surface antigenic determinants and the
seminal plasma constituents antigenicseminal plasma constituents antigenic Sperm X-Y specific antigens induces immuneSperm X-Y specific antigens induces immune
responses.responses.
Fluid transport of spermatozoa (seminal plasma)Fluid transport of spermatozoa (seminal plasma)
contains variety of potentially antigeniccontains variety of potentially antigeniccomponents egcomponents eg Decapitation factors, immunosuppressiveDecapitation factors, immunosuppressive
substances,substances,
Low molecular weight nitrogenous substances,Low molecular weight nitrogenous substances,polyamines (spermine and spermidine),polyamines (spermine and spermidine),
Carbohydrates (fructose, inositol) andCarbohydrates (fructose, inositol) andprostaglandinsprostaglandins..
S A i
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Sperm Antigen contSperm Antigen contLactoferrinLactoferrin
Iron-binding proteinIron-binding protein Adsorbs onto the sperm and forms a majorAdsorbs onto the sperm and forms a major
component of sperm-coating antigen.component of sperm-coating antigen.
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Vaccine AgsVaccine Ags Live attenuated viruses (Sabin for polio,Live attenuated viruses (Sabin for polio,
measles, small pox, hepatitis, yellow fever);measles, small pox, hepatitis, yellow fever);
attenuated bacterial vaccines (BCG) orattenuated bacterial vaccines (BCG) or
Inactivated microorganisms (Salk for polio,Inactivated microorganisms (Salk for polio,
typhoid, cholera, Pertussis)typhoid, cholera, Pertussis)
Subunit vaccines (influenza, meningococcalSubunit vaccines (influenza, meningococcal
and Pertussis antigens).and Pertussis antigens).
All iAll ti
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AlloantigensAlloantigens
Transmembrane proteins egTransmembrane proteins eg Major histocompatibility complex (MHC)Major histocompatibility complex (MHC)
antigensantigens Blood group antigens.Blood group antigens. T cell independent antigens activate BT cell independent antigens activate B
cells directly (polysaccharides) without Tcells directly (polysaccharides) without T
cells helpcells help
T cell dependent antigens activate B cellsT cell dependent antigens activate B cellswith T cell help (mainly proteins).with T cell help (mainly proteins).
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SuperantigensSuperantigensMicrobial proteins produced by bacteria orMicrobial proteins produced by bacteria or
viruses capable of stimulating massive Tviruses capable of stimulating massive Tcell functions.cell functions.
Trigger diseases eg staphylococcal toxicTrigger diseases eg staphylococcal toxic
syndrome, staphylococcal food poisoningsyndrome, staphylococcal food poisoningand long-term effects includingand long-term effects including Autoimmune diseases (rheumatic arthritis,Autoimmune diseases (rheumatic arthritis,
multiple sclerosis, diabetes and rheumaticmultiple sclerosis, diabetes and rheumatic
fever), Kawasahi syndrome, atopicfever), Kawasahi syndrome, atopicdermatitis and periodontal disorders.dermatitis and periodontal disorders.
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M l l i d l iM l l i d l it
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Molecular size and complexityMolecular size and complexity
Epitopes or antigenic determinantsEpitopes or antigenic determinants
High molecular weight substances greater thanHigh molecular weight substances greater than
6kDa (albumin, tetanus toxoid) highly6kDa (albumin, tetanus toxoid) highly
immunogenicimmunogenic
Between 1-6 kDa (insulin, adrenocorticotropicBetween 1-6 kDa (insulin, adrenocorticotropichormone) less immunogenichormone) less immunogenic
Less than 1 kDa (penicillin, aspirin,Less than 1 kDa (penicillin, aspirin,
progesterons) not immunogenic.progesterons) not immunogenic.
Adj tAdj t
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AdjuvantsAdjuvants Substances administered together with antigensSubstances administered together with antigens
to improve their immunogenicity.to improve their immunogenicity. Facilitate activation of accessory cells andFacilitate activation of accessory cells and
production of cytokines &provide signals forproduction of cytokines &provide signals for
stimulation of lymphocytes.stimulation of lymphocytes.
