Genetics, autoantibodies and clinical features in understanding and predicting rheumatoid arthritis

Hele tekst

(1)Genetics, autoantibodies and clinical features in understanding and predicting rheumatoid arthritis Helm-van Mil, A.H.M. van der. Citation Helm-van Mil, A. H. M. van der. (2006, October 26). Genetics, autoantibodies and clinical features in understanding and predicting rheumatoid arthritis. Retrieved from https://hdl.handle.net/1887/4929 Version:. Corrected Publisher’s Version. License:. Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden. Downloaded from:. https://hdl.handle.net/1887/4929. Note: To cite this publication please use the final published version (if applicable)..

(2) #HAPTER¬. !N¬INDEPENDENT¬ROLE¬FOR¬PROTECTIVE¬(,! #LASS¬))¬ALLELES¬IN¬RHEUMATOID¬ARTHRITIS SEVERITY¬AND¬SUSCEPTIBILITY. !(-¬VAN¬DER¬(ELM¬ ¬VAN¬-IL 47*¬(UIZINGA '-4¬3CHREUDER &#¬"REEDVELD 220¬DE¬6RIES 2%-¬4OES !RTHRITIS¬2HEUM¬ .

(3) !"342!#4. /BJECTIVES¬4HE¬MOST¬IMPORTANT¬GENETIC¬RISK¬FACTOR¬FOR¬RHEUMATOID¬ARTHRITIS¬2! ¬IS¬LO CATED¬ WITHIN¬ THE¬ (UMAN¬ ,EUCOCYTE¬ !NTIGEN¬ (,! REGION¬ (,! $2"¬ ALLELES¬ ENCODING FOR¬THE¬SHARED¬EPITOPE¬3% ¬PREDISPOSE¬TO¬2!¬AND¬TO¬MORE¬SEVERE¬DISEASE¬/THER¬(,! $2" ALLELES¬ HARBOURING¬ A¬ DIFFERENT¬ EPITOPE

(4) ¬ ENCODED¬ BY¬ THE¬ AMINO¬ ACIDS¬ $%2!!

(5) ¬ HAVE¬ BEEN¬ ASSOCIATED¬ WITH¬ PROTECTION¬ $UE¬ TO¬ SMALL¬ COHORT¬ SIZES

(6) ¬ THE¬ PROTECTIVE¬ EFFECT¬ ON¬ DISEASE¬ SEVERITY¬IS¬STILL¬CONTROVERSIAL¬AND¬HAS¬NEVER¬BEEN¬DISCERNED¬FROM¬NON PREDISPOSITION¬NOT CARRYING¬3% ALLELES ¬4HIS¬STUDY¬INVESTIGATES¬THE¬EFFECT¬OF¬THE¬$%2!! ENCODING¬ALLELES¬ON¬ 2!¬SEVERITY¬AND¬SUSCEPTIBILITY¬IN¬A¬LARGE¬PROSPECTIVE¬COHORT¬AND¬DIFFERENTIATES¬PROTECTIVE¬EF FECTS¬FROM¬NON PREDISPOSITION¬BY¬COMPARING¬SUBGROUPS¬OF¬PATIENTS¬WITH¬AN¬EQUAL¬AMOUNT¬ OF¬PREDISPOSITION¬ALLELES -ETHODS )N¬¬EARLY¬2!¬PATIENTS¬AND¬¬HEALTHY¬CONTROLS¬THE¬(,!¬CLASS¬))¬ALLELES¬WERE¬ DETERMINED¬4O¬STUDY¬THE¬EFFECT¬OF¬(,!¬ON¬DISEASE¬SEVERITY

(7) ¬RADIOLOGICAL¬JOINT¬DESTRUCTION MODIl¬ED¬3HARP VAN¬DER¬(EIJDE¬METHOD ¬WAS¬DETERMINED¬DURING¬ YEARS¬FOLLOW UP¬ 2ESULTS¬4HE¬PRESENCE¬OF¬$%2!! ENCODING¬(,! $2" ALLELLES¬CONFERRED¬A¬LOWER¬RISK¬TO¬ DEVELOP¬2!¬BOTH¬IN¬THE¬PRESENCE¬AND¬IN¬THE¬ABSENCE¬OF¬3% ALLELES¬/2¬ ¬)N¬THE¬PRESENCE #HAPTER¬. OF¬ONE¬3% ALLELE

(8) ¬THE¬GROUP¬OF¬PATIENTS¬THAT¬CARRIED¬$%2!!¬HAD¬SIGNIl¬CANT¬LESS¬SEVERE¬RA. . DIOLOGICAL¬DESTRUCTION¬AT¬ALL¬TIME¬POINTS¬COMPARED¬TO¬$%2!! NEGATIVE¬PATIENT GROUP¬WITH ONE¬3% ALLELE¬!DDITIONALLY

(9) ¬THE¬PROTECTIVE¬EFFECT¬OF¬$%2!!¬WAS¬DETECTED¬IN¬THE¬GROUPS¬OF¬ PATIENTS¬THAT¬WERE¬PRONE¬TO¬MORE¬SEVERE¬DISEASE¬DUE¬TO¬THE¬PRESENCE¬OF¬ANTI ##0 ANTIBOD IES¬OR¬SMOKING #ONCLUSIONS $%2!! ENCODING (,! $2" ALLELES¬INDEPENDENTLY¬PROTECT¬AGAINST¬2!¬AND¬ ARE¬ASSOCIATED¬WITH¬LESS¬SEVERE¬DISEASE.

(10) 0ROTECTIVE¬(,!¬#LASS¬))¬ALLELES¬IN¬2!. ).42/$5#4)/.. 2HEUMATOID¬ ARTHRITIS¬ 2! ¬ IS¬ A¬ COMPLEX¬ GENETIC¬ DISORDER¬ WITH¬ AN¬ ESTIMATED¬ HERITABILITY OF¬¬ ¬(UMAN¬,EUCOCYTE¬!NTIGENS¬(,! ¬#LASS¬))¬MOLECULES¬ARE¬THE¬MOST¬POWERFUL RECOGNIZED¬GENETIC¬FACTORS¬AND¬CONTRIBUTE¬TO¬AT¬LEAST¬¬OF¬THE¬TOTAL¬GENETIC¬EFFECT¬ ¬ %XTENSIVE¬EVIDENCE¬EXISTS¬SHOWING¬THE¬ASSOCIATION¬BETWEEN¬CERTAIN¬FREQUENTLY¬OCCURRING¬ (,! $2"¬ ALLELES¬

(11) ¬

(12) ¬

(13) ¬

(14) ¬

(15) ¬

(16) ¬ ¬

(17) ¬ ¬ AND SUSCEPTIBILITY¬TO¬AND¬SEVERITY¬OF¬2!¬ ¬4HE¬INDICATED¬ALLELES¬SHARE¬A¬CONSERVED¬AMINO ACID¬ SEQUENCE¬ 1+2!!

(18) ¬ 122!!¬ OR¬ 222!!¬ ALSO¬ CALLED¬ THE¬ SHARED¬ EPITOPE ¬ AT¬ POSITION ¬IN¬THE¬THIRD¬HYPERVARIABLE¬REGION¬OF¬THE¬$2`¬CHAIN¬4HESE¬RESIDUES¬ARE¬PART¬OF¬AN _ HELICAL¬ DOMAIN¬ FORMING¬ ONE¬ SIDE¬ OF¬ THE¬ ANTIGEN¬ PRESENTING¬ BINDING¬ SITE¬ 4HE¬ 3HARED %PITOPE¬HYPOTHESIS¬POSTULATES¬THAT¬THE¬SHARED¬EPITOPE¬MOTIF¬ITSELF¬IS¬DIRECTLY¬INVOLVED¬IN THE¬PATHOGENESIS¬OF¬2!¬BY¬ALLOWING¬THE¬PRESENTATION¬OF¬A¬PEPTIDE¬TO¬ARTHRITOGENIC¬4¬CELLS !LTHOUGH¬ THE¬ PREDISPOSING¬ EFFECTS¬ OF¬ SHARED¬ EPITOPE¬ ENCODING¬ (,! $2"¬ ALLELES¬ ARE¬ GENERALLY¬ ACCEPTED

(19) ¬ CONTROVERSY¬ EXISTS¬ ON¬ THE¬ EXISTENCE¬ OF¬ PROTECTIVE¬ EFFECTS¬ BY¬ CERTAIN (,! $2"¬ALLELES¬4HESE¬ALLELES¬CONTAIN

(20) ¬INSTEAD¬OF¬THE¬SHARED¬EPITOPE

(21) ¬ANOTHER¬COMMON ANCHOR REGION¬CONSISTING¬OF¬THE¬AMINO¬ACIDS¬$%2!!¬(,! $2"¬ALLELES¬THAT¬EXPRESS¬THIS¬ $%2!!¬ SEQUENCE¬ $2"

(22) ¬

(23) ¬

(24) ¬

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(26) ¬

(27) ¬ ¬ MAY¬ PROTECT AGAINST¬2!¬ ¬4HERE¬IS¬SOME¬EVIDENCE¬THAT¬PATIENTS¬CARRYING¬THE¬$%2!!¬SEQUENCE¬HAVE¬ ALSO¬LESS¬EROSIVE¬DISEASE¬(OWEVER

