ANLGOEJ1FJMJL92B3646C04A0C1B4363DH400E2 BBKJPHHGL9 590566L9406042833 ID: 958506
Download Pdf The PPT/PDF document "B9KA83464B3400" is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.
B9?K"A?!8'34($*!+,!)#(64.$&!B('#!.$)3..$&
'!(&,$)'(+&!4$/+&*'.0'$!'#0'!D.(/0.1!(//3
&+4$,()($&)1!I-2JK!#0*!0!*(L&(,()0&'!L$&$
'()!)+/D+&$&'E!2&!-2JA!+H$.!@MM!L$&$*!+,!
#(L#!D$&$'.0&)$!($.('$4!/+*'61!(&!03'+*
+/06!.$)$**(H$!/0&&$.!#0H$!06.$041!G$$&!(
4$&'(,($4E!N+B$H$.A!/0&1!)#(64.$&A!(&)634
(&L!'#+*$!B('#!$0.61!+&*$'!(//3&+4$,()($&
)1!#0H$!&+'!.$)$(H$4!0!L$&$'()!4(0L&+*(*A
!4$*D('$!3*$!+,!'0.L$'$4!*$O3$&)(&L!/$'#+
4*E!!!2!D$.,+./$4!G(+(&,+./0'()!0&061*(*!
(&!B#+6$!L$&+/$!*$O3$&)(&L!40'0!(&!D0'($&
'*!B('#!(//3&+4$,()($&)1E!"#$*$!0&061*$*!
B$.$!(&('(0661!(&!0!*/066!)+#+.'!+,!0,,$)
'$4!)#(64.$&!0'!%.$0'!P./+&4!8'.$$'!(&!B#
+/!0!L$&$'()!4(0L&+*(*!B0*!&+'!C&+B&E!2!4
$H(*$4!0&4!3'(6(*$4!G(+(&,+./0'()!D.+L.0/
*!'+!(4$&'(,1!&+H$6!L$&$'()!H0.(0&'*!(&!'
#(*!)+#+.'E!2!$H0630'$4!'#$!D$.,+./0&)$!+
,!B#+6$!L$&+/$!*$O3$&)$!0&061*$*!B('#!'0.
L$'$4!L$&$!D0&$6!0&061*$*A!B#()#!(*!'#$!/
+*'!3'(6(*$4!/$'#+4!+,!L$&$'()!4(0L&+*(*E
!"+!$QD0&4!/1!0&061*(*A!2!6++C$4!0'!0!60.
L$.!)+#+.'!+,!1+3&L!D$+D6$!0&4!0436'*!B('
#!(//3&+4$,()($&)1!0*!D0.'!+,!'#$!60.L$!&
0'(+&06!)+660G+.0'(H$!D.+R$)'!:2NS!T(+.$*
+3.)$!S0.$!J(*$0*$*!TS2J%UV-2J!D.+R$)'E!2
!O30&'(,($4!'#$!G3.4$&!+,!.0.$!)+4(&L!H0.
(0'(+&!(&!0!)0*$!)+#+.'!)+/D0.$4!'+!)+&'.
+6*!0&4!3*$4!.0.$!H0.(0&'!0**+)(0'(+&!0&0
61*(*!'+!(4$&'(,1!D+'$&'(06!&+H$6!)0&4(40
'$!L$&$*!(&!D.(/0.1!(//3&+4$,()($&)1E!"#$
!,(&06!)#0D'$.!,+)3*$*!+&!W!&+H$6!L$&$'()
!H0.(0&'*!,+3&4!(&!'#$!)+#+.'!0&4!+3.!(&(
'(06!,3&)'(+&06!'$*'(&L!'+!H$.(,1!L$&$'()
!4(0L&+*(*E!!!"#$!B+.C!D.$*$&'$4!(&!'#(*!
'#$*(*!4$/+&*'.0'$*!&+H$6!L$&$'()!)03*$*!
+,!(//3&+4$,()($&)1!0&4!'#$(.!,3&)'(+&06!