Most common inorganic adjuvantsMost common inorganic adjuvants
Aluminium hydroxide (alum); aluminiumAluminium hydroxide (alum); aluminium
phosphate; potassium ammonium sulphate andphosphate; potassium ammonium sulphate and
calcium phosphate.calcium phosphate.
A ti Ad i i t tiA ti Ad i i t ti
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Antigen AdministrationAntigen AdministrationRoutes employedRoutes employed
Intravenous; intradermal; intraperitoneal;Intravenous; intradermal; intraperitoneal;subcutaneous; submucosal and direct antigensubcutaneous; submucosal and direct antigenplacement on/or in the mucosa.placement on/or in the mucosa.
GenerallyGenerally High immune responses induced when antigensHigh immune responses induced when antigens
administered subcutaneously or intradermallyadministered subcutaneously or intradermally Intravenous applications tend to activateIntravenous applications tend to activate
suppressor or inhibitory mechanismssuppressor or inhibitory mechanisms Subcutaneous inoculation superior toSubcutaneous inoculation superior to
intramuscular antigen administration.intramuscular antigen administration.
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Age determinantAge determinant
Immature/preterm and old age individualsImmature/preterm and old age individualsassociated with diminished immune activityassociated with diminished immune activity
Poor and high responders associated withPoor and high responders associated with
immune response genesimmune response genes
S I i it Ch t i tiS I i it Ch t i ti
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Summary Immunogenicity CharacteristicsSummary Immunogenicity Characteristics
Molecular sizeMolecular size
Degree of foreignnessDegree of foreignness Chemical composition and textureChemical composition and texture
Dose and route of antigen administrationDose and route of antigen administration
Genetic constitution and age of theGenetic constitution and age of the
individualindividual
H iti S tH iti S t
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Haemopoitic SystemHaemopoitic SystemHaemopoiesis occursHaemopoiesis occurs
First in the yolk sac and foetal liver at 6 weeks, spleenFirst in the yolk sac and foetal liver at 6 weeks, spleenat 12 weeks and finallyat 12 weeks and finally
Bone marrow at 20 weeks of gestation as well as inBone marrow at 20 weeks of gestation as well as in
adult life.adult life.
Lymphoid lineage pathway gives rise toLymphoid lineage pathway gives rise to Thymus-derived (T) and bone marrow derived (B)Thymus-derived (T) and bone marrow derived (B)
lymphocyteslymphocytes
Myeloid stem cells generateMyeloid stem cells generate
Mononuclear phagocytes (monocytes andMononuclear phagocytes (monocytes andmacrophages); polymorphonuclear lymphocytes;macrophages); polymorphonuclear lymphocytes;
mast cells; megakaryocytes and platelets.mast cells; megakaryocytes and platelets.
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Fig 3. Haemopoetic Cell Differentiation: Multipotent stem cells differentiate through either myeloid or lymphoid
pathways. Myeloid progenitor cells arte stimulated granulocyte-macrophage colony stimulating factor (GM-CSF) into
granulocyte-macrophage proginators, which differentiate into basophils, neutrophils or eosinophils, enhanced by IL-3,
G-CSF or IL-5 respectively. Monocyte- colony stimulating factor (M-CSF) stimulates granulocyte-macrophage
proginators into monocytes while EPO, TPO and IL-11 stimulate myeloid proginator cell differentiation into eventual
red blood cells and platelets. In the lymphoid pathway, B and T lymphocytes are derived from lymphoid progenitors
through differentiation of stem cells enhanced by IL-6 and IL-7 cytokines. Myeloid differentiation pattern is further
illustrated in Figs 3A and 3C.
Growth Factors and Biological Activities
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Growth Factors and Biological Activities
Growth Factors Source Biological Functions
PDGF
(Platelet Derived Growth
Factor)
Platelets, endothelial
cells, placenta
Promotes proliferation of
connective tissue, glial and
smooth muscle cells
EGF
(Epidermal Growth Factor)
Sub-maxillary gland,
Brunners gland
Promotes proliferation of
mesenchymal, glial and
epithelial cells
TGF- (Transforming GrowthFactor alpha)
Common in transformed
cells
May be important for normal
wound healing
FGF (Fibroblast Growth
Factor)
Wide range of cells Promotes proliferation of many
cells; inhibits some stem cells
and embryos
EPO (Erythropoietin) Kidney Promotes proliferation and
differentiation of erythrocytes
TGF- (Transforming GrowthFactor beta)
Activated Th1cells and
natural killer (NK) cells
Anti-inflammatory; promotes
wound healing; inhibits
macrophage and lymphocyte
proliferation.
