խࣝፓ࿯ᛰނ (υᘋન) ݯᕍᄌ܄ B ࠠطݹ

Ҟ߻୯ሞ໔ςਡ঑ϐᄌ܄ B ࠠطݹݯᕍᛰނࣁυᘋન (interferon) کਡ㧿ᜪ

՟ނ!(nucleos(t)ide analogues)Ƕ೭ٿᜪᇙᏊ೿Ԗ׭ڋੰࢥޑਏ݀ǴՠυᘋનᗋԖ խࣝፓ࿯ޑфૈ (Lok and McMahon 2007)ǶLamivudine ࢂಃ΋ᅿ࿶ਡ঑ёаݯ ᕍᄌ܄ B ࠠطݹޑਡ㧿ᜪ՟ނǴՠࢂځౢғלᛰ܄ੰࢥਲ਼ޑᐒ౗Кၨଯ (Huang et al. 2012a; Lok and McMahon 2007)Ƕਡ㧿ᜪ՟ނჹܭ᏾ӝࠠ (integrated) HBV DNA ܈ځᙯᒵނǵਡᗐਡለޑፄᇙύ໔ౢނؒԖ׭ڋޑਏ݀ (Doong et al.

1991)Ƕ೭ёૈ٬ਡ㧿ᜪ՟ނሡाคज़යޑ٬Ҕа࡭ុ׭ڋੰࢥǶךॺϷځдᏢ

ޣޑࣴز߄ܴӧ lamivudine ݯᕍ྽ύǴՈమύੰࢥਡᗐਡለ (HBV RNA) ёа

೏ᔠෳډǶ೭ࢂӢ๱ਡᗐਡለፄᇙޑύ໔ౢނ҂೏ਡ 㧿ᜪ՟ނ׭ڋǴаϷ೏ύᘐ ޑϸᙯᒵϸᔈޑ่݀ (Hatakeyama et al. 2007; Huang et al. 2008b; Zhang et al.

2003)ǶԜѦǴՈమ HBV RNA ᗋёаԐයႣෳӧ lamivudine ݯᕍය໔ੰࢥวғ ޑँᡂ (Hatakeyama et al. 2007)Ƕ࣬ϸޑǴυᘋનޑݯᕍᕍำڰۓǴԶЪჹܭ B

ࠠطݹ߄य़לচޑՈమమନ౗Кਡ㧿ᜪ՟ނाଯ (Dienstag 2008)Ƕυᘋનޑલᗺ ࣁځୋբҔǴхࡴՈౚեΠǴวᐨϷኁᢠੱ (Huang et al. 2012b)Ƕ

ϐ ߻ ޑ ࣴ ز ᛾ ܴ Α ӝ ٳ ਡ㧿 ᜪ ՟ ނ (lamivudine) ک υ ᘋ ન ޑ ݯ ᕍ К lamivudine ൂ΋ݯᕍޑਏ݀ӳǺගଯΑݯᕍ่״ࡕ 24 ຼޑ HbeAg Ոమᙯ഍౗

(Lau et al. 2005; Sarin et al. 2005) ǵALT ҅தϯک HBV DNA ᔠෳόډޑᐒ౗

(Marcellin et al. 2004; Sarin et al. 2005)Ƕ೭ঁว౜ޑᐒڋϝόమཱǴࢂցᆶਡ㧿ᜪ

՟ނൂ΋ݯᕍคݤ׭ڋਡᗐਡለፄᇙύ໔ౢނԖᜢ໪຾΋؁ࣴزǶ

ࣴ

ࣴزୢᚒϷख़ा܄

΋ǵҞ߻๊εӭኧ B ࠠطݹੰࢥགࢉϐխࣝᒪ໺ӢηϷխࣝڙᡏӭ׎܄ࣴز೿

௖૸੯ੰܰག܄܈ܢל܄ϐ࣬ᜢ܄Ƕᖏ׉΢ख़ाޑୢᚒࢂব΋٤எЬӢનቹៜᄌ

܄གࢉ B ࠠطݹਔϐᖏ׉߄౜ࠠϷႣࡕǶ!

ÆΑှቹៜᄌ܄གࢉ B ࠠطݹᖏ׉߄౜ࠠϷႣࡕϐխࣝᒪ໺ϷխࣝڙᡏӢηǴ ஒԖշܭुрԖਏϷ಄ӝ࿶ᔮਏ੻ϐଓᙫϷݯᕍࡹ฼Ƕ!

ΒǵԐය!(ջ҆ᓻ໺ኞ) གࢉޑ B ࠠطݹ஥চޣޑԾฅੰўё୷ܭੰࢥஎЬϕ୏

ϩࣁѤঁ୏ᄊ໘ࢤǺխࣝऐڙයǴխࣝమନයǴ൪Ε܈ූӸයکൺวය!(Chen 1993)ǶӧխࣝమନයǴϸൺطݹ࡚܄วբёૈ཮уೲᄌ܄طݹ຾৖ࣁطฯϯǴ ᏤठႣࡕό٫Ƕe-לচޑ࡭ុ໚܄ΨࢂᏤठఁයطੰޑଯ॥ᓀǶᄌ܄˾ࠠطݹ஥

চޣطݹ࡚܄วբޑᓎ౗کᝄख़ࡋаϷ e-לচޑ໚܄܈഍܄ϐঁᡏৡ౦܄ࡐ εǶҞ߻ϝฅ҂ޕٗ٤Ӣનቹៜᄌ܄˾ࠠطݹ࡚܄วբޑᓎ౗کᝄख़ࡋϷ e-לচ ޑ௃ݩǶ

Æᇡ᛽ব٤எЬխࣝᒪ໺ϷխࣝڙᡏӢન،ۓᄌ܄˾ࠠطݹϸൺ܄࡚܄วբ܈ e לচރᄊஒԖշܭΑှ஻ޣϐᖏ׉ੰำϷႣࡕǴ຾Զۓрݯᕍϐ،฼Ƕ!

Οǵ ߈ԃٰǴךॺჹӃϺխࣝޑ౛ှҗܭว౜ੰচᡏ࣬ᜢޑᒣᇡڙᡏኳԄԶε ࣁׯ๓Ǵхࡴᜪ៕ڙᡏ (TLR)Ƕᜪ៕ڙᡏ-3Ǵ7Ǵ8 ک 9 ςޕૈᒣᇡੰࢥਡለǴ ЪΓᜪޑᜪ៕ڙᡏ-3 ᆶᜪ៕ڙᡏ-7Ǵ8 ک 9 ڀԖᡉ๱ӕྍ܄ (Iwasaki and Medzhitov 2004)Ƕᜪ៕ڙᡏ-3 ୷Ӣᡂ౦ϐੰ஻ᆶᄌ܄˾ࠠطݹԖ࣬ᜢᖄǴԶЪځ ӧੰࢥϐወҷ΢ёૈתᄽΑࢌᅿفՅǶ

Æ௖૸ӃϺխࣝޑᜪ៕ڙᡏ-3 ӧᄌ܄˾ࠠطݹ஻ޣаϷ࿶Ԗਏݯᕍਔϐ߄౜ໆ ஒԖշܭΑှԜڙᡏӧᄌ܄གࢉރᄊޑفՅǴ຾Զۓрёૈϐᇶշݯᕍ،฼Ƕ!

Ѥǵϐ߻ޑࣴز᛾ܴΑӝٳਡ㧿ᜪ՟ނکυᘋનޑݯᕍКਡ㧿ᜪ՟ނൂ΋ݯᕍޑ ਏ݀ाӳǶ೭ঁว౜ޑᐒᙯёૈᆶխࣝፓှᛰނυᘋનᏱԖԖձܭਡ㧿ᜪ՟ނޑ բ Ҕ ܌ ठ Ƕ ς ޕ ਡ㧿 ᜪ ՟ ނ ค ݤ ׭ ڋ ਡ ᗐ ਡ ለ ፄ ᇙ ύ ໔ ౢ ނ (HBV RNA replicative intermediates)ǴԶךॺӧਡ㧿ᜪ՟ނݯᕍ྽ύǴёаᔠෳډՈమύੰ

ࢥਡᗐਡለ (HBV RNA)Ƕௗڙӝٳխࣝፓ࿯ᛰނ (υᘋન) کਡ㧿ᜪ՟ނݯᕍ ޑੰ஻ǴдॺՈమύ HBV RNA ೏׭ڋޑำࡋϝ҂ޕǶ

Æ

Æ௖૸խࣝፓ࿯ᛰނ (υᘋન) ჹܭ˾طੰࢥՈమਡᗐਡለϐ׭ڋ௃׎ஒԖշ ܭΑှυᘋનჹ˾طፄᇙၸำޑቹៜǴ຾Զۓрന٫ᛰނݯᕍಔӝޑኳԄǶ

ࣴزബཥ܄

΋ǵ ΓᜪқՈౚלচ (human leukocyte antigenǴHLA) ࢂ΋ঁख़ाޑխࣝᒪ໺

ϷஎЬ୷ӢӢηǶԐයޑൔ֋٬ҔКၨಉౣޑБԄुрΓᜪқՈౚלচޑჹଽ୷ Ӣ (allele) Ǵ ु р ϩ ࠠ ՠ ࢂ ٠ ҂ ु р ځ ԛ ϩ ࠠ Ǵ ӵ ु р HLA-DR3 Զ ߚ HLA-DRB1*0301܈*0302 ฻ǶHLA-DRB1 ࢂᏱԖനӭჹଽ୷Ӣ (allele) ޑΓᜪ қՈౚלচϐ΋Ƕ΋٤ൔ֋ᡉҢ࡚܄ B ࠠطݹ೏మନ܈࡭ុ܄ޑགࢉᆶ HLA-DRB1ӭ׎܄ԖᜢǶ

Æխࣝᒪ໺Ӣη HLA-DRB1 ӭ׎܄ᆶᄌ܄ B ࠠطݹ஻ޣطݹޑᝄख़ำࡋϐ࣬ᜢ

܄ϝόమཱǶ

Βǵ Ӣࣁ΋ঁঁᡏѝԖٿঁΓᜪқՈౚלচჹଽ୷Ӣ (allele)ǴԶΓᜪқՈౚל চхࡴ HLA-DRB1 ԖኧΜঁа΢ޑჹଽ୷ӢǴ܌а؂ঁঁᡏޑ HLA-DRB1 ჹଽ

୷Ӣ཮Ԗ࣬྽ޑৡ౦܄Ƕाפрٗ٤ჹଽ୷Ӣᆶᄌ܄ B ࠠطݹ஻ޣطݹᝄख़ࡋ ϐ࣬ᜢ܄Ǵ൩Ѹ໪வၨ৒ܰطݹ࡚܄วբϐ௼ဂѐ௖૸Ƕت܄࣬ၨܭζ܄ޑ B

ࠠطݹ஥চޣ׳ࣁ৒ܰౢғطݹ࡚܄วբ (Chu et al. 1983)ǶԜѦǴჹܭ B ࠠط ݹ߄य़לচ໚܄౗ޑࢬՉੰᏢࣴزΨ᛾ჴᄌ܄˾ࠠطݹੰࢥགࢉޑ஻ޣаت܄

ࣁЬ (Chen et al. 2000)Ƕ Æ

Æت܄ᄌ܄ B ࠠطݹ஻ޣطݹޑᝄख़ำࡋᆶխࣝᒪ໺Ӣη HLA-DRB1 ӭ׎܄ϐ

࣬ᜢ܄ϝόమཱǶ!

