bbs2 mb-k24-cellular mediated immune response k-24

8/2/2019 BBS2 MB-K24-Cellular Mediated Immune Response K-24

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CELLULAR MEDIATEDIMMUNE RESPONSE

Departemen Mikrobiologi FK USU


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SLO:

Menjelaskan respon imun non spesifik

selular

Menjelaskan respon imun spesifik selular

Menjelaskan interaksi kerja respon imun

non spesifk dan respon imun spesifik


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Kepustakaan

Levinson, W. 2004. Medical Microbiology

& Immunology: Examination & Board

Review, 8th ed. McGraw-Hill.

Paul, W.E., 1998. Fundamental

Immunology, 4th ed. Lippincott Williams &

Wilkins. USA.


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Cell-Mediated Responses

Two intracellular compartments:

1.Cytosolic:

cytosol and nucleus connected via nuclear

pores site of viruses and some bacteria

2.Vesicular:

membrane-bound entities (endoplasmicreticulum, endosomes, lysosomes, Golgiapparatus)

site of some bacteria, some parasites


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Location of Pathogen Determines

Which T Cell Population Responds

1. Cytosolic: cytotoxic T cells (Tc) thatexpress CD8

2. Vesicular: subpopulation of helper Tcells (Th1) that express CD4

3. Extracellular: subpopulation ofhelper T cells (Th2) that express CD4


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Cytotoxic (Tc) T Cells

Virus infects cell

A B

C

Cell expresses

viral antigens

Cytotoxic

T cell

Infected cell is killed by cytotoxic T cell

by activation of nucleases that cleavehost and viral DNA


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Helper (Th1) T Cells

Macrophage MacrophageTh1

cell

lysosome

mycobacteria

antigen

Infected macrophage Activated infected

macrophage


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Specificity of Immune Responses

Resides in Receptors

T cell receptor (TCR) recognizes peptide

associated with major histocompatibility

complex (MHC) and is univalent.

T

cell

B cell receptor (surface immunoglobulin)

recognizes antigen and is bivalent

B

cell


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Diversity of Receptor Specificity

(Repertoire)Historically two different hypotheses

to explain diversity:

Instructional (template)

Clonal selection

Instructional hypothesis, althoughsimpler, does not explain how hostdistinguishes self from non-selfantigens


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Four Basic Principles of

Clonal Selection

1. Each lymphocyte bears a single type of

receptor of a unique specificity.

2. Interaction between a foreignmolecule and a lymphocyte receptor

capable of binding that molecule with

high affinity leads to lymphocyteactivation.


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Clonal Selection

3. Differentiated effector cells derivedfrom an activated lymphocyte will

bear receptors of identical specificity

to those of parental cell from whichthe lymphocyte was derived.

4. Lymphocytes bearing receptors for

self molecules are deleted at an earlystage in lymphoid cell development.


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Class I MHC Molecules

Expressed on surface of all nucleated

cells

Recognized by TCR of cytotoxic T cells

CD8 binds to class I MHC-peptide

complex

Source of peptide is cytosoliccompartment


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Class II MHC Molecules

Expressed on surface of some nucleatedcells, mainly antigen presenting cells(APC)

Recognized by TCR of helper T cells

CD4 binds to class II MHC-peptidecomplex

Source of peptide is vesicularcompartment


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Cells Expressing Class I and

Class II MHC

Class I MHC

Class II

MHC

All nucleated cells

express class I

MHC

Cells expressingclass II MHC also

express class I

MHC


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Non-specific and Specific

Immunity: ContrastsSpecific (acquired, adaptive) immunity

is induced and enhanced by antigen

shows fine discrimination

has memory

The non-specific and specific immune

systems interact with each other!