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Lymphoid CellsLymphoid Cells
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Lymphoid CellsLymphoid CellsDistinguished by expression ofDistinguished by expression of
Surface immunoglobulin (SmIg) on their cellSurface immunoglobulin (SmIg) on their cellmembranes.membranes.
Stimulation of B cells lead to the production ofStimulation of B cells lead to the production of Various immunoglubulins mediatingVarious immunoglubulins mediating
humoral (antibody) immune responses.humoral (antibody) immune responses.Lymphocyte differentiation antigensLymphocyte differentiation antigens
Most common cluster of human lymphocyteMost common cluster of human lymphocytelineage differentiation antigens (CD) exist forlineage differentiation antigens (CD) exist for
both B cells and T cells.both B cells and T cells.
TABLE 6: Major B Cell And T Cell Differentiation Antigens
B Cell Types Expressing the
Antigen
T Cell Types Expressing the
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Antigen
Cluster (CD)
B Cell Types Expressing the
Antigen
Antigen
Cluster
(CD)
T Cell Types Expressing the
Antigen
CD 10 Committed B cell progenitors;
Pre-B cells
CD 1 Thymocytes, dendritic cells
CD 19 All cells from early pre-B stage
to plasma stage (>90% of blood
B cells)
CD 2
E-resetting T cells
CD 20 Late pre-B to plasma stage cells
CD 3
T cell (pan T) associated with
TCR
CD 21 All B cells in blood and
lymphoid tissues
CD 4
Helper/Inducer T cells
CD 22 Early pre-B cell stages to
terminal plasma cell phase
CD 5
T cell (Pan T)
CD 23 Small activated B cells in tissue
CD 6
T cell (Pan T): some B cells
CD 24 B cell progenitors
CD 7
T cell (Pan T)
CD 25 Activated T and B cells
CD 8
Cytotoxic/suppressor T cells
CD 37 Late-B cell stage and early
terminal plasma
CD 10
Early B cells, some T cells and
granulocytes
CD 38 Germinal center B cells
CD 30
Activated T and B cells
CD 39 Mentlezone B cells
CD 38
Thymocytes; active
lymphocytes
CD 40 B cells; follicular dentritic cells(FDC)
CD 45R
Supp/indu/T cells; B cells
Organs of Immune SystemOrgans of Immune System
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Organs of Immune SystemOrgans of Immune SystemPluripotent stem cells in the bone marrowPluripotent stem cells in the bone marrow
Differentiate into B lymphocytes and TDifferentiate into B lymphocytes and Tlymphocyteslymphocytes..
Lymphoid immune system consists ofLymphoid immune system consists of
Primary lymphoid (1Primary lymphoid (100 ) organs and) organs and Secondary lymphoid (2Secondary lymphoid (200) organs.)) organs.)
Primary Lymphoid OrgansPrimary Lymphoid Organs
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Primary Lymphoid OrgansPrimary Lymphoid OrgansThree human primary lymphoid organsThree human primary lymphoid organs
Thymus, bone marrow and Peyers patchesThymus, bone marrow and Peyers patchesThymus arises from endoderm of the thirdThymus arises from endoderm of the third
and fourth pharyngeal pouchesand fourth pharyngeal pouches
A flat and bilobed organ above heart andA flat and bilobed organ above heart andbelow the thyroid glandbelow the thyroid gland Largest relative size at birth and actualLargest relative size at birth and actual
largest size at puberty.largest size at puberty.
Thymus contThymus cont
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Thymus contThymus contAfter puberty the thymus shrinks and T cellAfter puberty the thymus shrinks and T cell
production declinesproduction declines
Children born without a thymus suffer fromChildren born without a thymus suffer fromDiGeorge syndrome.DiGeorge syndrome.
Each lobule organized intoEach lobule organized into
Cortex (infiltrated with rapidly dividingCortex (infiltrated with rapidly dividinglymphocytes, thymocytes)lymphocytes, thymocytes)
Medulla (containing visible epithelial cells).Medulla (containing visible epithelial cells).
