慢性B型肝炎患者免疫遺傳、免疫受體與免疫調節之研究

୯ҥᆵ᡼εᏢᖏ׉ᙴᏢࣴز܌!

റγፕЎ!

Graduate Institute of Clinical Medicine College of Medicine

National Taiwan University doctoral dissertation

ᄌ܄ C ࠠطݹ஻ޣխࣝᒪ໺ǵխࣝڙᡏᆶխࣝፓ࿯ϐ

ࣴز!

Studies on Immunogenetics, Immune-Receptors, and Immunomodulation in Chronic Hepatitis B Patients

໳ࠧЎኗ!

Yi-Wen Huang

ࡰᏤ௲௤ȅଯ჏ֻ܌ߏ Jia-Horng Kao, M.D., PhD

೚ޚჱ௲௤!

Ping-Ning Hsu, M.D, PhD ύ๮҇୯΃႟ΒԃϖД!

May, 2013

Ҟ Ҟ ᒵ

α၂ہ঩཮ቩۓਜ……….… 2

ᇞᖴ………...….. 6

ύЎᄔा……….… 7

मЎᄔा……….... 10

റγፕЎϣ৒ ᆣፕ ङඳ ಃ΋ക B ࠠطݹੰࢥགࢉ……… 14

1.1 BࠠطݹੰࢥᏢ……….……… 15

1.2 ࡚܄ B ࠠطݹ……… 15

1.3 ᄌ܄ B ࠠطݹ……… 16

ಃΒക ᄌ܄ B ࠠطݹޑխࣝᒪ໺……… 18

2.1 ΓᜪқՈౚלচ………..……… 18

2.2 ΓᜪқՈౚלচᆶ B ࠠطݹགࢉ……… 19

2.3 ᆵ᡼௼ဂϐΓᜪқՈౚלচᆶ B ࠠطݹགࢉϷᄌ܄གࢉޑᖏ׉ੰ ำ……… 22

ಃΟക ᄌ܄ B ࠠطݹޑխࣝڙᡏ... 22

3.1 ᆢғન D խࣝڙᡏ... 22

3.2 ӃϺխࣝᜪ៕ڙᡏ... 24

ಃѤക ᄌ܄ B ࠠطݹޑխࣝፓ࿯... 26

4.1 ੰࢥᆶӃϺխࣝ……….….. 26

4.2 எЬᆶ B ࠠطݹੰࢥϐҬϕբҔ... 27

4.3 խࣝፓ࿯ᛰނ (υᘋન) ݯᕍᄌ܄ B ࠠطݹ... 28

ࣴزୢᚒϷख़ा܄………... 30

ࣴزബཥ܄……….…….. 31

ࣴزޑଷᇥᆶ੝ۓҞޑ……… 33

ࣴزБݤᆶ׷਑……… 34

ੰ஻……….… 34

ჴᡍᔠᡍ໨Ҟ……… 37

խࣝᒪ໺Ӣη HLA-DRB1 ჹଽ୷ӢޑुۓǵϩࠠϷԛϩࠠ………….. 38

ᆢғન D խࣝڙᡏ୷Ӣࠠکൂᡏࠠޑुۓ………... 38

ຼᜐՈనൂਡౚಒझޑӃϺխࣝᜪ៕ڙᡏ (TLR)- 3 ߄౜ໆޑෳۓ….. 39

طಒझ΢ӃϺխࣝᜪ៕ڙᡏ (TLR)- 3 ߄౜ໆޑෳۓ……….. 39

طಒझ΢ӃϺխࣝᜪ៕ڙᡏ (TLR)-3 խࣝಔᙃϯᏢࢉՅ…………...… 40

Ոమ B ࠠطݹੰࢥਡᗐਡለ (HBV RNA) ջਔ PCR ޑෳۓ……….... 41

಍ीϩ݋………... 42

่݀ ΃ǵխࣝᒪ໺Ӣη HLA-DRB1 ӭ׎܄ᆶت܄ᄌ܄ B ࠠطݹޑطݹᝄख़ำࡋ ϐ࣬ᜢ܄……….. 43

Βǵᆢғન D խࣝڙᡏ୷Ӣӭ׎܄ᆶᄌ܄ B طޑطݹ࡚܄วբǵe לচ௃ݩ аϷطಒझᕎౢғϐ࣬ᜢ܄……….. 44

Οǵᄌ܄ B ࠠطݹੰ஻ຼᜐՈనൂਡౚಒझکط᠌ಒझ΢ӃϺխࣝᜪ៕ڙᡏ -3ϐ߄౜ໆǴ٠Ъځᆶխࣝፓ࿯ᛰނߏਏࠠυᘋનݯᕍᕍਏޑ࣬ᜢ܄.. 45

Ѥǵխࣝፓ࿯ᛰނ (υᘋન) ჹܭᄌ܄ B طੰ஻Ոమੰࢥਡᗐਡለ (HBV RNA) ޑ׭ڋਏ݀………... 48

૸ፕ ಃ΃ക խࣝᒪ໺Ӣη HLA-DRB1 ӭ׎܄ᆶت܄ᄌ܄ B ࠠطݹޑطݹᝄख़ ำࡋϐ࣬ᜢ܄……….. 50

ಃΒക ᆢғન D խࣝڙᡏ୷Ӣӭ׎܄ᆶᄌ܄ B طޑطݹ࡚܄วբǵe לচ ௃ݩаϷطಒझᕎౢғϐ࣬ᜢ܄………. 54

ಃΟക ᄌ܄ B ࠠطݹੰ஻ຼᜐՈనൂਡౚಒझکط᠌ಒझ΢ӃϺխࣝᜪ៕

ڙᡏ-3 ϐ߄౜ໆǴ٠Ъځᆶխࣝፓ࿯ᛰނߏਏࠠυᘋનݯᕍᕍਏޑ࣬

ᜢ܄………. 60

ಃѤക խࣝፓ࿯ᛰނ (υᘋન) ჹܭᄌ܄ B طੰ஻Ոమੰࢥਡᗐਡለ (HBV RNA) ޑ׭ڋਏ݀……….. 64

৖ఈ………...…. 70

ፕЎमЎᙁॊ (summary) ………... 80

ୖԵЎ᝘………...…. 91

კ………. ………...….120

߄………. ………...….132

ߕᒵ………...….. 145

ᇞ ᇞᖴ

གᖴ΢ࡆவᅺγޔϲډറγ੤Ǵ๏ܭך೭Ζԃᝊ຦ϐᏢಞԋߏޑᐒ཮Ƕ೭྽ύ፥๏ךΎ

ঁ୯ሞϷѤঁ୯ϣᙴᏢࣴزዛރǴЍ࡭ךᝩុ۳߻ՉԶόܫక! ჴӧόࢂӢࣁך቉্ǴԶࢂӢ๱

᭘ޑৱڂᆶઔᅽǶ

གᖴݿ༰๏ϒךᑈཱུ຾ڗϷԾךा؃ޑᄦኬǵಞᄍϷႴᓰǴ٠Ъ࡭ុ܄ޑᡏፊǵЍ࡭ᆶ жᛗǶགᖴε࠰༰ޑжᛗᆶਔதޑፊှϷᜢЈǶགᖴઓ܌፥ന፾ӝךޑངΓۑޱǴӴӄБՏ ޑངǴததהऐϷх৒ךჹӴᆶλ࠸ྣ៝ޑόىǴ٠ЪᒿਔᒿӦႴᓰǵЍ࡭ǵжᛗǵගᒬᆶ

ྣ៝ᡣךёаӼЈֹԋᏢ཰ǶགᖴεζٽཁৱޑᡏຠᆶᡏፊǴԾ୏ԾวόҔךᏹЈǹΒٽη

଻ৱޑಒЈǵᡏፊᆶഉՔǹλٽηֻৱޑᔉ٣ᆶᡏຠǶགᖴεঢε༳ӧᏢಞ΢ޑႴᓰᆶගᒬǹ ΒঢΒ༳ᒿਔྣ៝ε࠰༰ǴᡣךؒԖࡕ៝ϐኁǹ׌Ϸ׌ۂᒿਔڐշݿ༰ޑྣ៝ǹаϷλۂ൩ ߈ྣ៝ݿ༰Ƕ

གᖴଯ჏ֻ܌ߏЇሦך຾ΕᙴᏢࣴزሦୱǴගٮך׷਑ǵၗྍǵࣴزᚒҞǵБݤǵ୯ϣ Ѧᄽᖱᐒ཮ǵ१Րু኷Ǵ௲Ꮴךኗቪǵว߄ϷຑቩፕЎǴҔӚᅿБݤႴᓰךϷх৒ךޑόىǴ Їϟ୯ϣѦᏢޣϷԿ୯ੀᙴଣ୍ܺǶགᖴഋۓߞଣγჹךಃ΋ጇ୯ሞፕЎޑႴᓰǴගٮၗྍ

ᆶᒿਔޑࡰᏤϷ௴วǶགᖴᒘܴ໚௲௤ޑႴᓰϷ܌ගٮޑၗྍᆶᐒ཮Ƕགᖴഋ୻ণଣγޑᒿ ਔႴᓰǴ௴ว܄ޑࡰᏤǴ๏ϒךࣴزၗྍϷᐒ཮ǶགᖴቅߪΓ௲௤ᡏຠޑႴᓰǵਔதޑࡰᏤǵ ڐշǴԋࣁךޑኳጄǶགᖴ೚ޚჱ௲௤๏ϒךࣴز΢ϐගᒬᆶࡰᏤǴаϷፕЎޑቩࢗǶགᖴ ᙁᄪࠄ௲௤ǵ݅ߪࡏୋ௲௤ჹፕЎ዗ЈޑࡰᏤϷႴᓰǶ

གᖴླྀ፣ធ௲௤ޑගܘǴ௲ᏤךࣁΓೀ٣Ǵх৒ךޑόىǴ๏ϒךᙴᕍǵ௲Ꮲǵࣴزǵ Ꮲ཮୍ܺǵ୯ϣϷ୯ሞӚঁቫय़ว৖ޑᐒ཮ǴᜢᚶךޑғࢲϷৎ৥Ƕགᖴचྷ৥ЬҺಒЈޑ

ྣ៝ǵᡏፊϷЍ࡭Ǵ๏ϒቸ܄ᆶޜ໔ǴόਔޑගᒬǴᙴᕍ΢ޑࡰᏤᆶЍජǶགᖴ݅ߪᡕᙴৣ

ޑྣ៝ǵႴᓰϷЍ࡭Ƕགᖴ஭఼ॕᙴৣᡏፊᆶЍ࡭Ϸᙴᕍ΢ਔதϐڐշǶགᖴֆ჏௵ᙴৣᙴ ᕍπբ΢ޑڐշǶགᖴநҁ߃ᙴৣϷ஭ᅴݒᙴৣᖏ׉πբϐᔅԆǶ

གᖴ୯ੀᙴଣ໳మН៝ୢǵ݅דܴଣߏǵ໳ࡹ๮ୋଣߏǵࢫงໜୋଣߏǵ׵วงୋଣߏǵ

׵ᙦ㋏ୋଣߏǵϣࣽ೽Ϸط᠌गဉࣽӕϘॺޑЍ࡭ǵڐշϷႴᓰǶགᖴ݅Шܱ೽ߏޑࡰᏤ٠ගٮ ჴᡍ࠻ޜ໔Ϸ೛ഢǶགᖴ᚟ల㼵ᙴৣࡰᏤჴᡍמೌϷ๏ϒЍජǶགᖴఉণᆢᙴৣࡰᏤխࣝࢉՅǶ གᖴךၸѐϷ౜ӧޑշ౛ॺǺෞች࣓ǵ׵ᘑҺϷ೚ԋഩᅺγӧჴᡍמೌϷᏹբǴ٠ЪՉࡹ٣୍ޑ ڐշǶགᖴ݅דഊЬҺჹךಃ΋ጇ୯ሞፕЎޑঅ҅Ƕགᖴླֻྀדǵ೚ඳ౰ᙴৣޑႴᓰᆶࡰᏤǶ གᖴଯ௲௤ჴᡍ࠻շ౛ഋ໥࣓ǵڬॕ๭λۆჴᡍᏹբ΢ޑЈΚǹЦ๋࣑λۆϷᎄඁӵǵഋߜϐ റγғޑڐշǹᆵεᙴᏢᔠᡍᄤғނמೌᏢسच۸܃ԴৣϷഋٵᆺλۆޑႴᓰϷמೌࡰᏤǶ

གᖴВҁ Prof. Kazuaki Chayama, Dr. Shoichi Takahashi, Dr. Masataka Tsuge, Miss Hiromi Abe ϐࡰᏤᆶௗࡑϷВҁ੃ϯᏔੰᏢ཮ගٮϐр୯ࣴزዛᏢߎǶགᖴՉࡹଣ୯ৎࣽᏢہ঩཮റγғр ୯ࣴزϐ࿶຤ံշϷࣴزीჄ(NSC 99-2314-B-281-002-MY3)ک୯ੀᆕӝᙴଣ - ୯ҥѠ᡼εᏢ ᙴᏢଣߕ೛ᙴଣᖄӝࣴزीჄ(97-CGN01)ޑ࿶຤Ѝ࡭Ƕ

ᜫа΢܌ගޑ؂΋Տ೿ሦڙઓӧओᑋ୷࿎㚊ޑৱڂᆶઔᅽǴԶيᡏ଼நǵπբ໩ճǵيЈ ᡫѳӼǶ

Sola Gratia! Soli Deo Gloria!

