Antigen, the initiator of the immune system

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Immunology & Disease

Edward H SugitaLecture 4a

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IntroductionAntigen / Ag = molecules to which Antibodies / Abs bind. Ag = Antibody generators

each Ab mol binds to one of many mols on the microorganism’s surface Ab mol do not bind to the whole of an infectious agent

different Abs will bind to different Ags each Ab is specific for a particular Ag

a particular Ag specifically induces the production of the Abs which can bind to it each Ab binds to a particular part of the Ag called an antigenic determinant or epitopeepitope

a particular Ag can have several different epitopes or may have several identical epitopes.

antigen antibody

Ag3

Ag1

Ag2

recognition

recognition

recognition

foreign mols which generate Abs

antigenic determinants / epitopes

the epitopes on one Ag are usual- ly different from those on another

some Ags (Ag3) have repeated epitopes

epitopes are molecular shapes

of the adaptive IS recognized by the Abs and cells

each cell recognizes one epitoperather the whole Ag

even simple microorganisms have many different Ags

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Antigena foreign substance which induce a detectable immune response when intro-

duce to the body ( Immunogen)

Ag

T-dth

T-cytotoxic

T-helper

T-suppressor

B cells

Plasma cell

3rd population cellsmacrophagemonocyte

Mast cell

basophil

neutrophil

eosinophil

platelets

Immune Reaction

Tolerant

CMI

Ab (specific)

elicitation depends on the .

the lymphocytes way the Ag is presented to

Tolerance: a state of specific immunological unresponsiveness.

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Antigenic determinants-large molecule but only restricted portions are involved in actual bind-

-determinant area of specificity on Ag molecule varies with size and che- ing with Ab combining site

mical complexicity minimum value = valence estimated on the basis of the number of Ab mol bound per mol Ag

- 5 Ag determinants for 42.000 MW albumin- 40 Ag determinants for 700.000 MW thyroglobulin

Haptens

c.h

en

c.p

-substances non-immunogenic but can react with Ab of appropiate specificity

-usually small molecules Immunogenicity !

Carier - protein linked to a hapten- has a set of native / integral determinants + the new determinants introduced by the conjugated haptens Hapten

Hapten: A small mole which can act as an epitope but which is incapable by itself of eliciting an Ab response.

Carrier: An immunogenic mol or part of a mol which is recognized by T cells in an Ab response.

a mol which renders a hapten linked to it, able to stimulate Ab production

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X-reaction = The reaction of an Ab directed against one Ag with a 2nd Ag.This occurs because the 2 Ags possess epitopes in common.

Immunodominant : describing the epitope on a mol that provokes the most intense IR

Epitopesthe simplest form of an antigenic determinant present on a complex antigenic molecule

Cross reactionthe reaction of an antibody with an antigen other than the one that induced

Cross reacting Aga type of tumor Ag present on all tumors induced by the same or a similar

its formation

carcinogen

Size and localization of Ag determinants - Ab complementary is directed against limited parts of the Ag molecule

Ag determinant is of the order of 4-6 AA or sugar residue

Subunit determinant: AA in peptide chain / Sugar in saccharide chain

Ab subsite

Ab combining site

Antigenic determinant group

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Cardinal factor in determinant’s selection

Evokes Tyr specific AbEvokes Ala specific Ab

Polylysine backbone

L-Glutamic acid

L-Tyr

Poly DL Ala

the AA subunit of a determinant contributes unequally to bind Ab, the degree

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Immunodominance

Component of the influence of the reactivity is a measure of immunodominance of the

Immunogenicity: the property of a substance making it capable of inducing a detectable immune response immunogen & antigen Immunogenicity: The ability of a mol to elicit an IR

* immnogenicity is not an inherent property of a molecule

Foreigness, Molecular size, Chemical complexity, Genetic constitution of

Characters for immunogenicity:

Conditions for immunogenicity:

* immunogenicity is dependent on the system’s condition Ag, mode of im- munization, immunized organism, sensitivity of the method to detect the response. Capable to induce cellular immunity mediated by T cell

the living target, Method of Ag administration Chemical nature of immunogens:

