12 ໌͕Γ; IPF 13 ໌Ν؜΋࣯ؔ੓഑Ԏ ׳ं16 ໌͹݄ੜΝ༽͏ͱɾϜ΢έϫΠϪ΢๑Ͳમఈͪ͢10 झྪ͹ࣙހ߇ରͶͯ͏ͱɾProtoplex™ͶΓΖൔఈྖΝߨͮ (6)5 ͪɿ10 झྪ͹ࣙހ߇ର͹஦Ͳɾ߇ UBE2T ߇ର͹ܮޭکౕ ͹஦ԟ஍ (൥ҕ) ͺɾ࣯ؔ੓഑Ԏ׳ं܊Ͳ ɾ ݊৙ं܊Ͳ Ͳ͍Εɾ࣯ؔ੓഑Ԏ܊Ͳܮޭکౕ ༙͗қͶ߶஍Ν

㛫㉁ᛶ⫵⅖࡟࠾ࡅࡿ᪂つ⾑୰⮬ᕫᢠయࡢ᥈⣴

㸦せ⣙㸧

᪥ᮏ኱Ꮫ኱Ꮫ㝔་Ꮫ◊✲⛉༤ኈㄢ⛬

ෆ⛉⣔࿧྾ჾෆ⛉Ꮫᑓᨷ ᘬᆅ 㯞᲍

ಟ஢ᖺ 2019 ᖺ ᣦᑟᩍဨ Ḓ ᑀ༤

1

პ ॻॻݶ

࣯ؔ੓഑Ԏͺɾ഑๖྘ҮΏࡋـ؇ࢩ྘Ү͹࣯ؔͶતңԿ Νਫ਼ͣΖ഑࣮׳͹૱সͲ͍Εɾಝ൅੓Ͷਫ਼ͣΖ΍͹Νಝ൅

੓࣯ؔ੓഑Ԏ (idiopathic interstitial pneumonias: IIPs)¹⁾ͳݼস

ͤΖɿIIPs ͹஦Ͷͺɾཱི֮ͪ͢᡾ݬබͳ͢ͱ͹ਏஇΝຮͪ

͠͵͏΍͹͹ɾࣙހ໖ӺഐܢΝ༙ͤΖͳߡ͓ΔΗΖ঳ྭ͗

਼ଡ͚ଚࡑ͢ɾ͞ΗΔͺ׳ंഐܢΏ࣮׳͹༩ޛͶҲఈ͹ಝ

௅Ν΍ͯγϔήϩʖϕͳ͢ͱߡ͓ΔΗͱ͏Ζ ^2~4)ɿIIPs ͹஦

Ͳɾ࠹΍༩ޛ͹ѳ͏ಝ൅੓഑તң঳ʤidiopathic pulmonary fibrosis: IPFʥ⁵⁾ͺɾࣙހ໖ӺഐܢΝ༙ͤΖ࣯ؔ੓഑ԎΝوఈ

ͪ͢ਏஇخ६Ͳ͍Ζ interstitial pneumonia with auto-immune features (IPAF) ͖Δঈ֐͠Ηͱ͏Ζ͗⁶⁾ɾҲ๏Ͳͺ IPF ͹බ ସͶࣙހ໖Ӻ͗ؖ༫ͤΖ͞ͳΝࢨఢͤΖๅࠄ΍ଡ͚ଚࡑͤ

Ζ^7~9)ɿ͞͹͞ͳΓΕɾࠕΉͲࣙހ໖ӺഐܢΝ΍࣯ͯؔ੓഑

Ԏ͹ਏஇ࣎Ͷ༽͏ͱ͏ͪعଚ͹݄஦ࣙހ߇ର͗ɾࣙހ໖Ӻ බସΝ༙ͤΖ IPF Νॉ෾Ͷபड़Ͳ͘ͱ͏͵͏ͳ͏͑ՀઈΝ

ͪͱɾ͞ΗΝݗৄͤΖͪΌͶɾࣙހ໖ӺබସͶಝҡద͵৿

و݄஦ࣙހ߇ର͹ݗड़ΝࢾΊͪɿΉͪɾݗड़ͪࣙ͢ހ߇ର

2

͹ೳౕ଎ఈ๑Νཱི֮͢ɾଠ͹࣯ؔ੓഑ԎͳർֳͤΖ͞ͳͲɾ

৿ͪͶݗड़ͪࣙ͢ހ߇ର͹࣯ؔ੓഑ԎͶ͕͜ΖҒ஖Ͱ͜Ώ

ྡজదՃ஍Νݗ౾ͪ͢.