(/D6()0'(+&*E!"#$!.$*36'*!+,!/1!B+.C!#0H$
!(/D.+H$4!3&4$.*'0&4(&L!+,!'#$!L$&$'()!0.
)#('$)'3.$!+,!D.(/0.1!(//3&+4$,()($&)($*!
0&4!#0*!)6(&()06!3'(6('1!(&!'#$!4(0L&+*(*
!0&4!*3G*$O3$&'!'.$0'/$&'!+,!(//3&+4$,()(
$&)1E! "ANLGOEJ1FJMJL?9!2!B+364!6(C$!,(.*
'!0&4!,+.$/+*'A!'+!'#0&C!/1!B+&4$.,36!*3D
$.H(*+.!\4.(0&!"#.0*#$.E!2! "BBKJPH"?HGL9
!!!%$&+/$*!\59%!!!\/$.()0&!5+66$L$!+,!9$
4()06!%$&$'()*!0&4!%$&+/()*!\28!!!\3'+(//
3&('1!*1&4.+/$!T\9!!!T(&0.1V)+/D.$**$4!8\
9!!GD!!!T0*$!D0(.!TF\!!!T3..+B*VF#$$6$.!\
6(L&$. J$+Q1.(G+&3)6$+'(4$!'.(D#+*D#0'$!U
T`!!!UD*'$(&!T0..!H(.3*!U5[!!!U&)$4!)#
$/(63/(&$*)$&)$!UQ\5UQ+/$!\LL.$L0'(+&!5+&
*+.'(3/!L!!!%.0/*!%\"_!!!!%$&+/$!\&061*(*
!"++6C('!%US-!!!%$&+/()!UH+63'(+&0.1!S0'$
!-.+,(6(&L!%S5#!!!%$&+/$!S$,$.$&)$!5+&*+.
'(3/!\**$/G61!%"-!!!%30&+*(&$!'.(D#+*D#0'
$!%F\8!!!%$&+/$VB(4$!\**+)(0'(+&!8'341!L`
5X!!!%$&+/$!`0.(0&'!5066!X+./0'!,(6$ 9J"!
!!936'(V4(*)(D6(&0.1!'$0/!/L!!!9(66(L.0/*
!/6!!!9(66(6('.$*!/9!!!9(66(/+60.!/S:\!!!
9$**$&L$.!.(G+&3)6$()!0)(4 AGL?JL?9!!!"#$
%&'()$"**!!787$9#,%)#&$:%%*/"0(-,;,(/;&
$,3()3(3$7$78=$ 4 0;2".($?(/"%($@(A*(/
;,/1$7B$78B$C(;2)/,3%3$"-$?(/(+,;$,3()3(7
8E$?(/(+,;$3+*0,(3$,/$F#,%)#&$,%%*/"0(-,;
,(/;& L9BUU EH9?!GQ!QHFDKJ9!"#"!!$%&&'()!
*+!,-.-/01!1'%2-2!*+!$345!!!!!!!6!"#7!3*&
8*.-./2!*+!9:;5!*=0 -6 ;'2-!1*&8?-=!*+
!8@',*1)/-2!!!!"A!"#6!B$-C%-.10.,!D)!2)./
@-202E!&-/@* -6 ;!!!!!!!"F!"#F!3*&8*.-
./2!*+!,-.-/01!'(1@0/-1/%(-!!!!!!!77!!7#"
!;(0.108'?!3*&8*.-./!:.'?)202!2@*G0.,!1*@
*(/!8*8%?'/0*.!'8H'8!&'(I-(2!!6"!7#7!$-C%
-.10.,!C%'?0/)!1*./(*?!&-/(012!+*(!/@-!;4
5!8'/0-./!1*@*(/!!!!6F!7#6!;'/0-./!8@-.*/
)8-2!G@*!@' 10 ;!D*/@!J4KLM!,-.-!8'.-?
!'. 10 ;!NK$!!!6O!7#F!P-2/!;('1/01-!G*
(I+?*G!*+!2-C%-.10.,! 10 ;'/'!+0?-2!!!