(28) ¬THERE¬ARE¬FEW¬STUDIES¬ADDRESSING¬THE¬EFFECT¬OF¬$%2!! ON¬DISEASE¬SEVERITY

(29) ¬AND¬INTERPRETATION¬IS¬HAMPERED¬EITHER¬BY¬A¬RETROSPECTIVE¬DESIGN¬WITH¬ VARIABLE¬DISEASE¬DURATION¬

(30) ¬OR¬BY¬SMALL¬NUMBERS¬OF¬PATIENTS¬CARRYING¬THE¬$%2!! SE QUENCE¬7AGNER¬ET¬AL¬PERFORMED¬A¬PROSPECTIVE¬STUDY

(31) ¬BUT¬ONLY¬¬$%2!! POSITIVE¬PATIENTS WERE¬ FOLLOWED¬ FOR¬ ¬ YEARS¬ ¬ -OREOVER

(32) ¬ IT¬ IS¬ NOT¬ CLEAR¬ WHETHER¬ THE¬ EFFECT¬ OF¬ $%2!! ENCODING¬(,! $2"¬ALLELES¬IS¬TRULY¬PROTECTIVE¬OR¬IS¬DUE¬TO¬THE¬EFFECT¬OF¬THE¬CONCOMITANT ABSENCE¬OF¬PREDISPOSING¬SHARED¬EPITOPE¬ENCODING¬(,! $2"¬ALLELES !¬NUMBER¬OF¬THE¬INITIAL¬REPORTS¬ON¬THE¬PROTECTIVE¬EFFECTS¬OF¬THE¬$%2!!¬HAPLOTYPE¬ARE¬BASED¬ ON¬THE¬,EIDEN¬%ARLY¬!RTHRITIS¬#LINIC¬

(33) ¬4HIS¬COHORT¬STARTED¬IN¬¬AND¬HAS¬SINCE¬THEN EXPANDED¬ CONSIDERABLY¬ 0RESENTLY¬ MORE¬ THAN¬ ¬ PATIENTS¬ ARE¬ INCLUDED¬ "Y¬ USING¬ THIS EXPANDED¬COHORT¬WE¬AIM¬TO¬ASSESS¬THE¬ASSOCIATION¬OF¬$%2!!¬ENCODING¬(,! $2"¬ALLELES WITH¬ ¬2!¬SEVERITY

(34) ¬TAKING¬ADVANTAGE¬OF¬THE¬FACT¬THAT¬AT¬PRESENT¬A¬SUBSTANTIAL¬NUMBER¬OF¬ PATIENTS¬IS¬FOLLOWED¬PROSPECTIVELY¬AND¬ ¬SUSCEPTIBILITY¬TO¬2!¬4HIS¬LARGE¬COHORT¬ALLOWS¬THE¬ DETERMINATION¬OF¬THE¬POSSIBLE¬PROTECTIVE¬EFFECTS¬OF¬$%2!!¬ENCODING¬(,! $2"¬ALLELES¬IN¬ THE¬PRESENCE¬OF¬AN¬EQUAL¬NUMBER¬OF¬SHARED¬EPITOPE¬ENCODING¬(,! $2"¬ALLELES

(35) ¬THEREBY PERMITTING¬DIFFERENTIATION¬BETWEEN¬PROTECTION¬AND¬NON PREDISPOSITION¬&URTHERMORE

(36) ¬THE¬ AVAILABLE¬CLINICAL¬DATA¬ALLOWED¬TO¬DETERMINE¬WHETHER¬2!¬PATIENTS¬EXHIBITING¬AN¬EXTREME¬OF¬ THE¬PHENOTYPIC¬SPECTRUM¬BY¬ACHIEVING¬CLINICAL¬REMISSION¬HARBOUR¬A¬DIFFERENT¬DISTRIBUTION¬. .

(37) OF¬(,! ALLELES¬COMPARED¬TO¬PATIENTS¬WITH¬PERSISTENT¬DISEASE¬4HE¬PRESENT¬DATA¬SHOW¬THAT (,! $2"¬ALLELES¬ENCODING¬THE¬$%2!! SEQUENCE¬ARE¬ASSOCIATED¬WITH¬LESS¬SEVERE¬DISEASE¬AT¬ ALL¬TIME¬POINTS¬DURING¬¬YEARS¬FOLLOW UP¬AND¬CONFER¬A¬LOWER¬RISK¬TO¬DEVELOP¬2!. 0!4)%.43¬!.$¬-%4(/$3. 3TUDY¬0OPULATION )N¬¬AN¬%ARLY¬!RTHRITIS¬#LINIC¬WAS¬STARTED¬AT¬THE¬$EPARTMENT¬OF¬2HEUMATOLOGY¬OF¬THE ,EIDEN¬5NIVERSITY¬-EDICAL¬#ENTER

(38) ¬THE¬ONLY¬REFERRAL¬CENTER¬FOR¬2HEUMATOLOGY¬IN¬A¬HEALTH CARE¬REGION¬OF¬ABOUT¬

(39) ¬INHABITANTS¬IN¬THE¬WESTERN¬PART¬OF¬THE¬.ETHERLANDS¬ ¬'EN ERAL¬PRACTITIONERS¬WERE¬ENCOURAGED¬TO¬REFER¬PATIENTS¬DIRECTLY¬WHEN¬ARTHRITIS¬WAS¬SUSPECTED 0ATIENTS¬REFERRED¬TO¬THE¬EARLY¬ARTHRITIS¬CLINIC¬COULD¬BE¬SEEN¬WITHIN¬TWO¬WEEKS¬AND¬WERE¬IN CLUDED¬IN¬THE¬PROGRAM¬WHEN¬THE¬PHYSICIANS¬EXAMINATION¬OF¬THE¬PATIENT¬REVEALED¬ARTHRITIS¬ AND¬THE¬SYMPTOMS¬HAD¬LASTED¬LESS¬THEN¬TWO¬YEARS¬&OR¬EVERY¬PATIENT

(40) ¬ROUTINE¬DIAGNOSTIC¬ LABORATORY¬SCREENING¬WAS¬PERFORMED¬!¬¬JOINT¬COUNT¬OF¬SWOLLEN¬JOINTS¬WAS¬PERFORMED¬ON ENTERING¬THE¬STUDY¬AND¬YEARLY¬THEREAFTER¬4HE¬SMOKING¬HISTORY¬WAS¬ASSESSED¬)N¬THIS¬STUDY #HAPTER¬. SMOKERS¬WERE¬PATIENTS¬THAT¬SMOKED¬CIGARETTES

(41) ¬CIGARS ¬AT¬INCLUSION¬OR¬PATIENTS¬THAT¬HAD. . SMOKED¬PREVIOUSLY¬4HE¬NUMBERS¬OF¬SMOKED¬PACK¬YEARS¬WAS¬NOT¬ADDRESSED¬.ON SMOKERS¬ HAVE¬NEVER¬SMOKED¬!T¬PRESENT¬MORE¬THAN¬¬PATIENTS¬ARE¬INCLUDED¬IN¬THE¬%ARLY¬!RTHRITIS #LINIC

(42) ¬OF¬WHICH¬APPROXIMATELY¬¬PATIENTS¬HAVE¬AT¬LEAST¬ONE¬YEAR¬OF¬FOLLOW UP¬¬OF¬ THESE¬PATIENTS¬FULl¬LLED¬THE¬DIAGNOSIS¬OF¬2!¬ACCORDING¬TO¬THE¬!MERICAN¬#OLLEGE¬OF¬2HEUMA TOLOGY¬¬YEAR¬AFTER¬INCLUSION¬IN¬THE¬STUDY¬¬DEl¬NITE¬2!¬AND¬¬PROBABLE¬2!

(43) ¬ACCORDING TO¬THE¬!#2¬CRITERIA¬OF¬¬AND¬¬RESPECTIVELY ¬AND¬HAD¬$.!¬AVAILABLE¬FOR¬GENOTYPING¬ !S¬IT¬WAS¬OBSERVED¬THAT¬IN¬THE¬CURRENT¬INCEPTION¬COHORT

(44) ¬OVER¬¬OF¬PROBABLE¬2!¬PATIENTS¬ DEVELOPED¬DEl¬NITE¬2!¬IN¬THE¬NEXT¬YEAR

(45) ¬THESE¬PROBABLE¬2!¬PATIENTS¬WERE¬INCLUDED¬IN¬THE¬ STUDY¬!¬SMALL¬PROPORTION¬OF¬THE¬PATIENTS¬INVOLVED¬IN¬THE¬PRESENT¬STUDY¬ABOUT¬ONE¬THIRD WERE¬ALSO¬INCLUDED¬IN¬PREVIOUS¬STUDIES¬EXAMINING¬THE¬ASSOCIATION¬BETWEEN¬(,! $2"¬AL LELES¬ AND¬ 2!¬ USING¬ THE¬ ,EIDEN¬ %ARLY¬ !RTHRITIS¬ #LINIC¬ ¬ )NFORMED¬ PATIENT¬ CONSENT¬ WAS OBTAINED¬AND¬THE¬STUDY¬WAS¬APPROVED¬BY¬THE¬LOCAL¬MEDICAL¬ETHICS¬COMMITTEE¬!¬RANDOM PANEL¬OF¬¬HEALTHY¬UNRELATED¬$UTCH¬INDIVIDUALS¬SERVED¬AS¬CONTROL (,!¬GENOTYPING 4HE¬(,!¬CLASS¬))¬ALLELES¬WERE¬DETERMINED¬IN¬ALL¬2!¬PATIENTS¬AND¬CONTROLS¬4HE¬(,! $2"¬ SUB TYPING¬ WAS¬ PERFORMED¬ BY¬ POLYMERASE¬ CHAIN¬ REACTION¬ USING¬ SPECIl¬C¬ PRIMERS¬ AND HYBRIDISATION¬ WITH¬ SEQUENCE SPECIl¬C¬ OLIGONUCLEOTIDES¬ 4HE¬ PREDISPOSING¬ SHARED¬ EPITOPE¬ ALLELES¬ WERE¬ $2"¬

(46) ¬

(47) ¬

(48) ¬

(49) ¬

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(51) ¬ ¬

(52) ¬ AND¬ ¬ 4HE¬$%2!!¬ENCODING¬ALLELES¬WERE¬(,! $2"

(53) ¬

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(58) ¬ AND¬ ¬ &OR¬ CLARITY

(59) ¬ THIS¬ STUDY¬ USES¬ CONSEQUENTLY¬ THE¬ TERM¬ $%2!! ENCODING¬ ALLELES.