Οǵ ᆢғન D ڙᡏ t/t ୷Ӣᡂ౦ᆶ B ࠠطݹੰࢥమନԖᜢǴԶЪᆢғન D ޑࢲ

܄׎Ԅૈ୼׭ڋᡏѦکᡏϣޑطᕎಒझቚ෗ (Bellamy et al. 1999; Pourgholami et al. 2000)Ƕ

Æᆢғન D խࣝڙᡏ୷Ӣӭ׎܄ᆶᄌ܄ B ࠠطݹੰࢥ஥চޣޑόӕᖏ׉߄ࠠх

ࡴطݹ࡚܄วբᆶ e לচ௃ݩаϷ B طЇଆϐطᕎޑ࣬ᜢ܄ϝόమཱǶ

Ѥǵ ΓᡏӃϺ܄խࣝӧᄌ܄˾ࠠطݹགࢉϐفՅࢂ΋ঁӄཥޑሦୱǶᜪ៕ڙᡏ -3೏᛾ܴࢂᚈި RNA ޑڙᡏǴаϷୀෳ΋٤ RNA ੰࢥǴΨёаୀෳӧғڮຼ

යౢғᚈި RNA ϐ DNA ੰࢥ (Yoneyama and Fujita 2010)Ƕ ÆӃϺխࣝᜪ៕ڙᡏ-3 ӧᄌ܄˾ࠠطݹϐቹៜϝόమཱǶ

ϖǵ ךॺඓඝΑӧਡ㧿ᜪ՟ނݯᕍ྽ύǴՈమੰࢥਡᗐਡለ (HBV RNA) ཥЪ ԖਏϐᔠෳמೌǶ

Æխࣝፓ࿯ᛰނ (υᘋન) ჹܭਡ㧿ᜪ՟ނݯᕍ྽ύ܌ౢғޑՈమੰࢥਡᗐਡ ለϐ׭ڋਏ݀Ϸᖏ׉ݯᕍᕍਏϐቹៜϝ҂ޕǶ

ࣴ

ࣴزޑଷᇥᆶ੝ۓҞޑ

ଷᇥ΋ǵӧت܄ᄌ܄˾ࠠطݹੰ஻ύǴ੝ۓޑխࣝᒪ໺Ӣη HLA-DRB1 ӭ׎܄

ёૈᆶ˾ططݹޑᝄख़ำࡋԖᜢǶ

Ҟޑ΋ǵ௖૸խࣝᒪ໺Ӣη HLA-DRB1 ӭ׎܄ᆶت܄ᄌ܄ B ࠠطݹϐطݹᝄख़ ำࡋϐ໔ޑ࣬ᜢ܄Ƕ

ଷᇥΒǵᆢғન D խࣝڙᡏ୷Ӣӭ׎܄ᆶᄌ܄ B ࠠطݹޑόӕᖏ׉߄ࠠаϷځ วғطಒझᕎ௃׎ёૈԖᜢǶ

ҞޑΒǵ௖૸ᆢғન D խࣝڙᡏ୷Ӣӭ׎܄ᆶᄌ܄ B ࠠطݹޑόӕᖏ׉߄ࠠа Ϸวғطಒझᕎϐ໔ޑ࣬ᜢ܄Ƕ

ଷᇥΟǵᄌ܄ B ࠠطݹੰ஻ຼᜐՈనൂਡౚಒझکط᠌ಒझ΢ӃϺխࣝᜪ៕ڙ ᡏ-3 ߄౜ໆёૈᆶᄌ܄ੰࢥགࢉރᄊԖᜢǶ

ҞޑΟǵ௖૸ᄌ܄ B ࠠطݹੰ஻ຼᜐՈనൂਡౚಒझکط᠌ಒझ΢ӃϺխࣝᜪ

៕ڙᡏ-3 ϐ߄౜ໆǴ٠Ъځᆶխࣝፓ࿯ᛰނߏਏࠠυᘋનݯᕍᕍਏޑ࣬ᜢ܄Ƕ

ଷᇥѤǵխࣝፓ࿯ᛰނ (υᘋન) ёаԖਏޑ׭ڋਡ㧿ᜪ՟ނݯᕍύ܌֛ᑈϷౢ

ғޑՈమੰࢥਡᗐਡለ (HBV RNA)Ƕ

ҞޑѤǵ௖૸ᄌ܄ B ࠠطݹ஻ޣௗڙխࣝፓ࿯ᛰނ (υᘋન) ჹܭਡ㧿ᜪ՟ނ܌

ౢғޑՈమ HBV RNA ϐ׭ڋਏ݀Ƕ

ࣴ

ࣴزБݤᆶ׷਑

ੰ஻

΋ǵխࣝᒪ໺Ӣη HLA-DRB1 ӭ׎܄ᆶت܄ᄌ܄ B ࠠطݹޑطݹᝄख़ำࡋϐ࣬

ᜢ܄ࣴز

ӧԜ߻ᘳ܄ШжࣴزύǴӅયΕΑ 204 Ӝᄌ܄˾ࠠطݹ஥চޣ (131 Ӝت܄

ک 73 Ӝζ܄)Ƕ೭٤஥চޣӧѠ᡼εᏢߕ೛ᙴଣޑߐບ೽ଓᙫ΋ԃа΢ޑਔ໔Ƕ

٬Ҕਡ㧿ᜪ՟ނǴխࣝፓ࿯ᏊǴᜪڰᎇǴϯᕍ܈ڀطࢥ܄ޑᛰނݯᕍޑੰΓǹ஻

Ԗ C ࠠطݹǴD ࠠطݹ܈གࢉΓᜪխࣝલഐੰࢥޑੰΓǹᔲҔଚᆒޑੰΓǹ஥

ԖԾᡏխࣝלᡏ܈жᖴ܄طੰޑੰΓǹ஻Ԗطฯϯ܈طᕎޑੰΓǴکӧଓᙫϐ߻

܈ϐ໔ௗڙ౽෌ЋೌޑੰΓ೿೏௨ନӧѦǶ

٩Ᏽᄌ܄˾ࠠطݹ஥চޣځطݹޑᝄख़ࡋע಄ӝచҹޑੰΓϩࣁٿಔǶطݹ ᝄख़ࡋޑղۓࢂ೸ၸۓයᔠෳՈమ ALT ॶǶҁࣴز٬Ҕऍ୯طੰࣴزᏢ཮ޑᖏ

׉ࡰЇǴ٩ᏵՈమ ALT ॶεܭ܈฻ܭٿ७҅தॶ΢ज़ޑᇡۓࣁ“ࢲ୏܄طݹ”

(Lok and McMahon 2007)Ƕಃ΋ಔયΕΑ 50 Ӝ ALT λܭٿ७҅தॶ΢ज़ޑᄌ܄

˾ࠠطݹ஥চޣ (25 Ӝت܄ک 25 Ӝζ܄)ǴΨ൩ࢂӧѳ֡ 83.6 ঁД (வ 12 ঁД ډ 382 ঁД) ޑଓᙫύǴALT ӧख़ፄෳໆϐΠλܭ 80 U/LǶಃΒಔયΕΑ 154 Ӝӧѳ֡ 81.3 ঁД (வ 12 ঁДډ 231 ঁД) ޑଓᙫύǴALT ӧख़ፄෳໆϐΠε ܭ܈฻ܭٿ७҅தॶ΢ज़ޑᄌ܄˾ࠠطݹ஥চޣ (106 Ӝت܄ک 48 Ӝζ܄)Ƕऩ ALT ॶѝԖ΋ԛεܭ܈฻ܭٿ७҅தॶ΢ज़Ψ཮ᘜډಃΒಔǶҁࣴز܌યΕޑ

܌Ԗ஥চޣࣁᅇ௼Ǵᆵ᡼നࣁදၹޑᅿ௼ǶՈమ ALT ॶԖ΢ϲޑ஥চޣǴ؂ 2 Կ 3 ঁДᔠෳ ALT ॶǶՈమ ALT ॶ҅தޑ஥চޣǴ؂ 6 Կ 12 ঁДᔠෳ΋ԛǶ ՈమኬҁӸܫӧ -20⁰Cޔډ٬ҔࣁЗǶ؂ 6 Կ 12 ঁД೭٤஥চޣௗڙဎ೽ຬॣ

ݢᔠࢗࢂցр౜طฯϯ܈طᕎǶҁࣴزᕇள܌Ԗୖᆶޣޑޕ௃ӕཀǴ٠ЪᒥӺբ

ޣᙴଣޑΓᡏ၂ᡍࡰࠄǶ Ԝ኱ྗਔǴ٬Ҕطࢲᔠບᘐ (Bruix and Sherman 2005)Ƕطݹ࡚܄วբࢂࡰՈమ ALT (40 IU/L) ॶँฅቚуǴၲډ҅த΢ज़ॶޑ 5 ७ (200 IU/L) а΢ (Kao et al.

2001)ǶჹܭՈమ ALT ϲଯޑୖᆶޣǴ؂ 3 ঁДᔠෳ΋ԛՈమ ALT ॶǴჹܭՈమ ALTॶ҅தޑୖᆶޣǴ؂ 6 ঁДᔠෳ΋ԛՈమ ALT ॶǶՈమᔠᡏӧ٬Ҕ߻Ǵӧ -20ʚޑచҹΠߥӸǶჹܭ܌ԖୖᆶޣǴ؂ 6 ঁДᔠෳ΋ԛՈమҘࠠजٽೈқॶǴ ٠຾ՉຬॣݢᔠࢗǴаᅱෳطಒझᕎǶҁࣴزᒥൻӚ฽ޣ܌ឦᐒᄬޑΓᡏჴᡍࡰ

ЇǴԶЪǴ؂ঁ஻ޣ೿ᛝ࿿Αޕ௃ӕཀਜǶ

ᔠᡏӧ٬Ҕ߻֡ߥӸܭ-80ʚޑᕉნΠǶ؂΋Տ஻ޣ೿ς೏֋ޕ٠Ъӕཀ٬Ҕځ ᔠᡏǶ

ჴ

ჴᡍᔠᡍ໨Ҟ

Ոమל C ࠠطݹלᡏ (anti-HCV) کל D ࠠطݹלᡏ (anti-HDV) ϩձҔ Murex anti-HCVک Murex anti-delta ၂Ꮚ౯ (Murex Biotech, Kyalami, South Africa ک Murex Biotech, Dartford, UK) ᔠෳǶՈమ B ࠠطݹੰࢥѐ਼ਡᑗਡለ (HBV DNA) ۓໆᆶ B ࠠطݹੰࢥ୷Ӣࠠϐ᠙ۓϩձҔջਔ PCR کᅙှԔጕϩ݋ݤ຾

Չ (Yeh et al. 2004)Ƕ

΋ǵխࣝᒪ໺Ӣη HLA-DRB1 ӭ׎܄ᆶت܄ᄌ܄ B ࠠطݹޑطݹᝄख़ำࡋϐ࣬

ᜢ܄ࣴز

ғϯᔠᡍޑෳໆ٬ҔதೕԾ୏ϯБݤǶՈమ߄य़לচ (HBsAg) کלᡏ (anti-HBs) ޑෳ၂٬Ҕ Enzygnost HBsAg 5.0 ک anti-HBs II (Dade BehringǴ MarburgǴGermany)Ƕ

Βǵᆢғન D խࣝڙᡏ୷Ӣӭ׎܄ᆶᄌ܄ B طޑطݹ࡚܄วբǵe-לচ௃ݩа Ϸطಒझᕎౢғϐ࣬ᜢ܄ࣴز

Ոమ HBsAg ک HBeAg ॶϩձҔ Ausria-II ک IMx HBe ၂Ꮚಔ (Abbott Laboratories, North Chicago, IL, USA) ᔠෳǶ

Οǵ ᄌ܄ B ࠠطݹੰ஻ຼᜐՈనൂਡౚಒझکط᠌ಒझ΢ӃϺխࣝᜪ៕ڙᡏ-3 ϐ߄౜ໆǴ٠Ъځᆶխࣝፓ࿯ᛰނߏਏࠠυᘋનݯᕍᕍਏޑ࣬ᜢ܄ࣴز

Ոమۓໆ B ط߄य़לচ (qHBsAg)ǵ B ط e-לচ (HBeAg)ǵC طלᡏа Architect i2000 SR (Abbott Laboratories, Abbott Park, IL, USA) ຾ՉᔠෳǶՈమύ

Bطੰࢥ DNA а Abbott m2000 sp (Abbott Laboratories, Abbott Park, IL, USA) ۓ ໆᔠෳǶ

Ѥ

Ѥǵխࣝፓ࿯ᛰނ (υᘋન) ჹܭᄌ܄ B طੰ஻Ոమੰࢥਡᗐਡለ (HBV RNA) ޑ׭ڋਏ݀ϐࣴز

Ո మ B ط e- ל চ (HBeAg) ک B ط e- ל ᡏ (anti-HBe) ॶ ࢂ ೯ ၸ chemiluminescent immunoassay (Architect HBeAg and Architect HBeAb, Abbott Japan, Tokyo, Japan) ܌ෳ၂рǶ

խࣝᒪ໺Ӣη HLA-DRB1 ჹଽ୷ӢޑुۓǵϩࠠϷԛϩࠠ

வڬᜐՈనൂਡಒझύ٬Ҕ QIAamp ၂Ꮚಔ (QiagenǴInc.ValenciaǴCA) ๧ ڗ୷Ӣύޑѐ਼ਡᑗਡለ (genomic DNA)Ƕӵϐ߻ޑЎ᝘܌௶ॊǴ೯ၸᆫӝ 䁙᜘

ϸᔈ-ׇӈ੝ۓჲਡ㧿ለ௖ଞᚇҬ᠙ۓ HLA-DRB1 ჹଽ୷Ӣ (Scharf et al.

1991)Ƕᙁౣ௶ॊӵΠǴHLA-DRB1 ୷ӢޑಃΒঁѦᡉη (exon) җ੝ۓޑЇη ಔ঺ (primer set) ܫεǶ٬ᆫӝ䁙᜘ϸᔈϐౢނᡂ܄ࡕڰۓԿѭᓪጢ΢Ƕϖᆄғ ނનϯ (5’-biotinylated) ׇӈ੝ۓ܄ჲਡ㧿ለ௖ଞಔҔܭᔠෳ ӭ׎܄Ѧᡉηޑ ଯᡂ౦୔ୱǴฅࡕ൩ࣁ؂ঁѐ਼ਡᑗਡለኬҁࡌҥ୷ӢࠠǶ

ᆢғન D խࣝڙᡏ୷Ӣࠠکൂᡏࠠޑुۓ

୷Ӣಔѐ਼ਡᑗਡለ (genomic DNA) வڬᜐՈనқՈౚύ๧ڗ (Riggs et al. 1995)Ƕ ٬Ҕᆫӝ䁙ೱᙹϸᔈ (polymerase chain reactionǴPCR) аϷа߻ൔ֋

ׯጓޑज़ڋ܄Тࢤߏࡋӭ׎܄ (restriction fragment length polymorphism, RFLP) ݤዴۓΑΟঁӭ׎܄ज़ڋՏᗺޑ୷Ӣࠠ (BsmI Տᗺ [rs1544410] ک ApaI Տᗺ [rs7975232] ϩձՏܭᆢғન D ڙᡏ୷Ӣޑಃ 7 ϣ֖ηکಃ 8 ϣ֖ηǴԶ TaqI Տᗺ [rs731236] Տܭಃ 9 Ѧᡉη) (Riggs et al. 1995)ǶᙁقϐǴՏܭಃ 7 Ѧᡉη ޑ BsmI ӭ׎܄҅ӛЇηࣁ 5’- CAACCAAGACTACAAGTACCGCGTCAGTGA

-3’ǴՏܭಃ 7 ϣ֖ηޑ BsmI ӭ׎܄ϸӛЇηࣁ 5’- AACCAGCGGGAAGAGGTCA AGGG -3’Ƕ Տ ܭ ಃ 8 ϣ ֖ η ޑ ApaI ک TaqI ӭ ׎ ܄ ҅ ӛ Ї η ࣁ 5’- CAGAGCATGGACAGGGAGC -3’ǴՏܭಃ 9 Ѧᡉηޑ ApaI ک TaqI ӭ׎܄ϸӛ Їηࣁ 5’- AGGAGAGGCAGCGGTACTG -3’ǶBsmI ӭ׎܄ޑ PCR ϸᔈచҹࣁǺ 94⁰C 5ϩដǴฅࡕࡪаΠྕࡋ଺ 35 ঁൻᕉǺ 94⁰C 30ࣾǴ66⁰C 30ࣾǴ72⁰C 30

ᗐᏉጤႝݚ (agarose gels) ϩᚆǴ٠ҔྜྷϯΌᒭ (ethidium bromide)ࢉՅǶ

ຼ

ຼᜐՈనൂਡౚಒझޑӃϺխࣝᜪ៕ڙᡏ (TLR)- 3 ߄౜ໆޑෳۓ

ךॺܜڗჹྣޣયΕਔکᄌ܄ B ࠠطݹ஻ޣݯᕍ߻کݯᕍύޑཥᗲӄՈǶ ךॺ٬Ҕ CD14-FITCǵTLR3-PE (eBioscienceǴSan DiegoǴCAǴUSA) ଺ಒझ߄ य़ࢉՅǶ٬Ҕᆶᜪ៕ڙᡏ-3 לᡏӕࠠޑλႵ IgG1 ࣁלᡏޑჹྣ (eBioscienceǴ San DiegoǴCAǴUSA)Ƕӧ FACSCalibur ࢬԄಒझሺ (Becton DickinsonǴSan JoseǴ CAǴUSA) ΢ԏ໣ᕴӅ 50,000 ঁࢲಒझǶךॺᒧڗൂਡౚࢂ٩ᏵՏܭరЃౚࡕ

೽ک CD14+ ಒझޑණթკ (scatter profile)Ƕךॺԏ໣؂ঁᔠᡏ٩Ᏽځණթკک CD14+ ಒझ܌ᒧڗޑѳ֡ᅞӀமࡋ (mean fluorescence intensityǴMFI) کځԭϩ КǶ؂ঁᔠᡏ೿ᕴӅவ 50,000 ঁಒझύ᠐ڗ CD14+ ൂਡౚǶኧᏵϩ݋٬Ҕ WinMDI೬ᡏ (Becton Dickinson and CompanyǴFranklin LakesǴNJǴUSA)Ƕ