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Cells of the Immune System

All derive from the bone marrow

Two main lineages derive from the bonemarrow hematopoietic stem cells:

1. Lymphoid lineage

T cells, B cells, Natural Killer (NK) cells

2. Myeloid lineage

Monocytes, Macrophages, Dendritic cells,Megakaryocytes, Granulocytes


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Hematopoiesis

NK

Myeloid

progenitorLymphoid

progenitor

Tccell

TH

cell

Hematopoietic

Stem cell

B cell

Granulocyte

Platelets Megakaryocyte

Macrophage Monocyte

Dendritic cell AFC

Plasmacell

Mast cell


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Lymphocyte Recirculation

Secondary lymphoid tissues (lymphnodes, spleen) main sites wherelymphocytes encounter antigen

Frequency of lymphocytes having areceptor specific for a given antigen islow

Recirculation of lymphocytes throughlymphoid tissues optimizes productiveencounters with antigen to initiateresponse


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Lymphocyte Recirculation

Nave lymphocytes

enter lymph nodes

from the blood circulation

Lymphocytes return

to blood

via the thoracic duct

Antigens from infected area

go to lymph nodes

via the lymphatic system


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Leukocyte Migration and

Localization

Bone marrow and thymus (primarylymphoid tissues) produce B cells and Tcells, respectively

B cells and T cells recirculate throughspleen and lymph nodes (secondarylymphoid tissues)

Antigen presenting cells (APC) pick upantigen and migrate to secondary lymphoidtissues and interact with T cells and B cells

k i i d li i


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Leukocyte Migration and Localization

T

cell

Tcell

T

cell

B

cell

Bcell

B

cell

APC

T

cell

B

cell

Naive

lymphocytes

Bone marrow

Thymus

Spleen and lymph nodes Tissues

Primed lymphocytes

Dendritic

cell

Macrophage


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Critical Role of Th Cells in Specific Immunity

Select effector mechanisms

Induce proliferation in appropriate effectors

Enhance functional activities of effectorsAPC

Thcell

B cell

Tc

cellNK

AgAg

Ag

NK cell

Cytokines

Granulocyte Macrophage

Cytokines

Antigen-presenting cell


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Nave Th Cells Can Differentiate

Into Th1 or Th2 Cells

ThPcell

ThOcell

Th1cell

Th2cell

ThMcell

IL-2 IFN

IL-2

IL-4

IL-5

IL-10

IL-4

IL-5

IL-6

IL-10

IL-2

IFN

IL-2

Naive Th cells Short-term

stimulationChronic

stimulation

Long term

Memory cells


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Functions of Th1 and Th2 Cells

Th1cell Th2cell

Macrophage B cell

IFN

Activates

IL-4 IL-5

IL-10

Activates

Inhibits production

Mast cellEosinophil

Antibodies (including IgE)


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Cytokines Regulate Ig Class Switching

Fc region of antibodies determineseffector function in different anatomical

locations

Class (isotype) switching produces classor subclass of antibody most effective in

host defense

Cytokines acting alone or in

combination regulate class switching


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Macrophage Macrophage

Thcell

Macrophage

Cytokines Lymphokines

Cytokines

Anti-microbial functions

Anti-tumor functions

Invading agent Antigen presentation Activated macrophage

Central Role of Macrophages in

Natural and Specific Immunity

Involved in initial defense and antigenpresentation and have effector functions

l d f h


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Detailed Functions of MacrophagesInflammation Fever, Production

of: IL-6, TNF-alpha, IL-1 act as

pyrogen

ImmunitySelection of lymphocytes to be

activated:

IL-12 results in Th1 activation

IL-4 results in Th2 activation

Activation of lymphocytes:

Production of IL-1

Processing and presentation of

antigen

Reorganization of tissues,Secretion of a variety of factors:

Degradative enzymes(elastase,

hyaluronidase, collagenase)

Fibroblast stimulation factors

Stimulation of angiogenesis

Damage to tissues

Hydrolases, Hydrogen peroxide production

Complement C3aTNF alpha production

Antimicrobial action

O2dependent production of:

hydrogen peroxide, superoxide,

hydroxyl radical, hypochlorous acidO2-independent production of:

acid hydrolases, cationic proteins,

lysozyme

Anti-tumor activity produced by:

Toxic factorsHydrogen peroxide

Complement C3a

Proteases, Arginase

Nitric oxide

TNF alpha


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Macrophage Activation

Macrophage activation results fromalterations in gene products thatgovern new functions.

