immunology in haematology (part 1)

8/14/2019 Immunology in Haematology (part 1)

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Dr C G Lopez

Ex Transfusion Medicine Unit

University Malaya Medical Centre


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Protects body from infectionAllows recovery from infectious disease

Comprises - Leucocytes

Organs thymus, spleen, lymph nodes ,lymphatic channels

Complex interaction between cells located in blood,lymph nodes , body tissues

Recognition of non self in any potential pathogen orforeign cells - e.g. red cells when transfused, transplanttissue

Capacity to produce a highly specific response to


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Immune Bo

IMMUNE

SYSTEM

Protects body

from infections

Infections

andotherharmfulagents
http://d/AppData/Roaming/Microsoft/Windows/Recent/Immune%20Body.lnkhttp://d/AppData/Roaming/Microsoft/Windows/Recent/Immune%20Body.lnk


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INDUCERS OF THE IMMUME RESPONSE

Only large molecules, infectious agents, or insoluble

foreign matter can elicit an immune response in the

body.)

A small molecule hapten - can elicit an immune

response but only when attached to a large carrier such

as a protein

Once antibodies are generated to a hapten-carriermolecule the small hapten can also bind antibody, but by

itself does not initiate an immune response


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Immunogen: substance that causes derectableimmune response. Mol wt ususally > 10,0000daltons. If less than 5000 daltons seldom causes

antibody formation

Antigen: a substance that is capable of reactingwith a product of an immune response e .g antigen

combines with antibody ( product of immuneresponse )

Hapten: Small molecules if coupled with largercarrier moleclules can become immunogenic .Once immune response initiated by the complex ,


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Small part of the immunogen that isrecognised by the cells ( antigenic determinant) may comprise as few as 5 6 amino acids orsugars.

Small epitopic region responsible forspecificity i.e contains the molecular

configuration that allows recognition bycorresponding A/B

Many epitopes present on single large

immunogen can produce many antibodies with

Definitions ----continuedEpitopes


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Epitopes

Antigens


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Type of Defences

Non specificResponse

Surface barrier

Innate immunityPrimitive

Non-specific

No memory

Specific ImmuneResponse

Response specificallyinduced towards the agentwhich stimulated it

Mechanism : Humoral andCell-mediated immuneresponse

Memory: Previousencounters


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Antigen presenting cell

Helper T 4Cytotoxic T 8


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Structural barriers Skin, mucosal membranes

Acidity Lactic acid in sweat, HCl in

stomach

Proteins Complement, lysozyme,interferons

Phagocytic cells Monocytes, macrophages,

neutrophils, eosinophils

Non-phagocytic cells NK cells, basophilsPhysiological responses Inflammation, the acute

phase response

Non-specific immunological response


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Specific immunological response


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Specific Immune Response

involvesLeucocytesB cells derived from bone marrow stemcells

T cells also derived from bone marrowstem cells but undergoes processing in

Thymus where self reacting T cells areeliminated by contact with epithelial anddendritic cells

The immune system must distinguish


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Immune Competance

By 4 6 months after birth external

substances encountered in the bodyby leucocytes will be regarded as nonself

Before this period the Immune Systemis immature unresponsive toantigens


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Antigen binding to- structures on lymphocytes or- A/B

Each antigen has specific receptor onlymphocyte or antibody molecule

Receptors will bind only specific set ofantigens

Clones then induced to proliferate and

Specific Immune Responseinvolves


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Foreign particles are engulfed and degradedby phagocytic cells such as macrophages,neutrophils and monocytes = phagocytosis

Degraded particles i.e. nonself antigens arepresented on MHC Class II molecules

If host cell was infected by a bacterium or

virus, or was cancerous, antigens displayed onsurface of cells with a Class I MHC molecule.

Specific immunological response


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Role of MacrophagesSpecialised macrophages (Antigen Presenting

Cells, or

APCs )phagocytose A/B or complement coated

particles ,

processes particles - enzymes degrade

particlespresent antigens to T and B lymphocytes as

peptides

( degraded proteins )or polysaccharides in

association with molecules of Major


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Stimulation through CD28 in addition to

the TCR provides a potent co-stimulatory

signal to T cells for the production of

various interleukins (IL-2 and IL-6 in

particular).

CD28


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Killer cellsLarge granular Lymphocytes with no T or Bcell markersCytotoxic activity against tumour cells

Have Fc receptors . Can therefore bind Ab alreadybound to tumour cells and destroy them usingperforin mechanism

Cytokines activate and release granules in CTLscytoplasm which contain protein Perforin

Perforin kills virus infected cells by establishing

channels in virus infected cell ; rapid influx ofCa++ prevents viral replication


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NK (Natural Killer )CellsLarge granular Lymphocytes with no

T or B cell markers

Cytotoxic activity against variety ofvirally infected and tumour cells

Activated by - Inteferon and IL- 2

Do not have specific receptors butrecognise target structures.