ύ

ύЎᄔा

Ҟ߻ϝฅ҂ޕٗ٤எЬխࣝᒪ໺ϷխࣝڙᡏӢનቹៜᄌ܄˾ࠠطݹ࡚܄ว բޑᝄख़ࡋǶךॺޑҞޑӧܭ௖૸խࣝᒪ໺Ӣη HLA-DRB1 ӭ׎܄ᆶت܄ᄌ܄

Bࠠطݹϐطݹᝄख़ำࡋϐ໔ޑ࣬ᜢ܄ǶӧԜ߻ᘳ܄ШжࣴزύǴӅયΕΑ 204 Ӝӧߐບςଓᙫ΋ԃа΢ޑ˾ط஥চޣ (131 Ӝت܄ک 73 Ӝζ܄)Ƕ50 Ӝ ALT <

2X҅தॶ΢ज़ (ಃ΋ಔǵѳ֡ଓᙫ 83.6 ঁД) ᆶ 154 Ӝ ALT ɪ 2X ҅தॶ΢ज़ (ಃΒಔǵѳ֡ၟᙫ 81.3 ঁД)ޑ஥চޣ຾ՉКၨǶHLA-DRB1 ޑჹଽ୷Ӣ௦Ҕ ᆫӝ䁙᜘ϸᔈ-ׇӈ੝ۓჲਡ㧿ለ௖ଞᚇҬݤǴԶੰࢥ୷ӢࠠаᅙှԔጕϩ݋᠙ ۓǶӧت܄஥চޣύว౜ಃ΋ಔϐ 18% کಃΒಔϐ 8%஥Ԗ HLA-DRB1*1101(ፓ

᏾ԃសࡕ OR 0.23Ǵ p = 0.020)Ǵζ܄஥চޣࢂ 4% ࣬ၨܭ 9.4%(p = 0.094)Ƕت

܄ឫ஥ DRB1*1101 ޣǴځ B طੰࢥ୷Ӣࠠޑϩթӧٿಔϐ໔ࢂ࣬՟ޑǶ HLA-DRB1*1101ᆶᆵ᡼ت܄ᄌ܄ B ط஥চޣޑᇸࡋطݹԖᜢǶ

ჹܭᄌ܄གࢉکᕎੱǴᆢғન D ё೯ၸᆢғન D ڙᡏ (VDR) วචխࣝፓ

࿯کלቚ෗բҔǶךॺुۓϩࣁ 6 ঁόӕಔձޑ 250 Ӝᆵ᡼ᄌ܄ B ط஥চޣϐ Οঁӭ׎܄ज़ڋՏᗺޑ୷Ӣࠠ (BsmI (rs1544410)ǵApaI (rs7975232) Ϸ TaqI (rs731236))Ƕፓ᏾ԃសک܄ձࡕǴطݹ࡚܄วբ஻ޣޑᆢғન D ڙᡏ B/bǵB/aǵ B/TǵB/a/T ᓎ౗֡եܭ҂วғ࡚܄วբޣ (7% ࣬ၨܭ 20%Ǵp=0.009ǹ1% ࣬ၨ

ܭ 9%Ǵp=0.004ǹ3% ࣬ၨܭ 10%Ǵp=0.007ǹ1% ࣬ၨܭ 9%Ǵp=0.005)ǹ࣬ϸ ޑǴطݹ࡚܄วբ஻ޣޑ T/tǵA/TǵA/tǵb/A/t ᓎ౗ϩթ֡ၨଯ (8% ࣬ၨܭ 3%Ǵ p=0.003ǹ49% ࣬ၨܭ 34%Ǵp=0.027ǹ2% ࣬ၨܭ 1%ǴP=0.004ǹ0.5% ࣬ၨܭ 0%Ǵp=0.001)ǶԜѦǴHBeAg ໚܄஻ޣޑ B/bǵB/BǵT/tǵb/AǵB/aǵB/AǵB/Tǵ B/tǵA/tǵb/A/TǵB/a/TǵB/A/TǵB/A/tǵb/A/t ᓎ౗ၨଯǶჹܭٳวᆶ҂ٳวط ಒझᕎޑ஥চޣǴځᆢғન D ڙᡏޑᓎ౗ϩթ࣬՟Ƕᆢғન D ڙᡏޑ୷Ӣӭ׎

܄ᆶᆵ᡼ B ࠠطݹੰࢥ஥চޣޑόӕᖏ׉߄ࠠԖᜢǴՠᆶౢғطಒझᕎคᜢǶ ӃϺխࣝᜪ៕ڙᡏ-3 ޑ୷Ӣᡂ౦ᆶᄌ܄ B ࠠطݹԖᜢǶךॺޑҞޑࢂ௖૸

ᄌ܄ B ࠠطݹ஻ޣຼᜐՈనൂਡౚಒझᆶط᠌ಒझޑᜪ៕ڙᡏ-3 ߄౜ໆکௗڙ խࣝፓ࿯ᛰނߏਏࠠυᘋનݯᕍਔϐᡂϯǶךॺયΕ 127 ٯᄌ܄ B ࠠطݹ஻ޣ ᆶ 64 ٯ B ࠠطݹ߄य़לচ഍܄Ϸ C ࠠطݹלᡏ഍܄ϐ௓ڋޣǶᐱҥܭԃសǵ܄

ձک ALT ॶϐΠ (-13.466Ǵ95% ߞᒘ୔໔ -17.202 ȉ- 9.730Ǵp < 0.001)Ǵ࣬ၨ

ܭჹྣޣǴᄌ܄ B طੰ஻ӧຼᜐՈనൂਡౚಒझ΢Ԗၨեޑᜪ៕ڙᡏ-3 ѳ֡ᅞ Ӏமࡋ (14.61 ± 13.49 ࣬ၨܭ 9.70 ± 4.61Ǵp < 0.001)Ƕᄌ܄ B طੰ஻ޑᜪ៕ڙ ᡏ-3 խࣝಔᙃϯᏢࢉՅЬा߳ज़ӧ৤МಒझǴԶ௓ڋޣޑࢉՅණթӧ৤Мಒझک طಒझ΢Ƕੰ஻ޑط᠌ಒझᜪ៕ڙᡏ-3 mRNA ߄౜ໆΨКჹྣޣե (0.47 ± 0.30 ७࣬ၨܭ 1 ७)Ƕӧ 12 ٯௗڙߏਏࠠυᘋનݯᕍޑੰ஻ύǴ5 ٯၲډ࡭ុੰࢥᏢ ϸᔈǶ٬Ҕݯᕍ߻ᜪ៕ڙᡏ-3 ޑѳ֡ᅞӀமࡋࣁჹྣǴ೭ 5 ٯੰ஻ϐᜪ៕ڙᡏ-3 ޑѳ֡ᅞӀமࡋӧݯᕍࡕҥջӣϲډѳ֡ 1.5 Կ 1.7 ७ǶӧΎٯݯᕍคϸᔈ܈ൺ วੰ஻ύǴᜪ៕ڙᡏ-3 ѳ֡ᅞӀமࡋ෧Ͽډѳ֡ 0.5 Կ 0.7 ७Ƕӧ 10 ٯௗڙن኷

լݯᕍЪڀԖݯᕍύੰࢥᏢϸᔈޑ஻ޣǴӧ 48 ঁࢃයޑݯᕍύǴᜪ៕ڙᡏ-3 ѳ

֡ᅞӀமࡋ೴ᅌӣϲډѳ֡ 1.2 ७Ƕᄌ܄ B ࠠطݹੰ஻ϐຼᜐՈనൂਡౚಒझ

΢ǴӧᐱҥޑԃសǴ܄ձϷ ALT ॶϐΠǴаϷطಒझ΢ޑᜪ៕ڙᡏ-3 ޑ߄౜ໆ फ़եǶߏਏࠠυᘋનݯᕍԶၲډ࡭ុੰࢥϸᔈޑ஻ޣϐᜪ៕ڙᡏ-3 ߄౜ޑӣϲၨ

ن኷լݯᕍޣ׳ࣁᡉ๱Ƕ

ӧ lamivudine ݯᕍύ܌ᔠෳډޑՈమ HBV RNA ࢂӢࣁ RNA ޑፄᇙύ໔ౢ

ނ҂ڙᛰނݯᕍϐቹៜǶךॺޑҞޑӧܭ௖૸ᄌ܄ B ࠠطݹ஻ޣύխࣝፓ࿯ᛰ ނ (υᘋન) ჹܭՈమ HBV RNA ޑ׭ڋਏ݀ǶՈమᔠᡏύޑ HBV DNA ک RNA ೯ၸ B طੰࢥਡለ๧ڗނޑ଍ᙯᒵکջਔ PCR ԶۓໆϐǶஒჹٰԾаΠΟಔ஻

ޣϐ؂ 2 ຼډ 3 ঁДޑᔠᡏ຾Չϩ݋Ǻ10 Ӝت܄஻ޣǴௗڙਡ㧿ᜪ՟ނൂ΋ݯ ᕍ 44 Կ 48 ຼ(5 ӜҔ lamivudineǴ5 ӜҔ entecavir)ǹ6 Ӝت܄஻ޣǴௗڙ࣬ᝩυ ᘋનک lamivudine ӝٳݯᕍǹаϷ 3 Ӝت܄஻ޣǴௗڙ lamivudine ൂ΋ݯᕍ 20 Կ 24 ຼǶௗڙݯᕍ߻ǴؒԖҺՖ஻ޣՈమύᔠෳډ HBV RNAǴՠӧௗڙݯᕍ ය໔ǴԖ 15 Ӝ஻ޣՈమύᔠෳр HBV RNAǶӧ೭ΟಔύǴݯᕍ߻ HBV DNA (8.1

± 2.4 ࣬ၨܭ 7.7 ± 1.4 ࣬ၨܭ 5.1 ± 0.3 log10copies/mlǴp = 0.06)аϷݯᕍکଓᙫ ය໔ (45.5 ± 2.0 ࣬ၨܭ 49.7 ± 5.6 ࣬ၨܭ 48.7 ± 6.4 ຼǴp = 0.32) ࣬՟ǶHBV RNA ӧ܌Ԗௗڙൂ΋ݯᕍޑ஻ޣϐݯᕍ่״ਔаϷଓᙫ่״ਔ೿ёᔠෳډǴՠ ӧ ௗ ڙ ࣬ ᝩӝ ٳ ݯ ᕍ஻ ޣ ύ ࠅ ؒԖ ΋ Տ ೏ᔠ ෳ ډ (100% ࣬ ၨ ܭ 0% Ǵ pɦ 0.001)Ƕᆶ lamivudine ݯᕍԶᔠෳډՈమ HBV RNA ࣬КǴխࣝፓ࿯ᛰނυᘋન ݯᕍё೯ၸ׭ڋ HBV RNA ޑፄᇙύ໔ౢނٰफ़ե HBV DNA ޑፄᇙǴவԶ٬

Ոమ HBV RNA ੃ѨǶ

ᜢ

ᜢᗖຒǺB ࠠطݹǹխࣝޑǹΓᜪқՈౚלচǹᆢғન D ڙᡏǹᜪ៕ڙᡏ 3ǹ ਡᗐਡለǹυᘋન!

म

मЎᄔा

Which host immunogenetic factors and immune receptors correlate with hepatitis

severity in chronic hepatitis B (CHB) patients (pts) remain unclear. We aimed to study

association of HLA-DRB1 with hepatitis severity in male HBV carriers. 204 HBV

carriers (131 men, 73 women) who were followed-up for >1y were enrolled. 50 HBV

carriers (group I) with ALT <2x ULN (mean f/u 83.6m) were compared with 154

CHB patients (group II) with ALT •2x ULN (mean f/u 81.3m). HLA-DRB1 alleles

were typed by PCR-sequence specific oligonucleotide probe hybridization and HBV

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

vs. 8% of group II in male (OR 0.23, p=0.020, adjusted for age) and 4% vs. 9.4% in

female (p=0.094). In male harboring DRB1*1101, distribution of HBV genotype was

comparable between 2 groups. HLA-DRB1*1101 correlates with less severe hepatitis

in Taiwanese male carriers of HBV.

Vitamin D receptor (VDR) has immunomodulatory and antiproliferative effects.

