AUTOIMMUNITY S1

7/23/2019 AUTOIMMUNITY S1

1/22

IMMUNOLOGICTOLERANCE

ANDAUTOIMMUNITY..


2/22

Immunolgic tolerance B Cell ToleranceT Cell Tolerance

Clonal Deletion Clonal Anergy

Immunogen v Tolerogen

Mec!ani m o" #rea$ing B an% T CellTolerance &autoimmunity'


3/22

CLONAL DELETIONT!i (roce involve% t!e elimination o" immature B orT cell a"ter antigen #in% to t!eir rece(tor.

B or T CELL TOLERANCEi a (roce t!at involve t!e "aillure o" B or T cell to re (on%to el" antigen &normal' or "oreign antigen &a#normal'

CLONAL ANERGYT!i (roce involve t!e ina#ility o" mature B or T cellto re (on% to antigen even a"ter it #in% to it rece(tor.

IMMUNOGEN

T!e antigen i calle% an immunogen i" it in%uceactivation o" a B or T cell

TOLEROGENT!e antigen i calle% tolerogen i" it %oe not activate

a B or T cell &It in%uce B or T cell clonal anergy'.


4/22

Stem Cell Pro-B Pre-B Immature B Mature B

Bone Marrow Peripheral lymphoidorgan or tissue

IgM,IgD

No antigen dependence Self antigen Foreign antigen

Selection Performanceffector function !

ffector B

CentralTolerance )eri(!erial Tolerance

Clonal Deletion&a(o(to i '

Clonal anergy

B CELL TOLERANCE

Rece(tor E%iting

RAG*+ an% RAG*,

Clonal %eletio


5/22

Stem Cell Pro-" Pre-" Immature " Mature "

BM Periphery

"C#

No respon to antigen Pos$Neg selec-tion %self ant&

acti'ation (yForeign ant

#)* + $ #)* e pression

Nai'e mature "

. /

"hymus

" C 00S "10 #)NC

CentralTolerance )eri(!erial Tolerance

Clonal Deletion&a(o(to i '

Clonal anergyT cell regulator

Clonal %eletion


6/22

-igure ++* Central T cell tolerance. Recognition o" el" antigen #y immature T cell int!e t!ymu may lea% to %eat! o" t!e cell &negative election/ or %eletion' or t!e

%evelo(ment o" regulatory T cell t!at enter (eri(!eral ti ue .

2005 Elsevier


7/22

Contri#ution o" %i""erent mec!ani m to t!egeneration o" %iver ity in Ig an% TCR gene .

V segments 85(heavy chain), 35() 64(TCR),67(TCR) segments !7(heavy chain), "()

"(TCR),!(TCR) # $egi%n &ive$si'cati%nV , (heavy chain),#%ne()

V (TCR),V , (TCR)

segments 6(heavy chain), 5() 6*(TCR),4(TCR) T%ta+ %tentia+ $e e$t%i$e

-*" ** ( g), -*" *6 (TCR)


8/22

-igure ++*, Central an% (eri(!eraltolerance to el" antigen . Immature

lym(!ocyte (eci"ic "or el" antigen mayencounter t!e e antigen in t!e generativelym(!oi% organ an% are %elete%/ c!ange

t!eir (eci"icity &B cell only'/ or &in t!eca e o" CD01 T cell ' %evelo( intoregulatory lym(!ocyte &centraltolerance'. 2ome el"*reactive

lym(!ocyte may mature an% enter(eri(!eral ti ue an% may #e inactivate%or %elete% #y encounter 3it! el" antigenin t!e e ti ue / or are u((re e% #y t!eregulatory T cell &(eri(!eral tolerance'.

&Note t!at T cell recogni4e antigen(re ente% #y antigen*(re enting cell /

3!ic! are not !o3n.'

2005 Elsevier

Central an% (eri(!eral tolerance to el" antigen .


9/22

-igure ++*+ -ate o" lym(!ocyte a"ter encounter 3it! antigen . In a normal immune re (on e/ micro#etimulate t!e (roli"eration an% %i""erentiation o" antigen* (eci"ic lym(!ocyte . &Micro#ial antigen are

ty(ically recogni4e% #y lym(!ocyte in t!e (re ence o" co timulator an% innate immune re (on e /3!ic! are not !o3n.' 2el" antigen may in%uce "unctional unre (on ivene or %eat! o" antigen*(eci"ic lym(!ocyte or a c!ange in t!e (eci"icity o" t!e rece(tor / ma$ing t!e e cell inca(a#le o"re (on%ing to t!e antigen & el"*tolerance'. 2ome antigen elicit no re (on e &ignorance'/ #ut t!e

lym(!ocyte are a#le to re (on% to u# e5uent antigen c!allenge &not !o3n'. T!i illu tration %e(ict Blym(!ocyte 6 t!e ame general (rinci(le a((ly to T lym(!ocyte .

2005 Elsevier

-ATE2 O- LYM)7OCYTE2 A-TER ENCOUNTER 8IT7 ANTIGEN.