Two major mechanisms that activatemacrophages:

IFN- produced by Th or Th1 cells plusbacterial endotoxin (LPS)

IFN- produced by Th or Th1 cells plusTNF-


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Mechanism of Macrophage Activation

Macrophage Activated

Macrophage

Bacterial endotoxin

(lipopolysaccharide)

triggers cytokineproductionTh1

cell

1

IFN gamma

IFN gamma

2Macrophage

Activated

Macrophage

TNF alpha

Various

products


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Cytolytic T (Tc) Cells

Tc exiting the thymus are pre-Tc cells,i.e. have TCR that can recognizeantigen, but are not mature and cannot

kill until armed To become armed requires two signals:

1. Recognition by TCR of specific antigen

associated with class I MHC, and

2. Exposure to cytokines (IL-2 and IFN-)


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Mechanism of Arming Tc Cells

Pre-Tc cell

Tc cell

T helpercell

Class IMHC

Class II MHC

APC

1. Cell expressing class I MHC

presents antigen ( )to a pre-Tc cell

IFNIL-2

2. Antigen-presenting

cell presents antigen in

association with

class II MHC to Th cell3. Th cell

makes cytokines

4. Pre-Tc cell

differentiates to

functional Tc cell

5. Tc recognizes antigen on

class I MHC-expressing target cell

6. Target cell

is killed


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Features of Tc Killing

Antigen-specific

Requires cell-cell contact

Each Tc capable of killing many target

cells


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Main Mechanism of Tc Killing

Tc granules contain perforin and granzymes

Upon contact with target cell, granule

contents released, perforin polymerizes andforms channel in target cell membrane

Granzymes (serine proteases) enter target

cell through channel, activate caspases andnucleases, lead to apoptosis of target cell


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Mechanism of Tc Killing

Tccell

Ca++

Perforin

monomersPerforin

polymerizes

Polyperforinchannels

Tccell

Target cell

Granzymes

Targetcell

St i T Killi


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Steps in Tc Killing

Tc cell

1. Tc recognizes antigen on

target cellTarget cell

Tc cell

2. A lethal hit is delivered by

the Tc using agents such asperforin or granzyme B

Target cell

Tc cell

3. The Tc detaches

from the target cellTarget cell

4. Target cell dies

by apoptosis

Target cell


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Natural Killer (NK) Cells

Derived from bone marrow Lack most markers for T and B cells (do not

haveTCR)

Do not undergo thymic maturation

Express CD56, a specific NK marker

Express a receptor for Fc portion of IgG,called FcRIII (CD16)

Cytokines (IL-2) promote differentiation intolymphokine-activated killer (LAK) cells


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NK Cell Effector Mechanisms

Mechanism of killing similar to those of Tccells

Not MHC-restricted

Susceptibility of target cell to killing is

inversely proportional to expression of

class I MHC (killer inhibitory receptors(KIR) on NK cells recognize class I MHC and

prevent killing)

NK Effector Mechanisms


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NK Effector Mechanisms

(continued)

IgG-coated target cells recognized by FcRIII

(CD16) are killed by antibody-dependentcell-mediated cytotoxicity (ADCC)

