JP2020090477A - 自己免疫性水疱症の診断 - Google Patents
自己免疫性水疱症の診断 Download PDFInfo
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- JP2020090477A JP2020090477A JP2019190722A JP2019190722A JP2020090477A JP 2020090477 A JP2020090477 A JP 2020090477A JP 2019190722 A JP2019190722 A JP 2019190722A JP 2019190722 A JP2019190722 A JP 2019190722A JP 2020090477 A JP2020090477 A JP 2020090477A
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Abstract
Description
a.試料が担体と接触したとき、試料中の少なくとも1つの自己抗体を捕捉するための手段を含む担体、
b.担体と接触したとき、捕捉された抗体と結合することができる検出手段、好ましくは、担体上に捕捉された抗体に結合することができる標識された二次抗体である検出手段、
c.任意選択的に、好ましくは洗浄によって、担体から試料を除去および検出手段を除去するための手段、
d.検出可能な手段の存在の検出のため、および結果を電子シグナルに変換するための検出器、ならびに、
e.任意選択的に、検出器からの電子シグナルを受け取り、かつ、シグナルの強度をバックグラウンドシグナルの強度または健常人の試料を使用して得られた入力参照値と比較することによってシグナルの強度が自己免疫疾患の可能性の増加を指し示すかどうか決定するための手段を含む器具を提供する。
<診断上関連する自己抗原としてのラミニンベータ4の同定>
<真皮抽出物の調製>
抗p200類天疱瘡のさらなる自己抗原は、まずヒト真皮の抽出物および精製した患者抗体の免疫沈降を実施することによって同定した。
抗p200類天疱瘡IgGは、プロテインGセファロース(Genscript)を使用して製造元の指示に従って精製した。その後、hLAMC1−cterm(ヒトラミニンガンマ1のC末端、アミノ酸1363−1609)特異的自己抗体は、親和性精製手法(Vafia K,Groth S,Beckmann T,Hirose M,Dworschak J,Recke A,Ludwig R J,Hashimoto T,Zillikens D,and Schmidt E,Pathogenicity of autoantibodies in anti−p200 pemphigoid.PLoS One,2012.7(7):p.e41769)を使用して単離した。患者抗体の特異的精製のために、hLAMC1−cterm−pQE40をまず大腸菌Rosetta2 DE3(Novagen−Merck、Darmstadt)に形質転換し、タンパク質を発現させて(IMACによって)精製した。最後に、組換えhLAMC1−ctermタンパク質を製造元の指示に従ってAffigel15(BIO RAD)に共有結合させた(Groth S,Recke A,Vafia K,Ludwig R J,Hashimoto T,Zillikens D,and Schmidt E,Development of a simple enzyme−linked immunosorbent assay for the detection of autoantibodies in anti−p200 pemphigoid.Br J Dermatol,2011.164(1):pp.76−82)。この特異的アフィニティークロマトグラフィーを用いて、抗p200類天疱瘡患者血清のIgG調製物からhLAMC1−cterm特異的自己抗体を除去することができた。
免疫沈降で使用されたのは、タンパク質源としての再緩衝化された真皮抽出物およびhLAMC1−cterm反応性を有しない精製患者IgG、hLAMC1−cterm抗体を有しない抗p200類天疱瘡血清、および健康な血液ドナーからの対応する対照であった。
1.hLAMC1−cterm反応性を有しない患者IgG(プール)30μg
2.患者血清20μl
3.NHIgG(健康な血液ドナーの正常なヒトIgG)30mg
4.NHS(健康な血液ドナーの正常なヒト血清)20μl
5.RIPA緩衝液のみ
において、RIPA緩衝液中で、回転させながら室温で1時間インキュベートし、その後RIPA緩衝液で洗浄した。その後、再緩衝化した真皮抽出物200μlを各反応試験管にピペットで入れ、次いで反応調製物を回転装置で4℃で一晩インキュベートした。RIPA緩衝液による洗浄ステップに続いてスクロース緩衝液(1Mスクロース、150mMのNaCl、10mMのEDTA、10mMのHNaPO4)による洗浄ステップを行った。最後に、RIPA緩衝液による洗浄をもう一度実施した。試料をそれぞれLaemmli緩衝液20μlと共に95℃で5分間加熱し、遠心分離し、試料を7.5%PROTEAN TGXタンパク質ゲル(BIORAD)に添加した。