10/22

-igure +9*: )o tulate% mec!ani m o" autoimmunity. In t!i (ro(o e% mo%el o" an organ*(eci"ic T cell*me%iate% autoimmune %i ea e/ variou genetic loci may con"er

u ce(ti#ility to autoimmunity/ in (art #y in"luencing t!e maintenance o" el"*tolerance.Environmental trigger / uc! a in"ection an% ot!er in"lammatory timuli/ (romote t!ein"lu; o" lym(!ocyte into ti ue an% t!e activation o" el"*reactive T cell / re ulting in

ti ue in


11/22

-igure +9*= 2u ce(ti#ility loci "or autoimmune %i ea e . T!e c!romo omal loci a ociate% 3it! omeautoimmune %i ea e are !o3n. T!e location o" can%i%ate gene o" immunologic intere t are in%icate%a oval on t!e le"t o" t!e c!romo ome . T!e e oval are color co%e% to in%icate t!e %i ea e to 3!ic!

t!e gene are lin$e%. 2LE/ y temic lu(u eryt!emato u 6 AITD/ autoimmune t!yroi% %i ea e6 RA/r!eumatoi% art!riti 6 T+D/ ty(e + %ia#ete . &Mo%i"ie% "rom Yama%a R an% > Ymamoto. Recent "in%ing on

gene a ociate% 3it! in"lammatory %i ea e . Mutation Re earc! ?= @+ :*+?+/ Co(yrig!t , ? 3it!(ermi ion "rom El evier.' 2005 Elsevier

2u ce(ti#ility loci "or autoimmune %i ea e


12/22

/01 +in2 imm n%+gic iseases

isease /01 a++e+e RR Rhe mat%i& 1$th$itis R4 4 ns +in e ia etes R3 5

R4 5 R3 R4 !5 +ti +e sc+e$%sis R! 4

0 R! R3 5 9em hig s v +ga$is R4 *4 1n2y+%sing %n&y+itis :!7 ;" *""


13/22

-igure +9*: )o tulate% mec!ani m o" autoimmunity. In t!i (ro(o e% mo%el o" an organ*(eci"ic T cell*me%iate% autoimmune %i ea e/ variou genetic loci may con"er

u ce(ti#ility to autoimmunity/ in (art #y in"luencing t!e maintenance o" el"*tolerance.Environmental trigger / uc! a in"ection an% ot!er in"lammatory timuli/ (romote t!ein"lu; o" lym(!ocyte into ti ue an% t!e activation o" el"*reactive T cell / re ulting in

ti ue in


14/22

MEC7ANI2M -OR BREA>INGB AND T CELL TOLERANCE

MOLECULAR MIMICRY

)OLYCLONALB CELL ACTI ATION

)OLYCLONALT CELL ACTI ATION

E )O2URE O- 7IDDEN2EL- ANTIGEN


15/22

B

IgMIgD

2tre(tococcuanti#o%y

2tre(tococcuAntigen &e(ito('

e(ito( on

!eart cell

De truction o" !eart ti ue

R7EUMATIC -E ER

CroReaction

MOLECULAR MIMICRY

T7E ROLE O- IN-ECTION IN T7EDE ELO)MENT O- AUTOIMMUNITY @


16/22

B

IgMIgD

T!B

IgM

2EL- ANTIGEN2

CLONAL DELETION

CLONAL ANERGY

DEAT7

ACTI ATED CLONE

B CELL TOLERANCE

MatureImmature

AUTOIMMUNE

T!

)olyclonal activation


17/22

B

IgMIgD

ANERGIFED B CELL2

2el" Antigen&!eart/>i%ney/In ulin/Lung'

B

IgMIgD

Anti L)2 Anti#o%y

Anti !eart Anti#o%yAnti $i%ney Anti#o%yAnti In ulin Anti#o%yAnti Lung Anti#o%y

LI)O)OLI2AC7ARIDE &L)2'

)OLYCLONAL 2TIMULANT


T!

2timulatory ignalCyto$ine ACTI ATED B CELL2


18/22

B

IgMIgD

ANERGIFED B CELL2

2el" Antigen&!eart/>i%ney/In ulin/Lung'

A)C

Anti !eart Anti#o%yAnti $i%ney Anti#o%yAnti In ulin Anti#o%yAnti Lung Anti#o%y

2U)ERANTIGEN O- BACTERIA

)OLYCLONAL 2TIMULANT


T!

2timulatory ignalCyto$ine ACTI ATED B CELL2


19/22


20/22

AUTOIMMUNE DISEASES

Rheumatoid Arthritis (antinuclear antibody)Rheumatic Fever (antistreptococcus antibody)

Goiter (antibody against thyroid epithelial cells)Diabetes Mellitus type I (antibody againstmaterials of cytoplasm/cell membrane ofpancreas cell! cytoto"icity of # cell to cell)$

%hronic #hyroiditis (&ashimoto)! (' and # cellinfiltration)

cleroderma (antinuclear antibody)ystemic upus *rythematosus (Antinuclear

antibody! anti D+A antibody)


21/22

CONCLU2ION2 All normal in%ivi%ual are tolerant o" t!eir o3n& el"' antigen & el" tolerance' T3o mec!ani m o" el" tolerance are central

tolerance an% (eri(!eral tolerance Central tolerance con i t o" clonal %eletion/

rece(tor e%iting &B cell' an% Regulatory T cell. )eri(!eral tolerance con i t o" Clonal Anergy/

clonal %eletion/ an% Regulatory T Cell. Autoimmune %i ea e re ult "rom t!e "aillure o"

el" tolerance %ue to t!e activation o" clonalanergy or t!e lac$ "unction o" Regulatory T cell. Multi(le "actor contri#ute to autoimmunity/

inclu%ing immunologic a#normality/

u ce(ti#ility gene / an% in"ection .


22/22

AUTOIMMUNITY S1

Documents

Transcript of AUTOIMMUNITY S1