(60) 0ROTECTIVE¬(,!¬#LASS¬))¬ALLELES¬IN¬2!. 4ABLE¬ (,! $2"¬GENOTYPES¬OF¬2!¬PATIENTS¬AND¬HEALTHY¬CONTROLS. 'ROUP. $2"¬GENOTYPE. 2!¬PATIENTS . N¬ . #ONTROLS . N¬ . ! ". 3%3%. ¬. . ¬. . 3%X¬. ¬. . ¬. . #. 3%$%2!!. $. XX. ¬. . ¬. . ¬. . ¬. %. X$%2!!. . ¬. . ¬. . &. $%2!!$%2!!¬. ¬. . ¬. . 'ROUP¬"¬VS¬#¬/2¬

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(62) ¬P 'ROUP¬$¬VS¬% &¬/2¬

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(64) ¬P 'ROUP¬! "¬VS¬$¬/2¬

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(66) ¬P 0ATIENTS¬AND¬CONTROLS¬WERE¬CATEGORIZED¬ACCORDING¬TO¬THE¬(,! $2"¬GENOTYPE 3%¬ALLELES¬ARE¬$2"¬

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(73) ¬ $%2!!¬ALLELES¬ARE¬$2"

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(79) ¬ X¬MEANS¬ALL¬OTHER¬$2"¬ALLELES. (OWEVER¬THIS¬STUDY¬DOES¬NOT¬DIFFERENTIATE¬BETWEEN¬THE¬DIRECT¬EFFECT¬OF¬THESE¬ALLELES¬AND¬ THE¬ EFFECT¬ OF¬ OTHER¬ ALLELES¬ IN¬ LINKAGE¬ WITH¬ THE¬ $%2!! ENCODING¬ (,! $2"¬ ALLELES¬ THE OBSERVED¬EFFECTS¬MIGHT¬THEREFORE¬ALSO¬BE¬THE¬RESULT¬OF¬A¬HAPLOTYPE¬CONTAINING¬THE¬$%2!! ENCODING¬ ALLELES¬ &OR¬ THE¬ ANALYSIS¬ A¬ DIVISION¬ IN¬ SIX¬ GROUPS¬ ACCORDING¬ TO¬ THE¬ (,! $2"¬ ALLELES¬WAS¬MADE¬HOMOZYGOUS¬FOR¬SHARED¬EPITOPE¬3%3%

(80) ¬GROUP¬!

(81) ¬ONE¬SHARED¬EPITOPE¬ ALLELE¬3%X

(82) ¬GROUP¬"

(83) ¬ONE¬SHARED¬EPITOPE¬AND¬ONE¬$%2!!¬ALLELE¬3%$%2!!

(84) ¬GROUP¬#

(85) ¬NO¬ SHARED¬EPITOPE¬OR¬$%2!!¬ALLELES¬XX

(86) ¬GROUP¬$

(87) ¬ONE¬$%2!!¬ALLELE¬X$%2!!

(88) ¬GROUP¬% ¬AND¬ TWO¬COPIES¬OF¬A¬$%2!!¬ENCODING¬ALLELE¬$%2!!$%2!!

(89) ¬GROUP¬&

(90) ¬SEE 4ABLE¬¬ 2ADIOGRAPHIC¬PROGRESSION 2ADIOGRAPHS¬ OF¬ HANDS¬ AND¬ FEET¬ WERE¬ MADE¬ AT¬ BASELINE

(91) ¬ AT¬ ONE¬ YEAR¬ AND¬ YEARLY¬ THEREAFTER¬ 2ADIOGRAPHS¬WERE¬SCORED¬USING¬THE¬MODIl¬ED¬3HARP 6AN¬DER¬(EIJDE¬METHOD¬ ¬4HE¬RHEU MATOLOGIST¬ THAT¬ SCORED¬ THE¬ RADIOGRAPHS¬ WAS¬ BLINDED¬ TO¬ THE¬ CLINICAL¬ DATA¬ AND¬ UNAWARE¬ OF¬ THE¬STUDY¬QUESTION¬!T¬INCLUSION¬RADIOGRAPHS¬WERE¬SCORED¬OF¬¬PATIENTS

(92) ¬¬PATIENTS¬HAD¬ RADIOGRAPHS¬AT¬¬YEAR¬FOLLOW UP

(93) ¬¬PATIENTS¬AT¬¬YEAR¬FOLLOW UP

(94) ¬¬PATIENTS¬AT¬¬YEAR¬FOL LOW UP¬AND¬¬PATIENTS¬AT¬¬YEARS¬FOLLOW UP¬4HE¬FACT¬THAT¬AT¬THE¬MOMENT¬OF¬ANALYSIS¬NOT¬ALL¬ PATIENTS¬HAD¬ACHIEVED¬¬YEARS¬FOLLOW UP¬IS¬INHERENT¬TO¬THE¬DESIGN¬OF¬AN¬INCEPTION¬COHORT %XTREMES¬OF¬THE¬PHENOTYPES¬CLINICAL¬REMISSION #OMPARING¬THE¬EXTREME¬PHENOTYPES¬OF¬A¬DISEASE¬CAN¬ELUCIDATE¬THE¬PRESENCE¬OR¬ABSENCE¬OF¬ AN¬ASSOCIATION¬BETWEEN¬AN¬ALLELE¬AND¬DISEASE¬SEVERITY¬

(95) ¬&OR¬THIS¬STUDY¬PATIENTS¬THAT DEVELOPED¬CLINICAL¬REMISSION

(96) ¬THE¬BEST¬CLINICAL¬COURSE¬POSSIBLE

(97) ¬WERE¬SELECTED¬0ATIENTS¬IN REMISSION¬HAD¬NO¬SIGNS¬OF¬ARTHRITIS¬IN¬THE¬ABSENCE¬OF¬DISEASE MODIFYING¬DRUGS¬AND¬WERE¬ THEREFORE¬DISCHARGED¬FROM¬THE¬OUTPATIENT¬CLINIC¬0ATIENTS¬WERE¬ONLY¬DISCHARGED¬AFTER¬THEY¬. .

(98) HAD¬BEEN¬AT¬LEAST¬ONE¬YEAR¬IN¬REMISSION¬WITHOUT¬THE¬USE¬OF¬DISEASE MODIFYING¬DRUGS¬%IGHTY PATIENTS¬ACHIEVED¬CLINICAL¬REMISSION¬ALL¬HAD¬FULl¬LLED¬THE¬!#2¬CRITERIA¬FOR¬2!¬¬PATIENTS¬ FOR¬DEl¬NITE¬2!¬AND¬¬PATIENTS¬FOR¬PROBABLE¬2!

(99) ¬ACCORDING¬TO¬THE¬!#2¬CRITERIA¬OF¬¬AND ¬RESPECTIVELY 3TATISTICAL¬ANALYSIS 4O¬DIFFERENTIATE¬THE¬PROTECTIVE¬EFFECTS¬FROM¬THE¬EFFECTS¬DUE¬TO¬NON PREDISPOSITION

(100) ¬ANALYSIS WAS¬PERFORMED¬USING¬SUBGROUPS¬OF¬PATIENTS¬WITH¬AN¬EQUAL¬AMOUNT¬OF¬PREDISPOSING¬SHARED EPITOPE¬ALLELES¬4O¬DETERMINE¬THE¬EFFECT¬OF¬THE¬$%2!! ENCODING¬ALLELES¬IN¬THE¬PRESENCE¬OF¬ ONE¬SHARED¬EPITOPE¬ALLELE¬THE¬SUBGROUPS¬3%$%2!!¬AND¬3%X¬WERE¬COMPARED¬GROUP¬"¬VS #

(101) ¬SEE TABLE¬ ¬TO¬ASSESS¬THE¬EFFECT¬OF¬THE¬$%2!! ENCODING¬ALLELES¬IN¬THE¬ABSENCE¬OF¬SHARED EPITOPE¬ ALLELES¬ THE¬ SUBGROUPS¬ 8$%2!!¬ AND¬ $%2!!$%2!!¬ WERE¬ COMPARED¬ WITH¬ XX¬ GROUP¬% &¬VS¬$

(102) ¬SEE¬TABLE¬ ¬!N¬ALTERNATIVE¬METHOD¬TO¬IDENTIFY¬THE¬CAUSATIVE¬(,! FACTOR¬ TRULY¬RESPONSIBLE¬FOR¬THE¬ASSOCIATION¬IS¬DESCRIBED¬BY¬3VEJGAARD¬AND¬2YDER¬ ¬4HIS¬METHOD¬ USES¬ A¬ TWO BY FOUR¬ TABLE¬ THAT¬ IS¬ SUBSEQUENTLY¬ ANALYSED¬ USING¬ VARIOUS¬ TWO BY TWO¬ TABLES¬ INVOLVING¬STRATIl¬CATION¬OF¬EACH¬OF¬THE¬TWO¬FACTORS¬AGAINST¬EACH¬OTHER¬4HE¬ASSOCIATION¬OF¬ $%2!!¬ WITH¬ 2!¬ SUSCEPTIBILITY¬ WAS¬ ANALYSED¬ AND¬ PRESENTED¬ ACCORDING¬ TO¬ BOTH¬ METHODS¬ #HAPTER¬. &OR¬ THE¬ ANALYSIS¬ OF¬ THE¬ SEVERITY¬ DATA

(103) ¬ SUBGROUPS¬ WITH¬ AN¬ EQUAL¬ AMOUNT¬ OF¬ PREDISPOSING¬. . SHARED¬EPITOPE¬ALLELES¬WERE¬COMPARED¬/DDS¬RATIOS¬/2 ¬WITH¬¬CONl¬DENCE¬INTERVALS¬ ¬#) ¬WERE¬CALCULATED¬USING¬THE¬METHOD¬OF¬7OOLF¬(ALDANE¬P¬VALUES¬WERE¬CALCULATED USING¬THE¬CHI¬SQUARE¬TEST¬$IFFERENCES¬IN¬MEANS¬BETWEEN¬GROUPS¬WERE¬ANALYSED¬WITH¬THE -ANN¬7HITNEY¬TEST¬OR¬T TEST¬WHEN¬APPROPRIATE¬)N¬ALL¬TESTS

(104) ¬P¬VALUES¬LESS¬THAN¬¬WERE¬ CONSIDERED¬SIGNIl¬CANT¬. 2%35,43. 3USCEPTIBILITY 4O¬ STUDY¬ THE¬ EFFECT¬ OF¬ THE¬ PRESENCE¬ OF¬ $%2!!¬ ON¬ THE¬ SUSCEPTIBILITY¬ TO¬ 2!

