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CELLLULAR AND CELLLULAR AND
CELLLULAR AND
CELLLULAR AND

MOLECECUULAR

MOL

LAR BBASASISIS OFOF

IMMUNI IMMUNITTYY

MMUHUHAMAMMA

MADD JJUNUNAAIIDD

0077--AArriidd-1-1665577

St

Strructure

ucture Of

Of AAnti

ntibboodi

dieess

St St r r ucture ucture Of Of A A nti nti b b o o

ntibododieiess aarere pprote

roteins

AAntib

ins pprroodduucceded bbyy BB cceellll aanndd

pplasm

lasmaa cecellslls..

BB cceellll iinnccoorrppooraratete aanntibtibododyy mole moleccule ule ininttoo ththeeirir

pplasm

lasmaa mmeemmbbran

ranee wh

wheerere ththeyey seserve

rve asas aanntitiggeenn

rerececepptotorr..

WWheherere aass pplalassma

ma ccells

ells seseccrreetete ththeessee pro

proteteiinnss inintoto

bbloo

loodd aanndd ooththerer boboddyy flufluiidds.s.

Contd…

St Strructure ucture Of Of AAnti ntibboodi dieess  Antibodies are globular proteins
St
Strructure
ucture Of
Of AAnti
ntibboodi
dieess
 Antibodies
are
globular
proteins

immunoglobulins.

called

These are built of two types of chains.

A larger heavy chains (50,000-70,000 daltons)

And a smaller light chains (23,000 daltons)

These are linked by disulfide bond.

44

55

55

AAnti

ntibody

body Structur

Structuree

A A nti nti body body Structur Structur e e  Domains comprising a constant region

Domains comprising a constant region are indicated by C.

Domains comprising the variable are V.

Each heavy chains contain three C regions (C 1 , C 2, C 3) one V regions and N-terminus of polypeptide.

Each light chains contain one

C

L regions

one V

regions at its N terminus. The V regions forms the antigen combining site.

66

77

77

88

88

VVaarriiati

ationon InIn TThehe AAnti

ntibody

body

alf of each

alf of each

 

light

light

chain

chain

s has

s has

 

H

H

a variable region V.

a variable region V.

OOnene ququaarter rter ooff eeaacchh hheeavavyy chchaainin isis vvaria ariabblele V. V.

The The rreemmaainining ing tthhrereee reregio gionnss aarere ccononsta stant nt ..

The

The vvaaria

riable

ble ppoortrtioionn ooff lligighhtt aandnd heheaavvyy cchahaininss

ccoonta

ntainin susubre

breggiioonnss ccaalled

lled hyhyppeerva

rvariariable

ble rereggion

ionss..

HHype

ypervrvaria

ariabblele rereggiioonnss pplay

lay aa pproromminineent

nt role

role inin

forminingg aannttigigeenn ccoommbbiinniningg site.

form

site.

VVaria

ariatitioonn inin aammininoo aaccidid seseqquueencncee ooff ththeessee reregio

gionnss

reressuultlt inin ggrea

reatt div

diveerrsity

sity ooff aanntitibbooddyy spspececifi

ificcity.

ity.

Contd…

99

VVaarriiati

ationon InIn TThehe AAnti

ntibody

body

V V a a r r i i ati In In T T he he A

The combining site has

The combining site has

a complementary portion

a complementary portion

ooff the the aanntige tigenn wh which ich iiss ccalle alledd eeppiitotoppee..

BBececaauussee ooff ththeeirir cclloosese fit

fit ,a,anntibo

tiboddieiess aandnd anantigtigenen

formss sstatabbllee ccomple

form

omplexxeses

1100

DDNNAA RReeaarrrang

rangeemmeent

nt Of

Of Ge

Genes

nes

Encoding B-and T-

Encoding B-and T-

Cell Antigen

Cell Antigen

Receptors Receptors
Receptors
Receptors

EaEacchh IgIg mmoolelecuculele ccoonnsisistst ooff ligh

lightt anandd hheeaavvyy

cchahainins.s.

BoBothth hhaaveve aa vvaria

ariabbllee poportio

rtionsns VV..

Wh

Whoosese aammininoo seq

sequueencncee vvaaries

ries ffroromm oonnee aanntibo

tiboddyy

ttoo aanonoththeerr..

TThhee ccoonnsstatanntt reregio

gionn CC reremmaainin ththee samsamee iinn bobothth

ccllaasses.

sses.