طಒझ΢ӃϺխࣝᜪ៕ڙᡏ (TLR)- 3 ߄౜ໆޑෳۓ

ஒᄌ܄ B ࠠطݹ஻ޣک଼நჹྣޣޑط᠌ϪТᔠᡏ࿶ၸཥᗲհএ܈੆Εന

٫Ϫߺྕࡋϯӝނ (optimal cutting temperatureǴOCT) (Ames CompanyǴElkhartǴ

IN)Ǵ٠ߥ࡭ӧ -80 ^oCޔډ٬ҔਔǶ

RNA๧ڗکջਔϸᙯᒵᆫӝ䁙ೱᙹϸᔈ (RT-PCR)

ӄ೽ޑ RNA (total RNA) ٬Ҕ RNeasy ၂Ꮚಔϩᚆ (Qiagen Inc., Valencia, CA, USA)Ƕ а 1 ༾լ total RNA ٬Ҕ iScript cDNA ӝԋ၂Ꮚಔ (Bio-Rad, Hercules, CA)

຾ՉϸᙯᒵϸᔈǶ ٬Ҕ iQ SYBR Green Supermix (Bio-Rad) ӧ DNA Engine Opticon 2 (Bio-Rad) ຾Չջਔϸᙯᒵᆫӝ䁙ೱᙹϸᔈǶᜪ៕ڙᡏ-3 ЇηӵΠǺ҅

ިЇη 5'- TTG CCT TGT ATC TAC TTT TGG GG -3'ǴϸިЇη 5'- GCG GCT GGT AAT CTT CTG AGT T -3'Ƕ GAPDH ЇηӵΠǺ҅ިЇη 5'- GTC CAC TGG CGT GTT CAC CA -3'ǴϸިЇη 5'- GTG GCA GTG ATG GCA TGG AC -3'Ƕᘉቚ షӝన (20 ༾ϲ) ֖Ԗ 25 ng ᔠᡏޑ RNA (5 ༾ϲ)Ǵ2x Master Mix (10 ༾ϲ)Ǵ 5 uM ޑ҅ިЇηکϸިЇη (2 ༾ϲ)Ǵک 3 ༾ϲ ddH20 (Kapa Biosystems, Inc, Woburn, MA, United States)Ƕᆫӝ䁙ೱᙹϸᔈ዗ൻᕉୖኧӵΠǺϩձࢂሇનࢲϯ ӧ 1 ঁൻᕉޑ 95^oCၲ 3 ϩដǴ ฅࡕᕴӅ 40 ঁൻᕉޑᡂ܄کᗹӝ/ۯ՜໘ࢤӧ 95^oC

طಒझ΢ӃϺխࣝᜪ៕ڙᡏ-3 խࣝಔᙃϯᏢࢉՅ (immunohistochemical, IHC stain)

ᡏ (ab13915) (Abcam, Cambridge, MA, USA) ӧ࠻ྕ୻ᎦٿλਔǴฅࡕҔ PBS ࢱ ᅗǴϐࡕᆶ NovoLink Polymer (Leica Biosystems, Newcastle, United Kingdom) բ Ҕ 30 ϩដǴӆҔёаᡉҢלᡏՏ࿼ޑ DAB բҔన୻Ꭶ (Leica Biosystems, Newcastle, United Kingdom)ǴЪಔᙃӆа Mayer’s haematoxylin ჹࢉǶаӕྍࠠ

לᡏ྽բ഍܄ࢉՅჹྣǶ

Ո

Ոమ B ࠠطݹੰࢥਡᗐਡለ (HBV RNA) ջਔ PCR ޑෳۓ

B ࠠطݹੰࢥਡለޑ๧ڗک଍ᙯᒵ؁ᡯаϷۓໆ٩Ᏽϐ߻ޑൔ֋຾Չ

(Hatakeyama et al. 2007)Ƕ٬Ҕ SMI TEST EX-R&D ၂Ꮚಔ (Genome Science Laboratories, Tokyo, Japan) வ 100ul Ոమύ๧ڗਡለǴฅࡕྋှܭ 18ul ޑคਡᗐ ਡለ䁙ޑНύǶӆஒ๧ڗނϩԋٿҽ࣬ӕޑ৒ໆǴϩձᆀࣁྋన I ک IIǶஒྋన Iᆶ฻ໆޑНషӝࡕǴुрѐ਼ਡᗐਡለ (DNA) ޑᐚࡋǶྋన II ٬ҔᒿᐒЇη (random primer) (Takara Bio Inc., Shiga, Japan) ک M-MLV ଍ᙯᒵ䁙 (ReverTra Ace, TOYOBO Co., Osaka, Japan) ຾Չ଍ᙯᒵ؁ᡯǴฅࡕुр DNA у΢ cDNA ޑᐚࡋǶ଍ᙯᒵޑ؁ᡯӵΠǺуΕ 25pM ޑᒿᐒЇηǴஒᔠᡏу዗ډ 65ʚᆢ࡭ 5 ϩដǹฅࡕעᔠᡏܫ࿼ܭӇύ 5 ϩដǹуΕ 5 × ଍ᙯᒵ጗ፂᏊ (4ul)Ǵ10mM ޑ dNTP (2ul)Ǵ0.1M ޑΒ౷᝵ᑗᎇ (dithiothreitol) (2ul)Ǵ8 ঁൂՏޑਡᑗਡለ䁙׭

ڋᏊک 100 ঁൂՏޑ M-MLV ଍ᙯᒵ䁙ǹӧ 30ʚک 42ʚΠϩձ୻Ꭶᔠᡏ 10 ϩដ ک 60 ϩដǹനࡕӧ 99ʚΠ 5 ϩដ٬ځѨѐࢲ܄Ƕ

HBV DNAک cDNA ޑۓໆ٩Ᏽϐ߻ޑൔ֋຾Չ (Hatakeyama et al. 2007)Ƕ ࡪྣᇙ೷୘ޑᇥܴǴஒ 1ul ޑྋన I کྋన II аջਔ PCR ٬Ҕ ABI Prism 7300

ׇӈᔠෳس಍ (Sequence Detection System) (Applied Biosystems, Foster City, CA, USA) ϩձܫεǶ ܫεࢂӧ 25ul ϸᔈషӝనύ຾ՉޑǴషӝనϣ֖Ԗ SYBR Green PCR Master Mix (Applied Biosystems) Ǵ 200nM ҅ ӛ Ї η (5’-TTTGGGGCATGGACATTGAC-3’Ǵਡ㧿ለ 1893-1912)Ǵ200nM ϸӛЇη (5’-TTTGGGGCATGGACATTGAC-3’Ǵਡ㧿ለ 2029-2049)Ǵک 1ul ޑྋన I ܈ྋ

న IIǶջਔ PCR ύޑ؁ᡯӵΠǺӧ 50ʚΠ୻Ꭶ 2 ϩដǴฅࡕӧ 95ʚΠ 10 ϩដ

٬ϐᡂ܄Ϸ PCR ൻᕉх֖ 40 ԛٿ؁ൻᕉӧ 95ʚΠ 15 ࣾک 60ʚΠ 60 ࣾ຾ՉǶ Ԝ၂ᡍޑᔠෳΠज़ጄൎࢂ 10³ copies/mlǶHBV RNA ޑᐚࡋёа೯ၸྋన II ෧ѐ ྋన I ޑᐚࡋԶளр (Ψ൩ࢂҗջਔ PCR ଍ᙯᒵϸᔈၸࡕޑ B ࠠطݹੰࢥਡለ ෧ѐҗջਔ PCR ुۓޑ HBV DNA)Ƕ

಍

಍ीϩ݋

஥চޣޑ୷ҁ੝ቻǴхࡴԃសǵ܄ձǵଓᙫਔ໔ǵe-לচǵe-לᡏǵ୷Ӣࠠǵ ALTکੰࢥѐ਼ਡᑗਡለᐚࡋӧࣴزಔϐ໔຾ՉКၨǶೱុᡂ໨аѳ֡ॶ ± ኱

ྗৡ߄ҢǴ٠а Student t-test ᔠۓٿಔ໔ϐКၨǴЪа Kruskal-Wallis test ஒΟ ಔ຾ՉКၨǶᜪձᡂ໨߄ҢࣁКٯᓎ౗Ǵ٬Ҕ Pearson’s ьБᔠۓ ; ྽߄਱ύԖ

΋ঁ܈а΢ޑൂ਱р౜Ⴃයᓎ౗ɦ5 ਔǴ٬Ҕ Yates ਠ҅ݤ܈ Fisherȷs exact test

ٰКၨǶ܌Ԗᔠۓ೿ࢂᚈ׀Ǵp ॶλܭ 0.05 ೏ᇡۓࣁ಍ीᏢ΢ڀཀကǶੰࢥѐ਼

ਡᑗਡለᐚࡋӧϩ݋߻Ӄϒჹኧϯ (log-transformed)Ƕ

ಔձϐ໔ޑ HLA-DRB1 ჹଽ୷Ӣᓎ౗٬Ҕᡄᒠӣᘜϩ݋Ǵхࡴᔠෳٿಔ᏾

ᡏৡ౦ޑ᏾ᡏᔠۓ (global test) کᔠෳ࣬ჹയᆉ (relative odds) ޑ੝ۓᔠۓ (specific test)ǴԶЪ٬Ҕ“தـᜪࠠ” (common types) բࣁୖԵࠠձ(reference category)Ƕ

ಔձϐ໔ޑᆢғન D ڙᡏ୷Ӣࠠکൂᡏࠠᓎ౗࿶ᡍ p ॶҔ 10,000 ࿼ඤीᆉ (permutations)ǴѤ ௭ ϖΕډ λኧ ᗺࡕ ಃΟ ՏǶ࿼ ඤϩ ݋Ҕ ܭೀ ౛ӭԛ ᔠᡍ (multiple testing) ޑୢᚒǶ٬Ҕ SAS 9.2 ހ (SAS Institute, Inc, Cary, NC) ೬ᡏа

௢ᘐൂኳԄᅿǶќѦа SAS ޑጕ܄ӣᘜϩ݋ຼᜐՈనൂਡౚಒझᜪ៕ڙᡏ-3 ߄

౜ໆޑႣෳӢηǶ

่

നӭޑჹଽ୷Ӣ (ջ HLA-DRB1*09) բࣁୖԵࠠ (reference category)Ƕλܭ 5%

ޑჹଽ୷Ӣᓎ౗ӝٳࣁ“ځд”ࠠձǶፓ᏾ԃសࡕǴALT < 80 U/L ޑت܄஥চޣϐ HLA-DRB1*1101ᓎ౗ܴᡉଯܭٗ٤ ALT• 80U/L ޣ (18.0% vs. 8.0%ǴOR 0.23Ǵ pɨ0.020)ǶԜѦǴ ALT < 80U/L ޑت܄஥চޣϐ HLA-DRB1*14 ܴᡉКٗ٤ ALT

• 80U/L ޣ (16.0% vs. 8.0%ǴOR 0.23Ǵpɨ0.025) ׳ࣁᓎᕷǶHLA-DRB1*14 ޑ HLA-DRB1*1101 ჹଽ୷Ӣᆶ܌Ԗځдჹଽ୷ӢКၨޑയᆉК (odds ratio) ࣁ 0.39 (95% CI 0.16 – 0.95)Ƕ

DRB1*1101ޑ B طੰࢥت܄஥চޣύǴALTɪ80U/L ޑ B ط஻ޣǴځੰࢥ

୷Ӣࠠϩթࣁ 67% B ࠠǴ20% C ࠠǴ0% B Ϸ C ࠠᆶ 0% ߚ B ܈ C ࠠǴԶ ALT < ϐ໔ޑ BsmI–ApaIǵBsmI–TaqIǵApaI–TaqI ک BsmI–ApaI–TaqI ൂᡏࠠᓎ౗և౜ᡉ

๱܄ৡ౦ (ϩձࣁ p = 0.010Ǵp = 0.004Ǵp = 0.013 ک p = 0.009)Ƕطݹ࡚܄วբ

஥চޣޑ A/TǵA/t ک b/A/t ൂᡏࠠᓎ౗ܴᡉଯܭ҂วғطݹ࡚܄วբޑ஥চޣ (ϩձࣁ 48% ࣬ၨܭ 34%Ǵp = 0.027ǹ2% ࣬ၨܭ 1%Ǵp = 0.004 ک 0.5% ࣬ၨ

ܭ 0%Ǵp = 0.001)Ƕ࣬ϸޑǴطݹ࡚܄วբ஥চޣޑ B/aǵB/T ک B/a/T ൂᡏࠠ

ᓎ౗ܴᡉեܭ҂วғطݹ࡚܄วբޑ஥চޣ (ϩձࣁ 1% ࣬ၨܭ 9%Ǵp = 0.004ǹ

3% ࣬ၨܭ 10%Ǵp = 0.007 ک 1% ࣬ၨܭ 9%Ǵp = 0.005)ǶΟᅿᆢғન D ڙᡏ୷ ϐ໔ޑᆢғન D ڙᡏ BsmI–ApaIǵBsmI–TaqIǵApaI–TaqI ک BsmI–ApaI–TaqI ൂ ᡏࠠᓎ౗և౜ᡉ๱܄ৡ౦ (ϩձࣁ p = 0.004, p = 0.002Ǵp = 0.021 ک p = 0.004)Ƕ HBeAg໚܄஥চޣޑ b/AǵB/aǵB/Aǵ B/TǵB/tǵA/tǵb/A/TǵB/a/TǵB/A/Tǵ B/A/t ک b/A/t ൂᡏࠠᓎ౗ܴᡉଯܭ HBeAg ഍܄஥চޣ (ϩձࣁ 45% ࣬ၨܭ

ॶǶᄌ܄ B ࠠطݹ஻ޣຼᜐՈనൂਡౚಒझޑᜪ៕ڙᡏ-3 ѳ֡ᅞӀமࡋ (MFI)

(sustained virological response, SVR)Ǵ࡭ុੰࢥᏢϸᔈۓကࣁݯᕍࡕ 6 ঁДՈమ B

-3 ѳ֡ᅞӀமࡋբࣁୖྣǴӧ 48 ຼޑݯᕍύᜪ៕ڙᡏ-3 ѳ֡ᅞӀமࡋ೴ᅌ΢ϲ ѳ֡ 1.2 ७ (კϖ)Ƕӧಃ 24 ຼک 48 ຼݯᕍࡕǴϩձᢀჸډ 60% ک 80% ஻ޣޑ ᜪ៕ڙᡏ-3 ѳ֡ᅞӀமࡋ೿ԿϿቚу 5% (კΖ)ǶݯᕍԿ 120 ຼਔǴᜪ៕ڙᡏ-3 ѳ֡ᅞӀமࡋ຾΋؁΢ϲԿѳ֡ 1.5 ७ (კΐ)Ƕᜪ៕ڙᡏ-3 ߄౜ໆᆶӚঁ஻ޣݯ ᕍ߻ϷݯᕍύǴௗڙυᘋન܈ن኷լݯᕍޣϐੰࢥໆ೿ค࣬ᜢ܄Ƕ