!!6Q!7#R!S'(0'./!2-.20/0T0/)!'. 10 ;!2
8-10+010/)!&'/(0=!!!!!!FF!7#U!;45!1'/-,*(
0-2!*+!8'/0-./!1*@*(/!!!!!!!FQ!!6#"!/-(*V
),*%2!'.- 18; 000;!@*&*V),*%2!$9S!&
#x- 18; 000;-/-1/0*.!2-.20/0T0/)!!!!UA
!6#7!/-(*V),*%2!'.- 18; 000;!@*&*V)
,*%2!$9S!- 18; 000;-/-1/0*.!28-10+0
10/)!!!!U7!6#6!S'(0'./!- 18; 000;-/
-1/0*.!2-.20/0T0/)!+*(!@-/-(*V),*%2!'.
- 18; 000;!@*&*V),*%2!$9S2!!!UR!6#F!S'
(0'./!- 18; 000;-/-1/0*.!2-.20/0T0/
)!+*(!@-/-(*V),*%2!'.- 18; 000;!@*&
*V),*%2!4.- 18; 000;-?2!!UU!6#R!W*G
!1*T-(',-!;45!,-.-2!0.!NL$!!!!!!!UX!6#U!M
'.,-!*+!(-'- 18; 000;!- 18; 0
00;-8/@2!0.!4YPYK!'1(*22!2'&8?-2!!!!!OA!!
F#"!ZT-(T0-G!*+!;45!T'(0'./!'.'?)202!808-
?0.-!!!!!!QU!F#7!S'(0'./!&-/(012!+*(!/@-!
8'/0-./!1*@*(/!!!!!!!QO!F#6!$1@-&'/01!(-8
(-2-./'/0*.!*+!/@-!8(*/-0.!- 18; 00
0;*&'0.2!*+!35OX:!!!!X6!F#F!$1@-&'/01 HL?
KG1DA?HGL!!4=4!0.'*7.8!H**(-+%,'@
'%@8!1'&%7&%&!4=4=4!AC''@
7C!G;%.;'%R!-.(/0.1!2//3&+4$,()($&)1!J(*$
0*$*!I-2JK!0.$!0!60.L$!#$'$.+L$&$+3*!L.+3
D!+,!($.('$4!4(*+.4$.*!'#0'!.$*36'!(&!4
$,$)'*!(&!(//3&$!*1*'$/!4$H$6+D/$&'!0&4h+
.!,3&)'(+&E!"#$1!4$*).(G$!0!4$,()('!+,!'#
$!(//3&$!*1*'$/A!B#$.$G1!'#$!D0'($&'!(*!3
&0G6$!'+!/+3&'!0!.$*D+&*$!'+!0!D0'#+L$&A!
.$*36'(&L!(&!0&!(&).$0*$4!*3*)$D'(G(6('1!
'+!(&,$)'(+&E!UQ0/D6$*!(&)634$!,0(63.$!+,
!T!)$66!4$H$6+D/$&'A!'#$!0G*$&)$!+,!)+/D6
$/$&'!)+/D+&$&'*A!+.!(/D0(.$4!L.0&36+)1'$
!,3&)'(+&E!-2J!0.$!'#$/*$6H$*!$&)+/D0**$4
!G1!'#$!B(4$.!L.+3D;!(&G+.&!$..+.*!+,!(//
3&('1E!"#(*!L.+3D!(&)634$!4(*$0*$*!+,!(//
3&$!41*.$L360'(+&!*3)#!0*!03'+(&,60//0'(+
&E!!-2J!H0.(0G61!0,,$)'*!G+'#!0436'*!0&4!
)#(64.$&A!0&4!(*!+,'$&!0**+)(0'$4!B('#!*3
G*'0&'(06!/+.G(4('1!(&)634(&L!)+/D6()0'(+
&*!+,!*$H$.$!(&,$)'(+&*A!/06(L&0&)1!0&4!D
.$/0'3.$!/+.'06('1E!!!-2J!)0&!H0.1!(&!*$H
$.('1!,.+/!G$&(L&!0&'(G+41!4$,()($&)($*A!