We genotyped BsmI (rs1544410), ApaI (rs7975232), TaqI (rs731236) of VDR gene in

250 HBV carriers who were categorized into 6 phenotypes. After adjustment for age

and sex, frequencies of VDR B/b, B/a, B/T, B/a/T in pts with hepatitis flare(s) were

lower than those without (7%vs.20%, p=0.009; 1%vs.9%, p=0.004; 3%vs.10%,

p=0.007; 1%vs.9%, p=0.005), in contrast, T/t, A/T, A/t, b/A/t were higher in flare(s)

(8% vs. 3%, p=0.003; 49% vs. 34%, p=0.027; 2% vs. 1%, p=0.004; 0.5% vs. 0%,

p=0.001). In addition, B/b, B/B, T/t, b/A, B/a, B/A, B/T, B/t, A/t, b/A/T, B/a/T, B/A/T,

B/A/t, b/A/t were higher in HBeAg positive pts. Distribution of VDR genotypes was

comparable between pts with and without hepatoma. VDR gene polymorphisms are

associated with distinct clinical phenotypes but not with hepatoma.

Innate immune receptor toll-like receptor-3 (TLR3) gene variants correlate with

CHB. We aimed to investigate TLR3 expression in PBMCs and liver cells of CHB pts

and its response to immunomodulation (pegylated-interferon therapy (peg-IFN)). We

enrolled 127 CHB pts and 64 HBsAg-negative, anti-HCV negative controls. Compare

to controls, pts 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). Pts had limited TLR3 stains on Kupffer

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

was lower in pts than controls (0.47 ± 0.30 versus 1 fold). Using pre-treatment TLR3

MFI as referent, among 5 of 12 peg-IFN treated pts with sustained virological

response (SVR), TLR3 MFI restored to a mean of 1.5-1.7 folds immediately after

therapy. Among 7 non-responders or relapsers, TLR3 MFI reduced to a mean of

0.5-0.7 fold. Among 10 entecavir (ETV)-treated pts with on-treatment virological

response, TLR3 MFI gradually restored to a mean of 1.2 folds during 48-week therapy.

CHB pts have reduced TLR3 expressions on PBMCs, independent of age, gender,

ALT and on liver cells. Pts with peg-IFN induced SVR have a more significant

restoration of TLR3 expression than those under ETV.

Serum HBV RNA is detected during lamivudine therapy as the consequence of

unaffected RNA replicative intermediates. We aimed to determine inhibitory effect of

immunomodulation (interferon, IFN) on serum HBV RNA in CHB pts. HBV DNA

and RNA were quantified by reverse transcription of HBV nucleic acid extract and

real-time PCR; every 2 wks to 3m in 10 male treated with nucleoside analogue

monotherapy for 44-48wks (5 lamivudine (LMV), 5 ETV), 6 males with sequential

IFN and LMV combination, and 3 males with LMV monotherapy for 20-24 wks.

HBV RNA was not detectable in all pts before any therapy, but became detectable in

15 during therapy. Among the 3 groups, pretreatment HBV DNA (8.1±2.4 vs. 7.7±1.4

vs. 5.1±0.3 log cp/mL, p=0.06), treatment and follow-up durations (45.5±2.0 vs.

49.7±5.6 vs. 48.7±6.4 wks, p=0.32) were comparable. HBV RNA was detectable at

end of therapy or follow-up in all pts with monotherapy, but none of sequential

combination (100% vs. 0%, p<0.001). Compared to LMV with detectable serum HBV

RNA, immunomodulation of IFN may reduce HBV DNA replication through

inhibition of HBV RNA replicative intermediates, resulting in loss of serum HBV

RNA.

Keywords: hepatitis B; immune; human leukocyte antigen; vitamin D receptor;

toll-like receptor-3; ribonucleic acid; interferon

ᆣ ᆣፕ ङඳ

ಃ΋ക B ࠠطݹੰࢥགࢉ

Bࠠطݹੰࢥ (hepatitis B virusǴHBV) ว౜ܭ 1965 ԃǴࢂӄౚЇଆᄌ܄ط ݹǵطฯϯϷطᕎޑЬӢ (Chen 1993; Kao and Chen 2000; Kao and Chen 2002;

Lee 1997)Ǵ؂ԃऊ೷ԋ΋ԭ࿤ΓԝΫǶਥᏵШࣚፁғಔᙃޑ՗ीǴӄౚ஥চޣς

ၲ 3 ሹ 5 ί࿤ډ 4 ሹΓϐӭǴځύ 6 ί࿤ΓനಖёૈԝܭطᕎǴԶ 4 ί 5 ԭ࿤Γ നಖёૈԝܭطฯϯǶᄌ܄ B ࠠطݹޑ౰Չ౗ǴШࣚӚӦԖࡐεޑৡ౦ǶӧՋ Б୯ৎǴᄌ܄ B ࠠطݹޑ౰Չ౗ၨեǴε೽ϩࢂԋԃаࡕωགࢉǴ౰Չ౗ࣁӄ Γαޑ 0.2% Կ 1%Ǵऊ՞܌Ԗᄌ܄طݹޑ 5%Կ 10%ǶԶӧ೽ϩଯࢬՉ୔Ǵӵ٥ ࢪǵߚࢪǵࠄኻϷ܎΍ऍࢪ฻ӦǴB ࠠطݹ஥চޣޑ౰Չ౗ଯၲ 2% Կ 20%Ƕε ӭኧ٥ࢪ B ࠠطݹੰࢥ஥চޣӧғڮԐයᕇளੰࢥǴӵຼౢය܈ٽูԐය (Steven et al. 1975)Ƕջ٬ӧ B ࠠطݹੰࢥགࢉ౗ၨեޑऍ୯Ǵӧ 2005 ԃǴεऊ 5400Γ஻Ԗ࡚܄ B ࠠطݹੰࢥགࢉ (Wasley et al. 2007)ǴԖ 120 ࿤Γࢂᄌ܄ B

ࠠطݹੰࢥ஥চޣ (McQuillan et al. 1989; CDC 1991)Ƕӧၸѐޑ൳Μԃ㚊Ǵҗܭ

ٰԾ B ࠠطݹੰࢥࢬՉӦ୔౽҇ޑ෢ΕǴऍ୯ޑ B ࠠطݹੰࢥ࣬ᜢϐط᠌੯ੰ

کطಒझᕎޑ౰Չ౗ቚу (Hann et al. 2007)ǶᏵ՗ीǴऍ୯؂ԃԖ 5000 Γԝܭ B

ࠠطݹޑٳวੱǴхࡴطฯϯکطಒझᕎ (Lin and Kirchner 2004)Ƕᆵ᡼Ԑޕࢂ B

ࠠطݹଯࡋ౰Չ୔Ǵ40 ྃа΢൳ЯԖ 90ʘޑΓགࢉၸ B ࠠطݹੰࢥǴЪऊԖ 15%

Կ 20ʘ ޑΓࣁ஥চޣǶ܌۩Ծவ҇୯ 73 ԃ໒ۈࡼՉཥғٽ B ࠠطݹࣝभݙ৔

ࡕǴᏢស߻ٽูϐ஥চ౗ςҗࣝभௗᅿ߻ 10%Ǵε൯फ़եډҞ߻ϐλܭ 1%Ǵԋ

݀ࡐӳǶӕਔٽูطᕎޑԃวғ౗ҭԖᡉ๱Πफ़ǶՠӧԋԃΓϐύϝԖࣁኧόϿ ޑ B ࠠطݹ஥চޣǴԶЪطฯϯᆶᄌ܄طݹϝࣁΜεԝӢϐಃ 8 ՏǴطᕎࣁت ζ܄ᕎੱԝӢϐಃ 2 ՏǴቹៜόёᒏόεǶ

1.1 BࠠطݹੰࢥᏢ

B ࠠطݹੰࢥࣁѐ਼ਡᗐਡለ (DNA) ੰࢥǴϏМᗭಈ (Dane particle) ࣁ 42-nmޑౚ׎่ᄬǴхࡴਡೈқ (core) ϷѦ঺ೈқ (envelope)Ƕਡೈқϣ֖όֹ

᏾ᕉރᚈި DNAǴDNA ᆫӝ䁙 (polymerase)ǴਡЈלচ (HBcAg) ک e-לচ (HBeAg)ǴѦ঺ೈқ߾Ԗ߄य़לচ (HBsAg)Ƕόֹ᏾ᕉރᚈި DNA Ԗ 3,200 ঁ ᡵ୷ჹ (base pairs)Ǵϩԋ 4 ঁ໒ܫጓ᎙ࢎᄬ (open reading frames) : ջ߄य़୷Ӣ (S gene)ǴਡЈ୷Ӣ (C gene)Ǵ ᆫӝ䁙୷Ӣ (P gene) ک X ୷Ӣ (X gene)ǶDNA ᆫӝ䁙ࣁ P ୷Ӣᇙ೷Ǵ ڀԖϸᙯᒵ (reverse transcription) Ϸӝԋᚈި DNA ф

ૈǶਡЈלচࣁ C ୷Ӣ܌ᇙ೷ޑೈқ፦ǴΓᡏ཮ౢғਡЈלᡏᆶϐჹלǴՠό ڀߥៈфૈǴ ਡЈלᡏ໚܄߄Ңම࿶གࢉၸ B ࠠطݹੰࢥǶe-לচҭࣁ C ୷Ӣ ᇙ೷Ǵ࿶ၸঅႬࡕҗطಒझញрǴe-לচ໚܄߄Ң B ࠠطݹੰࢥӧᡏϣεໆፄ ᇙǴ໺ࢉ܄ཱུமǶΓᡏ཮ౢғ e-לᡏჹל e-לচǴe-לᡏ໚܄߄Ңੰࢥࢲ܄फ़եǴ

໺ࢉ܄ΨեǶ߄य़לচࣁ Sǵpre-S1 Ϸ pre-S2 ୷Ӣᇙ೷ǶB ࠠطݹ߄य़לচ໚܄Ǵ ߄ҢᡏϣԖ B ࠠطݹੰࢥӸӧǴ൩ࢂ B ࠠطݹ஥চޣǶX ୷Ӣᇙ೷ 2 ᅿೈқ፦Ǵ ё྽଺ᙯᒵࢲϯނ (transcriptional activator)ǴᇶշੰࢥፄᇙǴ܈೚ᆶطಒझᕎϐ วғԖᜢǶ

HBVࢂ೯ၸ߻୷Ӣಔ RNA ፄᇙޑൂ΋ DNA ੰࢥǶӧ HBV ፄᇙၸำύԖ

൳ঁख़ा؁ᡯǺಃ΋ǵӧ೏གࢉޑطಒझਡϣǴੰࢥᡏϣޑόჹᆀ DNA ᙯඤࣁ Ӆሽഈᕉ DNA (cccDNA)ǹฅࡕǴcccDNA ᙯᒵࣁ߻୷Ӣಔ RNAǶௗΠٰǴੰࢥ DNAޑॄ᜘೯ၸ଍ᙯᒵ䁙຾ՉӝԋǶനࡕǴᆶӝԋޑ҅᜘׎ԋԋዕޑ୷Ӣಔ DNA (Ganem et al. 1987)Ƕ

1.2 ࡚܄ B ࠠطݹ

Bࠠطݹޑወҷයऊ 40 ډ 180 Ϻ (ѳ֡ 60 Ϻ)ǴӭኧؒԖੱރǴ໪࿶ᡍՈω

ૈዴۓǶ10-25% ޑ࡚܄གࢉԖܴᡉޑᖏ׉ੱރǴӵဉगό፾ǵ१ኅόਁǵੲ

॰ǵ⧋ЈǵჍӗ฻Ǵᝄख़஻ޣ཮р౜ૡՅֿࣗԿ໳੸Ǵځੰ௃ϐᇸख़໪ຎགࢉ

ޣޑԃសǵ܄ձǵխࣝΚԶۓǶڂࠠޑՈమ኱૶ᡂϯࣁ߄य़לচ (HBsAg)Ǵe- לচ (HBeAg) ک HBV DNA ܭགࢉࡕΟډѤຼϣёෳளǴ߄Ңੰࢥፄᇙܮ౰Ǵ Ԝਔੰ஻ۘೀܭወҷය໔Ƕط᠌ғϯᔠࢗ౦த܈ੱރр౜΋ډΒঁДࡕǴ HBsAg ک HBV DNA ੃ѨǴ߄य़לᡏ (anti-HBs) р౜Ǵՠځ໔཮Ԗኧຼό฻

ޑ"ޜืය"Ƕ߄य़לᡏߏΦ࡭ុ٠߄ҢԖխࣝΚǶe-לচӭӧനଯՈమᙯữሇન ॶ (ALT) ࡕǴ܈߄य़לচ੃Ѩ߻วғ഍ᙯǴԶ e-לᡏ (anti-HBe) ᒿࡕр౜Ƕ ऩ e-לচ࡭ុຬၸΟঁДǴ߾Ԗࡐଯޑᐒ཮ᙯᡂԋᄌ܄طݹǶ߄य़לচऩӸӧ εܭϤঁДǴᖏ׉΢ᆀࣁᄌ܄ B ࠠطݹǴѝԖϿኧੰٯᗨฅӭܭϤঁДǴՠ߄ य़לচനࡕϝ೏మନԶநൺǶਡЈלᡏ (anti-HBc) ӢਡЈלচ (HBcAg) ޑխ