(105) ¬ PATIENTS¬ AND¬ CONTROLS¬WERE¬DIVIDED¬IN¬¬GROUPS¬ACCORDING¬TO¬THEIR¬(,! $2"¬STATUS¬4ABLE¬ ¬)N¬TOTAL¬ ¬2!¬PATIENTS¬ ¬AND¬¬CONTROLS¬ ¬CARRIED¬$%2!!¬ENCODING¬(,! $2"¬ALLELES¬ /2¬

(106) ¬ #)¬

(107) ¬ P ¬ &IRST

(108) ¬ THE¬ EFFECT¬ OF¬ $%2!!¬ IN¬ THE¬ ABSENCE¬ OF¬ SHARED¬ EPITOPE¬ALLELE¬WAS¬ASSESSED¬BY¬COMPARING¬GROUP¬$¬WITH¬% &¬$%2!!¬POSITIVE¬PERSONS¬HAD¬ A¬ SIGNIl¬CANTLY¬ LOWER¬ RISK¬ TO¬ DEVELOP¬ 2!¬ /2¬

(109) ¬ #)¬

(110) ¬ P ¬ #OMPARING¬ GROUP¬"¬WITH¬GROUP¬#¬REVEALED¬THAT¬IN¬THE¬PRESENCE¬OF¬ONE¬SHARED¬EPITOPE¬ALLELE¬THE¬$% 2!! ENCODING¬ALLELES¬REDUCE¬THE¬RISK¬TO¬DEVELOP¬2!

(111) ¬ALTHOUGH¬THE¬OBSERVED¬EFFECT¬WAS¬NOT STATISTICALLY¬SIGNIl¬CANT¬/2¬

(112) ¬#)¬

(113) ¬P !DDITIONALLY¬ THE¬ SAME¬ DATA¬ WERE¬ ANALYSED¬ ACCORDING¬ TO¬ THE¬ 3VEJGAARD¬ APPROACH¬ SEE 4ABLE¬ ¬4HE¬PRESENCE¬OF¬$%2!!¬CONFERRED¬ A¬ SIGNIl¬CANT¬ LOWER¬ RISK¬ TO¬ DEVELOP¬ 2!¬ BOTH.

(114) 0ROTECTIVE¬(,!¬#LASS¬))¬ALLELES¬IN¬2!. 4ABLE¬ (,! $2"¬GENOTYPES¬OF¬2!¬PATIENTS¬AND¬HEALTHY¬CONTROLS

(115) ¬ANALYSED¬ACCORDING¬TO¬THE¬ APPROACH¬OF¬3VEJGAARD¬AND¬2YDER¬. 3HARED¬EPITOPE¬ENCODING $2". $%2!!¬ENCODING¬(,! $2". .UMBER¬OF¬PATIENTS .. .UMBER¬OF¬CONTROLS .. . . n. . . n. . . n. n. . . #OMPARISON. %NTRIES¬OF¬X¬¬TABLE A. B. C. D. 3%¬ ¬VS¬n. . . . . /2¬¬#)¬

(116) P. $%2!!¬ ¬VS¬n. . . . . /2¬¬#)¬ P. 3%¬IN¬$%2!!¬. . . . . /2¬¬#)¬

(117) P. 3%¬IN¬$%2!!¬n. . . . . /2¬¬#)¬

(118) P. $%2!!¬IN¬3%¬. . . . . /2¬¬#)¬ P. $%2!!¬IN¬3%¬n. . . . . /2¬¬#)¬

(119) P. IN¬SHARED¬EPITOPE¬NEGATIVE¬AND¬SHARED¬EPITOPE¬POSITIVE¬PATIENTS¬/2¬

(120) ¬#)¬

(121) ¬ P¬AND¬/2¬

(122) ¬#)¬

(123) ¬P¬RESPECTIVELY !S¬ANTI ##0¬ANTIBODIES¬ARE¬HIGHLY¬ASSOCIATED¬WITH¬2!

(124) ¬WE¬WISHED¬TO¬ANALYSE¬WHETHER¬THE¬ PRESENCE¬ OF¬ $%2!!¬ WAS¬ CORRELATED¬ WITH¬ THE¬ ANTI ##0¬ STATUS¬ OF¬ PATIENTS¬ 4HEREFORE¬ THE EFFECT¬OF¬$%2!!¬ON¬THE¬RISK¬TO¬DEVELOP¬2!¬WAS¬ASSESSED¬IN¬ANTI ##0¬POSITIVE¬AND¬ANTI ##0 NEGATIVE¬2!¬PATIENTS¬SEPARATELY¬4HE¬PRESENCE¬OF¬$%2!!¬CONFERRED¬A¬LOWER¬RISK¬TO¬DEVELOP¬ BOTH¬ANTI ##0¬POSITIVE¬2!¬/2¬

(125) ¬#)¬ ¬AND¬ANTI ##0¬NEGATIVE¬2!¬/2¬

(126) #)¬ ¬ 4HE¬EFFECT¬ON¬DISEASE¬SUSCEPTIBILITY¬OF¬SHARED¬EPITOPE¬ALLELES¬IN¬THE¬ABSENCE¬OF¬$%2!!¬WAS¬ ASSESSED¬BY¬COMPARING¬GROUP¬! "¬VERSUS¬$¬4ABLE¬ ¬AND¬SIMILARLY¬ACCORDING¬THE¬3VEJGAARD¬ APPROACH¬ 4ABLE¬ ¬ 3HARED¬ EPITOPE¬ POSITIVE¬ PERSONS¬ HAD¬ AN¬ ODDS¬ OF¬ ¬ TO¬ DEVELOP¬ 2!¬ COMPARED¬TO¬SHARED¬EPITOPE¬NEGATIVE¬PATIENTS¬#)¬

(127) ¬P¬ !S¬THE¬(,! $2"¬ALLELES¬ARE¬IN¬LINKAGE¬DISEQUILIBRIUM¬WITH¬CERTAIN¬(,! $1¬ALLELES¬$1 AND¬$1

(128) ¬SEE¬REF¬

(129) ¬THE¬ABOVE DESCRIBED¬ANALYSIS¬WAS¬ALSO¬PERFORMED¬USING¬(,! $2" $1¬GENOTYPES¬3IMILAR¬RESULTS¬ON¬PREDISPOSITION¬TO¬2!¬WERE¬FOUND¬USING¬(,! $2" $1¬ GENOTYPES¬INSTEAD¬OF¬USING¬(,! $2"¬ALLELES¬SOLELY¬4ABLE¬ . .

(130) #HAPTER¬. 4ABLE¬¬(,! $2"¬AND¬ $1¬GENOTYPES¬OF¬2!¬PATIENTS¬AND¬HEALTHY¬CONTROLS. . 'ROUP. $1¬GENOTYPE. $2"¬GENOTYPE. 2!¬PATIENTS¬. N¬ . #ONTROLS¬. N¬ . ¬A ¬B ¬C. . 3%3% 3%X XX. ¬ ¬ ¬. . ¬ ¬ ¬. . ¬A ¬B. . 3%3% 3%X. ¬ ¬. . ¬ ¬. . ¬A ¬B. . 3%3% 3%X. ¬ ¬. . ¬ ¬. . ¬A ¬B ¬C. X. 3%3% 3%X XX. ¬ ¬ ¬. . ¬ ¬ ¬. . ¬A ¬B. X. 3%X XX. ¬ ¬. . ¬ ¬. . ¬A ¬B. X. 3%$%2!! X$%2!!. ¬ ¬. . ¬ ¬. . ¬A¬ ¬B. X. 3%$%2!! X$%2!!. ¬ ¬. . ¬ ¬. . . XX. XX. ¬. . ¬. . . XX. X$%2!!. ¬. . ¬. . . XX. $%2!! $%2!!. ¬. . ¬. . 0REDISPOSITION¬ALLELES¬ ¬GR . ¬. . 0REDISPOSITION¬ALLELES¬n¬GR. . . 0ROTECTION¬ALLELES¬n¬GR¬B A. . . 0ROTECTION¬ALLELES¬ ¬GR¬A A. . . 0ROTECTION¬ALLELES¬n¬GR¬. . ª. 0ROTECTION¬ALLELES¬ ¬GR . . ¬ª. 0ATIENTS¬ WERE¬ CATEGORIZED¬ ACCORDING¬ TO¬ THE¬ PRESENCE¬ OR¬ ABSENCE¬ OF¬ $1¬ OR¬ $1¬ HETERODIMERS¬ AND¬ SUBDIVIDED¬ FOR¬ $2"¬ ALLELES¬ 3%¬ ALLELES¬ ARE¬ $2"¬

(131) ¬

(132) ¬

(133) ¬

(134) ¬

(135) ¬

(136) ¬

(137). ¬$1¬MEANS¬$1"

(138) ¬

(139) ¬

(140) ¬

(141) ¬

(142) ¬OR¬ ¬IN¬COMBINATION¬WITH¬$1! ¬ $1¬MEANS¬$1" ¬IN¬COMBINATION¬WITH¬$1! ¬OR¬ ¬$%2!!¬ALLELES¬ARE¬$2"

(143) ¬.