<ラミニンベータ4の局在の確認>
皮膚におけるラミニンベータ4の局在は、最初に間接的免疫蛍光法において市販の抗ラミニンベータ4抗体(ポリクローナル、Cloud−Clone;PAC079Hu01)を使用することによって確認した。陰性対照とは対照的に、抗ラミニンベータ4抗体は、抗p200類天疱瘡血清血清と同じように(示さず)、ヒト食塩剥離皮膚における人工的水疱の基部に結合する。さらに、抗ラミニンベータ4抗体はまた、真皮抽出物を用いたウエスタンブロットで試験した(手法は前記参照)。ヒト真皮抽出物によるウエスタンブロットは、抗p200類天疱瘡を診断するための現在の標準的診断法である。図2に示したように、抗ラミニンベータ4抗体(切片4)は、抗p200類天疱瘡血清(切片1および2)のシグナルと同じレベルに位置するタンパク質ハンドと反応する。市販のモノクローナルラミニンガンマ1抗体(クローンB−4、Santa Cruz)のシグナルは、わずかに上方に移動している。
<クローニング>
ラミニンベータ4(LAMB4)は、C末端にポリヒスチジンタグが融合したバリアントとして、および確実なバリアントとして、組換えによって生成した。ヒトラミニンベータ4のアイソフォーム1をコードするcDNAクローンIRCBp5005F2212Qは、Source BioScience(United Kingdom)から購入して、PCR用の鋳型として使用した。
<HEK細胞のトランスフェクションおよびウエスタンブロット分析>
ラミニンベータ4が実際に抗p200類天疱瘡の標的抗原であることを確認するために、HEK293細胞をLAMB4−pTriEx1(Hisタグを有する、配列番号7)または空のベクターをjetPRIME(ポリプラストランスフェクション)によりトランスフェクトし、発現を48時間後にウエスタンブロットにおいて市販の抗ラミニンベータ4抗体(上記参照)によって確認した。全体として、49個の抗p200類天疱瘡血清(1:50希釈)および20個の健康な血液ドナーの血清(NHS、正常ヒト血清、1:50希釈)のラミニンベータ4との反応性を、ラミニンベータ4−HEK293抽出物(RIPA緩衝液)を用いたウエスタンブロットで試験した。このために、完了したニトロセルロース膜を切片に切断した。市販の抗ラミニンベータ4抗体(1:2000希釈)を陽性対照として使用した。切片を一次抗体で4℃で一晩インキュベートした。本明細書ではまた、前述したように、抗ヒトIgG4HRP抗体およびマウス抗ウサギHRP抗体を二次抗体として使用した。ブロットはDABで1分間発色させた。全体として、49個の抗p200類天疱瘡血清のうち47個がラミニンベータ4と反応したが、一方陰性対照は反応を示さなかった。
<予備吸着試験>
ラミニンベータ4の正確な同定は、予備吸着試験によって確認した。このために、3つの抗p200類天疱瘡血清(ラミニンガンマ1反応性を有しない)をラミニンベータ4−HEK293抽出物で4℃で一晩予備吸着し、その後残存する反応性を真皮抽出物およびラミニンベータ4−HEK293抽出物を用いたウエスタンブロットで試験した(図4)。ウエスタンブロット分析は、前述のように実施した。予備吸着していない血清(図4、切片1、3および5)と比較して、予備吸着した血清はラミニンベータ4−HEK293抽出物とはもはや反応性を示さず、3つの予備吸着した血清のうち2つはまた、真皮抽出物中の200kDaの大きさのタンパク質ともはや反応しなかった。したがって、反応を中和することができた。血清番号2のみがまだ約200kDaに弱い反応を示した。この抗p200類天疱瘡血清は、実際にはラミニンガンマ1と反応性を示さないはずだが、それでもhLAMC1−ctermウエスタンブロットを使用して再度試験を実施した。血清番号2が実際にラミニンガンマ1自己抗体を有することがわかり、それによって真皮抽出物中における反応を説明することができた。
<おおまかなエピトープマッピング>
おおまかなエピトープを同定するために、ラミニンベータ4の6つのサブフラグメント(配列番号15、配列番号16、配列番号17、配列番号18、配列番号19および配列番号20)をクローニングし、標準的な方法を使用してC末端Hisタグを有するpET24dベクターで発現させた(配列番号21、配列番号22、配列番号23、配列番号24、配列番号25および配列番号26)。構築物がもともと4つのトリプトファン残基を有しなかった場合、濃度測定用に4つのトリプトファンを有するようにいくつかの各構築物に人工的に融合させた。
<正確なエピトープマッピング>