ࣝ܄ၨ߄य़לচமǴதӧ߄य़לচр౜ࡕ΋ډΒຼջᙯࣁ໚܄Ƕ࡚܄ B ࠠطݹ

ੰࢥགࢉࡕϤঁДϣǴа IgM ਡЈלᡏ (IgM anti-HBc) ϸᔈࣁЬǴϤঁДࡕ߾

IgG ਡЈלᡏڗԶжϐ٠ಖيӸӧǶIgM ਡЈלᡏӭӧΜΒঁДϣ੃ѨǴӢϐ IgM ਡЈלᡏж߄࡚܄ B ࠠطݹੰࢥགࢉǴԶ IgG ਡЈלᡏ໻߄ҢමڙགࢉԶ คݤϩձ࡚܄Ǵᄌ܄܈ࢂς࿶ӣൺЪԖխࣝΚǶךॺว౜୯Γޑ IgM ਡЈלᡏ ӧεऊ΋ъޑᄌ܄ B ࠠطݹ஻ޣև໚܄ϸᔈǹӢԜ୯Γޑ IgM ਡЈלᡏޑਏሽ

୔ձॶᔈ၀೛ۓࣁ 2.4 Կ 2.5 Զߚ၂Ꮚচቷ܌೛ۓޑ 0.8 Կ 1.2Ǵа҅ዴޑ୔ϩ

࡚܄ᆶᄌ܄ B ࠠطݹ)Huang et al. 2006a*Ƕ୯Γ IgM ਡЈלᡏޑၨଯਏሽ୔ձॶ ޑচӢࢂցᆶ୯Γჹܭ B ࠠطݹੰࢥԖၨமޑխࣝϸᔈϝ҂ޕǶ

ԜѦǴךॺว౜Ѡ᡼࡚܄ B ࠠطݹ஻ޣϐੰࢥ୷Ӣࠠа B Ϸ C ࠠࣁЬǴԶ Ъа B ࠠۚӭ!(Huang et al. 2008a)Ƕ೭ঁੰࢥ୷ӢࠠޑϩթᆶѠ᡼ᄌ܄ B ࠠطݹ

࣬՟ǶѠ᡼࡚܄ B ࠠطݹϐੰࢥ୷Ӣࠠ B ࠠ஻ޣޑᖏ׉߄౜ᆶੰࢥ୷Ӣࠠ C ࠠ

஻ޣޑᖏ׉߄౜࣬՟!(Huang et al. 2008a)Ƕ

1.3 ᄌ܄ B ࠠطݹ

ᄌ܄ B ࠠطݹޑԋӢࢂӢஎЬჹ B ࠠطݹੰࢥޑխࣝᐒૈό٫ϐࡺǶ΋૓

Զقࢥఠ܄ T రЃౚ (cytotoxic T lymphocyte, CTL) ёஒ೏ B ࠠطݹੰࢥགࢉޑ طಒझઇᚯǴԶ೷ԋطಒझᚯԝǶՠऩΓᡏϐխࣝᐒૈό٫Ǵߡคݤஒ B ࠠط ݹੰࢥֹӄమନǴԶ೷ԋᄌ܄طݹǶe-לচ໚܄ޑ҆ᒃ܌ғޑᓻ࠸ǴӢխࣝس಍

ۘ҂วػԋዕǴԖ 95% ᐒ཮ԋࣁ B ࠠطݹ஥চޣǶԶԋΓਔයགࢉ B ࠠطݹੰ

ࢥǴ೯தёஒੰࢥֹӄమନǴ໻ 3% Կ 5% ᐒ཮ԋࣁ B ࠠطݹ஥চޣǶ

ᄌ܄ B ࠠطݹޑԾฅੰўёа٩எЬխࣝᆶੰࢥϐҬϕբҔϩࣁ 4 ঁ໘ࢤ:

(1)խࣝऐڙය (immune tolerance): B ࠠطݹੰࢥӧطಒझύεໆፄᇙǴՈమ e- לচ໚܄ǴHBV DNA ᐚࡋሥଯǹطಒझཞ໾ሥᇸǴՈమᙯữሇનॶ ASTǵALT ॶ҅தǹطಔᙃϪТᡉҢᇸ༾ޑᄌ܄วݹǶ(2) խࣝᄂమය (immune clearance):

խࣝϸᔈቚமǴ ࢥఠ܄ T రЃౚװᔐ೏ B ࠠطݹੰࢥགࢉޑطಒझǴ தՔԖ طݹޑ࡚܄วբک e-לচՈమ഍ᙯ (HBeAg seroconversion)ǴHBV DNA ᐚࡋΠ फ़ǹطಔᙃϪТᡉҢᄌ܄ࢲ୏܄طݹ܈ᄌ܄λယ܄طݹǶ(3) ൪Ε܈ූӸය (integrated or residual phase): Ոమᙯữሇનॶ ASTǵALT ॶ҅தǴe-לচ഍܄Ǵ e-לᡏ໚܄ǴHBV DNA ൪ᢃܭطಒझ DNA ϣа൪Ε׎ԄӸӧǹطಔᙃϪТё ᡉҢᇸ༾ᡂϯ܈όࢲ୏܄طݹǶ(4) ൺวය (reactivation phase): Ψᆀࣁ e-לচ഍

܄ᄌ܄ B ࠠطݹǹe-לচᆢ࡭഍܄ޑރᄊΠǴطݹޑ࡚܄วբӆԛวғǶ྽எЬ խࣝᐒૈڙډ׭ڋӵ஥চޣௗڙϯᏢݯᕍ܈Ꮤ۔౽෌ਔǴᄌ܄ B ࠠطݹΨ৒ܰ

ൺว (Huang et al. 2006bǹHuang and Chung 2012)ǶӧխࣝమନයǴطݹϸൺ࡚

܄วբёૈ཮٬ᄌ܄طݹуೲ຾৖ԋఁයطੰǴԶЪႣࡕၨৡ (Huo et al. 2000;

Realdi et al. 1994)Ƕ΋૓ԶقǴطฯϯ܈طಒझᕎޑวғǴᆄຎխࣝᄂమයߏอ ک࡚܄วբϐᝄख़ࡋϷԛኧԶۓǶ

ᝄख़طੰςޕޑ࣬ᜢ॥ᓀхࡴǺଯՈమ B ࠠطݹੰࢥኧໆ (Iloeje et al.

2006)Ǵଯស܈གࢉਔ໔ၨߏǴϸൺޑطݹ࡚܄วբ (Realdi et al. 1994; Huo et al.

2000)Ǵت܄Ǵᑗֿੰ (Huo et al. 2000ǹ Huang et al. 2011)Ǵ HBeAg ࡭ុ໚܄

(Realdi et al. 1994)ǴB ࠠطݹੰࢥ୷Ӣࠠ C ࠠϐགࢉ (Kao et al. 2000)ǴC ࠠطݹ

ੰࢥޑӅӕགࢉ (Liu et al. 2005) ܈ D ࠠطݹੰࢥޑӅӕགࢉ (Tamura et al.

1993)Ǵੰࢥ pre-S લѨޑँᡂਲ਼ (Chen et al. 2006)ǴੰࢥਡЈ௴୏ηँᡂਲ਼ (Lin et al. 2005)ǴଚᆒᔲҔǴط᠌િެکஎЬխࣝރᄊޑׯᡂǴӵ HIV གࢉ܈౽෌ࡕ (Kao 2007)Ƕ

ಃΒക ᄌ܄ B ࠠطݹޑխࣝᒪ໺ ໳ᆶଯǴ҇୯ 97 ԃ

2.1 ΓᜪқՈౚלচ (Human Leukocyte AntigenǴHLA)

BࠠطݹޑੰำڙੰࢥϷஎЬխࣝҬϕբҔޑቹៜ (Chisari et al. 1995)ǶΓ ᜪқՈౚלচ (human leukocyte antigenǴHLA) ࢂ΋ঁख़ाޑஎЬ୷ӢӢηǴᙖ և౜לচቹៜ T-రЃౚޑխࣝፓ࿯ϸᔈ (Benichou et al. 1990)ǶςԖቶݱޑࣴز ᡉҢΓᜪқՈౚלচӭ׎܄ (HLA polymorphism) ᆶ੯ੰܰག܄܈ܢל܄࣬ᜢ (Tiwari and Terasaki 1989)Ǵՠࢂᆶᄌ܄ B ࠠطݹޑ࣬ᜢ܄ѝԖ೽ҽ೏ΑှǶ

ΓᜪқՈౚלচ୷Ӣ୔ୱڋۓܭಃϤჹࢉՅᡏޑอᖉϐ 6p21.3 (Campbell and Trowsdale 1993) ԶЪᏱԖӭঁॉၞ (locus) עಃ΋ǵΒǵΟᜪޑΓᜪқՈౚ לচϩηׯࣁஏዸǶಃ΋ᜪޑΓᜪқՈౚלচхࡴΟঁ alpha ᜘୷ӢǴջࣁ HLA-Aǵ-B Ϸ -CǶಃΒᜪޑΓᜪқՈౚלচЬाޑϩηࣁ HLA-DPǵ-DQ Ϸ -DRǶࡕޣ୔ୱεऊ 800kb ߏԶЪх֖ alpha Ϸ beta ୷ӢǶAlpha Ϸ beta ୷Ӣ

೏Ӽ௨ࣁ DRA Ϸ DRBǴDQA Ϸ DQBǴDPA Ϸ DPB ࣬ଛޑଛჹǶDRB ୷ӢϷ ଵ୷ӢޑኧҞёа٩ൂኳԄᅿԶόӕǶDR alphaǵ DQ alpha Ϸ DP alpha ೈ қᆶځ beta-᜘࣬ଛჹǴՠԖ᛾ᏵᡉҢҬΰଛჹǶ

ΓᜪқՈౚלচϩηև౜לচǴхࡴੰࢥᴏ两 (peptide)Ǵ๏ T-ಒझڙᡏǶ ځ่݀ჹܭੰচ๵ԶقਔதࢂԖ্ޑ (Ceppellini et al. 1989)ǶΓᜪқՈౚלচᏱ Ԗٿঁ੝܄٬ੰচ๵όܰ଒ಥխࣝϸᔈǶ२Ӄࢂӭϡ܄ (polygeny)Ǵཀࡰځ֖Ԗ ኧঁόӕޑಃ΋ᜪϷಃΒᜪΓᜪқՈౚלচ୷ӢǶ؂ঁঁᡏᏱԖ΋঺֖Ԗόӕᴏ 两่ӝ੝܄ޑΓᜪқՈౚלচϩηǶځԛࢂӭ׎܄ (polymorphism)ǴཀࡰΓαύ

ঁձ୷Ӣ֖Ԗӭঁᡂ౦Ƕ

ΓᜪқՈౚלচಃ΋ϷಃΒᜪϩηࢂΓᜪೈқύനڀӭ׎܄ޣǶёэᏵॉၞ

(locus) ޑᡂ౦୷Ӣᆀࣁჹଽ୷Ӣ (allele) ǶΓᜪқՈౚלচჹଽ୷Ӣӧ΋ঁࢉՅ

ᡏޑ੝ۓಔӝᆀࣁൂኳԄᅿ (haplotype)ǶHLA-DRB ॉၞᏱԖຬၸ 400 ঁჹଽ୷ ӢǶӭ׎܄ޑᎩኧ (residue) ௨ӈܭᴏ两่ӝྎኲ (peptide-binding groove) ԶЪ ޔௗᆶᴏ两܈ T-ಒझڙᡏբҔ (Bjorkman et al. 1987)ǶόӕޑΓᜪқՈౚלচჹ ଽ୷ӢϩηԖૈΚ่ӝόӕޑᴏ两Ƕ܌ԖಃΒᜪΓᜪқՈౚלচ୷Ӣӭ׎܄ޑॉ

ၞ೿ӧಃΒঁጓዸ໩ׇ (exon)Ǵځஒ alpha-beta ౦ࠠΒᆫނ (heterodimer) ϐᴏ 两่ӝྎኲ (peptide-binding cleft) ޑ alpha ᖥ௽ރᕅ (helical wall) Ϸ beta ᖩރ Тۭ೽ (pleated sheet floor) ׯࣁஏዸǶӢԜಃΒᜪॉၞޑӭ׎܄،ۓ่ӝྎኲޑ

ࠠރϷև౜๏ T ಒझޑᴏ两ǶBeta ᜘ॉၞࢂᏱԖଯࡋӭ׎܄ޑǶѝԖ alpha ᜘ॉ

ၞϐ DQA1 ҭᏱԖቶݱޑӭ׎܄Ƕ 2.2 ΓᜪқՈౚלচܭ B ࠠطݹགࢉ

೚ӭࣴزගрΓᜪқՈౚלচӭ׎܄ᆶ B ࠠطݹੰࢥ೏எЬᡏϣమନ܈࡭

ុགࢉஎЬԖᜢ (Almarri and Batchelor 1994; Forzani et al. 1984; Hohler et al.