ჟɿɿࡒྋɾ๏๑

ຌݜڂͺ࣯ؔ੓഑Ԏ͹݄ӹώ΢ΨϜʖΩʖ͹धཱིΝ໪ద Ͷೖຌ୉ָҫָ෨෡଒൚ڰබӅͲࣰࢬͪ͢ୱҲࢬઅͲ͹઴

޴͘؏ࡱݜڂͲɾೖຌ୉ָҫָ෨෡଒൚ڰබӅྡজݜڂྛ

ཀྵҗҽճ͹ট೟Νಚͱ͏Ζɿ݄ӹݗରͺೖຌ୉ָҫָ෨෡

଒൚ڰබӅݼٷح಼ՌΝणਏͪ͢׳ंΉͪ݊৙ϚϧϱτΡ ΠΓΕ఑ڛΝणͪ͜΍͹Ͳɾ഑ૌ৭ݗରͺಋӅͲ֐Ռघढ़ Νࢬߨ͢ɾఢड़ͪ͢഑͹࢔༪ݗରΝཤ༽ͪ͢ɿ͏ͥΗ΍ɾ ݗର͹ཤ༽Ͷͯ͏ͱ఑ڛंΓΕಋқΝಚͱ͏Ζɿ࣯ؔ੓഑

Ԏ׳ं͹݄஦ࣙހ߇ରΝηέϨʖωϱήͤΖͪΌͶɾϕϫ τ΢ϱϜ΢έϫΠϪ΢Ͳ͍ΖProtoArray v5.0 Human Protein Microarray® (Invitrogen. Carlsbad, CA) Ν༽͏ͪɿ͞͹Ϝ΢

έϫΠϪ΢ορϕͶͺɾ׮સௗϐφνϱϏέ࣯͗߻ܯ9,483 झྪΆʹݽ૮Կ͠Ηͱ͏ΖɿορϕͶ࣯ؔ੓഑Ԏ׳ं͕Γ

3

;݊৙ं͹݄ੜΝൕԢͦ͠ɾܮޭඬࣟͪ͢߇ϐφ IgG ߇ର Ν༽͏ͱɾݽ૮ԿνϱϏέΝࣙހ߇ݬͳͤΖ݄ੜ஦ࣙހ߇ ରΝܮޭ൅৯ͶΓΕݗड़ͪ͢ɿProtoplex™ͺɾܮޭϛϨΦο ϪϱϑʖθͶ߇ GST ߇ରΝղ͢ͱϐφʀϨαϱϑψϱφν ϱϏέΝ෉Յͪ͢෵߻ରͶɾ݄ੜγϱϕϩΝൕԢͦ͠Ζ͞

ͳͲɾ໪ద͹ࣙހ߇ରΝݗड़ͤΖ๏๑Ͳ͍ΖɿProtoplex™ͺ Ϝ΢έϫΠϪ΢๑ͶΓΕηέϨʖωϱή݄ͪ͢ੜ஦ࣙހ߇ ର͹ଁՅΝ࠸ౕݗৄͤΖͪΌͶࢬߨͪ͢ɿ߇ ubiquitin- conjugated enzyme E2T (UBE2T) ߇ ର ͹ ೳ ౕ ఈ ྖ ๑ ͺ ɾ enzyme-linked immuno sorbent assay (ELISA) ๑Ν༽͏ͱߨͮ