ラミニンベータ4に対する自己抗体を含む4つの患者血清をエピトープマッピングのために使用した。血液ドナーの血清を、非特異的反応を同定することを可能にするためにさらにインキュベートした。C末端部分に位置付けられる14個のアミノ酸が重複した直鎖状15マーペプチド、より正確にはサブフラグメント5(配列番号19)および6(配列番号20)を使用した。ペプチドは、インキュベーション緩衝液(0.05%Tween20および10%Rocklandブロッキング緩衝液MB−070を含有するPBS、pH7.4)で1:100に希釈した試料と接触させ、1:500、1:100および1:10の希釈でインキュベーション緩衝液中で140rpmで震盪しながら4℃で16時間インキュベートし、次いで二次(マウス抗ヒトIgG(Fc)DyLight680(0.5μg/ml))および対照(マウスモノクローナル抗HA(12CA5)DyLight680(0.2μg/ml))抗体で45分間染色した。読み取りは、LI−COR Odyssey Imaging Systemを使用して実施した。スポット強度の定量およびペプチド予測は、PepSlide分析装置を使用して実施した。一次データの例は図5に認めることができる。
Claims (16)
- 好ましくは組換え体および/または単離された形態の、ラミニンベータ4またはそのバリアントを含むポリペプチド。
- 固定されている、請求項1に記載のポリペプチド。
- ラミニンガンマ1、ラミニン332、BP180、BP230、デスモグレイン1、デスモグレイン3、エンボプラキン、グリアジンおよびVII型コラーゲンまたはそれらのバリアントおよび剥離皮膚を含む群からの少なくとも1つの抗原、好ましくは全ての抗原をさらに含む、請求項2に記載の担体。
- ガラススライド、好ましくは顕微鏡用スライド、さらにより好ましくはラミニンベータ4またはそのバリアントを過剰発現する真核細胞を有するスライド、バイオチップ、マイクロタイタープレート、ラテラルフローデバイス、試験片、膜、好ましくはブロット、より好ましくはラインブロット、クロマトグラフィーカラム材料およびビーズ、好ましくは磁気もしくは蛍光ビーズを含む群から選択される、請求項3に記載の担体。
- ヒト血液と前記ポリペプチドとの接触を可能にし、次いで患者の体内への前記血液の再循環を可能にする、好ましくはアフェレシス器具である、請求項1および2のいずれか1項に記載のポリペプチドを含む治療上有用な担体。
- 好ましくは単離された形態の、ラミニンベータ4に対する抗体、好ましくは自己抗体。
- 疾患の診断のための、請求項1〜6のいずれか1項に記載のポリペプチド、担体または自己抗体の使用。
- 診断上または治療上有用な担体を生成する方法であって、前記担体を請求項1に記載のポリペプチドでコーティングするステップを含む方法。
- 自己抗体を精製するための方法であって、
a)前記自己抗体を含む液体に請求項1に記載のポリペプチドを、前記自己抗体および前記ポリペプチドを含む複合体の形成を可能にする条件下で接触させるステップ、
b)ステップa)の複合体を単離するステップ、ならびに
c)任意選択的に、ステップa)の複合体を検出するステップ、またはステップb)で単離した複合体を解離させるステップ、その後、前記ポリペプチドから前記自己抗体を分離する、
を含む方法。 - 試料中のラミニンベータ4に対する自己抗体を検出するステップを含む方法。
- 請求項1に記載のポリペプチドまたはそのバリアントを、好ましくは薬学的に許容される担体と共に含む医薬組成物。
- 請求項1および2のいずれか1項に記載のポリペプチドまたは請求項3および4のいずれか1項に記載の担体を含むキットであって、洗浄溶液、キャリブレーター溶液、ラミニンベータ4に対する抗体、および好ましくは二次抗体などのラミニンベータ4に対する自己抗体の検出のための剤を含む群からの1つの試薬または複数の試薬を含有するキット。
- キットまたは診断上もしくは治療上有用な担体の生成のための、請求項1に記載のポリペプチド、請求項3および4のいずれか1項に記載の担体またはラミニンベータ4に対する抗体、好ましくは自己抗体の使用。
- ラミニンベータ4に対する自己抗体が、免疫拡散法、免疫電気泳動法、光散乱法、凝集法、放射能標識、酵素的標識、より好ましくはELISA、化学発光標識、より好ましくは電気化学発光標識および免疫蛍光標識、好ましくは間接的免疫蛍光による免疫測定法を含む群から選択されるものなどの標識による免疫測定法を含む群から選択される方法を使用して検出される、請求項7〜10、12および13のいずれか1項に記載の方法、使用またはキット。
- 診断装置もしくは治療装置の、またはラミニンベータ4に対する抗体に結合する診断もしくは治療試薬の能力、好ましくは潜在能力を決定するための、請求項1に記載のポリペプチドまたは請求項6に記載の抗体の使用。
- 前記自己抗体が、患者の組織試料中で検出される、または、ラミニンベータ4もしくはそのバリアントを含む担体、好ましくは請求項3もしくは4に記載の担体によって検出される、請求項10に記載の方法。
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