'+!'#$!/+.$!*$H$.$!0&4!.0.$!4(*+.4$.*!*3)
#!0*!*$H$.$!)+/G(&$4!(//3&+4$,()($&)1!I85
2JK!B#()#!)0&!)03*$!0&!0G*$&)$!+,!G+'#!T!
0&4!"!)$66*E!-2J!0,,$)'!0DD.+Q(/0'$61!=AM
MM!D$+D6$!'#.+3L#+3'!U3.+D$!ijE!2&!'#$!d_
A!'#$!D.$H06$&)$!+,!-2J!(*!@E=!(&!MMAMMME
!9+*'!0.$!(&4(H(430661!.0.$!B('#!D.$H06$&
)$!+,!!(&!MMAMMM!+.!6$**!iWjE!!!-2J!(*!0!
6(,$V6(/('(&L!4(*$0*$!0&4!(&4(H(4306!D.+L
&+*(*!4$D$&4*!+&!'#$!)6(&()06!,$0'3.$*A!(
&!D0.'()360.!'#$!D.$*$&)$!+,!4(*$0*$V.$60
'$4!)+/D6()0'(+&*!B#()#!)0&!*(L&(,()0&'61
!.$43)$!6(,$!$QD$)'0&)1!i@jE!"#$!/0(&*'01
!+,!'.$0'/$&'!(*!.$D60)$/$&'!(//3&+L6+G36
(&!I2`2%KE!"#$!3*$!+,!2`2%!'.$0'/$&'!#0*!
(/D.+H$4!+3')+/$*!(&!)#(64.$&!0&4!0436'*!
B('#!-2J!B('#!0&!$QD$)'$4!*3.H(H06!+,!=Yk
!?=!1$0.*!0,'$.!4(0L&+*(*! 4(,,$.$&'(0'$*
!'+!$H$&'30661!,+./!066!+,!+3.!(//3&$!)$6
6*E!-.(/0.1!(//3&+4$,()($&)1!(*!)03*$4!G1
!4(*.3D'(+&!(&!C$1!L$&$*!+,!#0$/0'+D+$'()
!4$H$6+D/$&'!ID0.'()360.61!*$H$.$!,+./*KA
!B#$.$!4(*'3.G0&)$!+,!$('#$.!&3/G$.!0&4h+
.!,3&)'(+&!+,!4(,,$.$&'(0'$4!)$66*!4$.(H$
4!,.+/!'#$!N85A!+.!$,,$)'+.!)$66*!)+&'.+6
6$4!G1!'#$!#0$/0'+D+$'()!D.+)$**!.$*36'!(
&!-2JE!!!"#$!G.+04!*D$)'.3/!+,!-2J!(*!.$,
6$)'$4!(&!'#$!B(4$!.0&L$!+,!)$66*!0&4!'(*
*3$*A!B#()#!)+/D.(*$!'#$!(//3&$!*1*'$/E!"
+!40'$A!@WM!L$&$*!#0H$!G$$&!0**+)(0'$4!B(
'#!-2J!0*!)0'$L+.(*$4!G1!'#$!2&'$.&0'(+&0
6!d&(+&!+,!2//3&+6+L()06!8+)($'($*!I2d28K
!-2J!$QD$.'! 4=4=4=4!9%;%.%!@-*)'
%+!'**(-+%,'@'%@88$H$.$!)