1997; Mota et al. 1987; Thio et al. 1999; Thio et al. 2003; Thursz et al. 1995; van Hattum et al. 1987; Wu et al. 2004; Yang et al. 1989)Ƕ೭٤ൔ֋εӭኧᡉҢ B ࠠط ݹੰࢥ೏எЬᡏϣమନ܈࡭ុགࢉᆶ HLA-DRB1 ӭ׎܄Ԗᜢ (Almarri and Batchelor 1994; Forzani et al. 1984; Hohler et al. 1997; Thio et al. 1999; Thio et al.

2003; Thursz et al. 1995; Wu et al. 2004; Yang et al. 1989)ǴځύхࡴٿঁѠ᡼௼ဂ ޑൔ֋ (Wu et al. 2004; Yang et al. 1989)Ƕ

ܭ 1984 ԃςԖൔ֋ᡉҢ 44 Տကεճ B ࠠطݹ߄य़לচ (HBsAg) ໚܄ᄌ܄

ࢲ୏܄طݹ஻ޣᆶ 526 Տԃសǵ܄ձǵӦ౛ٰྍ࣬ଛჹϐ଼நਈՈޣ࣬КǴ߻ޣ Ԗၨଯޑ HLA-DR3 ᓎ౗ (36.4% vs. 17.1%Ǵp=0.03) Ϸၨեޑ HLA-DR4 ᓎ౗

(0% vs. 18.5%Ǵp=0.002)ǴԶ HLA-AǴBǴC ୷Ӣϐᓎ౗٠คᡉ๱ৡ౦ (Forzani et al. 1984)Ƕ಻ើ௼ဂޑൔ֋ගр 37 Տᄌ܄ࢲ୏܄طݹ஻ޣᆶ 200 Տ HBsAg Ϸ anti-HBs ഍܄଼நਈՈޣ࣬КǴ߻ޣԖၨեޑ HLA-DQw1 ᓎ౗ (37.8% vs.

67.8%Ǵp=0.043) ǴԶ HLA-AǴBǴCǴDR ୷Ӣϐᓎ౗٠คᡉ๱ৡ౦ǶԜൔ֋٬

Ҕ኱ྗ༾ໆరЃౚࢥఠෳ၂ (standard microlymphocytotoxicity tests) Ψ൩ࢂՈమ ᏢБݤ (serological method) ٰुр HLA ϐלচ (van Hattum et al. 1987) ǶՋ٥ ϐьၲ (Qatar) ௼ဂޑൔ֋ᡉҢ 21 Տᄌ܄ B ࠠطݹ߄य़לচ໚܄஻ޣᆶ 100 Տ HBsAg Ϸ anti-HBs ഍܄଼நՈڹਈᜄޣ࣬КǴ߻ޣԖၨեޑ HLA-DR2 ᓎ౗

(14% vs. 46%Ǵp<0.01) Ϸၨଯޑ HLA-DR7 ᓎ౗ (57% vs. 28%Ǵp<0.05)ǴԶಃ

΋ᜪޑΓᜪқՈౚלচ (HLA class I) ϐᓎ౗٠คᡉ๱ৡ౦ǶԜൔ֋٬Ҕ኱ྗ༾

ໆరЃౚࢥఠෳ၂ٰुр HLA ϐלচǴฅࡕεӭኧঁᡏޑ DR Ϸ DQ לচ٬Ҕ ѐ਼ਡᑗਡለ (DNA) - ज़ڋሇનТࢤߏࡋӭ׎܄ (restriction fragment length polymorphismǴRFLP) Бݤٰዴᇡ (Almarri and Batchelor l994)Ƕ

1995ԃϐࡕޑൔ֋ǴಃΒᜪޑΓᜪқՈౚלচ (HLA class IIǴΨ൩ࢂ DR Ϸ DQ) ೿٬Ҕᆫӝ䁙ೱᙹϸᔈ (polymerase chain reactionǴ PCR) ࣁ୷ᘵޑБݤ

ुрǶӧߚࢪҒК٥ (Gambia) ௼ဂ܌଺ޑࣴزᡉр 40 Տ࡭ុ (persistent) གࢉ

ޣ (B ࠠطݹ߄य़לচ໚܄ǴB ࠠطݹਡЈלᡏ IgG (IgG anti-HBc) ໚܄Ϸ B ࠠ طݹਡЈלᡏ IgM (IgM anti-HBc) ഍܄஻ޣ) ᆶ 195 Տอኩ (transient) གࢉޣ (Bࠠطݹ߄य़לচ഍܄ǴB ࠠطݹਡЈלᡏ IgG (IgG anti-HBc) ໚܄Ϸ B ࠠطݹ ਡЈלᡏ IgM (IgM anti-HBc) ഍܄஻ޣ) ࣬КǴ߻ޣԖၨեޑ HLA-DRB1*1302 ᓎ౗ (7.5% vs. 25.6%Ǵp=0.012)ǴԶ HLA-A, B, C ୷Ӣϐᓎ౗٠คᡉ๱ৡ౦ (Thursz et al. 1995)Ƕ೭ൔ֋ޑ B ࠠطݹ࡭ុགࢉϐۓကǴؒԖхࡴ B ࠠطݹ߄ य़לᡏ (anti-HBs) ޑၗ਑ǴԶЪѝҔൂԛՈమᏢᔠᡍ่݀ǴԶ҂યΕϤঁДа

΢ϐᔠᡍϷᖏ׉ၗ਑Ǵࢂ੯ੰۓကϷੰΓϩᜪ΢ޑ΋εલᗺǶ

ቺ୯ଯу઩Γ (CaucasianǴқᅿΓ) ύޑൔ֋ගр 70 Տᄌ܄ B ࠠطݹ஻ޣ (߄य़לচ໚܄Ǵ߄य़לᡏ഍܄ǴIgG ਡЈלᡏ໚܄ԶЪ࿶ख़ፄᔠᡍՈమЧ਽ለ ᙯữሇન (ALT) ೿΢ϲϷ HBV DNA ೿໚܄) ᆶ 101 Տ଼நჹྣޣ࣬КǴ߻ޣ Ԗၨեޑ HLA-DRB1*1301 Ϸ*1302 ᓎ౗ (5.7% vs. 26.7%Ǵp=0.025)ǹ߻ޣӆᆶ 24Տςమନ B ࠠطݹੰࢥ (߄य़לᡏ໚܄ǴIgG ਡЈלᡏ໚܄) ޣ࣬КǴ٩ฅԖ

ၨեޑ HLA-DRB1*1301 Ϸ*1302 ᓎ౗ (5.7% vs. 33.3%Ǵp=0.004)ǴԶ HLA-AǴ BǴCǴDQA1 ୷Ӣϐᓎ౗٠คᡉ๱ৡ౦ (Hohler et al. 1997)Ƕ

ӧߚဴऍ୯Γޑ΋໨ൔ֋ᡉҢр 31 Տ࡭ុ B ࠠطݹੰࢥགࢉޣ (߄य़לচ ӧયΕჴᡍਔϷԿϿϤঁДаࡕ೿໚܄Ǵ߄य़לᡏ഍܄ǴIgG ਡЈלᡏ໚܄) ᆶ 60 Տςమନ B ࠠطݹੰࢥ (߄य़לচ഍܄Ǵ߄य़לᡏ໚܄ǴIgG ਡЈלᡏ໚܄) ޣ ࣬ К Ǵ ߻ ޣ Ԗ ၨ ଯ ޑ HLA-DQA1*0501 ᓎ ౗ (40% vs. 20% Ǵ p=0.05) Ϸ DQB1*0301ᓎ౗ (32% vs. 12%Ǵp=0.01)ǴԶ HLA-AǴBǴDRB1 ୷Ӣϐᓎ౗٠ คᡉ๱ৡ౦ǶԜൔ֋ϐಃ΋ᜪΓᜪқՈౚלচ٬Ҕᆫӝ䁙ೱᙹϸᔈ -ׇӈ஑΋܄

ϐЇη (PCR-sequence specific primer, PCR-SSP) БݤुрǶԶಃΒᜪΓᜪқՈ ౚלচ٬Ҕൂިׇӈࠠᄊӭ׎܄ (single-strand conformation polymorphism) Бݤ ϩ݋у΢ᆫӝ䁙ೱᙹϸᔈ - ׇӈ஑΋܄ϐЇηБݤዴᇡ (Thio et al. 1999)Ƕ

΋໨ଞჹऍ୯ଯу઩Γޑൔ֋ᡉҢ 194 Տ࡭ុ B ࠠطݹੰࢥགࢉޣ (߄य़ לচӧ໔႖ϤঁДа΢ޑٿԛᔠᡍ೿໚܄) ᆶ 342 Տ࣬ଛჹςమନ B ࠠطݹੰࢥ (ӧ໔႖ϤঁДа΢ޑٿԛᔠᡍ߄य़לচ೿഍܄Ǵ߄य़לᡏ೿໚܄Ϸ IgG ਡЈל ᡏ೿໚܄) ޣ࣬КǴ߻ޣԖၨեޑ HLA-A*0301 ᓎ౗(8.1% vs. 15.7%Ǵp=0.0005) Ϸ DRB1*1302 ᓎ౗ (4.9% vs. 2.1%Ǵp=0.03)ǴЪԖၨଯޑ HLA-B*08 ᓎ౗ (12.2%

vs. 8.1%Ǵp=0.03) Ϸ B*44 ᓎ౗ (19.4% vs. 11.9%Ǵp=0.001)ǶԜൔ֋ϐಃ΋ᜪΓ ᜪ қ Ո ౚ ל চ ٬ Ҕ ᆫ ӝ䁙 ೱ ᙹ ϸ ᔈ -ׇ ӈ ੝ ۓ ܄ ჲ ਡ ለ (sequence-specific oligonucleotideǴSSO) Бݤ،ۓϐǶԶಃΒᜪΓᜪқՈౚלচ٬Ҕൂިׇӈࠠᄊ ӭ׎܄ (single-strand conformation polymorphism) Бݤϩ݋у΢ᆫӝ䁙ೱᙹϸᔈ -ׇӈ੝ۓ܄ჲਡለБݤዴᇡ (Thio et al. 2003)Ƕ

а΢೭٤ൔ֋܌ගрᆶ B ࠠطݹੰࢥགࢉԖᜢϐჹଽ୷Ӣ٠ό΋ठǴځচ Ӣхࡴჹଽ୷Ӣϐᓎ౗ӧόӕϐ௼ဂ٠ό࣬ӕǶ߈ԃޑӄ୷ӢಔᜢᖄࣴزᡉҢ HLA-DP ޑᡂ౦ᆶ࡭ុޑ B ࠠطݹགࢉԖᜢǴԶЪӧ٥ࢪ୯ৎύόӕᅿ௼Ԗᜪ

՟ޑ௃׎ (Guo et al. 2011; Kamatani et al. 2009)Ƕࡕុޑࣴزว౜HLA-DQޑᡂ

౦ᆶ࡭ុޑ B ࠠطݹགࢉΨԖ࣬ᜢ (Mbarek et al. 2011)ǶฅԶǴΓᜪқՈౚלচ ӭ׎܄ᆶᄌ܄ B ࠠطݹόӕᖏ׉ੰำϐ࣬ᜢ܄ൔ֋߾ߚதϿǶ

2.3 ᆵ᡼௼ဂϐΓᜪқՈౚלচܭ B ࠠطݹགࢉϷᄌ܄གࢉޑᖏ׉ੰำ

ԖٿঁѠ᡼௼ဂ B ࠠطݹੰࢥ೏எЬᡏϣమନ܈࡭ុགࢉϷᄌ܄ࢲ୏܄ط ݹޑൔ֋Ǵ೿ᡉрᆶ HLA-DRB1 ϐ࣬ᜢ܄Ƕಃ΋ঁࣴزᡉҢ 74 Տᄌ܄ࢲ୏܄ط ݹ (chronic active hepatitis) ஻ޣᆶ 95 Տ HBsAg ଼ந஥চޣ࣬КǴ߻ޣԖၨଯޑ HLA-DR3 ᓎ౗(37% vs. 10%Ǵp<0.05)ǶԜൔ֋٬ҔՈమᏢБݤ (serological method) ٰुр HLA ϐלচǴࣁԐය܌٬ҔޑБݤǴ٠คݤुрჹଽ୷Ӣϐԛ ϩࠠ (Yang et al. 1989)ǶќѦ΋ঁࣴزගрӧѠ᡼ޑᅇΓύǴ98 Տᄌ܄߄य़לচ