1111

is is the What g g e e neti basi for the sy sy n

What isis the

What

the ggeeneti

neticc basi

basiss for

for the

the

sysynntthehesisiss ofof pol

polypepti

ypeptidede hahavin

vingg aa

ccoombi

mbinati

nationon ofof sha

sharree and

and unique

unique

aami

minono acid

acid seque

nces??

sequences

1122

One gene

One gene

polypeptide hypothesis

polypeptide hypothesis

one

one

One gene One gene polypeptide hypothesis polypeptide hypothesis one one Dre  InIn 11996565 WWilillialiamm aanndd

Dre

InIn 11996565 WWilillialiamm

Dreyeyerr aanndd JJ CCllaauuddee ggaavvee oonnee

gegennee oonnee ppoollyyppeepptitiddee hhypypootthheesis

sis..

TThheeyy pproropoposesedd tthhaatt eeaachch aanntibo tiboddyy isis eencncooddeedd byby

ttwwoo seseppara aratete ggeenneses CC gegennee aanndd VV

gegennee..

ccomombbininee toto form form oonene ggenenee..

ThThat

at

InIn 19197766 SSusu

usummuu Ton

Toneeggaawa

rovidideedd eevvididenenccee inin

wa pprov

ffaavvoourur ooff DNDNAA rreeaarran

rranggeemmeenntt..

1133

D D N N A A rearr rearr a a ngement ngement lead lead to to

DDNNAA rearr

rearraangement

ngement lead

lead toto the

the

foforrmmati

ationon ooff aa ffunc

uncttioional

nal ggeenene that

that

eencodes

ncodes anan imimmuno

munogl

globul

obulinin cchahainin

1144

1155

1155

MMecechhanis

anismm ofof rereaarrran

rangegemment

ent

M M ec ec h h anis of of re re a a r r ran

The variable region

The variable region

of each immunoglobulin heavy or

of each immunoglobulin heavy or

ligh lightt chain chain isis eennccooded ded inin several several ppieiececess knknown own aass gene gene

segm segments. ents.

TThese

hese segm

segments

ents are

are ccalle

alledd vvariable

ariable ((VV)),, ddivers

iversitityy (D)

(D)

aanndd join

joining

ing ((J)J) segm

segments.

ents.

V, DD aandnd JJ segm

V,

segments

ents are

are found

found inin IIgg hheaeavyvy chains,

chains, bubutt

ononlyly VV and

and JJ segm

segments

ents aarree foun

foundd inin IgIg liglight

ht cha

chainin..

DDeveveelop

loping

ing

BB

cecellll

will

will asse

assemmbblele anan imimmmuunonoglo

globulin

bulin

var variiable able rreeggion ion byby rand randomomlyly sele selecting cting aanndd comcombbiinning ing

ononee VV,, oonene DD aanndd ononee JJ ggene ene segm segmenentt

Contd…

1166

MMecechhanis

anismm ofof rereaarrran

rangegemment

ent

M M ec ec h h anis of of re re a a r r ran

As there are multiple copies of each type of gene

As there are

multiple copies of each type of gene

segmmeenntt

seg

DDififfeferen

rentt ccoommbbininatio

ationnss ooff gegennee seseggmmeents

nts ccaann bbee

uused

sed toto ggeennera

eratete eeaacchh imimmmuunnogoglolobbulin

ulin vvaaririaabblele

reregio

gionn

TThhisis pproroccess

ess ggeenneerraatetess aa hhuugege nunummbbeerr ooff

aantib

ntiboodie

dies,s, eaeacchh wwiithth diff

diffeererenntt ppaarraatotoppeses anandd

ththusus ddiff

iffeererent

nt aantig

ntigenen spe

speccifificiciitieties.s.

1177

CClalassss swswiitch

tchiingng

 

ce a cell is committed to

   

it produces.

 

Once a cell is committed to

On

form a specific antibody it can

form a specific antibody it can

switch the class of Ig

switch the class of Ig

it produces. By changing the heavy

By changing the heavy

cchhaainin inin ththee ccell.

ell.

TThi

hiss isis kknown

nown aass cla

classss sswwitch.

itch. Oc

Occur

curss withou

withoutt chang

changing

ing

the comcombbinin

the

iningg ssiteite ofof antib

antibododyy synthesize

synthesizedd..

CClalassss sswwitchin

itchingg allows

allows ddififfeferreenntt dau

daughter

ghter ccells

ells ffrromom tthehe

sasammee aactivate

ctivatedd BB cecellll ttoo pproroduce

duce aanntibo

tibodies

dies ofof diff

different

erent

isotypes.

isotypes.

