AUTOIMMUNITY S1
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Transcript of AUTOIMMUNITY S1
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IMMUNOLOGICTOLERANCE
ANDAUTOIMMUNITY..
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Immunolgic tolerance B Cell ToleranceT Cell Tolerance
Clonal Deletion Clonal Anergy
Immunogen v Tolerogen
Mec!ani m o" #rea$ing B an% T CellTolerance &autoimmunity'
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CLONAL DELETIONT!i (roce involve% t!e elimination o" immature B orT cell a"ter antigen #in% to t!eir rece(tor.
B or T CELL TOLERANCEi a (roce t!at involve t!e "aillure o" B or T cell to re (on%to el" antigen &normal' or "oreign antigen &a#normal'
CLONAL ANERGYT!i (roce involve t!e ina#ility o" mature B or T cellto re (on% to antigen even a"ter it #in% to it rece(tor.
IMMUNOGEN
T!e antigen i calle% an immunogen i" it in%uceactivation o" a B or T cell
TOLEROGENT!e antigen i calle% tolerogen i" it %oe not activate
a B or T cell &It in%uce B or T cell clonal anergy'.
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Stem Cell Pro-B Pre-B Immature B Mature B
Bone Marrow Peripheral lymphoidorgan or tissue
IgM,IgD
No antigen dependence Self antigen Foreign antigen
Selection Performanceffector function !
ffector B
CentralTolerance )eri(!erial Tolerance
Clonal Deletion&a(o(to i '
Clonal anergy
B CELL TOLERANCE
Rece(tor E%iting
RAG*+ an% RAG*,
Clonal %eletio
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Stem Cell Pro-" Pre-" Immature " Mature "
BM Periphery
"C#
No respon to antigen Pos$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
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-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
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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$e
-*" ** ( g), -*" *6 (TCR)
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-igure ++*, Central an% (eri(!eraltolerance to el" antigen . Immature
lym(!ocyte (eci"ic "or el" antigen mayencounter t!e e antigen in t!e generativelym(!oi% organ an% are %elete%/ c!ange
t!eir (eci"icity &B cell only'/ or &in t!eca e o" CD01 T cell ' %evelo( intoregulatory lym(!ocyte ¢raltolerance'. 2ome el"*reactive
lym(!ocyte may mature an% enter(eri(!eral ti ue an% may #e inactivate%or %elete% #y encounter 3it! el" antigenin t!e e ti ue / or are u((re e% #y t!eregulatory T cell &(eri(!eral tolerance'.
&Note t!at T cell recogni4e antigen(re ente% #y antigen*(re enting cell /
3!ic! are not !o3n.'
2005 Elsevier
Central an% (eri(!eral tolerance to el" antigen .
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-igure ++*+ -ate o" lym(!ocyte a"ter encounter 3it! antigen . In a normal immune re (on e/ micro#etimulate t!e (roli"eration an% %i""erentiation o" antigen* (eci"ic lym(!ocyte . &Micro#ial antigen are
ty(ically recogni4e% #y lym(!ocyte in t!e (re ence o" co timulator an% innate immune re (on e /3!ic! are not !o3n.' 2el" antigen may in%uce "unctional unre (on ivene or %eat! o" antigen*(eci"ic lym(!ocyte or a c!ange in t!e (eci"icity o" t!e rece(tor / ma$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 ¬ !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.
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-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
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-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$e%. 2LE/ y temic lu(u eryt!emato u 6 AITD/ autoimmune t!yroi% %i ea e6 RA/r!eumatoi% art!riti 6 T+D/ ty(e + %ia#ete . &Mo%i"ie% "rom Yama%a R an% > Ymamoto. Recent "in%ing on
gene a ociate% 3it! in"lammatory %i ea e . Mutation Re earc! ?= @+ :*+?+/ Co(yrig!t , ? 3it!(ermi ion "rom El evier.' 2005 Elsevier
2u ce(ti#ility loci "or autoimmune %i ea e
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/01 +in2 imm n%+gic iseases
isease /01 a++e+e RR Rhe mat%i& 1$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 ;" *""
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-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
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MEC7ANI2M -OR BREA>INGB AND T CELL TOLERANCE
MOLECULAR MIMICRY
)OLYCLONALB CELL ACTI ATION
)OLYCLONALT CELL ACTI ATION
E )O2URE O- 7IDDEN2EL- ANTIGEN
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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 @
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B
IgMIgD
T!B
IgM
2EL- ANTIGEN2
CLONAL DELETION
CLONAL ANERGY
DEAT7
ACTI ATED CLONE
B CELL TOLERANCE
MatureImmature
AUTOIMMUNE
T!
)olyclonal activation
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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 $i%ney Anti#o%yAnti In ulin Anti#o%yAnti Lung Anti#o%y
LI)O)OLI2AC7ARIDE &L)2'
)OLYCLONAL 2TIMULANT
T7E ROLE O- IN-ECTION IN T7EDE ELO)MENT O- AUTOIMMUNITY @
T!
2timulatory ignalCyto$ine ACTI ATED B CELL2
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B
IgMIgD
ANERGIFED B CELL2
2el" Antigen&!eart/>i%ney/In ulin/Lung'
A)C
Anti !eart Anti#o%yAnti $i%ney Anti#o%yAnti In ulin Anti#o%yAnti Lung Anti#o%y
2U)ERANTIGEN O- BACTERIA
)OLYCLONAL 2TIMULANT
T7E ROLE O- IN-ECTION IN T7EDE ELO)MENT O- AUTOIMMUNITY @
T!
2timulatory ignalCyto$ine ACTI ATED B CELL2
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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)
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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 .
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