Ѥ

Ѥǵխࣝፓ࿯ᛰނ (υᘋન) ჹܭᄌ܄ B طੰ஻Ոమੰࢥਡᗐਡለ (HBV RNA) ޑ׭ڋਏ݀

аਡ㧿ᜪ՟ނک/܈໺಍υᘋનݯᕍޑᄌ܄ B ࠠطݹ஻ޣޑ୷ҁ੝ቻӵ߄Μ

܌ҢǶ೭Οঁಔձύӧԃសǵ܄ձКٯǵALT ॶǵHBeAg ރᄊ܈ HBV DNA ॶ

΢คৡ౦Ƕ

ਡ㧿ᜪ՟ނݯᕍࡕޑՈమ HBV RNA ॶ

ӧਡ㧿ᜪ՟ނݯᕍ߻ǵύکݯᕍ܈ଓᙫ่״ਔՈమ HBV RNA ޑёᔠෳ܄ک ᐚࡋӵ߄Μ΋܌ҢǶӧਡ 㧿ᜪ՟ނݯᕍ໒ۈ߻ǴՈమHBV RNA ӧ܌Ԗ஻ޣύ೿

ᔠෳόډǹՠӧݯᕍࡕǴӧ 15 ঁ஻ޣ (79%) ΢ёᔠෳډǶ14 ঁௗڙ lamivudine ݯᕍޑ஻ޣύǴՈమ HBV RNA ӧ 10 ঁ஻ޣ (71%) ΢ёᔠෳډǶ࣬ϸޑǴӧ 5

ঁௗڙ entecavir ݯᕍޑ஻ޣύǴՈమ HBV RNA ӧ܌Ԗ஻ޣ (100%) ύ೿ёᔠ

ෳډǶӧௗڙ lamivudine ݯᕍޑ஻ޣύǴՈమ HBV RNA ޑനଯॶጄൎவ 4.2 ډ 7.0 log10copies/mlǴԶӧௗڙ entecavir ݯᕍޑ஻ޣύǴጄൎவ 7.2 ډ 9.6 log10copies /mlǶ

ௗڙӚԄݯᕍޑ஻ޣύՈమ HBV RNA ॶޑೱុᡂϯ

ӧௗڙਡ㧿ᜪ՟ނൂ΋ݯᕍࡕёаෳளՈమ HBV RNA ޑ஻ޣύǴޔډݯᕍ

่״ਔ HBV RNA ϝӸӧ (ಃ΋ಔǹ߄Μ΋)Ƕ࣬՟ޑǴӧอයޑ lamivudine ݯ ᕍࡕǴՈమ HBV RNA ϝฅࢂёаᔠෳளډ (ಃΟಔǹ߄Μ΋)Ƕ࣬ϸޑǴௗڙ

Α lamivudine کυᘋન࣬ᝩӝٳݯᕍޑ஻ޣǴӧݯᕍ่״ਔՈమ HBV RNA ൩ᔠ

ෳόډΑ (ಃΒಔǹ߄Μ΋)Ƕಃ΋ಔǵಃΒಔکಃΟಔ஻ޣύёෳள HBV RNA ޣޑՈమ HBV RNA ೱុᡂϯϩձӵკΜǵკΜ΋ کკΜΒ܌ҢǶӧௗڙਡ㧿 ᜪ՟ނݯᕍޑ߻य़ 2 Կ 4 ຼǴՈమ HBV RNA ӧ 13 Ӝ஻ޣ (87%) ύёᔠෳډ٠ Ъӧ 11 Ӝ (73%) ύၲډനଯॶǶ

૸

૸ፕ

ಃ΃ക խࣝᒪ໺Ӣη HLA-DRB1 ӭ׎܄ᆶت܄ᄌ܄ B ࠠطݹޑطݹᝄख़ำࡋ ϐ࣬ᜢ܄

BࠠطݹགࢉࡕᏤठቶݱޑᖏ׉߄౜Ϸ่݀ǶӧᓻѴٽਔයᕇள B ࠠطݹག

ࢉޑঁᡏύऊ 95% ຾৖ԋ࡭ុ܄གࢉǴԶԋΓਔයᕇளགࢉޣѝԖ 3% Կ 5%

ԋࣁ஥চޣǶ೽ҽ࡭ុ܄ޑ B ࠠطݹགࢉஒว৖ԋᄌ܄ B ࠠطݹǴаϸᙟ܄ޑ ALTॶ΢ϲٰ߄౜Ƕব΋٤எЬӢનቹៜᄌ܄ B ࠠطݹ஻ޣϸᙟ܄ ALT ॶ΢ϲ ϝόܴǶ

ΓᜪқՈౚלচ (human leukocyte antigen, HLA) Տ࿼ޑ୷Ӣӭ׎܄ᡣ HLA ϩηёаև౜ቶݱϐלচᅿᜪǴ٠Ъ٬ HLA ϩηޑלচ่ӝϷև౜ϐ੝܄ӭኬ ϯ (Martin and Carrington 2005)Ƕυᘋનݯᕍፓϲ HLA-DR, CD80 Ϸ ICAM-I ϩ ηӧᐋँಒझޑ߄౜Ǵ຾Զமϯխࣝϸᔈ (Yu et al. 2006)ǶHLA-DR Տ࿼՟Яࢂ

ቹៜυᘋનݯᕍϸᔈϐܴᡉޑխࣝᒪ໺Ӣη (Singh et al. 2007)Ƕ

ࢥఠ CD8+ T ಒझ (cytotoxic T lymphocyte, CTL) ᙖҗ T ಒझڙᡏ (TCR) ᆶ

೏ੰࢥགࢉޑಒझҬϕբҔǴࢂ೸ၸ CD4+ T ಒझޑᔅԆ (Schoenberger et al.

1998) Ϸᒣ᛽ӧ HLA ϩη߄य़܌և౜ੰࢥϐᴏ两 (Elahi and Horton 2012)Ƕ೭ᅿ ҬϕբҔ่݀཮ఠԝ೏ੰࢥགࢉޑಒझǴ೸ၸٿঁЬा೼৩Ǻߚ٩ᒘᗭಈޑ೼৩

ੋϷ Fas/FasL ҬϕբҔ (Poonia et al. 2009) ܈ॄၩྋှᗭಈޑऀϾનᆶᗭಈ䁙 B (Granzyme B, GzmB) (Migueles et al. 2008)ǶCD8+ T ಒझӧӚᅿᄌ܄ੰࢥགࢉύ วචख़ाޑբҔǶӧϿኧڙډ௓ڋϐགࢉޣ (Saez-Cirion et al. 2007) ک੯ੰߏය ᛙۓϐ஻ޣ (Betts et al. 2006ǹHorton et al. 2006)΢ς᛾ჴԖቚமϐࢥఠ CD8+ T ಒझޑфૈǶಃΒࠠ HLA ϩηஒלচև౜๏ CD4+ T ಒझ೏ᇡࣁࢂჹܭ B ࠠط ݹੰࢥགࢉख़ाޑஎЬխࣝϸᔈ (Penna et al. 1997)Ƕ೭ঁ T ಒझխࣝϸᔈӧᄌ

܄ B ࠠطݹགࢉޑੰ஻Ԗᡉ๱ޑ೏෧১ޑ౜ຝ (Vermehren et al. 2012)Ƕ

ੰࢥ੝ۓ܄ CD8+ T ಒझӧ HLA ज़ۓ܄ک T ಒझڙᡏޑᒃکΚБय़Ԗ܌ό ӕǶ೚ӭང෷ੰߏයᛙۓ஻ޣڀԖང෷ੰࢥ੝ۓ܄ԶЪ೏ HLA-B27 ܈ HLA-B57 (ߥៈ܄ჹଽ୷Ӣ) ज़ۓޑࢥఠ CD8+ T ಒझǴёаӧᄌ܄གࢉၸำύᝩុቚ෗Ƕ (Genome Wide Association Study) ᡉҢ࡭ុ܄ B ࠠطݹੰࢥགࢉᆶ HLA-DP ୷Ӣ Տ ࿼ Ǵ х ࡴ HLA-DPA1 Ϸ HLA-DPB1 ϐ Μ ΋ ঁ ൂ ਡ㧿 ለ ӭ ׎ ܄ (single nucleotide polymorphism, SNP) Ԗᡉ๱ޑ࣬ᜢ܄ (Kamatani et al. 2009)Ƕٿঁӧ HLA-DPՏ࿼ (ӧ HLA-DPA1 ޑ rs3077 Ϸ HLA-DPB1 ޑ rs9277535) നᡉ๱ޑൂ

ਡ㧿ለӭ׎܄ϐ࣬ᜢ܄ܭኧঁεࠠޑВҁǵύ୯Ϸੀ୯Γύ೏᛾ჴ (An et al.

2011; Guo et al. 2011; Kamatani et al. 2009; Li et al. 2011; Wang et al. 2011)Ƕ HLA-DPB1ޑ rs9277535 Ψᆶ୯Γᄌ܄ B ࠠطݹੰ஻ޑੰࢥ߄य़לচԾฅమନԖ

࣬ᜢ(Cheng et al. 2013)ǶܴᡉޑǴӧ HLA-DPA1 rs3077 Ϸ HLA-DPB1 rs9277535 ޑ A alleles ᡉ๱ޑᆶफ़եᕇள B ࠠطݹགࢉϐ॥ᓀԖᜢᖄǶᗨฅӵԜǴൔ֋ࡰ

ޣޑᇸࡋطݹԖᜢǶ೭΋ࠠჹଽ୷Ӣόӕܭੰࢥ࡭ុགࢉ܈ੰࢥమନޑჹଽ୷Ӣ (HLA DRB1*0403Ǵ*1302 ک *0901Ǵբޣ҂ว߄ޑၗ਑)ǴѬ߄ܴΑӧ B طੰࢥ ག ࢉ ޑ Ӛ ᅿ ᖏ ׉ ߄ ౜ ޑ HLA ჹ ଽ ୷ Ӣ ޑ ό ӕ ف Յ Ƕ а ۳ ޑ ࣴ ز ᡉ Ң HLA-DRB1*1101ᆶԾज़܄ C طੰࢥགࢉکᄌ܄ C طޑᇸࡋطݹԖ࣬ᜢ (Cramp et al. 1998; Thursz et al. 1999)Ƕ᠙ܭ܌Ԗޑ᛾ᏵǴHLA-DRB1*1101 ёᆶ B طک C طੰࢥགࢉޑஎЬխࣝߥៈख़ࡋطݹ࣬ᜢᖄǶӧ 400 Ӝ҅தᅇ௼Γύว౜ 35 Ӝ (8.8%) ஥Ԗ HLA-DRB1*1101 (բޣ҂ว߄ޑၗ਑)ǴԜ໨ࣴزว౜ 204 Ӝ B طੰ

ࢥ஥চޣύԖ 37 Ӝ (18.1%) ஥Ԗ HLA-DRB1*1101 (p=0.001)Ǵ೭߄ܴឫ஥

HLA-DRB1*1101ޑঁΓ׳ܰܭวғ࡭ុ܄ B طੰࢥགࢉǴԶ೭٤࡭ុ܄ B طག

ࢉޣޑت܄ӭࢂߏය੯ੰᛙۓϐ஻ޣǶ

൩ӵךॺ܌ଷ೛ޑǴHLA-DRB1*1101 ᆶᇸࡋطݹޑ࣬ᜢ܄ѝӧت܄ B طੰ

ࢥ஥চޣύว౜Ƕ೭ঁჹଽ୷Ӣޑᓎ౗Ψӧζ܄஥চޣٿಔੰ஻ύϩ݋Ǵՠࢂ҂

ӧ೭٤ᄌ܄ B طੰࢥ஥চޣύǴٗ٤Ոమ ALT ॶεܭ҅தॶ΢ज़ٿ७ޣޑ ѳ֡ԃइၨᇸǶ೭΋ว౜ёૈࢂӢࣁᆶ ALT λܭ҅தॶ΢ज़ٿ७ޣ࣬КǴ߻ޣ ޑ e לচ໚܄Кٯ (38% vs. 29%) ၨଯԖᜢǴ೭߄ܴࡕޣεӭኧ஥চޣࢂӧੰࢥ եፄᇙ໘ࢤǶൔ֋Ψࡰрӧեፄᇙ໘ࢤޑ஥চޣ೯தԃइၨεǴe לচࣁ഍܄а Ϸ ALT ॶ҅த (Chu 2000)Ƕ

ම࿶Ԗൔ֋ࡰр HLA-DRB1*1101/1104 ᆶჹᄌ܄ B طԖܢל܄Ԗᜢೱ (Jiang et al. 2003)ǶฅԶǴӧ೭ঁа۳ޑࣴزύǴ࡚܄کᄌ܄ B طޑບᘐ኱ྗؒ

Ԗ೏ܴዴޑۓကǶԜѦǴѬ໻х֖Ͽኧޑ஻ޣԶЪൂᐱޑ DRB1*1101 ჹଽ୷Ӣ ᆶᄌ܄ B طคᡉ๱ϐᜢೱǶќ΋໨ࣴزჹଯу઩ΓᡉҢჹ߄य़לচࣝभԖϸᔈ ޑΓځ஥ DRB1*11 ޑᓎ౗ቚу (Hohler et al. 1998)Ƕ೭໨ࣴزલЮჹܭ DRB1 ޑԛϩࠠԶज़ڋΑځჹଽ୷Ӣޑ੝౦܄Ƕόӕჹଽ୷Ӣޑԛϩࠠᆶόӕޑᖏ׉߄

ᝄख़ࡋޑж౛኱૶ǴԜ ALT ॶගٮΑख़ፄෳໆޑёૈ܄Ƕ

ӧᏱԖ HLA-DRB1*1101 ޑت܄஥চޣύǴALT λܭ 80U/L Ϸεܭ܈฻ܭ 80U/Lٿಔύ B طੰࢥ୷Ӣࠠϐϩթ࣬՟ǶӢԜǴᏱԖ DRB1*1101 ޑت܄ B ط

ၗ਑৤ύפډǶฅԶǴ೭٤ၗ਑৤ϝฅࢂόֹ᏾ޑǴ٠Ъଞჹ੝ۓޑ୷ӢǴѸ໪

Uitterlinden ฻Γᘉк VDR ୷Ӣޑკ᛼ (Uitterlinden et al. 2004)Ǵࡌҥ΋ঁ

ଯှ݋ࡋՏܭࢉՅᡏ 12q13 ୔ୱޑ VDR ୷Ӣკ᛼Ƕ೭٤ࣴزޣᔈҔᄇۭϐϩ݋ (Faraco et al. 1989)ǴBsmI (Morrison et al. 1992)ǴTaqI (Morrison et al. 1994) ӧ VDR