- Macromolecule proteins- Polysaccharides, Synthetic polypeptides, Synthetic polymers- Ab which react with Nucleic Acid (nucleoprotein immunization)

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Immunogenic determinants:Immunogens : normally, large molecule Immonogenicity : a function of molecular size and complexicity

Characteristic of immunogen: - Capable to induce cellular immunity mediated by T cell

- Possess at least 2 determinants in order to stimulate Ab formation by B cell Haptens and carriers

it is not sufficient that the Ag share a common antigenic determinant recognized

he determinant must also be attached to the same carrier molecule (= the carr- by the B cells

ier effect).

this implies that the cells involved in making the Ab response recognize at least 2 parts of the Ag

to obtain the optimum secondary response to an antigenic determinant which is not im- Ag in both the primary and secondary challenge munogenic by itself (eg hapten), it is necessary to immunize the subject with the same

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The carrier effect

primary Ag secondary Ag Ab response to DNP

DNP BSA DNP BSA

+ + + +

+

+

DNP BSA

DNP BSA

BSA

DNP OA

3 groups of mice were immunized (primary Ag) with DNP-BSA (dinitrophe-

DNP-BSA, BSA or DNP-OA (dinitrophenylated ovalbumin) nylated bovine serum albumin) and rechallenged (secondary Ag) with either

(rechallenged)

3 groups

measure

(=hapten)

optimal Ab response to same Ag

DNP (obtained with 2x immunization with the

BSA acts as a specific carrier for the Ab response to DNP

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Carrier priming

circumvented in the response to hapten-carrier conjugate

lymphocyte priming to the carier is required when there was a previous priming to the carier alone or receives spleen cells from donor primed to that carier

experiment

DNP-BSA

DNP-BSA DNP-OA DNP-OA

OA

spleen cell transfer

1 2 3

Ab response tp DNP

+ + + + + + + ++

3 groups of X-irradiated mice were reconstituted with the Ag-primed

groups of mice

spleen cells and challenged with Ag

Ags (challengers)

strong Ab response

weak Ab response (demonstrating the carrier effect)

received cells primed to both

strong response to DNP

challenged with DNP-OA DNP-BSA and to OA, then

primed spleen cells

demonstrating that the re- .quirement for carier prim- ing can be circumvented by supplying carrier-prim-

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T cell recognition of carier (OA)experiment

DNP-BSA OA

spleen cell transfer

complement andnormal serum anti-

DNP-OA

assay Ab response to DNP

result of anti-DNP response

response

normal serum anti-

an X-irradiated mouse, if re-

DNP

constituted with spleen cells primed to the OA carrier to DNP-BSA will, on subsequent challenge with DNP-OA pro- duce a normal Ab response to

1) this response is unaffected if

1)

the OA-primed cells were pre- viously treated with normal se- rum and complement

2) However, if the OA-primed

cell serum (anti-) and com-

cells were treated with anti-T plement, which destroys T is abrogated cells, the anti-DNP response

indicating that T cells recognize the carrier and give help to the hapten-primed B cells

removing T cells from the carrier-primed donor spleen cells, shows that the T cells are

cells which recognized the hapten responsible for recognizing carrier determinant on the Ag and delivering help to the B

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act as ‘living test tubes’

In these 2 experiments: * to determine their immunological activity: Ag-primed cells are injected into irradiat-

ed recipient mice

detailed analysis of the T cells responsible for this helper effect in the mouse shows

that they carry Ly1 surface markers but do not carry Ly2 or Ly3 markers

(=Ly1+(23)-

antigen

APC APCAFC

AFCBTH

Overview of the IR

surface of APC

T cells recognized separate deter-

presented in a highly immunogenic form to TH cells and B cells

B cells are stimulated to different-

minants on the Ag to those recog-

ver help to the appropriate B cells nized by the B cells but they deli-

iate and divide into AFCs (Ab Form- ing Cells)

Fragment is retained on the 1. Ag is processed by APC & Ag

helpproliferation

2. TH cell recognize the Ag via their surface R and provide help to

B cell. B by their surface R (Ig)

Ab secretion3. B cells are stimulated to proliferate

Cell) which secrete Ab and divide into AFC (Ab Forming

1. 2. 3.