ͪɿΉͥɾ96 ΤΥϩϕϪʖφͶ UBE2T ஁പΝݽ૮Կ͢ɾ 1% bovine serum albumin Ν༽͏ͱඉಝҡదٷ஥ൕԢΝϔϫ ρΫϱήͪ͢ɿକ͏ͱɾ׳ं݄ੜ͕Γ;0 ͖Δ 10 ng/ml Ή Ͳஊ֌سएͪ͢ݗྖતࡠ੔͹ͪΌ͹ඬ६߇ରͲ͍Ζ߇ϐη οζϱνή߇ରΝͨΗͩΗൕԢͦͪ͠ɿॉ෾͵જ৞ޛɾ್

࣏߇ରͲ͍ΖϑΨοϱඬࣟ߇ϐφIgG Fc߇ରͳηφϪϕφ Πϑζϱ-ϙʖηϧυΡρεϣϘϩΨΫεξʖκΝൕԢ͠

ͦɾ൅৯ࢾ༂ΝՅ͓Ζ͞ͳͲఆ৯ൕԢΝ༢಍ͪ͢ɿ1 ࣎ؔޛ

4

ͶԚ࢐ΝశՅͤΖ͞ͳͲఆ৯ൕԢΝంࢯ͢ɾ450nm Ͷ͕͜

ΖٷޭౕΝ଎ఈͪ͢ɿಚΔΗͪٷޭౕͳೳౕعஎ͹߇ϐη οζϱνή߇ର͹ೳౕΝ༽͏ͱݗྖતΝࡠ੔ͪ͢ɿࡠ੔͢

ͪݗྖતΝ΍ͳͶɾ֦݄ੜγϱϕϩ͹ٷޭౕ͖Δ߇ UBE2T ߇ରೳౕΝࢋड़ͪ͢ɿUBE2T ͹໖Ӻૌ৭ઝ৯ͲͺɾϙϩϜ ϨϱݽఈɾϏϧϓΡϱใດ͠Ηͪૌ৭ݗର͹മ઀ඬຌΝɾ

߇ UBE2T ߇ରͲઝ৯͢ɾޭָݨඏںͲඬຌ͹؏ࡱΝߨͮ

ͪɿ

რɿɿ݃Վ

Ϝ΢έϫΠϪ΢Ͳͺɾ݊৙ं 5 ໌͕Γ; IPF 7 ໌Ν؜΋

࣯ؔ੓഑Ԏ׳ं 9 ໌͹݄ੜΝͨΗͩΗ࢘༽͢ɾ࣯ؔ੓഑Ԏ Ͷಝҡద͵݄஦ࣙހ߇ରΝ୵ࡩͪ͢ɿ͞͹๏๑ͶΓΕɾؔ

࣯੓഑Ԏ܊ͲଁՅΝ೟Όͪࣙހ߇ରΝ 10 झྪΆʹમఈ͢

ͪɿ

କ͏ͱɾ݊৙ं 12 ໌͕Γ; IPF 13 ໌Ν؜΋࣯ؔ੓഑Ԏ

׳ं16 ໌͹݄ੜΝ༽͏ͱɾϜ΢έϫΠϪ΢๑Ͳમఈͪ͢10 झྪ͹ࣙހ߇ରͶͯ͏ͱɾProtoplex™ͶΓΖൔఈྖΝߨͮ

5

ͪɿ10 झྪ͹ࣙހ߇ର͹஦Ͳɾ߇ UBE2T ߇ର͹ܮޭکౕ

͹஦ԟ஍ (൥ҕ) ͺɾ࣯ؔ੓഑Ԏ׳ं܊Ͳ 979 (331-7910) ɾ

݊৙ं܊Ͳ297 (236-464) Ͳ͍Εɾ࣯ؔ੓഑Ԏ܊Ͳܮޭکౕ

༙͗қͶ߶஍Νࣖͪ͢ (p<0.05)ɿҐ৏͹݃ՎΓΕɼ࣯ؔ੓

഑Ԏ׳ं͹݄஦ࣙހ߇ରͳ͢ͱɾ߇ UBE2T ߇ର͹ಝҡ੓͗

࠹΍߶͏͞ͳ͗໎Δ͖Ͷ͠Ηͪ͹Ͳɾ݄஦߇ UBE2T߇ରΝ

஦ৼͶݜڂΝ਒ΌΖ͞ͳͶͪ͢ɿ

༹ʓ͵झྪ͹࣯ؔ੓഑Ԏͳ͹ർֳΝߨ͑ͪΌͶɾELISA ๑ͶΓΖ߇ UBE2T ߇ର͹ೳౕ଎ఈ๑Νཱི֮ͪ͢ɿ݊৙ं

61 ໌ɾIPF 43 ໌ɾIPAF 10 ໌ɾ͠ΔͶ್࣏੓͹࣯ؔ੓഑Ԏ Ͳ͍Ζ᡾ݬබͶ൒࣯͑ؔ੓഑Ԏ (connective tissue disease associated interstitial lung disease: CTD-ILD) 12 ྭɾγϩα΢

