INTRODUCTION TO IMMUNOLOGYII

8/14/2019 INTRODUCTION TO IMMUNOLOGYII

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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



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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).



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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.

INTRODUCTION TO IMMUNOLOGYII

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