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2 types of signal are required to activate a B cell:1. Ag interacting with B cell Ig-Rs and X-linking them,

2. A second signal (s) from TH cells.

A variety of T cell stimuli are needed for optimal growth and differentiation of B cells

T-dep and T-indep Ags

* large polymeric molecules with repeatingAg determinant

* many possess the ability, at high C, to acti-vate B cell clones other than those specificfor that Ag = polyclonal B cell activation

the response to an Ag depends on both T cell & B cell recognizing the Ag

Ag that is capable of activating B cell to produce Ab independently of T cell help

at a lower concentration they activate on- ly those B cells with specific Ag Rs for them

many of the T-indep Ags are particularly resistant to degradation

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T-indep Ags.

antigen polymeric polyclonalactivation

resistance todegradation

lipopolysaccharide(LPS)

Ficolldextran

levan

poly-D amino acids

polymeric bacterialflagellin

+ +++ +

+++ - +++

++ + ++

++ ++ +

++ + ++

+++ - +++

poly-L-amino acids and monomeric bacterial flagellin

the major common properties of some of the main T-indep Ags

T-dep Ags.

the primary Ab responses to T-indep Ags in vitro are generally weaker than the responses to T-dep Ags and that they peak fractionally earlier

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Comparison of the primary IRs to T-dep and T-indep Agsthe response to T-indep Ags is weaker than to T-dep Ags and peaks earlier

primary antigen

plaqueforming

cell responseper 106 cells

2000

1000

00 1 2 3 4 5 6 7 8 9 10 11 12

days

ming cell assay, to a T dep Ag and a T-indep Ag

* the primary response as assessed by plaque for-

* the secondary response in vitro also differs between T-dep and T-indep Ags

far stronger and

resembles the primary response,

ly confined to IgM production by being weak and almost entire-

appears earlier

memory induction is also relatively poor

T-indep Ags do not usually induce the maturation of response involving class switching to IgG and increase in affinity seen with T-dep Ags

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Comparison of the secondary IRs to T-dep and T-indep Ags

secondary antigen

plaqueforming

cell responseper 106 cells

5000

2000

00 1 2 3 4 5 6 7 8 9 10 11 12

days

1000

30004000

the IgM PFC (Plaque Forming Cell) response is similar for T-indep and T-dep Ags but only T-dep Ags produce an IgG PFC response

Affinity maturationAffinity maturation involves the selective expansion of clones of high affinity Ab producing cells since lymphocytes do not change the specificity of their Ag-Rs. Abs produced in a secondary response to a T-dep Ags have a higher

average affinity than those produced in the primary response associates with the switch from IgM to IgG production no affinity maturation of IgM response and the degree of affinity maturation

is dependent on Ag dose administered

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Affinity maturation

primary Ag secondary Ag

mean Abaffinity (L/M)

10-5

10-11

10-9

10-7

days0 1 2 3 4 5 6 7 8 9

IgM

IgG-low [Ag]

IgG-high [Ag]

the average affinity of the IgM and IgG Ab responses folowing primary and secondary challenge with a T-dep Ag

the affinity of the IgM response is constant throughout

the affinity maturation of the IgG of the Ag response depends on the dose

low Ag does produce higher affinity Ig than high Ag does

low Ag concentrations: only B cells with high affinity Rs bind the Ag and are triggered to divide high Ag concentrations: there is sufficient to bind and trigger both high and low affinity B cells

and differentiate

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* high Ag doses allow triggering of more B cell clones and therefore produce

Postulated mechanism of affinity maturation* low Ag doses bind to, and trigger only those B cells with high affinity Rs

Ab responses with lower average affinity

Ag (low dose)