χʖεη 14 ྭɾອ੓գෆ੓഑Ԏ (chronic hypersensitivity pneumonitis: CHPʥ 6ྭ͹݄஦߇ UBE2T߇ର଎ఈΝߨͮͪɿ

߇ UBE2T ߇ରೳౕ͹ฑۋ஍±ඬ६ޣࠫͺɾ݊৙ं 196±19

ng/mlɾIPF 425±42 ng/ml Ͳ͍Εɾ߇UBE2T ߇ରೳౕͺ IPF

܊Ͳ༙қͶ߶஍Ͳ͍ͮͪ (p< 0.05)ɿΉͪɾଠ࣮׳͹߇ UBE2T߇ରೳౕΝ IPF ͳർֳͤΖͳɾCTD-ILD 1102ʸ294

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ng/ml, IPAF 440±176 ng/mlɾγϩα΢χʖεη 246±22 ng/mlɾ CHP 182±25 ng/mlͲ͍ΕɾIPF ͹߇ UBE2T ߇ରͺɾ݊৙ं

ΏCHPɾγϩα΢χʖεηͳ͹ർֳ͢߶஍Ͳ͍ͮͪɿCTD-

ILD ͹߇ UBE2T ߇ରೳౕ͗߶஍Ͳ͍ͮͪҲ๏ͲɾIPAF Ͷ

͕͏ͱͺఁ஍͖Δ߶஍ΉͲɾ߇ UBE2T ߇ରೳౕͺ෱߁͏෾

ාΝࣖ͢ɾ݊৙ंͳർֳ༙͢қࠫͺಚΔΗ͵͖ͮͪɿ

࣯ؔ੓഑Ԏ܊Ͷ͕͜Ζ߇ UBE2T ߇ର͹ਏஇ੠ౕΝݗ౾

ͤ Ζ ͪ Ό Ͷ ɾ ݊ ৙ ं ͳ ർ ֳ ͢ ͪ ࡏ ͹ receiver operating characteristicۄતΝඵ͏ͪɿۄતԾ໚੷ͺɾCTD-ILD͗89%ɾ IPF ͗ 84%Ͳɾ߇ UBE2T ߇ରͺ CTD-ILD ΝਏஇͤΖࡏͶ

࠹΍༙༽͵ࣙހ߇ରͲ͍Ζ͞ͳ͗൓໎ͪ͢ɿ

ROCۄતΓΕٽΌΔΗΖCTD-ILDਏஇ࣎͹߇UBE2T߇ ରೳౕ͹ΩρφΨϓ஍Ν241.1ng/ml ʤ״ౕ 83.3ˍɾಝҡౕ

85.3ˍʥͳઅఈͪ͢ɿ͞͹ΩρφΨϓ஍Ν༽͏ͱɾCTD-ILDɾ

IPFɾIPAF ͹࣯ؔ੓഑Ԏ׳ं (n=65) ΝଲেͶɾ߇ UBE2T ߇ରཇ੓͍Ζ͏ͺӆ੓ͳ೧ྺɾ੓พɾ٦Ԑྼɾ෯ਝൿ࣯η τϫ΢χΉͪͺ໖Ӻཊ੏ࡐͶΓΖ࣑ྏྼɾѳ੓ञ ߻ญ͹

༙ໃɾhigh-resolution computed tomography Ͷ͕͜Ζ usual

7

interstitial pneumonia Ϗνʖϱ͹༙ໃɾݼٷؽ೵ݗࠬߴ໪Ͳ

͍ Ζ%forced expiratory volume 1.0ɾ%forced vital capacity (%FVC)ɾdiffusing capacity for carbon monoxide (%DL_CO)ɾ࣪