(144) ¬

(145) ¬

(146) ¬

(147) ¬

(148) ¬ ¬X¬MEANS¬ALL¬OTHER¬$1¬OR¬$2"¬ALLELES ¬/2¬¬#)¬

(149) ¬P. ¬/2¬

(150) ¬#)¬

(151) ¬P ª¬/2¬

(152) ¬#)¬

(153) ¬P. !LL¬THE¬ABOVE MENTIONED¬RESULTS¬DID¬NOT¬CHANGE¬WHEN¬THE¬¬PATIENTS¬WITH¬PROBABLE¬2! WERE¬EXCLUDED¬AND¬THE¬¬PATIENTS¬WITH¬DEl¬NITE¬2!¬WERE¬ANALYSED¬COMPARISON¬OF¬GROUP¬ "¬WITH¬#¬/2¬

(154) ¬#)¬

(155) ¬P¬COMPARISON¬OF¬GROUP¬$¬WITH¬% &¬/2¬

(156) ¬#)¬

(157) ¬P¬COMPARISON¬OF¬GROUPS¬! "¬WITH¬$¬/2¬

(158) ¬#)¬

(159) ¬P .

(160) 0ROTECTIVE¬(,!¬#LASS¬))¬ALLELES¬IN¬2!. )N¬ CONCLUSION

(161) ¬ THESE¬ DATA¬ SHOW¬ THAT¬ CARRIERSHIP¬ OF¬ $%2!! ENCODING¬ (,! $2"¬ ALLELES PROTECTS¬TO¬DEVELOP¬2!¬IN¬INDIVIDUALS¬WITH¬A¬SHARED¬EPITOPE¬ALLELE¬AS¬WELL¬AS¬IN¬INDIVIDUALS¬ WITHOUT¬SHARED¬EPITOPE¬ALLELES 3EVERITY 4O¬ ASSES¬ THE¬ INm¬UENCE¬ OF¬ THE¬ PRESENCE¬ OF¬ $%2!!¬ ENCODING¬ (,! $2"¬ ALLELES¬ ON¬ RADIO LOGICAL¬ JOINT¬ DESTRUCTION

(162) ¬ 3HARP VAN¬ DER¬ (EIJDE¬ SCORES¬ DURING¬ ¬ YEARS¬ OF¬ FOLLOW UP¬ WERE COMPARED¬IN¬SUBGROUPS¬OF¬PATIENTS¬WITH¬AN¬EQUAL¬OF¬AMOUNT¬OF¬SHARED¬EPITOPE¬ENCODING¬ (,! $2"¬ALLELES

(163) ¬THEREBY¬EXCLUDING¬A¬POSSIBLE¬CONFOUNDING¬EFFECT¬DUE¬TO¬A¬DIFFERENCE¬IN¬ PREDISPOSING¬ALLELES¬!LTHOUGH¬THE¬RATE¬OF¬JOINT¬DESTRUCTION¬IN¬THE¬WHOLE¬GROUP¬OF¬SHARED EPITOPE¬NEGATIVE¬PATIENTS¬WAS¬VERY¬LOW

(164) ¬THE¬EFFECT¬OF¬CARRYING¬ONE¬OR¬TWO¬$%2!!¬ALLELES¬IN¬ THE¬ABSENCE¬OF¬SHARED¬EPITOPE¬ALLELES¬WAS¬DETERMINED¬BY¬COMPARING¬THE¬RADIOLOGICAL¬SCORES¬ OF¬GROUP¬% &¬VERSUS¬$¬4HE¬MEAN¬¢¬3%- ¬3HARP VAN¬DER¬(EIJDE¬SCORES¬AT¬INCLUSION¬AND

(165) ¬¬AND¬¬YEARS¬OF¬FOLLOW¬UP¬WERE¬RESPECTIVELY¬¬¢¬

(166) ¬¬¢¬

(167) ¬¬¢¬

(168) ¬AND¬¬¢ ¬IN¬THE¬PATIENTS¬NOT¬CARRYING¬A¬PROTECTION¬ALLELE¬GROUP¬$ ¬AND¬¬¢¬

(169) ¬¬¢¬

(170) ¬¬¢

(171) ¬AND¬¬¢¬¬IN¬THE¬PATIENTS¬WITH¬ONE¬OR¬TWO¬PROTECTION¬ALLELES¬GROUP¬% & ¬P¬¬

(172) ¬

(173) ¬¬AND¬¬RESPECTIVELY ¬4HUS

(174) ¬THE¬PRESENCE¬OF¬$%2!! ENCODING¬ALLELES¬IN¬PATIENTS¬ WITH¬ABSENCE¬OF¬SHARED¬EPITOPE¬DOES¬NOT¬RESULT¬IN¬SIGNIl¬CANTLY¬LOWER¬RADIOLOGICAL¬SCORES¬ !S¬ANTI ##0¬ANTIBODIES¬ARE¬ASSOCIATED¬WITH¬MORE¬SEVERE¬DISEASE¬

(175) ¬WE¬ASSESSED¬THE¬INm¬U ENCE¬OF¬$%2!!¬ON¬DISEASE¬SEVERITY¬IN¬ANTI ##0¬POSITIVE¬AND¬NEGATIVE¬PATIENTS¬SEPARATELY 4HIS¬ANALYSIS¬REVEALED¬THAT¬IN¬SHARED¬EPITOPE¬NEGATIVE¬ANTI ##0¬POSITIVE¬2!¬PATIENTS

(176) ¬THE PRESENCE¬OF¬$%2!!¬ASSOCIATES¬WITH¬SIGNIl¬CANTLY¬LESS¬SEVERE¬DISEASE¬AT¬ALL¬POINTS¬IN¬TIME EXCEPT¬INCLUSION¬SEE¬&IGURE¬ ¬)N¬SHARED¬EPITOPE¬NEGATIVE

(177) ¬ANTI ##0¬NEGATIVE¬PATIENTS¬THE¬ RATE¬OF¬JOINT¬DESTRUCTION¬WAS¬TOO¬LOW¬TO¬OBSERVE¬DIFFERENCES¬BETWEEN¬$%2!!¬POSITIVE¬AND¬ NEGATIVE¬PATIENTS. &IGURE¬¬3HARP VAN¬DER¬(EIJDE¬SCORES¬MEAN¬AND¬3%- ¬AT¬INCLUSION¬AND¬¬YEARS¬FOLLOW UP¬OF¬SHARED¬EPITOPE¬NEGATIVE¬ANTI ##0¬POSITIVE¬2!¬PATIENTS¬IN¬THE¬PRESENCE¬AND¬ ABSENCE¬OF¬$%2!! ENCODING¬ALLELES¬ ¬0¬. .

(178) "ECAUSE¬PATIENTS¬NOT¬CARRYING¬SHARED¬EPITOPE¬ALLELES¬HAVE¬A¬LESS¬DESTRUCTIVE¬DISEASE¬COM PARED¬TO¬SHARED¬EPITOPE¬POSITIVE¬PATIENTS¬COMPARISON¬OF¬GROUPS¬$¬VERSUS¬! "

(179) &IGURE¬

(180) WE¬SUBSEQUENTLY¬ASSESSED¬THE¬EFFECT¬OF¬$%2!!¬ON¬DISEASE¬SEVERITY¬IN¬SHARED¬EPITOPE¬POSI TIVE¬PATIENTS

(181) ¬AS¬IN¬THIS¬GROUP¬OF¬PATIENTS¬WITH¬MORE¬SEVERE¬DISEASE¬THE¬WINDOW¬TO¬READ¬OUT¬ AN¬EVENTUAL¬PROTECTIVE¬EFFECT¬IS¬LARGER¬-OREOVER

(182) ¬BY¬ANALYSING¬THE¬SUBGROUPS¬OF¬PATIENTS WITH¬AN¬EQUAL¬AMOUNT¬OF¬SHARED¬EPITOPE¬ALLELES¬A¬POSSIBLE¬CONFOUNDING¬EFFECT¬DUE¬TO¬DIF FERENCES¬IN¬PREDISPOSING¬ALLELES¬WAS¬EXCLUDED¬#OMPARING¬THE¬3HARP VAN¬DER¬(EIJDE¬SCORES OF¬GROUP¬"¬WITH¬GROUP¬#¬SEE¬4ABLE¬¬FOR¬THE¬DIVISION¬IN¬GROUPS ¬SHOWED¬SIGNIl¬CANT¬LOWER¬ 3HARP VAN¬DER¬(EIJDE¬SCORES¬AT¬ALL¬TIME¬POINTS¬DURING¬¬YEARS¬FOLLOW UP¬IN¬THE¬$%2!!¬POSI TIVE¬GROUP¬&IGURE¬

(183) ¬P¬AT¬INCLUSION

(184) ¬¬AND¬¬YEARS¬FOLLOW UP

(185) ¬P¬AT¬¬YEARS¬AND¬ P¬AT¬¬YEARS¬FOLLOW UP ¬4HUS

(186) ¬$%2!! ENCODING¬ALLELES¬PROTECT¬AGAINST¬SEVERE¬DISEASE¬ IN¬THE¬PRESENCE¬OF¬ONE¬SHARED¬EPITOPE¬ALLELE #ONSIDERING¬ THE¬ ASSOCIATION¬ BETWEEN¬ ANTI ##0¬ ANTIBODIES¬ AND¬ 2!¬ SEVERITY¬