B cells’ Ag-Rs activatedB cells

high affinity

antiserum Ag (high dose) B cells’ Ag-Rs B cells

activatedantiserum

moderate affinity10--9 L/M

10-11 L/M

10-10 L/M

10--7 L/M

10-11 L/M

10-10 L/M

10--9 L/M

10--8 L/M10--8 L/M

10--7 L/M

Ag presentationB and T cells are normally required for responses to T-dep Ags, which consti-tute the majority of the Ags encountering IS

Ag encountering the IS is presented to the lymphocytes in vivo this phase is complicated by the structural which react to it

organization of the lymphoid tissue

the Ag may be carried free in solution or it may be carried

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* Ag from the periphery moves via the lymphatics to the local lymph nodes.

on the surface of the APCs on reaching the lymph node different Ags selectively

mulating different populations of lymphocytes move to different areas and are thus capable of sti-

some Ags remain within the lymph node for long periods provid- ing a constant source of antigenic stimulation while others are fairly rapidly degraded or lost via the efferent lymphatics

Localization of Ag in lymph nodes area persistenceAPC Ag

++++

B cell areas

subcapsular (marginal) sinus

marginal zone MOs polysccharides Ficoll (T-indep)

+++

+

++

follicles and dendritic cellsfixing complexesAg/Ab Complement

interdigitating cells

medulla classical MOs

T cell areas

most Ags

skin sensitizing Ags

T & B

B

afferent

efferentT

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B

TT & B

efferent

afferent

schematic lymph node showing afferent and efferent lymphatics follicles, outer cortical B cells areas and the paracortical T cell area

lymphatic folicle

outer cortical B cell areapara-cortical T cell area

different APCs predominate demarcation is not absolute in these areas, although the

the different APCs selectively take

for variable periods

up different types of Ag which then persist on the sur face of the cells

= with recirculating MOs (class-

FDCFcR

C3RYAg/Ab complex

taken up

may persist for months or years

Ical MO; medulla) which last only for a few days or weeks

circulating ‘veiled’ cells (Langerhans cells) thought to arise from skin change their

contact with lymphocytes

morphology to become interdigitating cells within the secondary lymph node both these and the dendritic cells (skin’s MO) have long processes in intimate

the persistence of the different Ags varies between species the major APCs (based on Abs’ production): follicular dendritic cells MOs and marginal zone MOs of the skin appear to be more important presenting Ag to T

cells involved in delayed hypersensitivity reactions

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thus, responding B cells only recognize Ag on the MO surface provided that both the B

the presentation of Ag to responding lymphocytes is MHC restricted

cell and the MO share determinants of the HLA class 2 molAg presentation by Macrophage

associate recognitionindependent recognition

T cell T cell

Ia-R Ag-R

Ag

Ag/Ia-R

Ia Ag/Ia

MO MO

presentation of Ag by MO to T cells is MHC restricted individually or as a com- bination of determinants (lymphocyte will recognizes it as “altered self”

Rs on the lymphocytes are responsible

observed in Ag presentation

for recognition of MHC products on the MO and thus for the MHC restriction

the exact MHC restriction observed is de- are I nitially educated to discriminate self

self MHCAgs

from non-self during their development in the thymus by association with cells bearing

evidence suggests thatAg MOs has been extensively degraded and occur in the

with the HLA class 2 region gene productsform of small highly immunogenic peptides which are recognized in association

it is not known whether the T cell recognizes nition)

Ag and MHC independently (dual recogni-

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removal of surface Ag from MOs does not lead to replenishment from an intracellular Ag pool

phagocytosis of Ag and Ag presentation are 2 distinct functions

MOs lacking MHC 1 region products are limited in function to phagocytsis

Clonal expansion

proliferation

precursorcommon

maturation

T lineage B lineage

antigenicstimulation

antigen specific clone

subsetsubset

T & B cells derived from a single common precursor stem cell

the repertoire of B and T cells is ge- ent Ag binding specificities

nerated before contact with Ag to produce a range of cells with differ-

subsequent contact with Ag induces se- lective expansion of Ag specific clones

in this sense the Ag selects the

against it

particular lymphocytes which will be evolved in the response

the binding of Ag to particular lymphocytes is not necessary sufficient to produce an IR

Mechanisms of cell cooperationthe crucial event which determines the Ag specificity of an IR is the triggering