Both cortex and medulla contain stroma cellsBoth cortex and medulla contain stroma cells
Composed of loosely packed thymicComposed of loosely packed thymic
epithelial cells, intergitating dendriticepithelial cells, intergitating dendritic
cells and macrophagescells and macrophages
Thymus contThymus cont
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Thymus contThymus contDifferentiation and maturation of T cellsDifferentiation and maturation of T cells
mediated bymediated by Thymic epithelial cells and derivedThymic epithelial cells and derived
Hormonal factors (Hormonal factors (-thymosin,-thymosin, 44--
thymosin, thymopoietin, thymulin) andthymosin, thymopoietin, thymulin) andIL-7.IL-7.
A series of gene rearrangements selectA series of gene rearrangements select
antigenic diversity of T cell receptorantigenic diversity of T cell receptor(TCR).(TCR).
Thymus contThymus cont
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Thymus contThymus contThymocytes undergo thymic educationThymocytes undergo thymic education
Thymic cortical epithelial cells function inThymic cortical epithelial cells function in
positive selection process.positive selection process. T cells which bear TCR binding self-MHCT cells which bear TCR binding self-MHC
molecules are selected to survive andmolecules are selected to survive and
proliferate (positive selection)proliferate (positive selection) Vast majority of remaining (95-99%) areVast majority of remaining (95-99%) are
eliminated by programmed cell deatheliminated by programmed cell death(apoptosis(apoptosis).).
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Peyers patchesPeyers patches
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Peyer s patchesPeyer s patches Located in the human wall of theLocated in the human wall of the
intestine.intestine.PP exits withPP exits with
Primary lymphoid function and anotherPrimary lymphoid function and another
With secondary lymphoid functionWith secondary lymphoid function
Bursa of FabriciousBursa of Fabricious
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Bursa of FabriciousBursa of FabriciousBF a round, sac like structure located above theBF a round, sac like structure located above the
cloaca of birdscloaca of birds
Contain epithelial cells with lymphoid cells.Contain epithelial cells with lymphoid cells.
Follicles divided into cortex and medullaFollicles divided into cortex and medulla
Cortex contain macrophages, lymphocytes andCortex contain macrophages, lymphocytes and
plasma cells.plasma cells.
BF serves as site of B cell maturation andBF serves as site of B cell maturation and
differentiationdifferentiation
Secondary Lymphoid OrgansSecondary Lymphoid Organs
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Secondary Lymphoid OrgansSecondary Lymphoid OrgansSecondary lymphoid organsSecondary lymphoid organs
Sites where lymphocytes encounterSites where lymphocytes encounterantigensantigens
Interact with other cells and enlarge inInteract with other cells and enlarge in
response to antigenic stimulation.response to antigenic stimulation. Poorly developed in germ-free animals.Poorly developed in germ-free animals.
Lymphoid organs morphologically dividedLymphoid organs morphologically divided
into: cortex, paracortex and medullainto: cortex, paracortex and medulla
Second Lymph organ contSecond Lymph organ cont
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Second Lymph organ contSecond Lymph organ cont Cortex (outermost layer full of B lymphocytesCortex (outermost layer full of B lymphocytes
and macrophages arranged in primary follicles)and macrophages arranged in primary follicles) Paracortex (beneath the cortex, populated withParacortex (beneath the cortex, populated with
T lymphocytes and dendritic cells)T lymphocytes and dendritic cells) Medulla (innermost with sparsely populatedMedulla (innermost with sparsely populated
lymphocytes and plasma cells).lymphocytes and plasma cells).Lymphocyte circulation involveLymphocyte circulation involve
Nave T cells that bind to endothelium ofNave T cells that bind to endothelium of
venules in the paracortexvenules in the paracortex T cells leave the bloodstream viaT cells leave the bloodstream via
conventional blood vessels and carried toconventional blood vessels and carried to
the lymph nodes via tissue fluid (plasma).the lymph nodes via tissue fluid (plasma).
A schematic presentation of secondary lymphoidA schematic presentation of secondary lymphoid
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p y y pp y y p
organ is provided in Fig. 8organ is provided in Fig. 8..