(187) ¬ WE WISHED¬TO¬ASSESS¬WHETHER¬THE¬OBSERVED¬PROTECTIVE¬INm¬UENCE¬OF¬$%2!!¬IS¬DEPENDENT¬ON¬THE¬ PRESENCE¬OR¬ABSENCE¬OF¬ANTI ##0¬ANTIBODIES¬4HEREFORE

(188) ¬THE¬EFFECT¬OF¬$%2!!¬IN¬THE¬PRES ENCE¬OF¬ONE¬SHARED¬EPITOPE¬ALLELE¬WAS¬ANALYSED¬IN¬ANTI ##0¬POSITIVE¬AND¬NEGATIVE¬PATIENTS SEPARATELY¬4HE¬PROTECTIVE¬EFFECT¬OF¬$%2!!¬REMAINED¬IN¬BOTH¬ANTI ##0¬POSITIVE¬AND¬NEGA #HAPTER¬. TIVE¬2!¬PATIENTS¬&IGURE¬ ¬.OT¬ONLY¬ANTI ##0¬ANTIBODIES¬ARE¬KNOWN¬TO¬ASSOCIATE¬WITH¬2!¬. . SEVERITY

(189) ¬ALSO¬THE¬ENVIRONMENTAL¬FACTOR¬SMOKING¬IS¬REPORTED¬TO¬CORRELATE¬WITH¬MORE¬SEVERE¬ DISEASE¬ ¬4O¬FURTHER¬CONl¬RM¬THE¬PROTECTIVE¬EFFECTS¬OF¬THE¬$%2!! ENCODING¬ALLELES¬WE ANALYSED¬ THE¬ EFFECTS¬ OF¬ $%2!!¬ IN¬ PATIENTS¬ THAT¬ WERE¬ PRONE¬ TO¬ MORE¬ SEVERE¬ DISEASE¬ DUE TO¬SMOKING¬4HEREFORE

(190) ¬THE¬EFFECT¬OF¬$%2!!¬IN¬THE¬PRESENCE¬OF¬ONE¬SHARED¬EPITOPE¬ALLELE WAS¬ ASSESSED¬ FOR¬ SMOKERS¬ AND¬ NON SMOKERS¬ SEPARATELY¬ .ON SMOKING¬ PATIENTS¬ THAT¬ WERE $%2!! POSITIVE¬SHOWED¬A¬TREND¬FOR¬LOWER¬RADIOLOGICAL¬SCORES¬P¬AND¬¬AT¬¬AND¬. &IGURE¬¬3HARP ¬VAN¬DER¬(EIJDE¬SCORES MEAN¬AND¬3%- ¬AT¬INCLUSION¬AND¬¬YEARS FOLLOW UP¬OF¬2!¬PATIENTS¬WITH¬OR¬WITHOUT SHARED¬EPITOPE¬ALLELES¬IN¬THE¬ABSENCE¬OF¬ $%2!!¬nENCODING¬ALLELES ¬0. &IGURE¬¬3HARP ¬VAN¬DER¬(EIJDE¬SCORES MEAN¬AND¬3%- ¬AT¬INCLUSION¬AND¬ YEARS¬FOLLOW UP¬OF¬2!¬PATIENTS¬WITH¬AND WITHOUT¬$%2!! ENCODING¬(,! $2" ALLELES¬IN¬THE¬PRESENCE¬OF¬ONE¬SHARED EPITOPE¬ALLELE ¬0.

(191) 0ROTECTIVE¬(,!¬#LASS¬))¬ALLELES¬IN¬2!. &IGURE¬¬3HARP VAN¬DER¬(EIJDE¬SCORES¬ MEAN¬AND¬3%- ¬AT¬INCLUSION¬AND¬¬ YEARS¬FOLLOW UP¬OF¬2!¬PATIENTS¬WITH¬AND WITHOUT¬$%2!! ENCODING¬ALLELES¬IN¬THE PRESENCE¬OF¬ONE¬SHARED¬EPITOPE¬ENCODING¬ ALLELE

(192) ¬FOR¬ANTI ##0¬POSITIVE¬AND¬ANTI ##0 NEGATIVE¬PATIENTS¬SEPARATELY. &IGURE¬¬3HARP VAN¬DER¬(EIJDE¬SCORES MEAN¬AND¬3%- ¬AT¬INCLUSION¬AND¬¬YEARS¬ FOLLOW UP¬OF¬SHARED¬EPITOPE¬POSITIVE¬ SMOKING¬2!¬PATIENTS¬IN¬THE¬PRESENCE¬OR¬ ABSENCE¬OF¬$%2!!¬ ENCODING¬ALLELES¬ ¬ 0. YEAR¬FOLLOW UP¬RESPECTIVELY ¬)N¬SMOKERS¬THE¬PRESENCE¬OF¬$%2!!¬CORRELATED¬WITH¬SIGNIl¬CANT¬ LOWER¬3HARP 6AN¬DER¬(EIJDE¬SCORES¬AT¬ALL¬TIME¬POINTS¬EXCEPT¬INCLUSION¬P

(193) ¬&IGURE¬ ¬!S SMOKING¬MIGHT¬CORRELATE¬WITH¬ANTI ##0¬ANTIBODIES¬NON¬PUBLISHED¬DATA¬3¬,INN¬ 2ASKER A¬-ANTEL (AENSZEL¬ANALYSIS¬REVEALED¬THAT¬A¬TREND¬TO¬A¬PROTECTIVE¬EFFECT¬OF¬$%2!!¬IN¬BOTH¬ ANTI ##0¬POSITIVE¬AND¬NEGATIVE¬SMOKING¬2!¬PATIENTS¬WAS¬PRESENT¬DATA¬NOT¬SHOWN ¬ )N¬ CONCLUSION

(194) ¬ ¬ $%2!! ENCODING¬ (,! $2"¬ ALLELES¬ ARE¬ ASSOCIATED¬ WITH¬ LESS¬ SEVERE JOINT¬DESTRUCTION¬IN¬PATIENTS¬THAT¬ALSO¬CARRY¬A¬(,! $2"¬ENCODING¬SHARED¬EPITOPE¬ALLELE

(195) ¬ ¬THIS¬PROTECTIVE¬EFFECT¬REMAINS¬AFTER¬CORRECTION¬FOR¬ANTI ##0¬ANTIBODIES¬AND¬ ¬$%2!! ENCODING¬ALLELES¬ALSO¬EXHIBIT¬A¬PROTECTIVE¬EFFECT¬IN¬SEVERE¬DISEASE¬THAT¬IS¬ASSOCIATED¬WITH¬ SMOKING %XTREMES¬OF¬THE¬PHENOTYPES¬CLINICAL¬REMISSION 4O¬ASSESS¬A¬POSSIBLE¬ASSOCIATION¬BETWEEN¬(,!¬AND¬CLINICAL¬REMISSION

(196) ¬WE¬IDENTIl¬ED¬¬PA TIENTS¬THAT¬OBTAINED¬CLINICAL¬REMISSION¬WITHOUT¬THE¬USE¬OF¬DISEASE¬MODIFYING¬DRUGS¬#LINI CAL¬REMISSION¬WAS¬ACHIEVED¬AFTER¬A¬MEAN¬FOLLOW UP¬OF¬¬YEARS¬3$¬¬YEARS ¬4HE¬PATIENTS IN¬THE¬REMISSION¬GROUP¬WERE¬IN¬¬OF¬CASES¬FEMALE

(197) ¬HAD¬A¬MEAN¬AGE¬OF¬¬¢¬¬YEARS MEAN¬¢¬3$ ¬AND¬WERE¬IN¬¬ANTI ##0¬ANTIBODY¬POSITIVE¬4HE¬¬PATIENTS¬THAT¬DID¬HAVE PERSISTENT¬2!¬WERE¬IN¬¬OF¬CASES¬FEMALE

(198) ¬HAD¬A¬MEAN¬AGE¬OF¬¬¢¬¬YEARS¬AND¬WERE¬ IN¬ ¬ ANTI ##0¬ ANTIBODY¬ POSITIVE¬ 4HERE¬ WAS¬ NO¬ DIFFERENT¬ DISTRIBUTION¬ OF¬ $%2!! EN CODING¬(,! $2"¬ALLELES¬IN¬PATIENTS¬THAT¬OBTAINED¬REMISSION¬COMPARED¬TO¬PATIENTS¬WITH¬ PERSISTENT¬ 2!¬ /VERALL

(199) ¬ ¬ OF¬ PATIENTS¬ THAT¬ OBTAINED¬ REMISSION¬ CARRIED¬ $%2!!¬ ALLELES

(200) VERSUS¬¬OF¬THE¬2!¬PATIENTS¬WITH¬PERSISTENT¬DISEASE¬,IKEWISE

(201) ¬WHEN¬THE¬DISTRIBUTION¬OF¬ $%2!!¬IN¬THE¬PRESENCE¬OR¬ABSENCE¬OF¬SHARED¬EPITOPE¬ALLELES¬WAS¬EVALUATED

(202) ¬NO¬DIFFERENCES WERE¬FOUND¬IN¬THE¬REMISSION¬OR¬PERSISTENT¬2!¬GROUP¬)N¬ADDITION

(203) ¬THE¬DISTRIBUTION¬OF¬SHARED¬ EPITOPE¬ENCODING¬(,! $2"¬ALLELES¬IN¬THE¬ABSENCE¬OF¬$%2!!¬ALLELES¬WAS¬STUDIED¬IN¬THE¬. .