୷Ӣޑ 3’҃ᆄ܌ว౜ޑज़ڋ܄Тࢤߏࡋӭࠠ܄ (RFLPs)Ƕ൨פ୷Ӣӭ׎܄ޑ΋ঁ

ᙁൂޑБݤࢂӧ΋٤όӕঁᡏύुр VDR ׇӈ࣬ӕ೽Տϐᡵ୷ଛჹׇӈǶҗܭ ԃសک܄ձࢂቹៜᄌ܄ B ࠠطݹੰࢥགࢉޣޑᖏ׉߄ࠠکႣࡕޑٿঁख़ाӢન

(Chu 2000; Chu and Liaw 2007a; Chu and Liaw 2007b; Chu et al. 2004)ǴӢԜǴҁࣴ

યΕՈమ ALT ॶ҅தаϷຬၸ҅த΢ज़ॶ 5 ७ޑ஻ޣǶӆޣǴа۳ޑࣴز่݀

ࠠ B/bǵB/BǵT/t ܈ൂᡏࠠ b/AǵB/aǵB/AǵB/TǵB/tǵA/tǵb/A/TǵB/a/TǵB/A/Tǵ B/A/tک b/A/t ޑ B ࠠطݹੰࢥ஥চޣΨᔈ၀ௗڙஏϪଓᙫޔډዴۓന٫ޑݯᕍ ਔᐒǶ

ҁࣴزעᆢғન D ڙᡏ୷Ӣӭ׎܄ᆶᆵ᡼ᄌ܄ B ࠠطݹੰࢥ஥চޣޑᖏ׉

ੰำೱௗଆٰǶ೭٤่݀Ѝ࡭΋ᅿଷ೛Ǵջংᒧ୷ӢԿϿӧ΋ۓำࡋ΢ቹៜ੯ੰ

຾৖ǴΨஒࢂׯ๓ᄌ܄ B ࠠطݹೀݯޑ΋ঁᜢᗖӢનǶӢԜǴ҂ٰሡჹ೭٤୷

Ӣӭ׎܄຾Չ຾΋؁ޑфૈ܄ࣴزǴаឍܴځϩηᐒڋǶ҅ӵᆢғન D ڙᡏ୷ Ӣӭ׎܄ᆶځд੯ੰϐ໔ޑ࣬ᜢ܄ࣴز܌ॊ (Valdivielso and Fernandez 2006)Ǵჹ ܭόӕᅿ௼Ǵᆢғન D ڙᡏ୷Ӣӭ׎܄ჹ B ࠠطݹੰࢥགࢉၸำޑቹៜΨёૈ

όӕǶ܌ᒏংᒧ୷ӢޑБݤǴӧፄᚇ܄ރޑᒪ໺ϩ݋΢ǴёаճҔೱᙹϩ݋ჹ୷ Ӣಔ຾Չཛྷ઩ (Risch and Merikangas 1996)Ƕךॺޑၗ਑٠ؒԖᡉҢ೭٤ᆢғન Dڙᡏ୷Ӣࠠϐ໔ޑೱᙹόѳᑽǴ೭ཀښ๱Ǵൂᡏࠠᜢᖄޑཀကӧܭჹଽ୷Ӣޑ

࣬ϕբҔ (allelic interaction)ǴԶόࢂೱᙹόѳᑽޑൂᡏࠠǶ

ᆢғન D ڙᡏ୷Ӣӭ׎܄ёૈᆶ B ࠠطݹੰࢥགࢉޑܰག܄࣬ᜢǴΨ൩ࢂ

ᇥǴᏱԖ B ࠠطݹੰࢥፄᇙ (HBeAg ໚܄) ࣬ᜢޑ୷Ӣࠠ܈ൂᡏࠠϐ஥চޣǴ

৒ܰགࢉ B ࠠطݹੰࢥǶ೭٤хࡴ୷Ӣࠠ B/bǵB/BǵT/t ܈ൂᡏࠠ b/AǵB/aǵ B/AǵB/TǵB/tǵA/tǵb/A/TǵB/a/Tǵ, B/A/TǵB/A/t ܈ b/A/tǶᏱԖ೭٤୷Ӣࠠ

܈ൂᡏࠠޑঁᡏࡐ৒ܰ೸ၸੰࢥፄᇙགࢉ B ࠠطݹੰࢥǶᏱԖ୷Ӣࠠ B/bǵൂᡏ (permutation test) լܺΑኬҁኧໆλޑज़ڋ (Potter 2005)Ƕ࿼ඤᔠۓࢂ΋ᅿค҆

ኧ಍ीБݤǴ೸ၸኳᔕჹڙ၂ޣख़ཥ௦ኬԶᕇள࿶ᡍ p ॶǶ၀ᔠۓҔܭ௓ڋӢኬ

ॶԖᜢᖄ (Pourgholami and Morris 2004)Ƕᆢғન D ᜪ՟ނ Seocalcitol ς೏Ҕܭ et al. 2004)ǶќѦǴBsm-Apa-Taq ൂኳԄᅿ (haplotype) baT ӧқᅿΓ 43%ǵ٥ࢪ Γ 75%ǵߚࢪΓ 26%Ǵhaplotype BAt ӧқᅿΓ 39%ǵ٥ࢪΓ 7%ǵߚࢪΓ 16%Ǵ Զ haplotype bAT ӧқᅿΓ 11%ǵ٥ࢪΓ 17%ǵߚࢪΓ 59% (Uitterlinden et al.

2004)Ƕࣁϙሶёа࣮ډ೭ኬޑৡ౦ګǻӧ΋૓௃ݩΠǴ܌Ԗӭ׎܄வँᡂޑว

2006)Ƕᆢғન D ڙᡏک 1,25(OH)2D₃ӧࡕϺխࣝޑբҔࢂКၨڀݾ᝼ޑǶғނ resistant rickets, HVDRR)Ǵᆶᓎᕷکᝄख़ޑགࢉԖᜢᖄ (Hayes et al. 2003)Ƕќ΋

Бय़Ǵಒ༾ޑӭ׎܄ӧڀԖى୼ޑ 1,25(OH)2D3 ӸӧΠ཮ቹៜխࣝϸᔈޑ੝܄

(Hayes et al. 2003)Ƕ

ӧҁࣴزύǴHBeAg ໚܄ޑ B ࠠطݹੰࢥ஥চޣܴᡉК HBeAg ഍܄ޣԃ Mocarski 2007)ǶԖ೚ӭᅿᜪޑڙᡏёаᒣᇡ PAMPǺᜪ៕ڙᡏ (TLR)ǹ่ӝਡ 㧿ለǴჲᆫ ϯᜪ่ᄬ ୱڙᡏ (nucleotide binding, oligomerization domain-like

receptors)ǹC ࠠᜪᏉ໣નڙᡏǹಒझ፦ᚈިޑ RNA (dsRNA) ک DNA (dsDNA) ޑ

қ୔ୱޑ߄౜཮׭ڋಒझჹυᘋન-alpha کυᘋન-gamma аϷᚈި RNA ޑϸᔈ (Foster et al. 1991)Ƕ

Ў᝘ӣ៝ᡉҢᜪ៕ڙᡏ-3 ёૈӧ B ࠠطݹੰࢥགࢉϐϸᔈ΢תᄽख़ाޑف

১ (Lai et al. 2011)Ƕ Lai et al. ว౜ੰࢥᚈި RNA ่ӝޑ B طੰࢥѦᓋೈқ H-cp183 (Porterfield et al. 2010)Ǵځх֖΋ঁ஥҅ႝ಻ޑӭᆒ਽ለ୔Ǵёаமਏ ޑቚ຾ᙖҗ poly (I:C)܈ੰࢥᚈި RNA ᇨᏤϐᜪ៕ڙᡏ-3 ૻ৲໺ሀ (Lai et al.

طݹ஻ޣǴдॺᜪ៕ڙᡏ-3 ϐ߄౜ໆ࣬ၨܭௗڙن኷լݯᕍޣԖ׳ِೲکᡉ๱ޑ

(Chew et al. 2012)Ƕυᘋનݯᕍคϸᔈ܈ൺวޑ஻ޣคݤࢲϯϷӣൺԾฅఠЋಒ झϷᡎኬᐋँಒझޑфૈǴ೭ёૈِೲޑफ़եᜪ៕ڙᡏ-3 ޑ߄౜ໆǶ طੰࢥ RNA (Hatakeyama et al. 2007)ǶӢࣁ entecavir ک lamivudine ѝբҔӧϸᙯ ᒵ؁ᡯǴcccDNA ᙯᒵޑ໘ࢤό཮೏೭٤ᛰނቹៜǶB طੰࢥ RNA ᗨฅ጗ᄌफ़ եǴࠅࢂ࡭ុޑӸӧϸࢀр cccDNA ϝฅӸӧط᠌ϣǴԶЪੰࢥፄᇙϐᐒڋϝฅ ࢲ៌ޑၮբύǶ೭ᆶϐ߻ൔᏤࢂ΋ठޑǴᡉҢط᠌ϣ cccDNA (Sung et al. 2005;

Yuen et al. 2005) کϸᔈطϣ cccDNA ޑՈమ cccDNA (Wong et al. 2004; Yuen et al.

2005)ǴёаႣෳ lamivudine ޑਏ݀ϷଶЗݯᕍਔੰࢥࢂցൺวޑ኱૶Ƕεໆޑ Bطੰࢥ RNA ࢂցٰԾܭطಒझύεໆޑ cccDNA ኳ݈܈வࢲ៌ޑᙯᒵ (܈ٿ ޣ) Ǵჴሞ΢ࢂ҂ޕޑǶ

Ոమ HBV RNA ӧᄌ܄ B ࠠطݹ஻ޣޑ੝ਸӸӧܭϐ߻ޑࣴزύς࿶೸ၸ ਡᗐਡለ䁙ޑբҔԶ೏ዴۓΑ (Hatakeyama et al. 2007)Ƕ೸ၸ଍ᙯᒵϸᔈࡕޑջ ਔ PCR ܌ᔠෳޑ HBV DNAǴਡᗐਡለ䁙բҔஒځफ़եԿচᔠෳॶޑ 1%

(Hatakeyama et al. 2007)ǶӧךॺޑࣴزύǴёᔠෳޑՈమ HBV RNA ӧਡ㧿ᜪ՟

ނݯᕍය໔࡭ុӸӧǴځύхࡴ lamivudine ک entecavir ޑݯᕍ (ಃ΋ಔ)Ǵՠӧ

࣬ᝩӝٳ lamivudine کυᘋનޑݯᕍ (ಃΒಔ) ΠளډΑ׭ڋǶջߡ஻ޣኧໆၨ

ϿǴٿಔϐ໔ޑৡ౦ϝΜϩܴᡉǴᡉҢΑυᘋનჹ HBV RNA ख़ाޑ׭ڋਏ݀Ƕ Ոమ HBV RNA ॶޑΠफ़ό໻໻ࢂ lamivudine ଶҔޑ่݀ǴӢࣁӧಃΟಔ஻ޣอ ය lamivudine ݯᕍଶЗࡕǴՈమ HBV RNA ϝёᔠෳډǶӧӃௗڙ lamivudine ݯ ᕍฅࡕᙯࣁ໺಍υᘋનݯᕍکӃௗڙ໺಍υᘋનݯᕍฅࡕᙯࣁ lamivudine ݯᕍ ޑ஻ޣύ೿р౜ΑՈమ HBV RNA ޑ׭ڋǶӧࡕ΋ᜪ஻ޣύǴՈమ HBV RNA ޑ

׭ڋёૈࢂӢࣁυᘋનޑۯࡕᕍਏǶ

൳ঁϐ߻ޑࣴز᛾ܴΑӝٳ lamivudine کυᘋનޑݯᕍК lamivudine ൂ΋ݯ ᕍޑਏ݀ाӳǶӧҁࣴزύǴυᘋનჹௗڙ lamivudine ݯᕍޑ஻ޣՈమ HBV RNA ޑ׭ڋਏ݀Ψ೚ёаှញࣁϙሶ೭٤஻ޣКௗڙ lamivudine ൂ΋ݯᕍޣԖ׳ଯ ਏࠠυᘋન (pegylated interferon) ӝٳ lamivudine ݯᕍޑ஻ޣΨёа׭ڋՈమ HBV RNAॶǶӧ೭ΟՏ஻ޣύǴՈమ HBV RNA ॶӧӕਔӝٳݯᕍޑ 12 Կ 24

ຼ໒ۈϲଯǴԶӧݯᕍޑ 48 Կ 72 ຼ൩ᔠෳόډ (Huang et al.Ǵ҂ว߄ޑၗ਑)Ƕ

ӧௗڙਡ㧿ᜪ՟ނݯᕍޑ஻ޣύՈమ HBV RNA ޑёୀෳ܄ёаவ B ࠠط ݹੰࢥ-ᙯ౽གࢉޑ HepG2.2.15 ಒझਲ਼ᕇளᡏѦၗ਑ٰှញǶ΋໨ࣴزᡉҢ࿶ၸ lamivudineکځдਡ㧿ᜪ՟ނݯᕍࡕǴӧಒझྋှނύ B ࠠطݹੰࢥ੝ۓޑ RNA

ؒԖ෧Ͽ (Doong et al. 1991)Ƕ ךॺ҂ว߄ޑၗ਑ΨᡉҢǴਡ㧿ᜪ՟ނݯᕍಃ 4 ϺଆԿ܌Ԗಒझ೿ԝΫޑಃ 17 ϺǴ΢మన࡭ុ܄ёаᔠෳډ HBV RNA (Huang et al.Ǵ҂ว߄ޑၗ਑)Ƕ Lamivudine کځдਡ㧿ᜪ՟ނؒԖቹៜډֹ᏾ޑ (integrated) HBV DNAǴHBV RNA ೏ᇡࣁࢂவ integrated HBV DNA ᙯᒵԶٰ (Doong et al.