಼ـͶ͕͜Ζಊຼ݄࢐ો෾ѻɾ݄஦Krebs von den Lungen-6 ͳ͹૮ؖΝݗ౾ͪ͢ɿ͞ΗΔ͹͏ͥΗ΍݄ੜ߇ UBE2T߇ର ͳ͹૮ؖΝ೟Όͥɾ߇ UBE2T ߇ର͹ड़ݳͳ͞ΗΔ׳ंഐܢ Ҿࢢͳ͹ؖ࿊ͺ͵͏ͳߡ͓ΔΗͪɿΉͪɾ IPF ΝଲেͶɾ

͞ΗΉͲࣙހ໖ӺഐܢΝ΍࣯ͯؔ੓഑Ԏ͹ਏஇ࣎Ͷ༽͏ͱ

͏ͪ߇֫߇ର͵ʹ͹عଚ͹݄஦ࣙހ߇ରͳ߇ UBE2T ߇ର ཇ੓͹༙ໃͳ͹ؖ࿊Νݗ౾͢ɾྈं͹݃ՎͶͺؖ࿊͗͵͏

͞ͳ͗ࣖ͠Ηͪɿ

IPF ഑͹໖Ӻૌ৭ઝ৯ͲͺɾUBE2T ͺ๚૧഑಼෨Νඅ෶

ͤΖ৏ൿࡋ๖Ͳک͏൅ݳΝ೟Όͪɿ

სɿɿߡࡱ

ຌݜڂͲͺɾϜ΢έϫΠϪ΢๑ɾProtoplex™ͶΓΖմ

ੵͶΓΕɾIPF Ν؜΋࣯ؔ੓഑Ԏ܊Ͳ༙қͶ৏তͤΖࣙ

ހ߇ରͳ͢ͱ߇ UBE2T ߇ରΝಋఈͪ͢ɿELISA ๑Ν༽

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͏ͱ࣯ؔ੓഑Ԏ܊͹݄஦߇ UBE2T ߇ରೳౕΝ࣮׳พͶ ݗ౾ͤΖͳɾCTD-ILD ͳ IPF Ͳ߶஍Ν೟Όͪɿ࣯ؔ੓഑

Ԏ܊͹஦Ͳ΍ CTD-ILD ͹ਏஇ੠ౕ͗࠹΍༑Ηͱ͕Εɾ߇

UBE2T ߇ରͺࣙހ໖ӺഐܢΝ༙ͤΖ࣯ؔ੓഑Ԏ͹பड़

ΝՆ೵ͶͤΖͳߡ͓ΔΗͪɿ߇ UBE2T ߇ରͺɾ೧ྺΏ੓

พɾ٦Ԑྼɾѳ੓ञ ߻ญ͹༙ໃɾժ଀Ϗνʖϱɾعଚ

͹ཱི֮ͪࣙ͢ހ߇ର͹ଚࡑ͵ʹ͹׳ंഐܢҾࢢͶؖ࿊͵

͚ཇ੓ΝࣖͤͪΌɾ͞ΗΉͲࣙހ໖ӺഐܢΝ΍ͯͳߡ͓

ΔΗͱ͏࣯ͪؔ੓഑Ԏ͹γϔήϩʖϕ ^3,4,10)ͳͺҡ͵Ζ ಝ௅Ν΍ͯ׳ं܊Νபड़Ͳ͘ΖՆ೵੓͍͗Ζͳ͏͓Ζɿ

Ήͪɾ߇ UBE2T ߇ରͺɾ࣮׳਒ߨౕΝوఈͤΖҾࢢͲ͍

ΖˍFVC ΏˍDLCOɾಊຼ݄࢐ો෾ѻͶ΍ΓΔ͵͏ͪΌɾ බॵغͶ͕͜ΖਏஇͶ΍࢘༽Ͳ͘Ζͳߡ͓ΔΗͪɿIPF ͺ഑๖৏ൿࡋ๖্֒ͳͨ͹र෰ҡ৙ͶΓΖອ੓͹તңԿ