(204) REMISSION¬ AND¬ PERSISTENT¬ 2!¬ GROUP¬ &IFTY l¬VE¬ PERCENT¬ OF¬ PATIENTS¬ THAT¬ ACHIEVED¬ CLINICAL REMISSION¬CARRIED¬SHARED¬EPITOPE¬ALLELES

(205) ¬COMPARED¬TO¬¬OF¬THE¬PATIENTS¬WITH¬PERSISTENT¬ 2!¬4HIS¬INDICATES¬THAT¬SHARED¬EPITOPE¬ALLELES¬OCCURRED¬SIGNIl¬CANTLY¬LESS¬FREQUENT¬IN¬THE PATIENTS¬THAT¬ACHIEVED¬CLINICAL¬REMISSION¬/2¬

(206) ¬#)¬

(207) ¬P ¬)N¬CONCLUSION

(208) 2!¬PATIENTS¬THAT¬ACHIEVE¬CLINICAL¬REMISSION¬HAVE¬SIGNIl¬CANTLY¬LESS¬FREQUENT¬SHARED¬EPITOPE ALLELES¬BUT¬DO¬NOT¬CARRY¬MORE¬$%2!! ENCODING¬(,! $2"¬ALLELES. $)3#533)/.. 4HIS¬STUDY¬INVESTIGATES¬THE¬ASSOCIATIONS¬BETWEEN¬(,!¬#LASS¬))¬ALLELES¬AND¬2!¬AND¬DESCRIBES¬ THE¬PROTECTIVE¬EFFECTS¬OF¬$%2!! ENCODING¬(,! $2"¬ALLELES¬ON¬2!¬SEVERITY¬AND¬SUSCEPTIBIL ITY¬4HE¬QUESTION¬WHETHER¬THE¬EFFECT¬OF¬$%2!!¬IS¬TRULY¬PROTECTIVE¬OR¬ONLY¬THE¬RESULT¬OF¬THE¬ ABSENCE¬OF¬PREDISPOSING¬SHARED¬EPITOPE ENCODING¬(,! $2"¬ALLELES¬HAS¬BEEN¬SURROUNDED¬ WITH¬ SOME¬ CONTROVERSY¬ )N¬ THE¬ CURRENT¬ STUDY¬ THE¬ COMPARISON¬ OF¬ SUBGROUPS¬ ALLOWED¬ TO¬ DIFFERENTIATE¬THE¬EFFECTS¬OF¬PROTECTION¬AND¬NON PREDISPOSITION¬4HIS¬STUDY¬SHOWS¬THAT¬THE¬. #HAPTER¬. $%2!! ENCODING¬(,! $2"¬ALLELES¬INDEPENDENTLY¬REDUCE¬THE¬RISK¬TO¬DEVELOP¬2!¬. . -ORE¬ IMPORTANTLY¬ HOWEVER

(209) ¬ OUR¬ STUDY¬ SHOWS¬ IN¬ A¬ LARGE¬ PROSPECTIVE¬ COHORT¬ THAT¬ $%2!! ENCODING¬ALLELES¬ARE¬ASSOCIATED¬WITH¬LESS¬SEVERE¬RADIOLOGICAL¬DESTRUCTION¬IN¬PATIENTS¬THAT¬ WERE¬PREDISPOSED¬TO¬SEVERE¬2!¬BY¬THE¬PRESENCE¬OF¬SHARED EPITOPE¬ALLELES¬AT¬ALL¬TIME¬POINT¬ DURING¬¬YEARS¬OF¬FOLLOW UP¬4HE¬PROTECTIVE¬EFFECT¬OF¬$%2!!¬REMAINED¬AFTER¬STRATIl¬CATION¬ FOR¬ANTI ##0¬ANTIBODIES¬3TRATIl¬CATION¬FOR¬SMOKING

(210) ¬ANOTHER¬RISK¬FACTOR¬FOR¬SEVERE¬DISEASE

(211) ¬ SHOWED¬THAT¬$%2!!¬PARTICULARLY¬PROTECTS¬IN¬PATIENTS¬THAT¬ARE¬ALSO¬PREDISPOSED¬TO¬MORE¬SE VERE¬DISEASE¬BY¬SMOKING¬!LL¬TOGETHER

(212) ¬THESE¬DATA¬INDICATE¬THAT¬THE¬PROTECTIVE¬INm¬UENCE¬OF¬ $%2!!¬CAN¬BE¬DETECTED¬IN¬PATIENTS¬THAT¬ARE¬PRONE¬TO¬SEVERE¬DISEASE

(213) ¬BY¬EITHER¬THE¬PRESENCE OF¬SHARED¬EPITOPE¬ALLELES

(214) ¬ANTI ##0¬ANTIBODIES¬OR¬SMOKING¬)N¬PATIENTS¬WITH¬A¬LOW¬RATE¬OF¬ JOINT¬DESTRUCTION¬SUCH¬AS¬SHARED¬EPITOPE¬NEGATIVE¬AND¬ANTI ##0¬NEGATIVE¬2!¬PATIENTS

(215) ¬THE CURRENT¬DATA¬SET¬IS¬NOT¬SUFl¬CIENTLY¬POWERED¬TO¬ANSWER¬THE¬QUESTION¬WHETHER¬A¬PROTECTIVE EFFECT¬OF¬$%2!!¬IS¬PRESENT¬IN¬THESE¬PATIENTS¬)NTRIGUINGLY

(216) ¬THE¬DIFFERENCES¬IN¬3HARP VAN¬DER¬ (EIJDE¬SCORES¬BETWEEN¬$%2!! POSITIVE¬AND¬NEGATIVE¬PATIENTS¬IN¬PRESENCE¬OF¬A¬SHARED¬EPI TOPE¬ALLELE ¬ARE¬AS¬LARGE¬AS¬THE¬DIFFERENCES¬IN¬3HARP VAN¬DER¬(EIJDE¬SCORES¬BETWEEN¬SHARED EPITOPE¬POSITIVE¬AND¬NEGATIVE¬PATIENTS¬SEE &IGURE¬ AND¬ ¬4HUS

(217) ¬THE¬PROTECTIVE¬EFFECT¬OF¬ $%2!! ENCODING¬ALLELES¬ON¬RADIOLOGICAL¬JOINT¬DESTRUCTION¬SEEMS¬TO¬BE¬OF¬A¬SIMILAR¬MAGNI TUDE¬AS¬THE¬PREDISPOSING¬EFFECT¬OF¬SHARED¬EPITOPE¬ALLELES¬ 4HE¬CHANCE¬TO¬ACHIEVE¬CLINICAL¬REMISSION¬IS¬LOWER¬FOR¬PATIENTS¬CARRYING¬A¬PREDISPOSITION¬ ALLELE

(218) ¬ BUT¬ IS¬ NOT¬ HIGHER¬ IN¬ PATIENTS¬ CARRYING¬ PROTECTION¬ ALLELES¬ !LTHOUGH¬ WE¬ CANNOT EXPLAIN¬THESE¬OBSERVATIONS¬AT¬THIS¬MOMENT

(219) ¬THESE¬l¬NDINGS¬SUGGEST¬THAT¬THE¬DISEASE PRO.

(220) 0ROTECTIVE¬(,!¬#LASS¬))¬ALLELES¬IN¬2!. MOTING¬MECHANISMS¬THAT¬ARE¬ASSOCIATED¬WITH¬SHARED¬EPITOPE¬ALLELES¬ARE¬DISTINCT¬FROM¬THE MECHANISMS¬INVOLVED¬IN¬TEMPERING¬DISEASE PROGRESSION¬)N¬THIS¬RESPECT

(221) ¬IT¬IS¬TEMPTING¬TO¬ SPECULATE¬THAT¬THE¬PROTECTIVE¬PATHWAYS¬ASSOCIATED¬WITH¬THE¬EXPRESSION¬OF¬$%2!! ENCOD ING¬(,! ALLELES¬ARE¬ABLE¬TO¬DAMPEN¬THE¬EFFECTOR¬PATHWAYS¬UNDERLYING¬BONE¬AND¬CARTILAGE¬ BREAKDOWN

(222) ¬BUT¬THAT¬THEY¬DO¬NOT¬AFFECT¬THE¬PRINCIPAL¬PATHWAY¬THAT¬DRIVES¬CHRONICITY !LTHOUGH¬THE¬NUMBER¬OF¬PATIENTS¬WITH¬¬YEARS¬FOLLOW UP¬IN¬THE¬CURRENT¬STUDY¬IS¬HIGHER COMPARED¬TO¬PREVIOUS¬STUDIES¬ON¬THE¬PROTECTIVE¬EFFECT¬OF¬$%2!!¬ON¬2!¬SEVERITY

(223) ¬THE¬PRES ENT¬STUDY¬LACKED¬SUFl¬CIENT¬POWER¬TO¬ADDRESS¬THE¬QUESTION¬OF¬A¬DOSE¬EFFECT¬OF¬$%2!!¬4HIS IS¬DUE¬TO¬THE¬l¬NDING¬THAT¬HOMOZYGOSITY¬FOR¬$%2!!¬IN¬2! PATIENTS¬IS¬RARE¬¬OF¬THE¬2!¬ PATIENTS¬IN¬THIS¬COHORT ¬/F¬THESE¬¬PATIENTS

(224) ¬¬PATIENTS¬HAD¬AT¬THE¬MOMENT¬OF¬ANALYSIS¬A¬ FOLLOW UP¬OF¬¬YEARS¬AND¬ONLY¬¬HAD¬A¬FOLLOW UP¬OF¬¬YEARS¬2EMARKABLY

(225) ¬THE¬TOTAL¬3HARP VAN¬DER¬(EIJDE¬SCORE¬OF¬THESE¬PATIENTS¬WAS¬¬¢¬¬AT¬INCLUSION

(226) ¬¬¢¬¬AND¬¬¢¬¬AT ¬ AND¬ ¬ YEARS¬ FOLLOW UP¬ MEAN¬ ¢¬ 3%-

(227) ¬ INDICATING¬ THAT¬ 2!¬ PATIENTS¬ WITH¬ TWO¬ COPIES¬ OF¬ $%2!!¬SEEMS¬TO¬HAVE¬A¬NON DESTRUCTIVE¬DISEASE¬COURSE¬!S¬THE¬RADIOLOGICAL¬SCORES¬OF¬THE¬ PATIENTS¬ THAT¬ ARE¬ HOMOZYGOUS¬ FOR¬ $%2!!¬ ARE¬ LOWER¬ THAN¬ THE¬ PATIENTS¬ HETEROZYGOUS¬ FOR $%2!!