1991)Ƕሡा຾΋؁ࣴزаຑ՗ߏයਡ 㧿ᜪ՟ނݯᕍჹܭՈమHBV RNA ޑਏ݀Ƕ υᘋન-alpha ჹܭՈమ HBV RNA ޑ׭ڋբҔёа೸ၸϐ߻ӧ୷Ӣᙯ෗Ⴕ΢

ޑࣴزளډЍ࡭Ƕ೯ၸݙ৔ൂ΋Ꮚໆυᘋન-alpha/beta ᇨᏤނᆫԼ㧿ለ-ᆫझ㧿ለ (polyinosinic-polycytidylic acidǹpoly I:C ࣁᜪ៕ڙᡏ-3 ଛՏᡏ)Ǵطϣ B ࠠطݹੰ

ࢥፄᇙޑύ໔ౢނ೏మନΑ(McClary et al. 2000)ǶᏵଷ೛Ǵυᘋનޑᐒᙯх֖ B

ࠠطݹੰࢥғڮຼයύᙯᒵࡕޑ؁ᡯǴ܌аطϣ B ࠠطݹੰࢥፄᇙޑύ໔ౢނ

೏మନǴԶᛙۓރᄊޑ HBV RNA ϣ৒҂ڙቹៜ (McClary et al. 2000)Ƕӕ΋ಔ

ࣴزΓ঩຾΋؁᛾ܴǴυᘋન-alpha/beta ޑ׭ڋਏ݀ࢂӧϣ֖߻୷Ӣಔ RNA ޑ Ѧᓋᡏ໘ࢤǴբҔܭߦ຾ځफ़ှ܈ߔЗځᆫӝ (Wieland et al. 2000)Ƕυᘋનёа ޔௗ׭ڋ B ࠠطݹੰࢥӝԋ܈೸ၸಒझխࣝϸᔈբҔܭ B ࠠطݹੰࢥགࢉޑط ಒझ (Thomas et al. 2003)Ƕаυᘋન-beta کυᘋન-gamma ׭ڋ B ࠠطݹੰࢥӧ

୷Ӣᙯ෗Ⴕޑόԝϐطಒझਲ਼΢ዴᇡΑߚಒझࢥ܄׭ڋޑၡ৩ (Pasquetto et al.

2002)Ƕ೭ᅿ׭ڋё೸ၸ 2’,5’-եᆫᑗဏ❥ᩫӝԋ䁙 (oligoadenyl synthetase) / RNAse L ၡ৩຾ՉբҔ (Lengyel 1981)ǶυᘋનёᇨᏤԜӭ䁙ၡ৩Ǵ၀ၡ৩хࡴ

եᆫᑗဏ❥ᩫӝԋ䁙ǵϣϪਡᑗਡለ䁙 (endoribonuclease) RNAse L ک 2’,5’-եᆫᑗဏ❥ᩫᕗለΒ✊䁙 (oligoadenyl phosphodiesterase)Ƕ೭٤䁙ύǴRNAse L

౛ፕ΢ё೯ၸ΋ঁ RNA ύ໔؁ᡯ׭ڋ܌Ԗੰࢥޑፄᇙ (Thomas et al. 2003)ǶԶ ЪǴԜਡᗐਡለ 䁙 (ribonuclease) ޑ௴୏೏ຎࣁυᘋન׭ڋੰࢥፄᇙޑЬा୏Κ (Lengyel 1981)Ƕ

ӧҞ߻ޑࣴزύǴךॺჹՈమ HBV DNA ک RNA ຾ՉᓎᕷޑᔠෳǴӧࢌ٤

௃ݩύၲډ؂ٿຼ΋ԛǴаዴۓӧൂ΋ݯᕍ܈ӝٳݯᕍύՈమ HBV DNA ک RNA ޑೱុᡂϯǶךॺޑၗ਑ᡉҢǴௗڙ entecavir ݯᕍޑՈమ HBV RNA നଯॶܴ

ᡉଯܭௗڙ lamivudine ޣ (8.6 ± 1.0 ࣬ၨܭ 5.6 ± 1.0ǹp ɦ 0.001)Ƕ࣬ӕޑǴௗ

ڙ entecavir ݯᕍ஻ޣޑՈమ HBV RNA ޑёᔠෳ܄ᖿӛܭଯၸௗڙ lamivudine ޣ (100% ࣬ၨܭ 71%ǹp = 0.48)Ƕ೭٤ว౜ᇥܴǴՈమ HBV RNA ॶёϸࢀਡ 㧿ᜪ՟ނޑלੰࢥਏΚ (Huang et al. 2009)Ƕՠᗋሡा຾΋؁ޑࣴزаឍܴ೭Ԗ ཀࡘΨࢂख़ाޑ᝼ᚒǶ

ᗨฅԖ΋໨ࣴز߄Ң HBV RNA ӧௗڙ lamivudine ݯᕍ߻ޑ 24 Ӝ஻ޣޑՈ మᔠᡏύёаᔠෳډ(Rokuhara et al. 2006)ǴՠԜᔠෳ౗٠҂၁ಒᇥܴǶځጧᑗᐚ ࡋఊࡋϩભࣴز (sucrose density gradient fractionation studies) ޑ่݀߄ܴӧ໒ ۈݯᕍਔǴа֖Ԗ HBV DNA ޑੰࢥಈηࣁЬǴԶӧݯᕍࡕಃ 1 Ϸಃ 2 ঁДǴ֖

Ԗ HBV RNA ޑੰࢥಈηᡂளၨᡉ๱ǶдॺΨӕኬ߄ܴǴӧؒԖݯᕍޑ௃׎ΠǴ

֖Ԗ HBV RNA ޑੰࢥಈη໻эᕴ B ࠠطݹੰࢥಈηޑ 1%ǶՠࢂǴ೭٤੝ਸޑ ಈηӧ lamivudine ޑݯᕍύᡂࣁЬाޑ೽ϩ (Zhang et al. 2003)ǶдॺӢԜᕴ่

рǴӧ҂٬Ҕ lamivudine ݯᕍޑ஻ޣύǴHBV RNA ಈηޑӸӧ՟Я՞ B ࠠطݹ

๏ᛰࡕёаᔠෳளډǶԜѦǴࣴزว౜ӧ lamivudine ݯᕍය໔ǴՈమ HBV DNA ॶК HBV RNA ॶΠफ़׳ࣁܴᡉ (Rokuhara et al. 2006)Ǵ೭ΨޭۓΑךॺޑว౜Ƕ

ӧಃΟಔ஻ޣௗڙอය lamivudine ݯᕍύᘐࡕǴՈమ HBV RNA ϝฅࢂёа ᔠෳளډǶ೭ঁว౜ᡉҢǴᗨฅཥ֖Ԗ HBV RNA ੰࢥಈηޣӧ lamivudine ଶҔ ࡕόӆౢғǴՠࢂӧ lamivudine ݯᕍය໔֖Ԗ HBV RNA ޑੰࢥಈη٠ؒԖِೲ

ޑ೏ϩှǶ΢ॊϐࣴزΨ߄ܴǴӧ lamivudine ݯᕍය໔ǴՈమ HBV DNA К RNA Πफ़׳ܴᡉ (Rokuhara et al. 2006)ǴΨޭۓΑךॺޑว౜ǴᡉҢਡ㧿ᜪ՟ނჹܭ Ոమ֖Ԗ HBV RNA ੰࢥಈηϐ׭ڋਏ݀ό٫ǶόၸǴᗋࢂሡा຾΋؁ޑࣴزа

᛾ܴ֖Ԗ HBV RNA ϐੰࢥಈηӧՈమύஒӸӧӭߏޑਔ໔Ƕ

Lamivudineک໺಍υᘋનޑ࣬ᝩӝٳݯᕍࡕǴՈమ HBV DNA ॶफ़եǴՠޔ ډݯᕍ่״ਔϝฅёаӧ܌Ԗ஻ޣύᔠෳளډǶ࣬ϸޑǴՈమ HBV RNA ڙډ׭

ڋǴ٠ӧݯᕍ่״ਔᔠෳόډΑǶՈమ HBV DNA ޑ࡭ុӸӧࢂҗܭਡ㧿ᜪ՟ނ ݯᕍޑಖЗǴӢԜǴલϿΑᛰނ࡭ុ׭ڋޑਏ݀Ƕᙯඤԋυᘋનݯᕍ٬Ոమ HBV RNA ளډ׭ڋǴՠυᘋનჹ HBV DNA ޑ׭ڋਏ݀όӵਡ㧿ᜪ՟ނԖਏ (Dienstag 2008)ǶᗨฅؒԖಒझϣ RNA ک DNA чБکࠄБᚇҬޑၗ਑Ǵךॺک ځдΓޑࣴز೿ޭۓΑᔠෳډՈమ HBV RNA ޑёૈ܄Ƕ

ᄌ܄ B ࠠطݹ஻ޣௗڙਡ㧿ᜪ՟ނݯᕍύǴB طੰࢥኧໆаᙯᒵፓှᘉቚᆶ ᚇҬߥៈϩ݋ݤ (Transcription-mediated amplification and hybridization protection assay, TMA-HPA) ᔠෳکа Amplicor B ࠠطݹੰࢥᅱຎෳۓ (HBV Monitor test)Ǵ܌ෳளޑ่݀ό΋ठǴࢂӢࣁ TMA-HPA ٬Ҕ T7 RNA ᆫӝ䁙຾Չ RNA ᙯᒵϷᘉቚᙯᒵౢނ (Kamisango et al. 1999)ǴӢԜӕਔᔠෳ B طੰࢥ DNA ᆶ B طੰࢥ RNA ٿޣǶᙖҗჴਔϸᙯᒵᆫӝ䁙ೱᙹϸᔈ܌ୀෳډޑ B طੰࢥਡለ࣬

՟ܭᙖҗ TMA-HPA ܌ୀෳޑ (Hatakeyama et al. 2007)Ƕ܌аǴٿঁБݤϐ໔ޑ

ෳໆৡ౦ёૈࢂҗܭӸӧεໆޑ B طੰࢥ RNAǶӸӧεໆޑ B طੰࢥ RNA ё

΋ঁჹኧޑৡ౦ǹԜᢀჸ߄ܴՈమύᄒอޑ B طੰࢥ RNA ӧךॺࣴزύቹៜཱུ

λǶ

ᕴԶقϐǴυᘋનёа׭ڋ lamivudine ݯᕍਔ܌ୀෳډޑՈమ HBV RNAǶ Ոమ HBV RNA ޑ࡭ុӸӧࢂӢࣁ HBV RNA ፄᇙύ໔ౢނ҂ڙ׭ڋޑ่݀Ǵ೭ ёૈᏤठਡ㧿ᜪ՟ނޑݯᕍѸ໪ߏΦ܈คज़යǶ࣬ϸޑǴυᘋનჹ HBV RNA ፄ ᇙύ໔ౢނޑ׭ڋёауமਡ㧿ᜪ՟ނ׭ڋ B ࠠطݹੰࢥፄᇙϐਏ݀Ƕ

৖

৖ఈ

ಃ΃ക խࣝᒪ໺Ӣη HLA-DRB1 ӭ׎܄ᆶت܄ᄌ܄ B ࠠطݹޑطݹᝄख़ำࡋ ϐ࣬ᜢ܄

Ҟ߻൳Я܌ԖΓᜪқՈౚלচӭ׎܄ϐൔ֋Ǵхࡴӄ୷Ӣಔᜢᖄ܄ࣴز (Genome Wide Association Study, GWAS)Ǵ೿ࡰрځᆶ࡚܄ය B ࠠطݹੰࢥϐమ ନ܈࡭ុགࢉϐ࣬ᜢ܄Ƕᖏ׉΢ख़ाޑୢᚒࢂব٤ᄌ܄ B ࠠطݹੰ஻ԖКၨᓎ ᕷޑطݹǴ٠ЪКၨ৒ܰ຾৖ډطฯϯϷطᕎǴӢԶሡाКၨஏϪޑଓᙫǴຑ՗

ݯᕍޑਔᐒǶGWAS ܌ว౜ޑൂਡ㧿ለӭ׎܄ (SNPs) ᆶᄌ܄ B طϐطݹᝄख़ ࡋ٠คᡉ๱ޑ࣬ᜢ (Vermehren et al. 2012)Ƕ܌аǴGWAS ܌ளޑ่݀คݤၮҔ ӧᖏ׉΢аႣ՗ᄌ܄ B طੰ஻ޑଓᙫᓎ౗܈Ⴃෳ஻ޣݯᕍޑଆۈਔ໔Ϸݯᕍሡ

؃ǶךॺޑࣴزዴᇡΓᜪқՈౚלচ-DRB1 ӭ׎܄ᆶᄌ܄ B طϐطݹᝄख़ࡋԖ

࣬ᜢǶΑှቹៜᄌ܄ B ࠠطݹᖏ׉߄౜ϷႣࡕϐխࣝᒪ໺ӢηǴஒԖշܭुр ᖏ׉΢ჴҔǵԖਏϷ಄ӝ࿶ᔮਏ੻ϐଓᙫϷݯᕍࡹ฼Ƕ!

HLA-DRB1*11Ϸ DQB1*0301 ჹ C طੰࢥགࢉԖߥៈ܄ǴԶЪᆶᄌ܄ B ࠠ طݹགࢉΨԖ࣬ᜢǶ೭ٿঁჹଽ୷Ӣჹ B ࠠϷ C ࠠطݹੰࢥགࢉޑόӕቹៜё

ૈ ࢂ Ӣ ࣁ ੰ ࢥ ੝ ۓ ܄ ל চ և ౜ ޑ ᡂ ౦ Ǵ ຾ Զ Ї ଆ խ ࣝ ϸ ᔈ ޑ ৡ ౦ Ƕ ࣴ ز HLA-DRB1*11మନ C ࠠطݹੰࢥ࣬ᜢޑϩηᐒᙯஒჹԜჹଽ୷ӢԖ׳ుΕӦΑ

ှǶว᝺ HLA-DRB1*11 ज़ۓϐ CD8+ಒझޑ C ࠠطݹੰࢥלচ߄Տ (epitope) ஒ ёаפр܈೛ी B ࠠطݹੰࢥ࣬՟ޑ੝ۓ܄לচ߄ՏǶࣴزխࣝᡉ܄ޑלচ߄ Տёаפр HLA ज़ۓޑ੝ۓ܄և౜Ǵ຾Զว৖ HLA ੝ۓ܄ࣝभϷаᴏ两ࣁ୷ ᘵޑխࣝݯᕍǶ

ന߈ൔ֋ࡰрచҹԄଛՏᡏ (conditional ligands)Ǵёаεໆౢрಃ΋ࠠ HLA

ၗ਑৤ (libraries)ǴԜ HLA ၗ਑৤և౜࿶ၸঅႬޑᴏ两 (Chang et al. 2013)Ƕा

ᅱෳಒझխࣝϸᔈሡाှ໒Ѭॺޑ౦፦܄ (heterogeneity)Ǵ೭ࢂӚᅿບᘐکݯᕍ ᔈҔޑ୷ᘵǶచҹԄଛՏᡏࢂ่ӝ MHC ࣁ୷ᘵޑӭᆫᡏତӈ (MHC-based multimer arrays) ϐ٬Ҕᆶלচ੝ۓ܄ T ಒझ࿶ၸεໆౢрϐࢬԄಒझሺϩ݋Ǵ ӢࣁѬॺϢ೚೸ၸᴏ两ҬඤБݤזೲӝԋᐱ੝ޑ MHC ϩηǶ׳ׯ੝ۓ܄ϐ HLA Ѥᆫᡏ (tetramers) ёаୀෳלচ੝౦ϐ CD8+ T ಒझჹܭ B ࠠطݹੰࢥϐϸ ᔈǶεӭኧޑלচ੝ۓޑ T ಒझϸᔈǴ࣬ၨܭ౜Չޑלচ،ۓ೽ՏႣෳݤǴ׳