໚܄஥চޣ (߄य़לচ࡭ុ໚܄ϤঁДа΢) ᆶ 324 Տςమନ B ࠠطݹੰࢥ (HBsAg഍܄Ǵanti-HBs ໚܄) ޣ࣬КǴ߻ޣԖၨեޑ HLA-DRB1*0406 ᓎ౗ (0%

vs. 4%Ǵp<0.001)ǴԶ HLA-AǴB ୷Ӣϐᓎ౗٠คᡉ๱ৡ౦ǶԜൔ֋ϐΓᜪқՈ ౚ ל চ а ᆫ ӝ䁙 ೱ ᙹ ϸ ᔈ - ׇ ӈ ੝ ۓ ܄ ჲ ਡ ለ ௖ ଞ ᚇ Ҭ (sequence-specific oligonucleotide probe hybridizationǴSSOPH) Бݤۓр (Wu et al. 2004)Ƕ

ќ΋ঁଞჹѠ᡼ᄌ܄ B ࠠطݹੰࢥགࢉϐٽูޑൔ֋ࡰр HLA-B61 Ϸ HLA-DQB1*0503ёႣෳၨଯޑ e לচՈమ഍ᙯϐᐒ౗ (Wu et al. 2006)Ƕᆵ᡼௼

ဂύ HLA-DRB1 ޑᡂ౦ࢂցቹៜ๱ךॺ୯ੰᄌ܄ B ࠠطݹޑ੯ੰᝄख़ࡋࢂߛሡ ӣเޑୢᚒǶ

ಃΟക ᄌ܄ B ࠠطݹޑխࣝڙᡏ

3.1 ᆢғન D խࣝڙᡏ

ᆢғન D բࣁ΋ᅿӄيᐟનǴό໻ୖᆶମᓝжᖴǴԶЪӧፓ࿯எЬխࣝϸ ᔈکᕎੱว৖ΨԖख़ाޑբҔ (Haussler et al. 1998)ǶٯӵǴᆢғન D ё׭ڋర Ѓಒझቚ෗ǴڈᐟൂਡಒझϩϯǴаϷٛЗ൳ᅿᕎಒझᘉණ (Uitterlinden et al.

2004)Ƕᆢғન D ޑࢲ܄׎Ԅ 1,25 - Β♏ᆢғન DǴ೯ၸᆢғન D ڙᡏวචխࣝ

ፓ࿯բҔ (Haussler et al. 1998)ǴԶЪǴѮᏘಒझک T రЃಒझύޑᆢғન D ڙ ᡏᐚࡋཱུଯǴЀځࢂ CD8 ໚܄ T రЃಒझ (Veldman et al. 2000)Ƕ

ᆢғન D ӸӧѮεޑঁᡏৡ౦ΨቶࣁΓޕǶ౛ှᆢғન D խࣝس಍ঁᡏৡ ౦ޑ΋ᅿБݤࢂࣴزӧԜس಍ύख़ाޑೈқ፦ځ DNA ׇӈᡂϯޑቹៜǶٯӵǴ ӧ VDR ୷ӢԖ্ޑँᡂǴᏤठ΋ᅿشـޑൂ୷Ӣ੯ੰ 1,25 - Β♏୷לᆢғન D

܄ը⒥ੱǶVDR ୷ӢׇӈޑϿໆᡂ౦ (ӭ׎܄) ӧΓဂύ׳ᓎᕷӦр౜ǴՠѬॺ ᗋؒԖ೏Ԗس಍ޑϩ݋ǴԶЪჹ VDR фૈޑቹៜޕϐࣗϿǶVDR ӭ׎܄ӧፄᚇ

܄੯ੰک܄ރޑ࣬ᜢ܄ॶள຾΋؁௖૸Ƕ

ӧ೭ঁεޑ୷ӢύѝԖϿኧӭ׎܄ς೏ࣴزǴځύε೽ϩࢂ٬Ҕज़ڋ܄Тࢤ ߏࡋӭ׎܄ (RFLP)ǴՠࢂځфૈբҔ҂ޕǶයࡑೱ่ډձೀ੿҅Ԗфૈޑӭ׎

܄ VDR ୷Ӣ (܈ӧߕ߈ޑ୷Ӣ)ǴฅࡕёаှញᢀჸډޑᜢᖄǶӢԜǴा౛ှ୷ ҁᜢᖄޑᐒڋǴ൩ाϩ݋ VDR ୷Ӣޑ୷Ӣಔ่ᄬǴዴۓব٤୷ӢӸӧܭࢉՅᡏ

୔ୱύǴϩᜪ܌ԖԖᜢޑ VDR ӭ׎܄Ǵዴۓ᏾ঁ୷Ӣޑൂ঺ࠠǴዴۓдॺᆶ٬

ҔԿϞޑ RFLP ኱ᇞϐ໔ޑᜢ߯Ǵ٠നಖᆶ࣬ᜢ୷Ӣࠠࡰ኱຾Չᜢᖄϩ݋ǴΨх

ࡴᆶ੯ੰࡰ኱Ƕ

ᆢғન D ڙᡏ୷ӢՏܭࢉՅᡏ 12q13.1 ΢Ǵӄߏຬၸ 100 kbǶԖᜢ൳ᅿ੯ੰ

ޑεໆࣴزൔ֋Ǵᆢғન D ڙᡏ୷ӢԖΟঁ࣬ᎃޑӭ׎܄ज़ڋՏᗺǴջ BsmI (rs1544410ǴA – Gᡵ୷ँᡂǴࡰۓࣁ୷Ӣࠠ B/BǵB/bǵb/b)ǴApaI (rs7975232Ǵ G – Tᡵ୷ँᡂǴࡰۓࣁ୷Ӣࠠ A/AǵA/aǵa/a) ک TaqI (rs731236ǴT – Cᡵ୷ँ

ᡂǴࡰۓࣁ୷Ӣࠠ T/TǵT/tǵt/t) (Uitterlinden et al. 2004)ǶᏵൔᏤǴt/t ୷Ӣࠠޑ ᆢғન D ڙᡏ୷Ӣᡂ౦ᆶ B ࠠطݹੰࢥమନԖᜢǴԶЪᆢғન D ޑࢲ܄׎Ԅૈ

୼׭ڋᡏѦکᡏϣޑطᕎಒझቚ෗ (Bellamy et al. 1999; Pourgholami et al.

2000)Ƕᆢғન D ڙᡏ୷Ӣᡂ౦ࢂց཮ቹៜᄌ܄ B ࠠطݹޑᖏ׉߄౜аϷځ࣬ᜢ ޑطᕎϐౢғࢂॶள௖૸ޑ᝼ᚒǶ

3.2 ӃϺխࣝᜪ៕ڙᡏ

߈ԃٰǴךॺჹӃϺխࣝޑ౛ှҗܭว౜ኳԄ᛽ձڙᡏ (Pattern recognition receptors, PRRs) Զεࣁׯ๓ǶኳԄ᛽ձڙᡏჸ᝺ੰচᡏޑੰচ࣬ᜢϩηኬԄ (pathogen-associated molecular patterns, PAMPs)Ǵ٠᝻วխࣝϸᔈǶPRRs хࡴᜪ NODڙᡏ (NLRs)Ǵᜪ RIG ڙᡏ (RLRs)Ǵᜪ៕ڙᡏ (TLRs) کന߈ว౜ޑಒझ

፦ DNA ڙᡏ (Carty and Bowie 2010; Hornung et al. 2009; Janeway 1992; Kawai and Akira 2009; Yanai et al. 2009)Ƕ

TLRsࢂಃ΋ࠠၠጢڙᡏǴځхࡴझѦቫ൤ߝ਽ለख़ፄ (Leucine-rich repeat, LRR) ่ᄬ୔Ǵၠጢ୔ک΋ঁಒझ፦៕-ϟқન-1 ڙᡏ-ܢל (Toll-interleukin-1 receptor-resistance, TIR) ่ᄬ୔Ƕᜪ៕ڙᡏёаεठ୔ϩࣁٗ٤Տܭಒझ߄य़ک

ٗ٤Տܭಒझϣޑਡϣᡏ࠻Ƕᜪ៕ڙᡏ-3ǵ7ǵ8 Ϸ 9 ߄౜ӧਡϣᡏ٠ჸ᝺༾ғނ ޑਡለ (Kumar et al. 2009)ǶࣁΑவ೭٤ᜪ៕ڙᡏౢғૻ৲໺ሀǴሡाਡϣᡏለ ϯکԋዕǴᏤठߦวݹಒझᐟનکಃ΋ࠠυᘋનޑౢғ (Uematsu and Akira 2007)Ƕ

ᜪ៕ڙᡏޑΠෞૻ৲໺ሀࢂ೯ၸ֖ᖄௗೈқ MyD88 (ᡎኬϩϯӢη 88)Ǵ MAL (ᜪ՟ MyD88 ᖄௗᏔǴΨ೏ᆀࣁ TIRAP)ǴTRIF (֖ TIR ่ᄬ୔ᖄௗೈқǴ ᇨᏤ IFN-betaǴΨ೏ᆀࣁ TICAM1) ک TRAM (TRIF ࣬ᜢᖄௗϩηǴΨᆀࣁ TICAM2) ޑझϣ TIR ่ᄬ୔ (O’Neill and Bowie 2007)Ƕ೭௼ဂޑಃϖঁԋ঩Ǵ SARM (sterile alpha- and armadillo-motif-containing protein)Ǵς೏ࡰрࢂ TRIF ޑ

׭ᇙᏊ (Carty et al. 2006)Ƕᜪ៕ڙᡏᆶ೭٤ TIR ᖄௗᏔௗӝᏤठझϣૻ৲໺ሀӝ ԋނޑࢲϯǴ೭٤ӝԋނ֖Ԗ TRAF ک IRAK ೈқǴനಖᏤठ NF-kappa B (ਡӢ η-kappa B) ک IRF (υᘋનፓ࿯Ӣη) ৎ௼ᙯᒵӢηޑࢲϯǶ೭ஒ᝻วߦวݹಒ झᐟનکಃ΋ࠠυᘋનޑౢғ (O’Neill and Bowie 2007)ǶNF-kappa B ӧ IL-6 ک ဍዦᚯԝӢη (TNF) ޑғౢύࢂѸ໪ޑǴIFN-beta ࡽሡा NF-kappa B Ψሡा

IRF3ǴԶౢғ IFN-alpha ሡा IRF7 (Takeuchi and Akira 2009)Ƕࣴزς৖Ңᜪ៕ڙ ᡏޑૻ৲໺ሀᐒᙯǺᜪ៕ڙᡏѝૈவਡϣᡏύᇨᏤ IRF3 ک IRF7 ޑࢲϯǴԶځ

дૻ৲ӵࢲϯ MAP ᐟ䁙ک NF-kappa B ёаவ፦ጢ܈ਡϣᡏ᝻ว (Barton and Kagan 2009)Ƕ

ךॺёаஒᜪ៕ڙᡏޑૻ৲໺ሀ᏾౛ԋ೯ၸٿঁ೼৩຾ՉǺᡎኬಒझϩϯӢ η 88 (MyD88) ፓ௓ޑၡ৩ǴϷ៕-ϟқન 1 ڙᡏ (TIR)-֖ᖄௗᏔϐ่ᄬ୔܌ᇨ Ꮴޑ IFN-beta (TRIF)-ፓ௓ޑၡ৩ (Kawai and Akira 2009; Takeuchi and Akira 2009;

Yokota et al. 2010)Ƕ߻ޣᏤठᙯᒵӢη NF-kappa B ޑࢲϯǴёࢲϯӚᅿ୷Ӣߦ຾

วݹϸᔈǶࡕޣ཮ᇨᏤυᘋનǴځڈᐟᏤठಒझޑלੰࢥރᄊǶTLR3 ѝࢲϯ TRIF ፓ௓ޑၡ৩ǶTLR3 ૻ৲໺ሀࢲϯ IRF-3Ǵࢂ IFN-beta ޑ΋ঁख़ाޑᙯᒵӢηǴ ځ཮ᇨᏤυᘋનϐౢғǶTLR2 ѝࢲϯ MyD88 ፓ௓ޑၡ৩ǶฅԶǴ೭ٿঁၡ৩ TLR4೿ёаࢲϯǴ܌а TLR4 ᐟࢲᏊёࢲϯ NF-kappa B کᇨᏤ IFN ғౢǶಒझ ྋ፦ޑኳԄ᛽ձڙᡏǴӵ RIG-IǴMDA5 ک DAIǴதࢲϯ IRF3ǶኳԄ᛽ձڙᡏޑ ߄౜٩ಒझᜪࠠԶԖ܌όӕǶ׳ख़ाޑࢂǴྍԾମᡎ܄༸ಒझ (ମᡎኬᐋँރಒ झ [mDCs]ǴൂਡಒझǴѮᏘಒझǴLangerhans ಒझǴک༐ύ܄қՈౚ) کྍԾ రЃ܄༸ಒझ (ዀಒझኬᐋँಒझ [pDCs]ǴT ಒझک B ಒझ) ޣό࣬ӕǶٯӵǴ TLR7ک TLR9 ࢂࡐϿ߄౜ӧ mDCsǴԶ TLR3 ک TLR8 ࡐϿ߄౜ӧ pDCsǶԶ TLR4 ӧ pDCs ک mDCs ޑ߄౜ໆߚதեǶ