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IS will have greater specificity in discriminating foreign Ag

of particular clones of lymphocytes via their Rs for Ag B cells responding to a T-dep Ag require T cell help to produce

ed effectively via two different antigenic determinants an optimum response and in these IRs the T dep Ig is recogniz-

effective cooperation between the lymphocytes re- cognizing the different determinants is essential

mechanism of B cell activation could be studied with T ind Ags

T-ind Ags have the inherent ability to deliver all necessary activating signals to B cells Properties of the T-ind Ags suggest a number of ways in which they could

themselves supply the 2nd signal

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2 mechanisms of B cell activation by T ind Agsmitogenic actionR X-linking

mitogen-R

AgAg

Ig Ig

B cellsignal signal

B cell

link the cell surface polymeric Ags (Ag) X-

Ig of the B cells

Ags with inherent mitogenic activity are bound to the B cells via the surface Ig and signal activation through a postulated R on the B cell

1. T ind Ags are polymeric can X-linked the B cell’s Ag-Rs

3. some of the T ind Ags fix comlement (C) by the classical or alternative pathways

2. most T ind Ags are mitogenic, it is possible that 2nd signal is delivered via the B cell’s mitogen R. (Ag-R serves to focus the mitogen onto the surface of the particular B cell.

however mitogen-Rs of B have not yet been identified, and this effect may be due to IL-1 released from MOs)

(B cells have C-Rs, 2nd signal may be delivered in this way)

these hypothesis’ are not mutually exclusive. It is possible that different mechanisms are valid for different Ags or B cells

the way in which T cells activate B cell shows evidence that some forms of

from T cells and subse-quently induce B cell activation interaction may be mediated by Ag specific T cell helper factors.(Released

2 mechanisms of Ag spec B cell activation by T-dep Ags

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T cell factors cellular interaction

APC

signal

T cell

B cell B cellsignal

TH factor

help help

Ia-R

Ia IaAg

IgIg

TRAg

helper factors (TH) spe-

triggers activation

cific for carrier deter- minant on the Ag and Ia mols bind to the Ag and delivers a help sig- nal, which in conjunc- tion with the signal from the B cell’s Ag R

T and B cells bind Ag via their Rs (TR and Ig) and help is delivered directly to B cell

this requires cell / cell

of Ia contact and recognition

T cell factorsthe evidence for the existence of Ag specific T helper factors come from culture cells by a membrane permeable to mols, but impermeable to cells systems in which the Ag-stimulated TH cells are separated from the target B

Demonstration of Ag induced T cell helper factors.

the effect of Ag specificT cells primed to

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Cultures were set up containing DNP-primed (DNP’) B cells and:

3) CGG (Chicken –Glob) primed T cells similarly separated from the B cells

1) KLH-primed T cells 2) KLH-primed T cells separated from B cells by a protein permeable membrane

IgM-PFCresponse

to DNP

CGG+

DNP+ KLH+

DNP+

T

B

B

T

104

2000

1000

00 107105 106

of activated T cells cell culturesystem

DNP+

B TKLH++1

2

3

all cultures contain KLH-DNP

the help given to the B cells was (PFC) assay measured by plaque forming cell

the number of activated T cells initially the B cell response depends in this

introduced into the culture is varied &

the response is unaffected by preventing sence of helper factors direct cell/cell contact, implying the pre-

the eventual decline in response may cells

CGG cannot substitute for KLH-primed

be due to TS cells Separation of B and T cells does not affect cooperation.

there is an optimum ratio of T:B cells to produce a maximum response

* TH factors were shown not to be genetically restricted (i.e recognizing Ia Ags on

= factors released during T cell activation and act on the factors can be demonstrated in superna-tants from MLC consisting of all allogeneic cells.