+/G(&$4!(//3&+4$,()($&)1!I852JK!+))3.*!B#
$&!'#$.$!(*!4(*.3D'$4!4$H$6+D/$&'!+,!G+'#
!T!0&4!"!)$66*!IX(L3.$!EKE!2&!'#$!0G*$&)$
!+,!&$BG+.&!*).$$&(&LA!D0'($&'*!'1D()0661
!D.$*$&'!G$'B$$&!W \C'!D0'#B01A!'#$!S\8V9
\-_!D0'#B01!0&4!'#$!7\_8"\"!D0'#B01E!"VTV
:_l!852J!4$,$)'*!0.$!'1D()0661!0**+)(0'$4
!B('#!4$,$)'*!(&!J:\!.$)+/G(&0'(+&!0&4!.$
D0(.!$&^1/$*!).('()06!,+.!`IJK7!.$)+/G(&0
'(+&!+,!'#$!"!0&4!T!)$66!.$)$D'+.!$ELE! F
luctuating neutropenia Low Ig levels High
IgM CD40 (AR) CD40LG (XR) Opportunistic
infections, Liver and biliary tract disea
se Impaired NK cell degranulation DOCK2 (
AR) Early onset invasive bacterial and fu
ngal infections Poor T cell proliferation
CARD11 (AR/AD) Opportunistic infections
Low memory T and T reg cells BCL10 (AR) G
astroenteritis Absent T reg and !" T cell
s IKBKB (AR/AD) Opportunistic infections
Variable T-cell dysfunction ICOS (AR) Aut
oimmunity, Granulomatous disease Poor T c
ell proliferation TFRC (AR) (AR) !"!"!"#!
$%&'()*+,*'-).*/.-,#$%$&'(!(*3-$-!,.!*+*2
2*+,/3'%*$2'*!*1$!+$%$1*0!(,%.'%$)!&,!+$%
$-!'%![:($!71,+$%'&,1!7*&6?*0-!'%!&6$!/,%
$!2*11,?!$4+4!G+! )$.'('$%(0!(*3-$)!/0!)$
.$(&-!'%!%456"4!86$%![!($!%32/$1-!*1$!1$)
3($)!/3&!%,&!$%&'1$0!*/-$%&!L\H]M=!*!2')$
1!76$%,&07$!2*0!71$-$%&!?'&6!1$(311$%&!'%
.$(&',%-!?'&6! ;7,7&,-'-!'-!*!(13('*!2$(6
*%'-2!'%!&6$!'223%$!-0-&$2!&,!6*&!*%!*771
,71'*&$!71,'.$1*&' -16; 000;$!1$-7,
%-$!&,!*!7*&6,+$%4!D$.'('$%(0!'%!9$0!71,&
$'%-!,.!&6$!*7,7&,-'-!2$(6*%'-2!(*3-$!71,
.,3%)!*3&,'223%$!)'-$*-$!*-!'%!*3&,'223%$
!276,71,$1*&'. 1; 00;'$!-0%)1,2$!L
b;C!L+-*$#*/M=!b;C:*%)!L+-*#*/M=!%"#&'8 9
)%6/%'&27,*/3/:&-,)3,;26):+&/,*/=/7);4/%&
,2%*,35%:&')%,K61,%'(!+1*%3,2*&,3-!)'-$*-
$!LK#DM!)$-(1'/$!-7$('.'(!)$.$(&-!'%!&6$!
'%&1*($3*1!,W')*&' -4 ;$!/31-&!,.!76*+
,(0&$-=!?'&6!/,&6!*3&,-,2*!1$($--' -18
; 000;$!L%@("=!-%*'=!-%*7 b'+31$!H4Ya!
K,27,%$%&-!,.!E;FDN!,W')*-$!(,27$W!,.!76*
+,(0&$-!?'&6!1$-7$(&' -10; 000;$!(,
)'%+!+$%$!'%!/1*(9$&-4!;(&' -10; 00
0;*&',%!,.!E;DFN!,W')*-$!)$7$%)-!,%!-3(($
--.3!*--$2/0!,.!(,27,%$%&-!)31'%+!*(&'
10 ;*&',%=!*%)!&6$1$.,1$!+$%$!)$.$(&-!(*
3-$!.*'31$!,.!,W')*&',%=!1$-3&'%+!'%!(61,
%'(!+1*%3,2*&,3-!)'-$*-$!LK#DM!!!!K,%+$%'
&*!)$.$(&-!,.!%$3&1,76'!%32/$1!,1!.3%(&',
%!1$-3&!.1,2!'-,&$)!7*&6,+$%'(!)$.$(&-!'%
!%$3&1,76'!)'..$1$%&'*&',%!+$%$-!L?."-?=!