Fig. 8 Structure of a Secondary Lymphoid Organ: Refer to text for the details. Source: http://www-immuno.path.com.oc.uk
Lymph NodeLymph Node
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Lymph NodeLymph NodeLymph nodesLymph nodes Encapsulated and packed with lymphocytes,Encapsulated and packed with lymphocytes,
macrophages and dendritic cells,macrophages and dendritic cells, Filter antigens from the lymph,Filter antigens from the lymph, Consist of cortex, paracortex and medulla.Consist of cortex, paracortex and medulla.
Cortex (outer most layer) containsCortex (outer most layer) contains Mostly B lymphocytes, follicular dendritic cellsMostly B lymphocytes, follicular dendritic cells
and macrophages all arranged in clustersand macrophages all arranged in clusters(designated primary follicles(designated primary follicles
Antigen StimulationAntigen Stimulation
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Antigen StimulationAntigen StimulationFollowing antigen stimulation the follicles becomeFollowing antigen stimulation the follicles become Secondary follicles consisting ofSecondary follicles consisting of Concentric rings (germinal centres) of denselyConcentric rings (germinal centres) of densely
packed lymphocytes, macrophages and dendriticpacked lymphocytes, macrophages and dendriticcells.cells.
Germinal centresGerminal centres Sites of intense B cell activation andSites of intense B cell activation and
differentiation into plasma cells and memory cells.differentiation into plasma cells and memory cells.
Paracortex (just beneath the cortex) designated TParacortex (just beneath the cortex) designated Tdependent regiondependent region
Populated with T lymphocytes and interdigitatingPopulated with T lymphocytes and interdigitatingdendritic cells important in T cell activation.dendritic cells important in T cell activation.
MedullaMedulla
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MedullaMedullaMedulla (inner most regions)Medulla (inner most regions)
Sparsely populated by plasma cells, activatedSparsely populated by plasma cells, activatedTh and Tc cells and high concentration of Igs.Th and Tc cells and high concentration of Igs.
Lymphocytes enter the lymph node betweenLymphocytes enter the lymph node between
specialized capillary endothelial cells in thespecialized capillary endothelial cells in the
postcapillary venules designated highpostcapillary venules designated high
endothelial venules (HEVS)endothelial venules (HEVS)
h i lL h i l
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Lymphatic vesselsLymphatic vessels
Lymphatic vessels responsible for flow ofLymphatic vessels responsible for flow oflymph within the lymphoid system.lymph within the lymphoid system.
Fuid from the tissues flows from theFuid from the tissues flows from the
intercellular tissue spaces into lymphaticintercellular tissue spaces into lymphaticcapillaries and then into lymphatic vessels.capillaries and then into lymphatic vessels.
Lymph flows through regional lymph nodesLymph flows through regional lymph nodes
and eventually enters the circulatoryand eventually enters the circulatory
systemsystem
Oth L h idOth L h id
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Other Lymphoid organsOther Lymphoid organsLess organized aggregates of lymphoidLess organized aggregates of lymphoid
organs includeorgans include Tonsils, appendix, Peyers patches in theTonsils, appendix, Peyers patches in the
lining of small intestine (gut associatedlining of small intestine (gut associated
lymphoid tissue or GALT)lymphoid tissue or GALT) Lymphoid tissue beneath the mucousLymphoid tissue beneath the mucous
membranes of the bronchi (bronchial-membranes of the bronchi (bronchial-
associated lymphoid tissue or BALTassociated lymphoid tissue or BALT
))
O h L h
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Other Lymph organ contOther Lymph organ cont Aggregates of lymphatic tissue throughoutAggregates of lymphatic tissue throughout
the mucous membranes (mucosalthe mucous membranes (mucosalassociated lymphoid tissue or MALT) andassociated lymphoid tissue or MALT) and
Beneath the skin (skin associated lymphoidBeneath the skin (skin associated lymphoid
tissue or SALT).tissue or SALT).Pathogens and other antigens enter tissues,Pathogens and other antigens enter tissues,
transported by tissue fluid into lymphatic vessels.transported by tissue fluid into lymphatic vessels.
R i l l h dR i l l h d
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Regional lymph nodesRegional lymph nodes
In the regional lymph nodesIn the regional lymph nodes Microbes and antigens in the lymphMicrobes and antigens in the lymph
encounter changing populations of B-encounter changing populations of B-
lymphocyteslymphocytes Filtered out and phagocytosed by fixedFiltered out and phagocytosed by fixed
macrophages and dendritic cells.macrophages and dendritic cells.