Non-specific T cell helper factors

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their targets) but like TH cells, they are restricted * there is also evidence for the action of Ag non-specific T cell helper factors

all clones of B cells

in this system T cells are stimulated by contact with allogeneic lymphocytes

a nude mouse (= mouse lacking T cells) has its spleen cells removed

Bnude A

spleen cells spleen cells

supernatant

24 hr MLC

culture 1 culture 2

Ab response to SRBC

- + + +

SRBCSRBC

2 cultures of these spleen cells are set up:

sheep red blood cells

the spleen cells are unable

(SRBCs; = a T-dep Ag)

sspleen cells +

to produce an Ab response

spleen cells + SRBCs + the supernatant 24 hours

of MLC produced by cultivating spleen cells from 2 different mouse strains for the supernatant stimulates the spleen cells to produce Ab against the SRBCs Conclusion: the supernatant contains non-specific

T cell helper factors

the cells stimulated in the MLC participates in a CM IR

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* the T cell factors produced are not Ag specific, ie, a T cell triggered by Ag X produces factors which can help a B cell produce Ab to Ag Y

only augment the response to some Ags

thus, Ab to particulate SRBC is enhanced by non-specific factors alone whereas

other Ags still require Ag specific help before an Ab response is generated

the response to most protein Ags is not

particular B cells’ clones may be selectively stimulated by n on-specific factors due to their close proximity to T cells releasing the factors (might occur in an Ag stimulated lymph node)

these factors act initially by binding to the APC before exerting their effect on the

helper factor that interacts directly with B cells, can have affinity for MOs and other APCs

target cell

TS cells may exert their suppressor factors which act in similar way to the helper factors

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The action of T cell helper factors

T

THF

THF

Ag

Ag IgAg

IaIa

APC

B

Il-1

factor release

1. 2. 3.

T cells encountering Ag on the specific helper factors (THF)

APC recognize the Ag through their Rs (TR) and release Ag

factors bind to the Ag

APCs possibly in association with

a B cell encountering the APC is

tivated APC (MO).

stimulated by the matrix of Ag and T helper factor and also pos- sibly by IL-1, release from the ac-

the interactions is thought to be MHC restricted

some of the factors carry determinants of The H-2I region in mice or its equivalent in humans (HLA-D)

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Characteristics of factors carrying I-region determinants

GRF

target

helperfactor factor

supressor

source

effect

Ag specificity

mol. wt.

serology V/C

MHC restriction

MHC 1

suppresses

macrophage

Ly123+ T cell

Ly1+ T cell Ly23+ T cell

Ly1+ macrophage T cellB cell

induces inducesT cellsB cellsTH cells

+ or

? + +

++

+ + or

55 –80K

I-A I-A (I-J) I-J

55 –75K 55 –80K

the three factors here are genetically restricted factor (GRF) produced by MOs, helper factor (carrying the Ly2, Ly3 marker) produced by TH cells (carrying the Ly1 marker) and suppresor factor produced by TS cells

V

this characteristic

tivity with antisera refers to their reac-

these antisera detect both V and C regions (= with V & C

on MO factors regions of Ig; but analogous) on T cell factors but not

the factors also share determinants in common with MHC-subregion mols

MHC restriction refers to the possible requirement for the cells interacting

on their surfaces

through these factors to be matched with respect to the MHC mols diplayed

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Ag nonspecific factors previously these factors had been defined by their effect in different assay sys-

these factors appear to fall into groups each with their own properties

tems A single factor with several biological actions could be known by va- rious names

source target effect

Interleukin 1(LAF)

Interleukin 2(TCGF)

T cell replacingfactor (TRF)

factor (BCGF)B cell growth

macrophage

macrophage& other cells

Ly1+.23- T cell

Ly1+.23- T cell

in presence of

in presence of

macrophage

Ly1+.23- T cellin presence ofmacrophage

T & B cells

B cells activation

T cells

B cells

B cells

B cellsdifferentiation

proliferation of

promotesmultiplication& activation

activated T cells

with IL-1 insynergizes

IL-1 ( = LAF, Lymphocyte Ac- priming of lymphocytes tivating Factor) acts during Ag

IL-2 (= TCGF, T Cell Growth Factor) activated T cells is essential for long term growth of

TRF (= T cell Replacing Factor) differentiation in response to Ag is required for optimal B cell