1*.'=!;" -16; 000;' 1/3/:&-,'%,?%%2
&/,?445%'&+,K$-!,.!&6$!'%%*&$!'223%$!-0-&
$2!71,&$(&!*+*'%-&!'% -4 ;*-' -4 ;$
!/*(&$1'*!*%)!.3%+*!'%.$(&',%-4!C$1',3-!/
*(&$1'*'%.$(&',%-!'%()'%+!2$%'%+'&'-!*%)!
-$7-'-!?'&6!(,22,%!7*&6,+$%-!-3(6!*-!#CDE
FCGHGHHIJBFKEILGKMNE!*%)!#CNFOPQGHGHHIJBN
IDEIJ!2*0!'%)'(*&$!3%)$1'%+!'%%*&$!'223%$
!)$.$(&-!-3(6!*-!)$"32 2'(1,($76*04!N,?$&
#x -10; 000;$1=!&07$!H!'%&$1.$1,%,7*&6
'$-!2*0!*-,!/$!2,1$!1$-&1'(&$)!'%!-(,7$!-
3(6!*-!$*10!,%-$&! -2 ;*-(3,7*&60!(*3-
$)!/0!23&*&',%-!'%!+,?,'5:=!)3$!&,!(,%-&'
&3&' -2 ;$!*(&' -2 ;*&',%!,.!'%&$1.
$1,%:#!71,)3(&',%! G%!71*(&'($=!*!+$%$&'(
!)'*+%,-'-!'-!%,&!2*%)*&$) !"B!C)7/,D/%)4
/,E/F5/%:'%6,!"B"!!G=/.='/H,86,$!+$%,2$!-
$V3$%('%+!L8#CM!'-!&6$!2$&6,),,+0!3-$)!&,
!)$&$12'%$!&6$!.3!DE;!-$V3$%($!,.!&6$!$%&
'1$!+$%,2$4!S6$!*%*0-'-!,.!&6$!?6,$!+$%,2
$!/$+*%!?'&6!C*%+$1!-$V3$%('%+!*2,-&!Y!)$
(*)$-!*+,!LG%&$1%*&',%*!N32*%!#$%,2$!K,%-
,1&'32!YIIJM4!C'%($!&6$%=!%$W&!+$%$1*&',%
!-$V3$%('%+!LE#CM!&$(6%,,+0!6*-!)$ -10
; 000;$,7$)!.,1!1+$!-(*!-$V3$%('%+!71,
f$(&-=!-3(6!&6*&!'&!?,3)!*((,22,)*&$!*!6'
+6$1!&61,3+673&!*%)!/$!2,1$!(,-&!$..$(&'&
#x 16 ;$4!G&!'3-&1*&$-!&6$!-6'.&!.1,2!-$V
3$%('%+!,%$!.1*+2$%&!*&!*!&'2$!&,!+$%$1*&
'%+!&6,3-*%)-!,.!-$V3$%($-!(,%(311$%&0!'%
!*!.*-&$1!&'2$!.1*2$4!C'%($!'&-!'%($7&',%
=!'&!6*-!)1*2*&'(*0!*(($$1*&$)!/',,+'(*!1
$-$*1(6!/0!*,?'%+!(,271$6$%-' -10;
000;$!*%*0-'-!,.!+$%,2$-!&,!/$(,2$!2,1$!1
,3&'%$!*%)!3%)$1&*9$%!'%!$--!&'2$4!!b,1!&
6'-!71,f$(&=!EGNO![',1$-,31($!O*1$!D'-$*-
$!LEGNO[ODM!(,*/,1*&$)!?'&6!&6$!/',&$(6%,
,+0!(,27*%0!G32'%*!&,!71, -16; 000;
')$!&6$!-$V3$%('%+!&$(6%,,+0!*%)!7*&.,124