Lymphokine-activated killer cells (LAK) kill

broader range of cells than do NK cells


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Mechanism of Hapten-Carrier

Hapten recognized by Ig receptor on Bcell

Hapten-carrier endocytosed

Carrier processed and presented onclass II MHC to Th cell

Activated Th cell produces cytokines

Cytokines enable B cell to be activatedto produce anti-hapten antibodies

Antigen


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CD40

Immunoglobulin

receptor

MHC II

B7 CD28

TCRT helpercell

g

1. Antigen presentation toTh cell

2. B7 expressed3. Th cell is

activated

and expresses

CD40 ligand,

Cytokines

secreted

CD40

ligand

Cytokine

Cytokine

receptor

B

cell

Bcell

Bcell

T helpercell

4. Cytokine

binds tocytokine

receptor,

CD40 ligand

binds to CD40

Bcell

Bcell

Bcell

5. B cell activated

6. B cells proliferate, differentiate, secrete Ig


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Class II MHC

APCTh cellB

cellTh cell

Bcell

Bcell

B cell takes up and

presents antigen

Th cell Th cell

B

cell

Th cells are primed by antigen-

presenting cell

B-T cell cooperationB cells receive signals from T cells

B cells divide

Bcell

Bcell

Bcell

Bcell

Antibody formingcell Antibody formingcell Antibody formingcell

B

memorycell


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B Cells In Secondary Responses

Memory cells created during primaryresponse

Have high-affinity Ig receptors Can therefore take up antigens at

much lower concentrations than other

antigen presenting cells that lack Igantigen receptors


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Cytokines

Non-antibody proteins acting as

mediators between cells, termed:

Monokines mononuclear phagocytes Lymphokines activated T cells, especially

helper T cells

Interleukins abbreviated IL with a

number


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Properties of Cytokines

1. Produced by cells involved in bothnatural and specific immunity

2. Mediate and regulate immune

responses

3. Secretion brief and limited - not stored

pre-formed - synthesis initiated by

gene transcription - mRNA short-lived

- cytokines produced as needed


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Properties of Cytokines

(continued)

4. Can be produced by many cell types and act on

many cell types (pleiotropic)

5. Can have similar actions (redundant)

IL2

R

IL2

R

IL2

R

IL15R

IL2

R

IL2

R

IL7R

IL2

R

?

IL9R

IL2

R

IL4R

IL2

R

IL-2 IL-15 IL-7 IL-9 IL-4Receptor for:


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Properties of Cytokines (continued)

6. Can influence synthesis of other cytokines

- produce cascades

- enhance or suppress production of othercytokines

- exert positive or negative regulatory

mechanisms for immune responses

7. Influence action of other cytokines - can be

antagonistic, additive, synergistic


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Properties of Cytokines (continued)

8. Bind to receptors with high affinity

9. Cells responding to cytokine can be:

- same cell (autocrine)

- nearby cell (paracrine)

- distant cell by circulation (endocrine)

10. Cellular responses to cytokines are slow,

require new mRNA and protein synthesis


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Tumor Necrosis Factor-alpha (TNF-)

Interleukin-1 (IL-1)

Chemokines (Chemotactic cytokines)

Type I Interferons (IFN- and IFN-)



Mediators and Regulators of

Natural Immunity


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Tumor Necrosis Factor (TNF-)

Produced by activated macrophages Most important mediator of acute

inflammation in response to microbes,

especially Gram-negative bacteria (LPS) Mediates recruitment of neutrophils and

macrophages to site of inflammation

Acts on hypothalamus to produce fever

Promotes production of acute phaseproteins


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Produced by activated macrophages

Effects similar to those of TNF-


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Chemokines

Produced by many different

leukocytes and tissue cells

Large family of >50 substances

Recruit leukocytes to sites of infection

Play a role in lymphocyte trafficking


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Type I Interferons (IFN- and )

IFN- a family of many proteinsproduced by macrophages, IFN- a

single protein produced by many cells Both IFNs inhibit viral replication

Both increase expression of class I

MHC Both activate NK cells


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Produced by activated macrophages and

dendritic cells

Stimulates production of IFN-

Induces differentiation of Th cells to

become Th1 cells

Enhances cytolytic functions of cytotoxic T

cells and NK cells


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Produced by activated macrophages,Th2 cells