Ԑයޑ᛾ᏵᡉҢᜪ៕ڙᡏӧჸ᝺ੰࢥ΢ёૈࢂख़ाޑǴ೭٤᛾Ᏽࢂவᢀჸډ

΋٤ੰࢥϐጓዸೈқаᜪ៕ڙᡏૻ৲໺ሀࣁҞ኱ǶٯӵǴФรੰࢥ (Vaccinia virus, VACV) ޑࣴزว౜ٿᅿ׭ڋᜪ៕ڙᡏس಍ޑೈқ፦ǶA46R ᆶ TIR ᖄௗᏔ่ӝ

٬ᜪ៕ڙᡏૻ৲໺ሀΠፓǴԶ A52R ᆶ IRAK2 ่ӝёа׭ڋᜪ៕ڙᡏፓ௓ޑ NF-kappa Bࢲϯ (Maloney et al. 2005; Stack et al. 2005)ǶC ࠠطݹੰࢥ (HCV) ࢂ ќ΋ᅿੰࢥаጓዸೈқ׭ڋᜪ៕ڙᡏፓ௓ૻ৲໺ሀǴӢࣁѬޑೈқ䁙 NS3/4A Ϫ ନ TRIFǴԶ NS5A ׭ڋ MyD88 (Abe et al. 2007; Li et al. 2005)Ƕ೭ԜϷځдੰࢥ ჹᜪ៕ڙᡏϐ׭ڋԖշܭੰࢥϐࢥ܄ (Bowie and Unterholzner 2008)Ƕᜪ៕ڙᡏ ৎ௼ԋ঩ୖᆶჹੰࢥགࢉౢғϸᔈޣԖ TLR1ǴTLR2ǴTLR3ǴTLR4ǴTLR6Ǵ TLR7ǴTLR8 ک TLR9 (Takeuchi and Akira 2009)Ƕ

ᜪ៕ڙᡏ-3Ǵ7Ǵ8 ک 9 ςޕૈᒣᇡੰࢥਡለǴЪΓᜪޑᜪ៕ڙᡏ-3 ᆶᜪ៕

ڙᡏ-7Ǵ8 ک 9 ڀԖᡉ๱ӕྍ܄ (Iwasaki and Medzhitov 2004)Ƕᜪ៕ڙᡏ-3 ϩѲ ӧ ಒ झ ጢ ܈ ਡ ϣ ᡏ ΢ Ǵ х ֖ ΋ ঁ ё ᆶ ଛ Տ ᡏ ่ ӝ ޑ Ѯ ε झ Ѧ ୔ ܌ ಔ ԋ (Matsumoto and Seya 2008; Ranjith-Kumar et al. 2007)Ƕᜪ៕ڙᡏ-3 ೏᛾ܴࢂᚈި

RNA ޑڙᡏǴаϷୀෳ΋٤ RNA ੰࢥǴΨёаୀෳӧғڮຼයౢғᚈި RNA ϐ DNA ੰࢥ (Yoneyama and Fujita 2010)Ƕ஥Ԗᜪ៕ڙᡏ-3 ୷Ӣँᡂϐੰ஻ᆶኧ ᅿᄌ܄ੰࢥགࢉԖ࣬ᜢᖄǴхࡴѮಒझੰࢥ܄طݹکੰࢥՈੱ (Nahum et al.

2011)Ǵ ࢬགੰࢥ࣬ᜢ܄တੰᡂ (Hidaka et al. 2006)ǴаϷൂપ੺੶ੰࢥ (HSV)

܄တݹ (Zhang et al. 2007)Ƕٿঁൂપ੺੶ੰࢥတݹޑൺวঁਢསҢΑᜪ៕ڙᡏ-3 ӧൂપ੺੶ੰࢥወҷޑفՅ (Bousfiha et al. 2010; Netea and van der Meer 2011)Ƕ ԜѦǴᜪ៕ڙᡏ-3 ૻ৲໺ሀёаፓ௓ࡕϺխࣝϸᔈаܢלੰࢥགࢉ (Schulz et al.

2005)Ƕᜪ៕ڙᡏ-3 ӧᄌ܄˾ࠠطݹ஻ޣϐفՅॶள຾΋؁ᙶమǶ

ಃѤക ᄌ܄ B ࠠطݹޑխࣝፓ࿯

4.1 ੰࢥᆶӃϺխࣝ

எЬޑխࣝس಍᛽ձک੃ନΕߟޑੰচ༾ғނǴӵੰࢥǴಒ๵ک੿๵Ƕӧথ ٢୏ނٛᑇޑಃ΋ጕǴࢂӃϺխࣝس಍ǶჹלੰࢥགࢉޑԐයϸᔈଆۈܭኳԄ᛽

ձϩηᒣᇡੰচ࣬ᜢϩηኬԄ (PAMPs)ǴԶЇวΑٿᅿϸᔈǶ΋ᅿࢂᇙ೷рυ ᘋન (IFNs) ᏤठלੰࢥރᄊǴԜࣁӃϺխࣝϸᔈޑ΋೽ϩǴಃΒࢂᐋँރಒझ (DC) ޑԋዕϯԶࡌҥࡕϺխࣝǶךॺޑࣴزขᗺӧܭஎЬٛᑇಃ΋ጕޑӃϺխ

ࣝǶ

ൂਡಒझǵѮᏘಒझǵT ಒझǵB ಒझǵpDC ک mDC ӧՈᆅǵరЃᆅϣൻ ᕉЪӧ໔፦ϣْᡄǶ೭٤܌ԖޑಒझࢂੰࢥགࢉޑወӧҞ኱Ƕੰࢥགࢉޑ΢Ҝಒ झکᠼᆢಒझౢғυᘋનǴЬाࢂ IFN-beta ک IFN-lambdaǴѬ٬ڬൎ҂གࢉޑ ಒझڀԖלੰࢥϐރᄊǶԜѦǴᖿϯનکಒझᐟનǴӵϟқન-1 beta (IL-1 beta)Ǵ

IL-6ǴIL-8Ǵᗭಈ܄ൂਡౚ- ѮᏘಒझ໣ပڈᐟӢη (GM-CSF) ϷဍዦᚯԝӢη -alpha (TNF-alpha) Ψ཮ౢғǶ೭٤ϩηගٮচԖޑ DCs (ڰԖቫᐋँಒझک Langerhansಒझ) ӛੰࢥགࢉϐಒझکԝಒझޑᖿϯբҔǶ༐ύ܄қՈౚǴൂਡ ౚǴѮᏘಒझǴዀಒझǴmDCs ک pDCs ΨவՈᆅ౽୏ډڙགࢉޑ೽ՏǶIFN-gamma ᇨᏤೈқ 10 (IP-10)Ǵൂਡౚᖿϯೈқ 1 (MCP-1)ǴѮᏘಒझวݹೈқ-2 (MIP-2)Ǵ MIP-3 alphaǴMIP-3 beta ჹՈనޑ DCs ౽୏ԖࡐεޑᔅշǶฅԶǴ೭٤࿶Ոన౽

୏ޑխࣝಒझΨёૈ೏ੰࢥགࢉǴฅࡕ೭٤խࣝಒझёаፓ࿯Ӛᅿಒझᐟનکᖿ ϯનޑౢғǶ

ࣁΑዴҥགࢉǴੰࢥሡा׭ڋஎЬϐ΋٤խࣝϸᔈǴٯӵυᘋનᇨᏤޑלੰ

ࢥࢲ܄Ǵᖿϯન܈ಒझᐟનᇨᏤϐխࣝಒझޑᖿϯբҔǴDCs ޑԋዕکࢲϯǴ NKک NKT ಒझޑࢲϯǴԋዕޑ DCs ϐ౽୏ԿరЃ่ǴᆶӧరЃ่ޑ T ಒझک BಒझޑϩϯϷࢲϯǶ྽ੰࢥགࢉխࣝಒझǴӵ DCsǴڙགࢉಒझޑԋዕکϩϯ

࿶த೏׭ڋǴಒझᐟનڙᡏکӅڈᐟϩηޑ߄౜Ψ೏׭ڋǴԶϩݜрᜪ՟ಒझᐟ નکಒझᐟનڙᡏޑϩηǶԜѦǴڙགࢉޑಒझ࿶தׯᡂдॺޑಒझᐟનࠠᄊǶ ೭٤ࢂੰࢥҔٰ׭ڋխࣝϸᔈޑ฼ౣǴԶЪੰࢥགࢉΨ཮ᇨᏤፓ᏾܄ T ಒझ (regulatory T cells)Ƕ

4.2 எЬᆶ B ࠠطݹੰࢥϐҬϕբҔ

ࣁΑዴҥགࢉஎЬǴੰࢥ൩Ѹ໪аӚᅿ฼ౣᘍಥک/܈׭ڋխࣝس಍Ƕੰࢥ ޑ΋ঁख़ा฼ౣࢂፓ࿯ PAMP ᇨᏤޑխࣝϸᔈǶᄌ܄ੰࢥޑགࢉёૈ٬எЬჹ ၀ੰࢥޑխࣝคΚ (immune anergy) ᆶऐڙ (immune tolerance)Ƕຫٰຫӭޑ᛾

ᏵᡉҢ B ࠠطݹੰࢥёаѐନಃ΋ࠠυᘋનǶӧᄌ܄ B ࠠطݹགࢉύǴЬाᇙ

೷υᘋન alpha ޑዀಒझ܄ᐋँಒझԖфૈ܄ϐߺ১ (van der Molen et al.

2004)ǶќѦǴᄌ܄ B ࠠطݹགࢉΨफ़եᐋँಒझ (dendritic cells) ଆ୏ T రЃಒ झޑфૈаϷफ़եಒझᐟનޑౢғ (Beckebaum et al. 2002, 2003; Milich et al.

1995; Zheng et al. 2004)ǶࣴزΨዂమ B ࠠطݹੰࢥ཮׭ڋᜪ៕ڙᡏᇨᏤޑط᠌ל

ੰࢥࢲ܄ (Wu et al. 2009)ǴԶЪ΋໨ൔ֋ࡰр B ࠠطݹੰࢥᆫӝ䁙ёаமਏޑ

׭ᇙᜪ៕ڙᡏ-3 ܌ፓှޑυᘋન-beta (Yu et al. 2010)ǶԐයޑࣴزΨ߄ܴ B ࠠط ݹੰࢥᆫӝ䁙ಖᆄೈқ୔ୱޑ߄౜཮׭ڋಒझჹυᘋન-alpha کυᘋન-gamma аϷᚈި RNA ޑϸᔈ (Foster et al. 1991)Ƕ

ӧ୷Ӣᙯ෗λႵኳࠠύǴଛՏᡏ่ӝӧᜪ៕ڙᡏ-3ǵᜪ៕ڙᡏ-4ǵᜪ៕ڙᡏ -5ǵᜪ៕ڙᡏ-7ǵᜪ៕ڙᡏ-9 ΢Їଆυᘋન alpha/beta - ٩ᒘ܄ϐБԄа׭ڋ B

ࠠطݹੰࢥޑፄᇙǴՠᜪ៕ڙᡏ-2 ߾ց (Isogawa et al. 2005)ǶࣴزΨ᛾ჴᜪ៕ڙ ᡏ-3 ܌ڈᐟϐλႵط᠌ߚჴ፦ಒझ (non-parenchymal cells, NPCs) ஒᇨᏤυᘋન -betaکᒿࡕ׭ڋ B ࠠطݹੰࢥϐፄᇙ (Wu et al. 2007)ǴԶЪᄌ܄ B ࠠطݹ஻ޣ ޑݹ܄طཞ໾ᆶ৤Мಒझޑ Fas-L ߄౜ໆቚуԖᜢ (Tang et al. 2003)ǶԜѦǴB

ࠠطݹੰࢥϐ࡭ុ܄གࢉёૈࢂҗܭط᠌ύલЮౢғלੰࢥಒझᐟનޑಒझ (Tang et al. 2003)Ƕ΋໨ࣴزᡉҢǴᆶ B ࠠطݹ e-לচ (HBeAg) ഍܄ޑ஻ޣ࣬

КǴB ࠠطݹ e-לচ໚܄ӧຼᜐՈనൂਡౚಒझ (Peripheral blood mononuclear cells, PBMC)ǵطಒझǵ৤Мಒझޑᜪ៕ڙᡏ-2 ߄౜ໆ෧ϿǴՠᜪ៕ڙᡏ-4 ߾ց (Visvanathan et al. 2007)ǶӧᡏѦ٬Ҕᜪ៕ڙᡏ-2 ଛՏᡏڈᐟ e-לচ໚܄ᄌ܄ B