Antigen UptakeAntigen Uptake
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Antigen UptakeAntigen UptakeWhen microorganisms and other antigens enterWhen microorganisms and other antigens enter
bloodblood Transported by blood vessels to the spleenTransported by blood vessels to the spleen
where they encounter changing population of Bwhere they encounter changing population of B
lymphocyteslymphocytes
Germinal centersGerminal centers Secondary follicles found in tissues containingSecondary follicles found in tissues containing
activated cells following continuous exposure toactivated cells following continuous exposure toantigen.antigen.
Sites of antigen driven activation of B cells inSites of antigen driven activation of B cells insecondary lymphoid organssecondary lymphoid organs Leads to the development of active B cells,Leads to the development of active B cells,
plasma cells and macrophages.plasma cells and macrophages.
B Cell PrimingB Cell Priming
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B Cell PrimingB Cell PrimingAntigen specific B cellsAntigen specific B cells
Activated in the T cell zones of secondaryActivated in the T cell zones of secondarylympoid tissue andlympoid tissue and
Migrate to B cell zones to form germinalMigrate to B cell zones to form germinal
centers within the reticulum of follicularcenters within the reticulum of folliculardentritic cells (FDCs).dentritic cells (FDCs). Primary follicles consist of aPrimary follicles consist of a Network of FDCs in which no antigen-Network of FDCs in which no antigen-
driven process is occurring.driven process is occurring.
Lymphocyte PrimingLymphocyte Priming
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Lymphocyte PrimingLymphocyte PrimingFDCsFDCs
Depot of native unprocessed antigen, in anDepot of native unprocessed antigen, in an
immune complex formimmune complex form Hold Ag in a nondegraded form for longHold Ag in a nondegraded form for long
periods.periods.
Follicular B cells canFollicular B cells can Take up antigen from FDCs and process andTake up antigen from FDCs and process and
present in a form that activates T cells.present in a form that activates T cells. T cell B cell collaboration essential in theT cell B cell collaboration essential in the
development of germinal centersdevelopment of germinal centers
MHC System GeneticsMHC System Genetics
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MHC System GeneticsMHC System Genetics9 MHC genes and include9 MHC genes and include HLA-A, HLA-B, HLA-C, HLA-DPA 1, HLA-HLA-A, HLA-B, HLA-C, HLA-DPA 1, HLA-
DPB1, HLA-DQA1, HLA-DQB1, HLA-DRADPB1, HLA-DQA1, HLA-DQB1, HLA-DRAand HLA-DRBI.and HLA-DRBI.
MHC region divided into three regionsMHC region divided into three regions Class I (HLA-A,B and C)Class I (HLA-A,B and C)
Class II (HLA-DP, DQ and DR) andClass II (HLA-DP, DQ and DR) and Class III genes encode complement componentsClass III genes encode complement components
(C2, C4 and Factor B), cytokines (TNF-)(C2, C4 and Factor B), cytokines (TNF-) MHC genes display high levels of allelicMHC genes display high levels of allelic
diversity (polymorphism).diversity (polymorphism).
Class 1 MHC MoleculesClass 1 MHC Molecules
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Class 1 MHC MoleculesClass 1 MHC MoleculesClass I MHC molecules consist one long heavyClass I MHC molecules consist one long heavy
chain of 346 amino acids and a short one of 99chain of 346 amino acids and a short one of 99amino acids.amino acids.
Heavy chain consists of five regionsHeavy chain consists of five regions A transmembrane domain and a cytotoplasmicA transmembrane domain and a cytotoplasmic
domain (with the C terminal).domain (with the C terminal). Three extracellular domains including N terminal,Three extracellular domains including N terminal,
Protein molecule beta-2 microglobulin (Protein molecule beta-2 microglobulin (22-M)-M)
non-covalently attached to the heavy chain.non-covalently attached to the heavy chain.
Cl I l hiCl I l hi
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Class I polymorphismClass I polymorphismClass I MHC region encodes HLA-A, BClass I MHC region encodes HLA-A, B
and C molecules.and C molecules.