TThhusus the

the prprogeny

ogeny

ofof

aa

ssingl

inglee

BB

cell ccanan prprododuce

cell

uce

aanntibod

tibodies,

ies, aallll spspeecif

cificic for

for tthehe samsamee antigen

antigen..

ItIt isis iinnitiat

itiateded byby cytok

cytokiinneess sec

secrrete

etedd bbyy TT cells.

cells. DDuurring

ing BB

ccell

ell iinnterac

teractiotions.

ns.

1188

1199

1199

MMembrane

embrane Bound

Bound AAnti

ntigegenn RRececeptor

eptor

     

Complex

Com

plexes

es

TThhee rereccogognnition

ition ofof aanntige

tigenn ooff BB aanndd TT ccell

ell ococccuurrss

aatt cecellll susurfrfaaccee..

BB ccell

ell rerecceepto

ptorr ccoommbbine

ine eeppitop

itopee..

TT cecellll rereccepeptotorr ccoommbbiinnee with

with aa frfraaggmmeenntt ooff

aantig

ntigeen.

n.

BoBothth rerececepptotorr aarere iinnvvoolvlveded inin ssigignnallin

allingg ppath

athwwaayy..

Wh

Whicichh aaccttivivaatete bobothth ththee cceellls.

ls.

2200

Pathwaayy ooff acti

Pathw

activavatitionon ooff TTCCRR

is phosphorylated is phosphorylated
is phosphorylated
is phosphorylated

TCR

TCR

by src Family

by src Family

LcLckk && FFyynn

Whic

Whichh rerecrui

cruitt zazap-70.

p-70. toto TTCRCR..

of

of

Map

Map ki

kinas

nasee cacascade

scade isis init

initiat

iated.

ed.

TThehe

CD45

CD45

proteinin

prote

ttyyrosine

rosine

phosphat

phosphateses

aact

ctivat

ivateses LLckck and

and FyFynn

requirreedd for

requi

for TTCRCR

aact

ctivat

ivation.

ion.

2211

2222

2222

Pathwayay Of

Pathw

Of AActi

ctivat

vatioionn Of

Of BBCCRR

   

tyrosine

tyrosine

   

phosphorylation

phosphorylation

Reversible

Reversible

important role in regulating B cell.

important role in regulating B cell.

An

Antige

tigenn

kin

kinaasese..

bbiinnddiningg

pprorommootteess

proteteiinn

pro

plays plays an an tytyrorosine sine
plays
plays
an
an
tytyrorosine
sine

PPhohospsphohoryla rylatitioonn ininccrreeaasesess..

SSrrcc ffaammilyily PPTKs TKs aarere aaccttivivaatetedd initia initialllyly aanndd seserve rve

ttoo phphoospsphohorylate rylate CCDD7979aa aanndd CCD7 D799bb ththeereb rebyy

ccrreeaating ting phphoosph sphootyrosin tyrosinee mmootif tifs.s.

BCBCRR cocommpplelexx lea leaddss toto ththee rec recruruititmen mentt aanndd

aactiv ctivatio ationn ooff ththee PPTKTK Syk Syk,, wwhhiicchh inin tuturnrn

prommootetess phphoosph

pro

sphooryla

rylattioionn ooff PPLCLCgg,, SShhcc aanndd VVaavv

Contd…

2233

Pathwayay Of

Pathw

Of AActi

ctivat

vatioionn Of

Of BBCCRR

to p.membrane Plcg a
to p.membrane Plcg a

Tec,btk recruited to p.membrane Plcg activated.

Tec,btk recruited

ctivated.

S S

LP-65/BLINK recruites effector proteins.

LP-65/BLINK recruit

es effector proteins.

Afte

Afterr

BCBCRR

acactivtivatio

ationn

nnuummero

erouuss

sseeccoonndd

mmeesssesennggerer PPPI3

PI3 IPIP

33..

DDAGAG aaccttivivaatete PPkckc..

IP3 IP3 pprorommootete Ca Ca ion ionss

Ra

Ras,s,

Ra

Rapp

aalsolso

aactiv

ctivate

atedd.Map

.Map

kkiinnaasese

aacta

ctavvaatteedd..

Incluluddiinngg EErkrk Jnk

Inc

Jnk anandd pp3388..

isis

aalsolso

SSeveveeral ral tra transc nscriptio riptionn fafaccttoorr acactivtivate atedd wwhhich ich

iinnitiate

itiate gegennee tran

transcscriptio

riptionn..

2244

2255

2255

MMaajor

jor Hi

Histocom

stocompat

patibi

ibililityty CCoompl

mpleexx

 

activ

 

activated by AP

ated by APC.

C.