(228) ¬A¬GENE DOSE¬EFFECT¬IS¬POSSIBLE¬(OWEVER

(229) ¬THE¬NUMBER¬OF¬HOMOZYGOUS¬PATIENTS¬IS¬ TOO¬LOW¬FOR¬DEl¬NITE¬CONCLUSIONS !LTHOUGH¬SO¬FAR¬NOT¬MUCH¬DATA¬ARE¬AVAILABLE¬ON¬THE¬ASSOCIATION¬BETWEEN¬PROTECTIVE¬(,!¬ #LASS¬))¬ALLELES¬AND¬2!¬SEVERITY

(230) ¬WELL DESIGNED¬STUDIES¬ARE¬AVAILABLE¬ON¬THE¬ASSOCIATION¬BE TWEEN¬PROTECTIVE¬(,!¬ALLELES¬AND¬DISEASE¬SUSCEPTIBILITY¬

(231)

(232) ¬(OWEVER

(233) ¬THE¬DEl¬NITION OF¬PROTECTIVE¬ALLELES¬DIFFERS¬IN¬THESE¬STUDIES¬$E¬6RIES¬ET¬AL¬CONSIDERED¬ALLELES¬WITH¬AMINO¬ ACID¬ $¬ AT¬ POSITION¬ ¬ AS¬ PROTECTING¬ )N¬ THIS¬ WAY¬ MORE¬ ALLELES¬ THAN¬ THOSE¬ ENCODING¬ FOR¬ $%2!!¬WERE¬CLASSIl¬ED¬AS¬PROTECTIVE¬EG¬(,! $2"¬

(234) ¬

(235) ¬ ¬ ¬2EVIRON¬ET¬AL CONCLUDED¬ON¬A¬DIFFERENT¬HYPOTHESIS¬ELECTRIC¬CHARGE¬OF¬THE¬(,!¬POCKET ¬THAT¬ALLELES¬WITH A¬NEUTRAL¬OR¬NEGATIVE¬CHARGE¬IN¬THEIR¬0¬POCKET¬PROTECT¬TO¬DEVELOP¬2!¬4HESE¬ALLELES¬CON TAIN¬NOT¬ONLY¬THE¬$%2!! ENCODING¬(,! $2"¬ALLELES¬BUT¬ALSO¬OTHER¬(,! ¬ALLELES

(236) ¬AMONG WHICH¬(,! $2" ¬ ¬/UR¬RESULTS¬CONl¬RM¬AND¬EXTEND¬THESE¬OBSERVATIONS¬BY¬FOCUS SING¬ON¬THE¬$%2!! ENCODING¬(,! ALLELES¬AND¬BY¬ANALYSING¬THE¬EFFECTS¬OF¬THESE¬ALLELES¬ON¬ DISEASE¬SEVERITY¬4HE¬OBSERVED¬EFFECTS¬OF¬THE¬PRESENCE¬OF¬$%2!!¬MIGHT¬BE¬THE¬DIRECT¬RESULT¬ OF¬THE¬$%2!! ENCODING¬ALLELES¬OR¬MIGHT¬BE¬THE¬RESULT¬OF¬(,! HAPLOTYPES¬THAT¬CONTAIN¬THE¬ $%2!! ENCODING¬(,! $2"¬ALLELES 4HE¬KNOWN¬PREDISPOSING¬EFFECT¬OF¬THE¬SHARED¬EPITOPE¬ALLELES¬ON¬2!¬SUSCEPTIBILITY¬AND¬SE VERITY¬IS¬CONl¬RMED¬IN¬THIS¬STUDY¬0REVIOUSLY

(237) ¬IT¬HAS¬BEEN¬HYPOTHESISED¬BY¬OUR¬GROUP¬THAT PREDISPOSITION¬TO¬2!¬IS¬NOT¬ONLY¬CONTROLLED¬BY¬SHARED¬EPITOPE¬ALLELES¬BUT¬IS¬ALSO¬CONFERRED¬ BY¬ (,! $1¬ ALLELES¬ ¬ 3UPPORT¬ FOR¬ A¬ ROLE¬ OF¬ (,! $1¬ CAME¬ FROM¬ STUDIES¬ ON¬ COLLAGEN INDUCED¬ARTHRITIS¬IN¬(,! $1¬TRANSGENIC¬MICE¬ ¬4HE¬SO CALLED¬2! PROTECTION¬HYPOTHESIS¬. .

(238) FURTHER¬ IMPLIED¬ THAT¬ $%2!!¬ IS¬ ONLY¬ PROTECTIVE¬ IN¬ THE¬ PRESENCE¬ OF¬ CERTAIN¬ $1¬ OR¬ $1¬ HETERODIMERS¬ ¬ 4HE¬ DATA¬ OF¬ THE¬ CURRENT¬ STUDY¬ WERE¬ ANALYSED¬ BOTH¬ USING¬ (,! $2"¬ GENOTYPES¬AND¬USING¬(,! $2 $1¬GENOTYPES

(239) ¬REVEALING¬SIMILAR¬RESULTS¬4HE¬PREDISPOSING (,! $1¬AND¬ $2"¬ALLELES¬ARE¬STRONGLY¬ASSOCIATED¬IN¬OUR¬POPULATION¬THEREFORE¬DIFFEREN TIATION¬ OF¬ THE¬ INDIVIDUAL¬ EFFECTS¬ OF¬ (,! $2¬ AND¬ (,! $1¬ WAS¬ NOT¬ FEASIBLE¬ !S¬ THE¬ PRES ENT¬STUDY¬REVEALS¬THAT¬$%2!!¬PROTECTS¬AGAINST¬2!¬NOT¬ONLY¬IN¬PATIENTS¬WITH¬PREDISPOSING¬ (,! $2¬ALLELES¬OR¬(,! $2 $1¬GENOTYPES¬BUT¬ALSO¬CONFERS¬A¬LOWER¬RISK¬TO¬DEVELOP¬2!¬IN¬ PATIENTS¬ WITHOUT¬ THESE¬ PREDISPOSING¬ GENOTYPES

(240) ¬ THE¬ PREVIOUSLY¬ PUBLISHED¬ 2! PROTECTION HYPOTHESIS¬SHOULD¬BE¬AMENDED )T¬HAS¬BEEN¬DEMONSTRATED¬THAT¬PEPTIDES¬CARRYING¬THE¬$%2!!¬MOTIF¬ARE¬NATURALLY¬PROCESSED¬ BY¬HUMAN¬!0#¬AND¬IT¬HAS¬BEEN¬SUGGESTED¬THAT¬THE¬PROTECTIVE¬EFFECT¬OF¬$%2!!¬IS¬MEDIATED BY¬A¬SPECIl¬C¬PROTECTIVE¬4¬CELL¬RESPONSE¬ ¬!LTHOUGH¬OUR¬RESULTS¬CLEARLY¬SHOW¬THAT¬THE PRESENCE¬OF¬A¬PREDISPOSING¬HAPLOTYPE¬IS¬NOT¬REQUIRED¬TO¬OBSERVE¬THE¬PROTECTIVE¬EFFECT¬ASSO CIATED¬WITH¬$%2!!

(241) ¬IT¬IS¬CONCEIVABLE¬THAT¬THE¬$%2!! SEQUENCE¬ITSELF¬IS¬PRESENTED¬TOWARDS¬ 4 CELLS¬WITH¬PROTECTIVE¬ACTIVITIES¬)NTERESTINGLY¬ALLELES¬CARRYING¬THE¬$%2!!¬SEQUENCE

(242) ¬PAR TICULARLY¬$2" ¬ALLELES

(243) ¬NOT¬ONLY¬PROTECT¬FROM¬SEVERE ¬2!¬BUT¬HAVE¬ALSO¬BEEN¬ASSOCIATED¬ #HAPTER¬. WITH¬A¬MILDER¬DISEASE¬OUTCOME¬IN¬OTHER¬DISEASES

(244) ¬SUCH¬AS¬A¬REDUCED¬PROGRESSION¬TO¬ACTIVE¬. . CHRONIC¬ HEPATITIS¬ #¬ AND¬ "¬

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(246) ¬ A¬ LOWER¬ INCIDENCE¬ OF¬ CERVICAL¬ CARCINOMA¬ ¬ AND¬ A REDUCED¬REJECTION¬OF¬RENAL¬TRANSPLANTS¬ ¬4HESE¬l¬NDINGS¬ARE¬INTRIGUING¬AND¬POINT¬TO¬THE IMPORTANCE¬ TO¬ ELUCIDATE¬ THE¬ BIOLOGICAL¬ PATHWAYS¬ UNDERLYING¬ THESE¬ ASSOCIATIONS

(247) ¬ AS¬ THEY¬ MIGHT¬UNVEIL¬NEW¬INSIGHTS¬ON¬IMMUNE¬REGULATION¬IN¬RELATION¬TO¬THE¬(,! SYSTEM¬.

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