HLA-A, -B and -C heavy chainHLA-A, -B and -C heavy chain
genes are highly polymorphic withgenes are highly polymorphic withknown 60, 138, and 40 alleles,known 60, 138, and 40 alleles,
respectively.respectively.
Class II MHC MoleculesClass II MHC Molecules
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Class II MHC MoleculesC ss C o ecu esHuman class II molecules are designated HLA-D andHuman class II molecules are designated HLA-D and
class II MHC region encodesclass II MHC region encodes
Molecules HLA-DP (,); HLA-DNA; HLA-DOB;Molecules HLA-DP (,); HLA-DNA; HLA-DOB;HLA-DQ (,) and HLA-DR (,).HLA-DQ (,) and HLA-DR (,).
Other encoded molecules areOther encoded molecules are Transporter proteins (TAP 1 and 2) involved in antigenTransporter proteins (TAP 1 and 2) involved in antigen
presentation;presentation;
Low molecular weight polypeptides (LMPs and 7) andLow molecular weight polypeptides (LMPs and 7) andHLA-DM gene products.HLA-DM gene products.
MHC Class II molecules are found only onMHC Class II molecules are found only on Professional antigen presenting cells (APCs) includingProfessional antigen presenting cells (APCs) including
macrophages/monocytes, dendritic cells, activated Tmacrophages/monocytes, dendritic cells, activated T
cells andcells andB cells.B cells.
Class III MHC MoleculesClass III MHC Molecules
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Class III MHC MoleculesClass III MHC regionClass III MHC region Located in the central part of the MHC systemLocated in the central part of the MHC system
andand Contains genes which code for complementContains genes which code for complement
componentscomponents Factor B (BF), C2, C4b and C4a]; tumour necrosisFactor B (BF), C2, C4b and C4a]; tumour necrosis
factor (TNF); lymphotoxin (LT); heat shockfactor (TNF); lymphotoxin (LT); heat shockproteins (HSP 70-1 and HSP 70-2).proteins (HSP 70-1 and HSP 70-2).
Proteins produced also include 21 Proteins produced also include 21 hydroxylase enzyme (21-Ohase), deficient inhydroxylase enzyme (21-Ohase), deficient inpatients with congenital adrenal hyperplasia.patients with congenital adrenal hyperplasia.
MHC S t C t
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MHC System Components
Class
MHC Loci
Tissue distribution of MHC gene
products
I HLA-A,B,C All nucleated cells, lymphoid, epithelial and
mesenchymal tissues
II HLA-DP, HLA-DNA,
HLA-DOB, HLA-DQ
HLA-DR
Accessory antigen presenting cells like
monocyte-macrophage lineage cells, B-cells
and activated T-cells
III Central MHC
region
C2,BF, C4b, C4a, and 21-hydroxylase
enzyme (21- Phase), tumour necrosis factor
(TNF), lymphotoxin and heat shock
proteins
MHC Region CharacteristicsMHC Region Characteristics
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C eg o C c e s csgMHC Region posses characteristicMHC Region posses characteristic
featuresfeatures Multiplicity, high polymorphism andMultiplicity, high polymorphism and
extensive heterozygosity.extensive heterozygosity.
High polymorphismHigh polymorphism Genes in the MHC loci exist in differentGenes in the MHC loci exist in different
or alternative multiple forms designatedor alternative multiple forms designated
alleles.alleles.
HLA Specificities (Alleles)HLA Specificities (Alleles)
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p ( )p ( )A
A1
A2
A3
A9A10
A11
AW19
A23(9)
A24(9)
A25(10)
A26(10)
A28
A29(W19)
A30(W19)
A31(W19)
AW34(10)
AW36
AW43
B
B5
B7
B8
B12B13
B14
B15
B16
B17
B18
B21
BW22
B27
B35
B37
B38(16)
B39(16)
B40
BW41
BW42
C
CW1
CW2
CW3
CW4
CW5
CW6
CW7
CW8
CW9(W3)
CW10(W3
)
CW11
D
DW1
DW2
DW3
DW4DW5
DW6
DW7
DW8
DW9
DW10
DW11(W7)
DW12
DW13
DW14
DW15
DW16
DW17(W7)
DW18(W6)
DW19(W6)
DR
DR1
DR2
DR3
DR4DR5
DRW6
DR7
DRW8
DR9
DRW10
DRW11(W7)
DRW12(5)
DRW13(W6)
DRW14(W6)
DRW15(2)
DRW16(2)
DRW17(3)
DRW18(3)
DRW19(3)
DRW52
DR21
DRW53
DQ
DQW1
DQW2
DQW3
DQW4DQW5(W1)
DQW6(W1)
DQW7(W3)
DQW8(W3)
DQW9(W3)
DP
DPW1
DPW2
DPW3
DPW3DPW5
DPW6
NB. The alleles that have been reported and provisionally given a number pending verification and
official recognition are referred to by the letter W before the number such as Aw33(w19).