 

T cells

T cells

SSmmaallll ffraragme

gment

nt ooff aanntitiggeenn aarere hheelldd iinn MMHHC.

C.

MMHHCC inte

interaracts

cts wwitithh TTCCR.

R.

TThhisis

interaractio

inte

ctionn

isis

furth

furtheerr

oreccepeptotorr CCDD 44,, CCDD 88..

ccore

strengngththenenss

stre

bbyy

2266

2277

2277

CCllasses

asses ofof MMHCHC

C C l l asses of of M M HC HC ooff MHC  TTwwoo cla

classes

sses ooff MHC

TTwwoo cla

MHC ddispispllaayy anantigtigeenn wh

whicichh

mmaayy bbee eennddogogeennoousus oror exexooggeenonouus.s.

CCllaassss II eenndodogegennoouuss..

CCllaassss IIII eexxogogeennoous.

us.

2288

2299

2299

Inhibititionon ofof TCTCRR

Inhibi

by Csk inh
by Csk inh

The phosphorylation of Lck by Csk inhibits T cell

The phosphorylation of Lck

ibits T cell

rec receepptor tor sigsignnalin alingg aanndd inh inhibibitsits TT ccell ell aacctiva tivatiotion. n.

Csk

Csk aacctivity

tivity isis reregguullaatetedd inin TT ccells

ells bbyy PPKKAA,, ththee

ccAMAMPP-d-deeppenenddeent

nt pro

proteteinin kkiinnaasese aactiv

ctivaatteedd byby the

the

sseeccoonndd mmeessen

ssenggeerr ccAMP

AMP..

TThhee aacctivity

tivity ooff ccsksk ddepepeenndd oonn CCBPBP..

TT cceellll rec

receepptor

tor cocomple

mplexx aarree loc

locaalilizzeedd..

direccttlyly acactivtivaatteess CCsksk..

dire

CBCBPP aalsolso

3300

3311

3311

DDiisstting

inguishi

uishingng SeSellff from

from NNonself

onself

TT

D D i i s s t t ing Se Se l l f f from

CCeelllsls aarere rereccoogngnizizeedd byby the

theirir rerecceepto

ptorsrs wh

whicichh

aarere ccododeedd bbyy tra

transc

nscripripttioionn fafacto

ctorsrs ccalle

alledd AAIIRREE..

TT Ce Cellslls wwhhoossee TCTCRs Rs hhaaveve hhigighh affi affinnityity for for bboodie diess

oonn pprorotitieenn are are dedestr strooyeyedd ththisis pproc roceessss isis neneggativ ativee

seselleecctitioonn ggrad radeelyly red reduucceses ththee cchhananccee ofof atta attacckk oonn

sesellf.f.

3322

Sum

Summa

maryry

Sum Sum ma ma ry ry  GGeneneess aarere rereaarran toto form BB aanndd TT ccell

GGeneneess aarere rereaarran

rranggeedd toto form

form BB aanndd TT ccell

ell aanndd

aannttigigeenn rerececepptors.

tors.

VV DD JJ uunnddeergo

recoommbbininatio

ationn toto pro

prodduucece mmaannyy

rgo rec

typeses ofof aanntibo

typ

tiboddieiess..

TT Ce

Cellslls are

are aacctitivvaatetedd bbyy MHC

MHCss wh

whicichh aarere oonn ththee

AAPCPCs.s.

Contd…

3333

Summary

Sum

mary

Summary Sum mary  TT Ce KKiinnaase. aarere aaccttivivaated ththrorougughh ddififfeferreenntt Ma  TT CCells aarere

TT

Cellslls

Ce

KKiinnaase.

se.

aarere

aaccttivivaated

ted

ththrorougughh

ddififfeferreenntt

Ma

Mapp

TT

CCells

ells aarere rereccoogngnizizeedd bbyy

ththrroouugghh ththeir

eir rerecceepto

ptors.

rs.

tthheeirir oown

wn system

system

3344

QQuouotete:: Do scscrreeww upup ththee bbeestst ththing inin yyour life jjust bbeeccause yyouou ddoon’ kno wwhhoo

QQuouotete::

Dont

Do

nt scscrreeww upup ththee bbeestst ththing

ingss inin yyour

our life

life jjust

ust

bbeeccause

ause yyouou ddoon’

ntt kno

knoww wwhhoo yyoouu rereally

ally aarere

BByy:: ZZiigg ZZaaggler

ler

3355

T T h h an an ks ks f f o o r r y y

TThhananksks ffoorr yyouou PaPatien

tiencece

Any Quest

Any

Questioionnss::

3377