৒ܰޑ೏คୃـϐว౜БݤୀෳрǶԜמೌࢂցёаၮҔӧಃΒࠠΓᜪқՈౚל চ΢ᗋሡ຾΋؁ࣴزǶ

ΓᜪқՈౚלচ཮ቹៜډஎЬჹੰࢥགࢉࡕϐ੯ੰ߄౜ǶੰࢥӧགࢉΓᡏϐ ࡕΨ཮ჹஎЬխࣝϸᔈౢғቹៜǴࣗԿჹஎЬխࣝᒪ໺Ӣηౢғਏ݀Ƕ൩ӵൔ֋

ࡰр൳Я܌Ԗޑੰࢥགࢉ೿Їวಃ΋ࠠυᘋનޑғౢǴ೸ၸಒझϣೈқፓှځל

ੰࢥࢲ܄Ǵ٠Ъ׭ڋᙯ᝿Ϸፓ࿯ΓᜪқՈౚלচ (Stark et al. 1998)ǶӢԜǴஎЬ խࣝᒪ໺ᆶੰࢥགࢉԖ๱࣬ϕբҔޑቹៜǴ೭Ψ೷ԋόӕᅿ௼ᆶӦ୔ჹܭӚᅿੰ

ࢥགࢉԖόӕޑܰག܄کܢל܄Ƕ

எЬᆶੰࢥϐҬϕբҔ܌ౢғޑᄌ܄ੰࢥ܄གࢉǴ٩ᒘಒझ܄խࣝϸᔈǴࡕ ޣڙஎЬ HLA ᜪࠠک HLA ज़ۓޑੰࢥँᡂಥ଒ϐፓ࿯ǶԖᜢ CD8 לচ߄Տ (epitope) ܈Ծฅࢥఠಒझӧόӕᅿ௼ύঁᡏᄌ܄གࢉޑୖᆶǴϷځ HLA ᜢᖄ܄

ᗋሡ׳ӭࣴزǶHLA ᆶ੯ੰႣࡕޑᜢᖄ܄ၗ਑ගٮΑ೛ीஎЬ੝ۓ܄ݯᕍ฼ౣ

คज़ޑ׆ఈǶᄌ܄ B ࠠطݹϐ HLA ࠠᄊёૈቹៜ᏾ᡏޑ T ಒझϸᔈϷځϸᔈޑ ໘ቫ (Singh et al. 2007)Ƕ҂ٰ HLA ϐࣴزБӛхࡴڐբ܄ޑϩ݋൳ঁஎЬխࣝ

ፓ࿯୷Ӣӵ T ಒझфૈϐᡂ౦Ƕ

ಃ

ಃΒക ᆢғન D խࣝڙᡏ୷Ӣӭ׎܄ᆶᄌ܄ B طޑطݹ࡚܄วբǵe לচ௃

ݩаϷطಒझᕎౢғϐ࣬ᜢ܄

җܭೈқ፦ׇӈޑᡂ౦ёૈ཮ᏤठᄒฅόӕޑфૈϷਏ݀ǴٯӵଛՏᡏޑᒃ

Bsm-Apa-Taq ൂኳԄᅿ (haplotype) ೭٤኱૶ൂኳԄᅿ (marker haplotypes) ϐᓎ౗ӧᅿ௼ϐ໔ߚதόӕǶ኱૶ൂኳԄᅿཀࡰ֖Ԗߚфૈ܄ϐӭ׎܄ࢂځдՏ

࿼੿҅фૈ܄ჹଽ୷Ӣ (allele) ޑ኱૶Ƕ׳ख़ाޑࢂǴᆶঁձൂኳԄᅿ࣬ᜢᖄޑ

੝ۓჹଽ୷ӢࡐёૈߚதόӕǶٯӵǴࢌൂኳԄᅿ೏ว౜ᆶ٥ࢪΓаϷߚࢪΓ࣬

ᜢᖄǴ೭ёૈࢂӢࣁᆶ΋ঁֹӄόӕޑфૈ܄ჹଽ୷Ӣϐೱᙹ (linkage) ᜢ߯Ƕ ќѦ΋ঁٯηǴӵ݀΋ঁ኱૶ൂኳԄᅿ (marker haplotype) ϐᜢᖄࢂӧ٥ࢪΓ೏

ว౜ԶؒԖӧқᅿΓύว౜Ǵ೭ঁှញࢂӢࣁ኱૶ᆶфૈ܄ჹଽ୷Ӣϐ໔ޑೱᙹ όѳᑽӧᅿ௼ϐ໔ࢂόӕޑǶ೭຾΋؁மፓѸ໪ࡌᄬόӕᅿ௼ϐᐉၠᆢғન D ڙᡏޑൂኳԄᅿკ᛼ (haplotype map)Ƕ

ςޕᆢғન D ڙᡏ୷Ӣޑ 3ȷᆄ UTR ୖᆶ୷Ӣ߄౜ޑፓ࿯Ǵ੝ձࢂ೸ၸ mRNAᛙۓ܄ޑፓ࿯ǶMorrison ฻Γ᛾ჴٿঁ 3ȷᆄ UTR ᡂ౦ϐ୔ձ܄ᑻӀન ࢲ܄ (differential luciferase activity) ࣬ೱܭ ٿঁനதـޑ haplotypes Ǵ൩ࢂ

ȸbaTȹϷȸBAtȹ(Morrison et al. 1994)ǶDurrin ฻Γ৖Ң UTR ύޑ੝ۓ೽ՏǴ ᆀࣁѐᛙۓ೽ҽ (destabilizing elements)Ǵୖᆶ،ۓᆢғન D ڙᡏ-mRNA ϐᛙۓ ࡋ (Durrin et al. 1999)ǶᗨฅӵԜǴдॺؒԖว౜ٗ΋ঁᆶ UTR ೱ่ޑȸbaTȹ

܈ȸBAtȹhaplotypeǴԶคݤ٩ mRNA ϐᛙۓࡋ୔ϩ (Durrin et al. 1999)ǶӢ๱

ςޕ 3ȷᆄ UTR ৖Ң੝ۓಒझࠠᄊ (cell-type-specific) ჹܭ mRNA ᛙۓࡋϐቹ

ѬϐཀကϷወӧᖏ׉ၮҔࢂߚதख़ाޑǶ

AmpligenǴΓ೷ኳᔕᜪ៕ڙᡏ-3 ޑᐟࢲᏊ poly(IǺC)Ǵӧ HIV ݯᕍ΢ς೏௖

઩ (Gowen et al. 2007)Ƕᖏ׉߻ࣴزᡉҢǴpoly(IǺC) ќ΋ᅿ़ғނǴpoly ICLC

(Polyinosinic – Polycytidylic Acid stabilized with Polylysine and ӕբҔޑख़ा܄аගٮלੰࢥխࣝϸᔈ(Sorensen et al. 2008)Ƕдॺว౜Ǵ୷Ӣক ନλႵӧჹל HSV-2 ϐխࣝϸᔈሡाᜪ៕ڙᡏ-2 کᜪ៕ڙᡏ-9 ӅӕբҔǶӧᜪ (Zucchini et al. 2008)ǶӧځдੰࢥགࢉޑٯηΨࡐᡉฅޑᡉҢᜪ៕ڙᡏᆶځд

PRRs ޑڐӕբҔаගٮלੰࢥϐխࣝϸᔈǶׯؼࡕϐФรੰࢥӼь܎ਲ਼

(Modified Vaccinia Ankara, MVA) ࢂҞ߻҅ӧ໒วٛݯ HIV/AIDS ޑࣝभၩᡏǴ ٠ЪӃϺխࣝୀෳ೭ᅿੰࢥࢂаᜪ៕ڙᡏ-2/-6ǵ໵Յનዦϩϯ࣬ᜢ୷Ӣ-5 (MDA-5) ک NALP3 วݹᡏϐፓ௓ (Delaloye et al. 2009)Ƕךॺࣴزޑଅ᝘ӧܭ ᡉҢᜪ៕ڙᡏ-3 ࢂᄌ܄ B ࠠطݹགࢉޑኳԄ᛽ձڙᡏϐ΋Ǵ҂ٰሡाࡕុ୷ᘵ Ϸᖏ׉ϐࣴزаዴᇡځдኳԄ᛽ձڙᡏӧᄌ܄ B ࠠطݹϐفՅǶ

୏ނޑ B ࠠطݹੰࢥӧགࢉϐന߃යǴੰࢥ٠ؒԖډၲط᠌ǴԶࢂ੮ӧځ дᏔ۔ǶβኘႵϐ B طੰࢥޑᕵӛϩ݋ᡉҢགࢉന߃ޑՏ࿼όӧط᠌ǴԶࢂӧ ମᡎ (Coffin and Michalak 1999)ǶՠࢂǴКଆΓᜪޑ B طੰࢥǴβኘႵ B طੰࢥ ޑరЃڗӛࢂКၨᡉ๱ǵቶݱϷ׳Ԗੰ౛Ꮲ΢ޑख़ा܄ (Coffin and Michalak 1999; Lew and Michalak 2001)Ƕᓥηϐ B طੰࢥന߃ӧط᠌ϣҜಒझ΢ёૈ೏ᗦ

(interferon-gamma inducible protein-10) ёаႣෳᕍਏ (Sonneveld et al. 2013)Ƕך ॺࣴزޑଅ᝘ӧܭዴᇡυᘋનݯᕍԋфԖਏࡠൺᜪ៕ڙᡏ-3 ϐ߄౜ໆǴԶЪࢂӧ ۓǶ൩ӵǴᜪ៕ڙᡏ-3 ӧΓᜪف፦ϯಒझǴගٮФรੰࢥ (Vaccinia Virus, VACV) གࢉਔޑߥៈ܄խࣝ (Howell et al. 2006)Ƕ౜ӧΨว౜ԿϿჹܭ΋٤ੰࢥགࢉޑ խࣝϸᔈሡा೚ӭኳԄ᛽ձڙᡏޑୖᆶǶ܌Ԗ೭٤ૻ৲ӵՖӧԾฅགࢉਔ೏ᆕӝ

ࢂ҂ޕޑǶ൩ᜪ៕ڙᡏૻ৲໺ሀٰᇥǴӧλႵکΓᜪޑख़ा୔ձς೏ᢀჸډǴӢ ԜǴᜪ៕ڙᡏޑݯᕍஒሡा׳ֹ᏾ޑ౛ှΓᜪس಍ (Bowie and Unterholzner 2008)Ƕҗܭᜪ៕ڙᡏёаፓ௓ੰࢥགࢉࡕԖ্ޑխࣝϸᔈǴᔈ຾΋؁ࣴزඟҢ

௓ڋᜪ៕ڙᡏૻ৲໺ሀၡ৩ϐᛰނ኱ޑǴаයׯ๓όӕੰࢥགࢉޑႣࡕǶࢌ٤ᛰ

ࠠޑυᘋનёа೏ᜪ៕ڙᡏ܈ᜪ RIG-I ှ௽䁙 (RIG-I-like helicases) ፓှϐૻ৲

໺ሀၡ৩ᇨวǶ΢ෞϐၡ৩Ӣ๱аΠٿঁόӕޑૻ৲Զౢғ୔ձ܄ǺTRIF ჹܭ

2000; Wieland et al. 2000)ǶB ࠠطݹੰࢥёૈςว৖рಥᚆஎЬന߃ޑלੰࢥᐒ ڋǴ೭ࢂҗᜪ៕ڙᡏ܈ځдኳԄ᛽ձڙᡏࢲϯޑǶᄌ܄ B ࠠطݹੰࢥགࢉޑ௃ ϐғౢ (Shin and Wherry 2007)ǶᗨฅςޕԜ૰ᆃวғϐ٣ჴǴՠࢂۘόమཱᇨ

Ꮴ೭ᅿфૈምᛖޑᐒڋǶӧ೭٤ಒझύǴ΋٤׭ڋ܄ڙᡏ՟Яڋۓ܄ޑ೏ፓϲǶ ಒझำׇ܄ԝΫ-1 (Programmed cell death-1, PD-1) ࢂ΋ঁ੝܄మཱޑ׭ڋ܄ڙ ᡏǴӧӚᅿࢲϯޑխࣝಒझύ߄౜Ǵхࡴӧ T ಒझύǴԶЪ PD-1 ᆶځଛՏᡏಒ झ ำ ׇ ܄ ԝ Ϋ ଛ Տ ᡏ -1 ܈ -2 (Programmed cell death ligand-1, PD-L1 ܈ Programmed cell death ligand-2, PD-L2) ϐ໔ޑҬϕբҔ׭ڋΑ T ಒझޑфૈ

(Barber et al. 2006)ǶB ࠠطݹϷځдੰࢥགࢉਔǴCD8+ T ಒझ࡭ុ܄߄౜ PD-1 (Rouse and Sehrawat 2010)Ƕࢥఠ T ಒझ࣬ᜢೈқ 4 (CTL-associated protein 4, CTLA-4) ࢂќ΋ঁڐӕ׭ڋޑڙᡏǴӧ B ࠠطݹϷځдੰࢥགࢉਔᆶ PD-1 ଛӝ բҔߦ٬ T ಒझ૰ᆃ (exhaustion) (Kaufmann et al. 2007ǹNeumann-Haefelin et al.

2006ǹSchurich et al. 2011)Ƕӧࢲϯޑ CD4+ T ಒझǴCTLA-4 ߄౜೏ፓϲǴ٠ᆶ CD80/CD86่ӝǴ٠Ъ೸ၸ෧Ͽ IL-2 ޑғౢکڋЗಒझຼය຾৖ٰ׭ڋ T ಒझ ޑࢲϯ (Kaufmann et al. 2007)ǶλႵޑࣴز᛾ܴǴӧੰࢥ੝ۓ܄CD8+ Tಒझ΢Ǵ

΋٤׭ڋ܄ڙᡏڋۓ܄ޑ೏ፓϲǴӵ 2B4ǵLAG-3 ک CD160 (Blackburn et al.

2009)ǶᡉฅӦǴಒझ૰ᆃޑຫᝄख़ǴѬॺ߄౜ຫӭޑ׭ڋϩηǶ೭٤ኧᏵ߄ܴǴ

RNAᗭಈޑӸӧᆶว৖ԋלᛰ܄ੰࢥԖᡉ๱࣬ᜢ (Hatakeyama et al. 2007)ǶԜว

౜ᡉҢ B طੰࢥ RNA ᗭಈޑӸӧёૈᆶ B طੰࢥፄᇙࢲ܄Ԗ࣬ᜢǴԖଯፄᇙࢲ

܄ޑੰࢥғౢεໆޑ B طੰࢥ RNAǶᖏ׉΢ǴB طੰࢥ RNA ёаႣෳਡ㧿ᜪ՟

ނݯᕍଶЗࡕੰࢥൺวޑ௃׎ (Tsuge et al. 2013)ǶќѦǴեՈమᐚࡋޑ B طੰ

ࢥ RNA ΨёаႣෳਡ㧿ᜪ՟ނݯᕍਔੰࢥԐය೏׭ڋޑϸᔈ (Huang et al.