Attack & kill atypical cells e.g tumour orvirus infected cells using perforin

mechanism


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LargegranularKiller Cellswith no T or Bmarkers

Killer Cells haveFc receptors . Canbind Ab alreadybound to tumourtargetProbably perforin

release mechanismkills cells

NK Cells bindtumour targets

NK Cells bind targetsby unknown mechanism. Kill cells thru perforin

release mechanism


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Function of T and B cells

Origin

Blood

Bone marrow

Function

Surfacemarkers

Gene rearranged

Growth & differentiation

factors


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Helper T40 60%

Cytotoxic /Suppressor T49 50 %

Recognises Class IIHLA

on macrophageAmplifies immuneresponse by producingcytokinesHelps activate B cellsproduce antibodies

Recognises Class 1 HLA oninfected body cell surfaceDown regulates immuneresponsesKills virus infected cellstumour cells , transplantedtissue

Has CD 4 Surface

protein

CD4 protein assistsHelper T bind itsspecific Ag receptorto Ag presented with

HLA Class II protein byMacrophage

Has CD8 Surface

protein

CD8 protein stabilisesinteraction of Ag receptorand viral Ag with HLA Class Imol on surface of infected

cell surface

Peripheral Blood Lymphocytes

BLymphocytes

20 30%

T Lymphocytes 70

80%


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T Lymphocytes

CD 4 T Helper CD 8 Cytotoxic /

Supressor T


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Originate in bone marrow

ThymusLymph nodes / spleenBlood stream ( 70 -80 % of all lymphocytes )

Half life > 2 years some live as long as 20 years

T cells protect against infection by viruses , fungi,

facultative microorganisms

Helper T CD 4 protein binds specific Ag receptor to Agpresented by macrophage in combination with MHC( HLA Class II molecules )

T Lymphocytes


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CD4 + T Helper Cell

ActivationAg displayed by macrophage with HLAclass II self protein

Helper T binds to specific Ag ; receivessignal from macrophage Together amplifies immune response by

producing a mixture of cytokines ( act asgrowth factors )

Hel s to activate other immune cells


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T Helper CD4 + Cell

cific Immune Response CD4 + T cell activat

Macrophage

Ag displayed by macrophage withHLA class II self protein


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T Cell Activation :Mounting the immune response

Cytokine

generation


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Th I Secrete mainly IL 2, IFN- Activates B cells - but no significant heavy chain

() IgM switching to () IgG heavy chain Participates in delayed hypersensitivity reaction

Th2

Secrete mainly IL 4, IL-5, IL- 10, IFN- Activates B cells maturation and antibodyproduction - switching from IgM to IgG Found in chronic inflammatory lesions


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Specific Ag receptor binds to specifictarget e.g.

viral Ag by recognizing HLA class I

molecules onsurface of infected cells

Cytokines activate and release granulesin CTLs

cytoplasm which contain protein Perforin


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Cytotoxic T Cells


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Cytotoxic T Cells


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B Lymphocytes and B cellImmune Response

How T Cells Help ToGenerate Antibodies


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Humoral Immune Response

B cells and Antibody Production

B lymphocyte recognises foreign Ag throughits specific surface Ag receptor ( antibody

molecule )

B lymphocyte receives cytokine signal fromhelper T cell

Divides and differentiates to become plasmacells which produce antibodies - large

amounts over 3- 4 days


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Each

antibodymolecule hasspecific Agbinding site


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Tetramer : 2 identical heavy and 2 identical light chains

Fab: variable region Ag binding

Fc : constant region effector function

Antigen binds to Fab and triggers effector function thro Fc portion

Fc

Fab

B cell

in

Plasma

Macrophage with Ag


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p g gpresentedto T helper lymphocyte

B CELLB CELL

Activated bycytokines

More Helper T cellsMore Cytotoxic T clls( CTLs)B cells to Plasma cells


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Humoral Immune ResponsePlasma cells secrete specific antibodies i. e

glycoproteins (protein - carbohydrate moieties) - into extracellular space

Antibodies bind to antigens with highspecificity

Initial production - IgM antibodies

Heterogenous group of antibodies collectivelycalled Immunoglobulins

IgG Immunoglobulins divided into 5 classes IgG ,

IgM , IgA, IgD , IgE

IgG Subclasses


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IgG Subclasses


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Primary Immune Response

First time T cell interacts with Ag response isslow may take 5 7 days to generateantibodies and activate a number of cells

Secondary Immune Response

If challenged by same Ag again, antibodiesare rapidly generated within 48 hourspredominantly IgG , peaks in out 6 days mayprevent occurrence of disease


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Primary and secondary immune response


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T-cell independent immune

response

Antigen can initiate B cell proliferation and A/Bsecretion without action of T helper cell

Always IgM; isotype switch does not occur


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A and B antigen is composed ofcarbohydratestructures that attach to cell surfaceglycolipids

Binding ofB lymphocyte SIg receptor torepetitive carbohydrate antigens on surface ofRBC - triggers proliferation of B cells

Natural occuring IgM antibodies foundagainst A & B antigens of red cells probablyantibody production is independent of T

helper cell activity ( T independent immune

Blood Group Antigens


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Summary of the main Specific

Immune Response activities


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Macrophage

Helper T cell CD 4

Macrophagepresentsantigen to Tcell

T c cell

Thcell

B cell


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To be continued

The complement system

Antigenantibody reaction

immunology in haematology (part 1)

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