BCGF (= B Cell Growth Factor) is a signal for B cell activation

TRF and BCGF are really groups of mols and not necessary single entities

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Adjuvants = substances which non-specifically enhance the IR to Ag.

in certain circumstances it is possible to completely change the mode of response (Tolerance vs Immunity; by administering Ag together with adjuvantit is possible to break self tolerance to a large number of self Ags by inject- ing them into the host animal in an appropriate adjuvant

- water-in-oil (w/o) emulsions with the Ag in the aqueous phase

Most frequently used adjuvant:

eg. Freund’s incomplete adjuvant

Ab responses toAgs in adjuvants are :Effect of adjuvants on the Ab rsponse following injection of Ag (KLH).

- frequently consist of different classes to the response obtained without -more prolonged -greater

Keyhole Limpet Haemocyanin

adjuvant Ag

primaryAb

response KLH + adjuvant

KLH

weeks 0 21 3 4 5 6 7 8 9

the response is greater and more prolonged

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Mechanism of adjuvant: 1. the Ag in emulsion is resistant to dispersal, and it therefore acts as a depot for pro-

tion leading to maturation of the response with class switching

longed Ag stimulation

2. microbial products activate MOs thus leading to the production of Ag non-specific factors which will enhance the response

3. the Ag somehow bypasses the requirement for the T cell signals in B cell differentia-

Summary:

communication between the cells involves products of the MHC and other

Ab response is a coordinated reaction of B cells, T cells and APCs, commu-nicating either directly or via Ag specific and non-specific factors.

failure to produce a properly coordinated response may lead to tolerance gene products

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Hypothesis to explain the T cell recognition of Ag

T T

TrT4 T8 TrT3 T3

class 2Ag

MHCMHC class 1

APC

antigen presenting cell

Ag

the MHC class 2 restricted cells (eg TH) possess a molecule, T4, which recognizes MHC protein and the Ag

the MHC protein and the Agthe activation signal is transmitted to the T cell via the T3

Tr, T cell receptor, recognizes peptide, which is associated with Tr (T cell receptor)

class 1 restricted cells have a molecule, T8, which recognizes MHC class 1 Ags

MHC molecules(both classes) have 4 globular domains and the T4 and T8 molecule recognize different domains to those recognized by the T cell receptor

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Chief characteristics of different APC

APCcharacteristicsantigen presenting cell

APC phago-cytosis

Fc/Creceptor

class 2MHC ex-pression

present to

marginal zonemacrophages

folliculardendritic cells

dendritic cells

macrophagesmonocytes/

Langerhans cell

+ +

+

+

+ +

+ +

+/ T & B

B

B

T

T

MHC but can be stimulated by

B cells do not need to recog- nize Ag in association with free Ag or complexed Ag which have bound to APCs with Fc and C3 receptors

to T cells have class 2 MHC

these cells which present Ag

molecules

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Activation of T cells by APC

proliferation

?

IL-2

IL-1 IL-1IL-2-R

AgMHC class 2

antigen presenting cell2 3

TT T

the activation of T cells is thought to occur in 3 phases

1) following binding the T cell to the Ag-presenting cell (APC) an

IL-1) unknown factor (?) from the T

2) this in association with Ag sti- mulation induces IL-2-Rs on

mulates T cells to release IL-2

the T cells (possibly a separate subset (3) from that which in- duced L-1 production) and sti-

3) which drives Ag activated cells into proliferation

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Cell mediated cytotoxicity

effector cells

target cells

TC NK K cytotoxiccell

1 2 3 4(experimental)

MHC/Ag

MHC Agreceptor NK-R

NK determinant

lectinIgGAg

FC-R surfaceglyco-

proteins

4 different types of cell binding in cell-mediated cytotoxicity

(1) Cytotoxic cell (TC) bind

nizies Ag and MHC de-their target which recog- terminants

(2) NK cells recognize determinants ex- pressed on neoplas- tic cells

(3) K cells recognize

the Fc of IgG Ab bound to Ag on the target surface

(4) experimentally glycopro- teins on the surface of ef-

cross-linked by lectins fector and target can be

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Thank You