2012c)ǶB طੰࢥ RNA ޑᖏ׉ཀကᗋሡ׳ӭޑࣴزٰว౜Ƕ

ᆶൂᐱਡ㧿ᜪ՟ނ࣬КǴυᘋનӝٳਡ㧿ᜪ՟ނԖ׳ӳޑݯᕍᕍਏ (Lau et al. 2005; Marcellin et al. 2004; Sarin et al. 2005)Ǵ೭ёૈᆶਡ㧿ᜪ՟ނԖਏ׭ڋੰ

ࢥϸᙯᒵၸำǴԶ֛ᑈϷϩݜԿՈమޑ HBV RNA ೏υᘋન׭ڋԖᜢǶਡ㧿ᜪ՟

ނӝٳߏਏࠠυᘋનݯᕍԖወΚԋࣁ҂ٰݯᕍᄌ܄ B ࠠطݹޑኳԄǶ!!

ፕ

ፕЎमЎᙁॊ (Summary)!

Hepatitis B virus (HBV, Family Hepadnaviridae, Genus Orthohepadnavirus)

infection is a global health problem. About 2 billion people in the world have been

infected by HBV, and 400 million of them are chronic carriers of the virus (Kao and

Chen 2002). Even in the United States where HBV infection is not endemic, an

estimated 1.25 million individuals are carriers of HBV (McQuillan et al. 1989). HBV

infection causes a wide spectrum of clinical manifestations, ranging from acute or

fulminant hepatitis to various forms of chronic liver diseases, including inactive

carrier states, chronic hepatitis, cirrhosis, and even hepatocellular carcinomas (Kao

and Chen 2002; Chen 1993).

The natural history of carriers of HBV who are infected early in life (i.e.

perinatal transmission) can be divided into four dynamic phases based on the

virus-host interaction: immune tolerance phase, immune clearance phase, integration

or low replication phase, and reactivation phase (Chen 1993). During the immune

clearance phase, repeated hepatitis may accelerate the progression of chronic hepatitis

to cirrhosis resulting in poor prognosis. HBV reactivation may also occur when the

patients receiving chemotherapy or organ transplantation (Huang et al. 2006b; Huang

and Chung 2012). Furthermore, the frequency and severity of hepatitis activity differ

greatly among individual carriers of HBV.

It is generally believed that the liver injury associated with HBV infection is

predominantly mediated through immune mechanisms such as vigorous multi-specific

T cell responses (Kao and Chen 2002; Chisari 1997). The known risk factors

associated with more severe liver diseases include: high serum HBV DNA level

(Iloeje et al. 2006), older age or longer duration of infection, repeated hepatitis flares

(Huo et al. 2000; Realdi et al. 1994), male gender, diabetes (Huo et al. 2000),

persistence of HBeAg (Realdi et al. 1994), HBV genotype C infection (Kao et al.

2000), co-infection with hepatitis C (Liu et al. 2005) or delta virus (Tamura et al.

1993), pre-S deletion mutants (Chen et al. 2006), basal core promoter mutants (Lin et

al. 2005), alcohol abuse, liver fat, and altered host’s immune status, such as HIV

infection or post transplantation (Kao 2007). Which host immunogenetic factors and

immune receptors correlate with hepatitis severity and HBeAg status in chronic

hepatitis B (CHB) patients remain largely unclear.

I. Immunogenetics in chronic hepatitis B (CHB): The association of HLA-DRB1

polymorphisms with hepatitis activity of male CHB patients

An important host factor which may correlate with severity of hepatitis is the

human leukocyte antigen (HLA). HLA is a crucial host genetic factor that regulates

immune responses by presenting antigens including viral peptides to T lymphocytes

(Ceppellini et al. 1989). Although the association of disease susceptibility or

resistance with HLA polymorphisms has been extensively investigated (Tiwari and

Terasaki 1989), the association between HBV infection and HLA polymorphisms is

only partially clarified. For example, specific HLA alleles are associated with

clearance or persistence of HBV after acute infection (Forzani et al. 1984; Almarri

and Batchelor 1994; Thursz et al. 1995; Hohler et al. 1997; Thio et al. 1999; Thio et al.

2003, Yang et al. 1989; Wu et al. 2004), such association has been linked to

HLA-DRB1 polymorphisms, in both Western (Forzani et al. 1984; Almarri and

Batchelor 1994; Thursz et al. 1995; Hohler et al. 1997; Thio et al. 1999; Thio et al.

2003) and Taiwanese populations (Yang et al. 1989; Wu et al. 2004).

Male gender is another apparent host factor associated with severity of hepatitis

in perinatally transmitted carriers of HBV. A study reported that abnormal alanine

aminotransferase (ALT) levels are much more frequent in male carriers of HBV than

female carriers (Chu et al. 1983). In addition, an epidemiological study focusing on

HBsAg seroprevalence also confirmed that subjects with chronic HBV infection are

predominantly males (Chen et al. 2000).

Much less data are available on the association between HLA-DRB1

polymorphisms with severity of hepatitis in CHB patients, especially male subjects

who have more severe hepatitis. The hypothesis of this study was that specific

HLA-DRB1 allele might be associated with severity of hepatitis in male CHB patients.

In this prospective cohort study, a total of 204 carriers of hepatitis B virus (131

men and 73 women) who have been followed-up for more than 1 year at the

outpatient clinic of a university hospital were collected consecutively. Fifty carriers of

hepatitis B virus (group I) with alanine aminotransferase < 2x upper limit of normal

(mean follow-up 83.6 months) were compared with 154 chronic hepatitis B patients

(group II) with alanine aminotransferase >= 2x upper limit of normal (mean follow-up

81.3 months). Alleles of HLA - DRB1 were typed by polymerase chain reaction -

sequence specific oligonucleotide probe hybridization and genotypes of hepatitis B

virus by melting curve analysis. HLA - DRB1*1101 was found in 18% of group I

versus 8% of group II in male carriers (OR 0.23, p=0.020, after adjustment for age)

and 4% versus 9.4% in female carriers (p=0.094). In male carriers harboring

DRB1*1101, the distribution of hepatitis B viral genotype was comparable between

the two groups.

In conclusion, in Taiwanese Han ethnic group, HLA-DRB1*1101 correlates with

less severe hepatitis in male carriers of HBV. Genotype of HBV has little impact on

the clinical course of carriers of HBV harbouring DRB1*1101.

II. Immune receptor in CHB: The association of vitamin D receptor gene

polymorphisms with distinct clinical phenotype of CHB patients

Vitamin D is involved in the metabolism of skeleton as a systemic hormone but

also plays important roles in the regulation of host immune responses and

development of cancer (Haussler et al. 1998). For example, vitamin D inhibits

lymphocyte proliferation, stimulates monocyte differentiation, and exhibits

anti-proliferation activities in several types of cancer cells (Uitterlinden et al. 2004).

The active form of vitamin D, 1,25-dihydroxyvitamin D, exerts immunomodulatory

effects via the vitamin D receptor (VDR) (Haussler et al. 1998), and high

concentration of VDR is detected in the macrophages and T lymphocytes, especially

CD8-positive lymphocytes (Veldman et al. 2000).

The VDR locus is located at chromosome 12q13.1 with a size of over 100 kb.

Three adjacent restriction polymorphic sites in the VDR gene, the BsmI (rs1544410, A

to G base change, designate as genotype B/B, B/b, b/b), ApaI (rs7975232, G to T base

change, designate as genotype A/A, A/a, a/a), and TaqI (rs731236, T to C base change,

designate as genotype T/T, T/t, t/t), have been reported and extensively studied in

several diseases (Uitterlinden et al. 2004). Although VDR gene variant of genotype t/t

was reported to be associated with HBV clearance and active form of vitamin D was

shown to inhibit HCC cell proliferation in vitro and in vivo (Bellamy et al. 1999;

Pourgholami et al. 2000), the association of VDR gene polymorphisms with distinct

clinical phenotypes of CHB patients remain largely unclear. Taking advantage of

rampant HBV infection in Taiwan, the aim of this study is to investigate the

association of vitamin D receptor gene polymorphisms with distinct clinical

phenotypes of Taiwanese CHB patients as well as the risk of HCC development.

We genotyped BsmI (rs1544410), ApaI (rs7975232), and TaqI (rs731236)

polymorphisms of VDR gene in 250 Taiwanese chronic HBV carriers, who were

categorized into 6 phenotypes. After adjustment for age and sex, the frequencies of

VDR B/b, B/a, B/T, B/a/T in patients with hepatitis flare(s) were lower than those

without (7% vs. 20%, p=0.01; 1% vs. 9%, p=0.007; 3% vs. 10%, p=0.01; 1% vs. 9%,

p=0.007; respectively), in contrast, b/A A/T, b/A/T were higher in flare(s) (47% vs.

33%, p=0.04; 49% vs. 34%, p=0.005; 46% vs. 33%, p=0.046; respectively). In

addition, B/b, T/t, b/A, B/a, B/A, B/T, B/t, A/T, A/t, b/A/T, B/a/T, B/A/t were higher in

patients positive for HBeAg. The distribution of VDR genotypes was comparable

between patients with and without hepatoma.

In summary, these findings convincingly demonstrated the association of VDR

genotype and haplotype polymorphisms with hepatitis flares and HBeAg positivity in

Taiwanese HBV carriers.

III. Innate immune receptor in CHB: TLR3 expressions in PBMCs and liver cells

of CHB patients with its response to immunomodulation (interferon therapy)

In recent years, our understanding of innate immunity is much improved due to

the discovery of pathogen-associated pattern recognition receptors, including the

toll-like receptors (TLR). In transgenic mice models, TLR3, TLR4, TLR5, TLR7, 7/5 EXW QRW 7/5 OLJDQGV ELQGLQJ LQKLELW +%9 UHSOLFDWLRQ LQ DQ Įȕ

interferon-dependent manner (Isogawa et al. 2005). In comparison with hepatitis B

e-antigen (HBeAg) -negative patients, HBeAg-positive had a reduced expression of

TLR2, but not TLR4, on peripheral blood mononuclear cells (PBMCs), hepatocytes,

and Kupffer cells (Visvanathan et al. 2007).

TLR3, 7, 8, and 9 are known to recognize nucleic acids of viruses, and human

TLR3 has a significant homology with TLR7, 8, and 9 (Iwasaki and Medzhitov 2004).

TLR3 is comprised of a huge ligand-binding ecto-domain, which localizes on plasma

membrane or endosome (Ranjith-Kumar et al. 2007). Patients with mutations in

TLR3 gene are associated with chronic cytomegalovirus disease including hepatitis

and viremia (Nahum et al. 2011), influenza-associated encephalopathy (Hidaka et al.

2006), as well as herpes simplex virus (HSV) encephalitis (Zhang et al. 2007).

Recurrences in two HSV encephalitis patients suggested the role of TLR3 in HSV

latency (Bousfiha et al. 2010; Netea and van der Meer 2011). Variants in TLR3 gene

have been correlated with CHB and/or HBV-related acute on chronic liver failure

(Al-Qahtani et al. 2012; Rong et al. 2012). Furthermore, TLR3 signaling may mediate

adaptive immunity against viral infections (Schulz et al. 2005). In this study, we

aimed to investigate the expression of TLR3 on PBMCs and liver cells of CHB

patients and its response to immunomodulation (pegylated-interferon therapy).

We consecutively enrolled 127 CHB patients and 64 HBsAg-negative,

anti-hepatitis C virus negative healthy individuals as controls. We compared the

TLR3 expressions on fresh PBMCs and liver cells from patients and controls, before

and during pegylated-interferon or nucleoside analogues therapy.

Compare to controls, patients had a lower TLR3 mean fluorescence intensity

(MFI) on PBMCs (14.61 ± 13.49 versus 9.70 ± 4.61,p < 0.001), independent of age,

gender and ALT (-13.466, 95% CI -17.202 – -9.730, p < 0.001). Patients had limited

TLR3 stains on Kupffer cells, controls had diffuse stains on Kupffer and hepatocytes.

Hepatic TLR3 mRNA was lower in patients than controls (0.47 ± 0.30 versus 1 fold).

Using pre-treatment TLR3 MFI as referent, among five of 12 pegylated-interferon

treated patients with sustained virological response (SVR), TLR3 MFI restored to a

mean of 1.5 to 1.7 folds immediately after treatment. Among seven non-responders or

relapsers, TLR3 MFI reduced to a mean of 0.5 to 0.7 fold. Among ten

entecavir-treated patients with on-treatment virological response, TLR3 MFI

gradually restored to a mean of 1.2 folds during 48-week therapy.

CHB patients have reduced TLR3 expressions on PBMCs, independent of age,

gender, ALT and on liver cells. Patients with pegylated-interferon induced SVR have

a more significant restoration of TLR3 expression than those under entecavir.

IV. Effect of immunomodulation (interferon therapy) on serum HBV RNA (HBV

replicative intermediates)

HBV is a unique DNA virus which replicates via pregenomic RNA. The steps in

HBV replication include: 1. In the nucleus of infected hepatocytes, the asymmetric

DNA in virions converts to covalently closed circular DNA (cccDNA); 2. cccDNA

was transcribed to pregenomic RNA; 3. synthesis of minus strand of viral DNA by

reverse transcriptase; 4. synthesis of plus strand to mature genomic DNA (Ganem et al.

1987). Both interferon and nucleos(t)ide analogues have been approved for the

treatment of chronic hepatitis B (CHB). All of these agents have viral suppression

effects, while interferon has additional immune modulatory properties (Lok and

McMahon 2007). Lamivudine is the first approved nucleoside analogue, however, the

development of resistant mutants are high (Huang et al. 2012a; Lok and McMahon

2007). Furthermore, it does not affect the integrated HBV DNAs and their transcripts,

the RNA replicative intermediates (Doong et al. 1991). Thus, lamivudine as well as

other nucleos(t)ide analogues need indefinite duration of therapy for continued viral

suppression. In contrast, interferon has a finite duration of therapy and a higher rate of

hepatitis B surface antigen (HBsAg) seroclearance than nucleos(t)ide analogues

(Dienstag 2008). Our study and others showed that serum HBV RNA could be

detected during lamivudine therapy as the consequence of unaffected RNA replicative

intermediates as well as interrupted reverse transcription (Hatakeyama et al. 2007;

Huang et al. 2008b; Zhang et al. 2003).

Previous clinical trials indicated that simultaneous combination therapy of

Previous clinical trials indicated that simultaneous combination therapy of

在文檔中 慢性B型肝炎患者免疫遺傳、免疫受體與免疫調節之研究 (頁 28-145)