͗බସͳ͠Ηͱ͏ΖɿUBE2T ͺ DNA ࠱ؔՏڰ͹र෰Ͷ

͖͖ͦ͵͏ϤϑΫοϱ݃߻߮ો͹ҲझͲ͍Ζ͗ɾUIP ഑

͹໖Ӻૌ৭ઝ৯ͲͺɾUBE2T ͺඅ෶৏ൿࡋ๖Ͷ߶൅ݳ͢

ͱ͕ΕɾIPF Ͷ͕͜Ζ഑๖৏ൿ্֒ͳ UBE2T ͹ؖ࿊͗ࣖ

9

ࠨ͠Ηͪɿ

ტɿɿ݃࿨

ຌݜڂͲͺɾIPF Ν؜΋࣯ؔ੓഑Ԏ܊͖Δࣙހ໖Ӻ බସΝ༙ͤΖήϩʖϕΝபड़ͤΖ৿ͪ͵݄஦ࣙހ߇ରͳ

͢ͱɾ߇ UBE2T ߇ରΝಋఈͪ͢ɽUBE2T ͺ IPF ഑Ͷ͕

͜Ζඅ෶৏ൿࡋ๖Ͷ߶൅ݳ͢ͱ͏ͪɿݳࡑɾ߇ UBE2T ߇

ର͕Γ; UBE2T ஁പ͹તңԿؽ঄΃͹ༀׄΝմ໎஦Ͳ

͍Εɾ͠ΔͶྡজద͕Γ;ਫ਼෼ָఈٝ͗໎Δ͖Ͷ͠ΗΖ

͞ͳ͗غଶ͠ΗΖɿ

უӀ༽ชݛ

1. Travis WD, Costabel U, Hansell DM, King TE, Jr., Lynch DA, Nicholson AG, et al. An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med.

2013;188(6):733-48.

2. Birney E, Stamatoyannopoulos JA, Dutta A, Guigo R, Gingeras TR, Margulies EH, et al. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature. 2007;447(7146):799-816.

3. Suda T, Kono M, Nakamura Y, Enomoto N, Kaida Y, Fujisawa T, et al. Distinct prognosis of idiopathic nonspecific interstitial pneumonia (NSIP) fulfilling criteria for undifferentiated connective tissue disease (UCTD). Respir Med.

2010;104(10):1527-34.

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4. Vij R, Noth I, Strek ME. Autoimmune-featured interstitial lung disease: a distinct entity. Chest. 2011;140(5):1292-9.

5. Natsuizaka M, Chiba H, Kuronuma K, Otsuka M, Kudo K, Mori M, et al.

Epidemiologic survey of Japanese patients with idiopathic pulmonary fibrosis and investigation of ethnic differences. Am J Respir Crit Care Med.

2014;190(7):773-9.

6. Fischer A, Antoniou KM, Brown KK, Cadranel J, Corte TJ, du Bois RM, et al.

An official European Respiratory Society/American Thoracic Society research statement: interstitial pneumonia with autoimmune features. Eur Respir J.

2015;46(4):976-87.

7. Feghali-Bostwick CA, Tsai CG, Valentine VG, Kantrow S, Stoner MW, Pilewski JM, et al. Cellular and humoral autoreactivity in idiopathic pulmonary fibrosis.

J Immunol. 2007;179(4):2592-9.

8. Xue J, Kass DJ, Bon J, Vuga L, Tan J, Csizmadia E, et al. Plasma B lymphocyte stimulator and B cell differentiation in idiopathic pulmonary fibrosis patients. J Immunol. 2013;191(5):2089-95.

9. Marchal-Somme J, Uzunhan Y, Marchand-Adam S, Kambouchner M, Valeyre D, Crestani B, et al. Dendritic cells accumulate in human fibrotic interstitial lung disease. Am J Respir Crit Care Med. 2007;176(10):1007-14.

10. Kim HC, Ji W, Kim MY, Colby TV, Jang SJ, Lee CK, et al. Interstitial pneumonia related to undifferentiated connective tissue disease: pathologic pattern and prognosis. Chest. 2015;147(1):165-72.