An inhibitory cytokine Inhibits cytokine production by

activated macrophages

Inhibits expression of class II MHC andcostimulatory molecules onmacrophages


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Mediators and Regulators of Specific

Immunity


Interleukin-4 (IL-4) Interleukin-5 (IL-5)


Interferon-gamma (IFN-)


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Produced by Th>>Tc Main growth factor for T cells

IL-2

secretion

T cell

NKIncrease in NK

Cell activity

B cell Stimulationof division

T cell

Stimulation

of division and IFN gamma

release (and other

mediators)

Monocyte

Activation

Autocrine Function of IL 2


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Autocrine Function of IL-2

Activated

T cell

Resting

T cell

Class II MHC

APC

T cell

T cell T cell T cell T cell

T cell T cell T cell T cell

IL2 IL4 IL7

Binds to IL-2 receptor

Receptor

decay

Division


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Produced by Th2 cells

Stimulates Ig class switching to IgE

isotype Stimulates development of Th2 cells

from nave Th cells

Promotes growth of differentiated Th2cells


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Produced by Th2 cells

Promotes growth and differentiation

of eosinophils Activates mature eosinophils

IL-4 and IL-5 can work together

Helminths opsonized with IgE can bekilled by activated eosinophils


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Produced by activated macrophages,

Th2 cells

Inhibits production of IFN- by Th1

cells needed to activate macrophages

Interferon gamma (IFN )


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Interferon-gamma (IFN-)

Produced by Th cells >> Tc and NK cells

Numerous functions in both natural and specificimmunity

Bcell

MacrophageNK

T cell

Th1 cell >

Tc cell

NK

Many cell types Many cell types

Induction of class I

and class II MHC

Increase in

NK

cell activity

Differentiation,

Stops cell divisionT cell activation

Weak anti-viral activity,

Stops cell division,Sto s hemato oiesis

Activation

Granulocyte

Activation

Endothelial cellActivation

IFN gamma

secretion

Stimulators of Hematopoiesis


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Stimulators of Hematopoiesis

Granulocyte-macrophage CSF (GM-CSF)

promotes growth and differentiation of

bone marrow progenitors

Macrophage CSF (M-CSF) is involved in

development and function of monocytes

and macrophages Granulocyte CSF (G-CSF) stimulates

production of polymorphonuclear

leucocytes (PMN)

Colony-Stimulating Factors (CSF)


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Cytokine Network

Many cytokines have effects on many

cells and organ systems in addition to

functions in immune systems

Referred to as the cytokine network

Effects on Cells of Immune System


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Effects on Cells of Immune System

LymphocyteMacrophage

Bcell T cell NK LAK

Proliferation,

Differentiation,

Ig secretion

and selection

Proliferation,

Differentiation,

Cytokine

production

Activation of cells of

immune system Cytokine production

cytokines

Cytokine Effects on Organ Systems


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Cytokine Effects on Organ Systems

Lymphocyte Macrophage

Hypothalmus

ACTH

Adrenal

gland

Corticosteroid

Liver

Acute phase proteins

Pituitary

Fever

cytokines

Cytokine Effects on Various Cells


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Cytokine Effects on Various Cells

Lymphocyte Macrophage

Fibrogenesis

Extracellular

matrix

cytokines

Endothelial cell

Fibroblasts

FibrinogenPermeability change

adhesion

Endothelial cells

cytokines

Hematopoiesis

Bone marrow

cytokines

Angiogenesis

Fibroblast

Extracellular

matrix

Osteoclasts

Tissue

remodelingTissue repair

IL1TNF

Anti-viral

state

Many cell types

IL1 TNF IFN

IFN IFN

Reg lation of Imm ne Responses


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Regulation of Immune Responses

Magnitude determined by balance between the

extent of lymphocyte activation and tolerance

induced by an antigen

Nature determined by specificities and

functional classes of lymphocytes activated

Regulatory mechanisms may act at the

recognition, activation, or effector phases of an

immune response

bbs2 mb-k24-cellular mediated immune response k-24

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