ࠠطݹ஻ޣޑڬᜐՈనൂਡౚ೷ԋ TNF-alpha ک IL-6 ޑᡉ๱׭ڋǶᜪ៕ڙᡏ-2 Տܭಒझጢ΢ǴԶЪѬޑଛՏᡏёૈӧಒ๵ޑિೈқύว౜Ƕ

4.3 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

Β

Βǵᆢғન D խࣝڙᡏ୷Ӣӭ׎܄ᆶᄌ܄ B ࠠطݹޑطݹ࡚܄วբǵe-לচ௃

ݩаϷطಒझᕎౢғϐ࣬ᜢ܄ࣴز

வ 1990 ԃԿ 1995 ԃ໔ǴѠεᙴଣगဉطᖌࣽۓයჹ 250 ٯᄌ܄ B ࠠطݹ

ੰࢥ஥চޣ (178 Ӝت܄ک 72 Ӝζ܄Ǵԃសӧ 16 Կ 70 ྃϐ໔) ຾Չ߻ᘳ܄Шж

ࣴزǶךॺଓᙫ೭٤஥চޣ࡭ុډ 2003 ԃ 10 ДǴ೭ਔ಄ӝచҹޑ஻ޣ໒ۈௗڙ ӄ଼҇நߥᓀ๏бޑלੰࢥݯᕍǶᄌ܄ B ࠠطݹੰࢥ஥চޣࢂࡰݯᕍ߻ B ࠠط ݹ߄य़לচ஥চԿϿၲ 6 ঁДޑ஻ޣǶ೭ࣴز௨ନΑ٬Ҕਡ㧿(ለ)ᜪ՟ނǵխࣝ

ፓ࿯Ꮚ܈Ҝ፦ᜪڰᎇݯᕍޑ஥চޣǵC ࠠطݹੰࢥ܈ D ࠠطݹੰࢥགࢉޣǵΓ ᜪխࣝલഐੰࢥགࢉޣǵଚᆒᔲҔޣ (؂Ϻຬၸ 50 լ)ǵᓉેݙ৔ࢥࠔޣǵطࢥ નኪ៛ޣǵԾᡏխࣝלᡏ໚܄஻ޣǵ஻Ԗςޕжᖴ܄طੰޑ஻ޣǵط᠌౽෌ࡕޑ

஻ޣǶ߄ѤӈрΑҁࣴز஥চޣޑ୷ҁ੝ቻǶ

Bࠠطݹੰࢥ஥চޣϩࣁ 6 ঁόӕޑಔձ (Kao et al. 2002)ǶA ಔǺୖуࣴ

زਔǴHBeAg և໚܄Ǵଓᙫය໔Ǵคطݹ࡚܄วբ܈ HBeAg Ոమ഍ᙯǹB ಔǺ

ୖуࣴزਔǴHBeAg և໚܄ǴHBeAg Ոమ഍ᙯ߻Ԗطݹ࡚܄วբ௃׎ǹC ಔǺ

ୖуࣴزਔǴHBeAg և໚܄ǴԖطݹ࡚܄วբǴଓᙫ่״ਔǴค HBeAg Ոమ഍

ᙯǹD ಔǺୖуࣴزਔǴHBeAg և഍܄Ǵଓᙫය໔ǴԖطݹ࡚܄วբ௃׎ǹE ಔǺୖуࣴزਔǴHBeAg և഍܄Ǵଓᙫය໔Ǵคطݹ࡚܄วբǹF ಔǺୖуࣴ

زਔ܈ଓᙫය໔ǴวғطಒझᕎǴطಒझᕎບᘐ٩คߟ᠍܄ບᘐ኱ྗ܈྽ό಄ӝ 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

Ο

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

ӧ೭໨߻ᘳ܄ШжࣴزύǴךॺӧ୯ੀᆕӝᙴଣᙴᏢύЈவ 2009 ԃ 6 ДԿ 2012ԃ 8 ДೱុયΕ 127 ٯᄌ܄ B ࠠطݹ஻ޣک 64 ٯ B ࠠطݹ߄य़לচ (HBsAg)

഍܄аϷ C ࠠطݹੰࢥלᡏ (anti-HCV) ഍܄ޑ଼நڙ၂ޣբࣁჹྣǶᄌ܄ B ࠠ طݹ೏ۓကࣁӧયΕҁࣴز߻ǴB ࠠطݹ߄य़לচ໚܄ԿϿ 6 ঁДǶ஻ޣӧ΋ԃ ϣௗڙၸਡ㧿ለᜪ՟ނ܈ (ߏਏࠠ) υᘋનݯᕍ܈٬Ҕխࣝፓ࿯Ꮚǵᜪڰᎇǵϯ ᕍᛰނǴӕਔགࢉ C ࠠطݹǵD ࠠطݹੰࢥǵΓᜪխࣝલЮੰࢥǴԖԾᡏխࣝ

לᡏǵҘރဏ੯ੰǵжᖴ܄طੰǵطฯϯǵطᕎǴ࿶ၸ౽෌܈ഀଚ೿೏௨ନӧѦǶ ୯ੀᆕӝᙴଣޑΓᡏ၂ᡍہ঩཮ਡ঑Α೭໨ࣴزǴ؂Տڙ၂ޣ೿ςᛝ࿿ޕ௃ӕཀ ਜǶ

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

ךॺયΕΑ 19 Ӝᄌ܄ B ࠠطݹ஻ޣǴхࡴ໻ௗڙਡ㧿ᜪ՟ނаϷ໺಍υᘋ નک lamivudine ࣬ᝩӝٳݯᕍޣǶ೭٤஻ޣ٩ᏵځόӕޑݯᕍБݤϩࣁΟಔǶಃ

΋ಔયΕ 10 Ӝت܄஻ޣ(ѳ֡ԃស 44.2 ྃǴጄൎ 30 Կ 74 ྃ)Ǵௗڙ 44 Կ 48 ຼ ޑਡ㧿ᜪ՟ނൂ΋ݯᕍǶಃΒಔયΕ 6 Ӝت܄஻ޣ(ѳ֡ԃស 47.3 ྃǴጄൎ 39 Կ 56 ྃ)Ƕځύ 5 Ӝௗڙ 34 Կ 52 ຼޑ lamivudine ݯᕍǴฅࡕׯࣁ 24 Կ 36 ຼޑ

໺಍υᘋનݯᕍǴځ໔ٿᅿᛰނԖ 4 Կ 20 ຼޑख़᠄Ƕ೭ಔύќѦޑ΋Տ஻ޣௗ

ڙ 36 ຼޑ໺಍υᘋનݯᕍǴฅࡕׯࣁ 32 ຼޑ lamivudine ݯᕍǴځ໔ٿᅿᛰԖ 12ຼޑख़᠄ǶಃΟಔયΕ 3 Ӝت܄஻ޣ(ѳ֡ԃស 51.3 ྃǴጄൎ 41 Կ 64 ྃ)Ǵ

ௗڙ 20 Կ 24 ຼޑ lamivudine ݯᕍǴଶᛰࡕଓᙫ 22 Կ 36 ຼǶ೭٤஻ޣޑՈమᔠ ᡏ௦໣ܭځ຾Չݯᕍ߻کݯᕍύ؂႖ 2 ຼԿ 3 ঁДǴޔډݯᕍ܈ଓᙫ่״Ƕ೭٤

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

ࣾǶӧ 72⁰CΠۯ՜ 5 ϩដࡕ่״ǶApaI ک TaqI ӭ׎܄ޑ PCR ϸᔈచҹӵ΢܌

ॊǴՠᗹӝྕࡋࣁ 68⁰CǶBsmI ӭ׎܄ޑ PCR ౢނߏࡋࣁ 800bpǴӧ BsmI 䁙Ϫ ՏᗺǴϪᘐࣁٿঁज़ڋ܄Тࢤ 600 bps ک 200 bpsǶApaI ک TaqI ӭ׎܄ PCR ౢނ ߏࡋࣁ 480 bpsǶӧӚԾޑ䁙Ϫज़ڋ܄ՏᗺǴApaI ޑज़ڋ܄Тࢤߏࡋࣁ 250 bps ک 230 bpsǴTaqI ޑज़ڋ܄Тࢤߏࡋࣁ 280 bps ک 200 bpsǶ䁙ϪТࢤҔ 2ʘ ᛏિ

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

ၲ 10 ࣾϷӧ 58 ^oCၲ 30 ࣾύ຾ՉǶ ؂ঁ၂ᡍхࡴΒख़ൺऊ 25 ngtotal RNA ޑᔠ ᡏǶךॺ٬Ҕ GAPDH mRNA ྽ϣ೽௓ڋǶط᠌ಔᙃޑᜪ៕ڙᡏ-3 mRNA ࣬ჹ

֖ໆࢂ٬Ҕ GAPDH mRNA ֖ໆа኱ྗϯϐǴ٠Ъа–ǻCT= - (CT(TLR3) - CT(GAPDH)) ߄ҢǶᜪ៕ڙᡏ-3 ޑ mRNA ኧໆ࣬ၨܭ GAPDH ޑ mRNA ኧໆϐК౗ीᆉࣁ 2^-ǻCT x KǴځύ K ࢂ΋ঁதኧǶ

ط

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

հএطಔᙃޑೱុϪТܫ࿼ӧᙟᇂ๱ᆫ-L-ᚆ਽ለ (poly-L-lysine) ၩ࣒Т

΢Ǵ٠٬ځଳᔿ 30 ϩដǴฅࡕڰۓӧ 100ʘЧ✉ύ 15 ϩដǶಔᙃϪТаᕗለᡶ

጗ፂన (phosphate buffered saline, PBS) ࢱᅗΟԛӚ 5 ϩដǴϐࡕ੆Ε֖Ԗ 2% ၸ

਼ ϯ ణ (H2O2) ޑ Ҙ ᎇ ύ 25 ϩ ដ а ѐ ࢲ ϯ ϣ ྍ ܄ ၸ ਼ ϯ䁙 (endogenous peroxidase)Ǵ٠Ҕ 1% ФՈమқೈқߔ႖Ƕߔ႖ࡕаีញ 1:50 ϐᜪ៕ڙᡏ-3 ל

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

่

่݀

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

ᜢ܄

204Ӝ B طੰࢥ஥চޣޑ୷ҁ੝ቻӵ߄΋܌ҢǶALTɪ80U/L ޑ஻ޣ (ѳ֡

42ྃǴவ 22 ྃډ 75 ྃ) ܴᡉК ALT < 80U/L (ѳ֡ 46 ྃǴவ 20 ྃډ 79 ྃ)ԃ ᇸ (p=0.042)ǴЪӭኧࣁت܄ (106 vs. 25Ǵp=0.016)Ƕӧଓᙫਔ໔کੰࢥӢન (e- לচǴe-לᡏǴੰࢥ୷ӢࠠǴੰࢥኧໆ) ΢ٿಔ٠ؒԖᡉ๱ৡ౦Ƕت܄کζ܄ B طੰࢥ஥চޣޑঁձ HLA-DRB1 ჹଽ୷Ӣᓎ౗ϩթϩձӵ߄Βک߄Ο܌ҢǶ՞

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

຾΋؁ԛϩࠠඟҢΑᡉ๱ၨᓎᕷࢂឦܭ“ځд”ࠠձǴ೭΋ࠠࢂӝٳ܌Ԗჹଽ୷Ӣ ᓎ౗եܭ 5% ޣǴԶόࢂᓎ౗നଯޑ DRB1*1401 ჹଽ୷Ӣηࠠ(8.0% vs. 4.7%Ǵ pɨ0.111)Ƕӧόӕ ALT ॶޑζ܄ B طੰࢥ஥চޣύؒԖว౜ HLA-DRB1 ჹଽ

୷Ӣᓎ౗ޑܴᡉৡձǶᗨฅӧӭԛෳ၂ਠ҅ࡕت܄஥চޣϐ໔ჹଽ୷Ӣᓎ౗ޑৡ ౦όӧܴᡉǴ٩ྣ ALT ॶଯեᗋࢂԖ΋ঁወӧޑቚуᖿ༈ǶӢႣ՗ޑ॥ᓀؒԖ ৡ౦Ǵ຾΋؁ޑϩ݋٬Ҕ܌Ԗځдޑჹଽ୷ӢբࣁୖԵࠠǴ࿶܄ձፓ᏾ࡕǴᡉҢ Ѝ࡭ HLA-DRB1*1101 ک ALT < 80U/L ϐ໔Ԗᜢೱ (კ΋)Ƕ೭ኬǴӧ଺ԃសፓ

᏾ࡕǴӧ ALT < 80U/L ᆶ ALT • 80U/L ޑ B طੰࢥ஥চޣޑКၨύǴت܄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