Inheritance of HaplotypesInheritance of Haplotypes
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p ypp ypMHC genes are co-dominant and the alleles equallyMHC genes are co-dominant and the alleles equally
expressed.expressed.
Given a simple Mendelian pattern of inheritance,Given a simple Mendelian pattern of inheritance, Distribution of MHC haplotypes in a family: 25%Distribution of MHC haplotypes in a family: 25%
identical; 25% non-identical and 50% partially identical; 25% non-identical and 50% partially identical.identical.
Linkage disequilibriumLinkage disequilibrium Certain gene combinations occur more frequentlyCertain gene combinations occur more frequently
than is expected given random Mendelianthan is expected given random Mendelian
combinations and permutationscombinations and permutations HLA-B8 and HLA-DR3 alleles more closelyHLA-B8 and HLA-DR3 alleles more closely
linked (97%)linked (97%)
Alleles in Linkage DysequilibriumAlleles in Linkage Dysequilibrium
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g y qg y qA1, B8
A1, BW17
A2, BW12
A2, BW16
A11, B5
A29, B12
AW30 B13
AW33, BW14
CW1, B5
CW1, BW16
CW3, BW15
CW4, BW35
CW5, B12
DW1, BW35
DW, BW7
DW4, BW15
Importance of MHC AntigensImportance of MHC Antigens
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p gp gMHC antigens-a group of cell membraneMHC antigens-a group of cell membrane
componentscomponents Expressed on cells by certain individualsExpressed on cells by certain individuals
in a population referred to asin a population referred to asalloantigens.alloantigens.
Clinical transplantationClinical transplantation Matching donor HLA antigens withMatching donor HLA antigens withthose of recipient to avoid induction ofthose of recipient to avoid induction ofgraft rejection reactionsgraft rejection reactions
Patenity identityPatenity identity
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y y
HLA gene products of a child compared withHLA gene products of a child compared with
Putative candidates to ascertain thePutative candidates to ascertain the
biological father in a given ethnic orbiological father in a given ethnic or
racial group.racial group.
Match between the HLA antigens ofMatch between the HLA antigens of
the child and candidates will establishthe child and candidates will establish
patenity.patenity.
Anthropological studiesAnthropological studies HLA closely linked and their distribution in theHLA closely linked and their distribution in the
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yypopulation markedly restricted.population markedly restricted.
HLA polymorphism showsHLA polymorphism shows Sub-Saharan African populationsSub-Saharan African populations
genetically most diverse (foundinggenetically most diverse (foundinghuman race probably of the Africanhuman race probably of the Africandescent).descent).
Migration patterns of peoples in populationsMigration patterns of peoples in populationsdetermined through HLA characterization.determined through HLA characterization.
Liberians appear more closely related toLiberians appear more closely related to
a distinct Malawian population than toa distinct Malawian population than totheir West African neighbours.their West African neighbours.
Forensic use of HLA typingForensic use of HLA typing
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yp gyp g DNA probes used in resolving inconclusiveDNA probes used in resolving inconclusive
blood group typing or finger print results inblood group typing or finger print results in
criminal investigations.criminal investigations.HLA and disease associationHLA and disease association
Theories includeTheories include Linkage disequilibrium,Linkage disequilibrium, Antigenic mimicryAntigenic mimicry Role of various infectious agentsRole of various infectious agents
Strong HLA disease association exists betweenStrong HLA disease association exists betweenM.tuberculosisM.tuberculosis and HLA-Bw 15,and HLA-Bw 15,M. lepraeM. leprae infections withinfections withHLA-DR3.HLA-DR3.