JP6312054B2 - Biomarker for interstitial pneumonia - Google Patents
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Description
本発明は、主に特発性間質性肺炎の検出方法若しくは診断方法、特発性間質性肺炎の検出若しくは診断に用いるためのマーカー、及び特発性間質性肺炎を検出若しくは診断するためのキットに関する。 The present invention mainly relates to a method for detecting or diagnosing idiopathic interstitial pneumonia, a marker for use in detecting or diagnosing idiopathic interstitial pneumonia, and a kit for detecting or diagnosing idiopathic interstitial pneumonia About.
間質性肺炎（interstitial pneumonia）は、肺において肺胞間の隔壁である、肺の間質組織における炎症性疾患の総称である。間質性肺炎の進行に伴い、間質組織の線維化が生じ、患者の呼吸困難の原因となる。間質性肺炎は、膠原病よるもの、薬剤誘起性、職業若しくは環境によるものなどの原因が明らかな一群と、原因不明の一群とに大別される。原因不明のものは、特発性間質性肺炎（idiopathic interstitial pneumonias、IIPs）と呼ばれる。 Interstitial pneumonia is a general term for inflammatory diseases in the interstitial tissue of the lung, which is the septum between alveoli in the lung. As the interstitial pneumonia progresses, fibrosis of the interstitial tissue occurs, causing the patient to have difficulty breathing. Interstitial pneumonia is broadly divided into a group with obvious causes such as those due to collagen disease, drug-induced, occupational or environmental causes, and a group with unknown causes. Those of unknown cause are called idiopathic interstitial pneumonias (IIPs).
特発性間質性肺炎は予後不良であり、我が国では難治性疾患として特定疾患に指定されている。このように難治性疾患である特発性間質性肺炎は、早期の診断が望ましい。しかしながら、我が国の日本呼吸器学会による診断ガイドライン（非特許文献１）、あるいは、アメリカ胸部医学会（American Thoracic Society、ATS）及びヨーロッパ胸部疾患学会（European Respiratory Society、ERS）による分類（非特許文献２）では、特発性間質性肺炎の確定診断を行うためには、臨床所見、画像所見、肺の機能評価、外科的肺生検による病理組織学的所見等に基づく総合判断を行う必要がある。さらに、病態の進行により初めて確定診断が可能となる場合がある。このような診断を行うことは、患者本人と医師等の医療従事者との双方に大きな負担となる。 Idiopathic interstitial pneumonia has a poor prognosis and is designated as a specific disease as an intractable disease in Japan. Thus, early diagnosis is desirable for idiopathic interstitial pneumonia, which is an intractable disease. However, diagnostic guidelines by the Japanese Respiratory Society (Non-patent Document 1), or classification by the American Thoracic Society (ATS) and the European Respiratory Society (ERS) (Non-patent Document 2) ) In order to make a definitive diagnosis of idiopathic interstitial pneumonia, it is necessary to make comprehensive judgment based on clinical findings, imaging findings, lung function evaluation, histopathological findings by surgical lung biopsy, etc. . In addition, a definitive diagnosis may be possible for the first time due to progression of the disease state. Performing such a diagnosis places a heavy burden on both the patient and a medical staff such as a doctor.
従って、より簡便に、かつ、高い陽性率及び特異性をもって特発性間質性肺炎を診断する方法が強く求められているのが現状である。 Therefore, there is a strong demand for a method for diagnosing idiopathic interstitial pneumonia more easily and with a high positive rate and specificity.
これまでに、血液検査による特発性間質性肺炎の診断が提唱されている（例えば、特許文献１）。しかしながら、陽性率や特異性の観点で十分なものであるとは言えない。 Until now, diagnosis of idiopathic interstitial pneumonia by blood test has been proposed (for example, Patent Document 1). However, it cannot be said that it is sufficient in terms of positive rate and specificity.
また、前記ガイドラインではKL-6、SP-D、SP-Aなどが血清マーカーとして挙げられている（非特許文献１）。これらのマーカーは特発性間質性肺炎において高い陽性率を示すものの、幅広い肺の疾患で陽性を示すマーカーであるため、特発性間質性肺炎の特異的な診断に用いることはできない。 In the above guidelines, KL-6, SP-D, SP-A and the like are listed as serum markers (Non-patent Document 1). Although these markers show a high positive rate in idiopathic interstitial pneumonia, they are markers that show positive in a wide range of lung diseases, and thus cannot be used for specific diagnosis of idiopathic interstitial pneumonia.
本発明は、特発性間質性肺炎の検出方法、特発性間質性肺炎の検出用いるためのマーカー、及び特発性間質性肺炎を検出するためのキットを提供することを主な課題とする。 The main object of the present invention is to provide a method for detecting idiopathic interstitial pneumonia, a marker for detecting idiopathic interstitial pneumonia, and a kit for detecting idiopathic interstitial pneumonia. .
本発明者は、上記課題を解決すべく鋭意検討を行ったところ、被験者のサンプルにおいて特定のタンパク質に対する抗体を指標として、特発性間質性肺炎の検出若しくは診断ができることを見出した。本発明は、斯かる知見に基づいてさらに検討を重ねることにより完成したものである。 The present inventor conducted intensive studies to solve the above problems, and found that idiopathic interstitial pneumonia can be detected or diagnosed using an antibody against a specific protein as an index in a sample of a subject. The present invention has been completed by further studies based on such findings.
即ち、本発明は、下記に掲げる態様の発明を包含する。 That is, this invention includes the invention of the aspect hung up below.
項１、被験者のサンプル中における、配列番号１〜１０で示されるアミノ酸配列のタンパク質から選択される少なくとも１種に対する抗体を指標とすることを特徴とする、特発性間質性肺炎の検出方法。 Item 1. A method for detecting idiopathic interstitial pneumonia, characterized by using, as an index, an antibody against at least one selected from proteins having the amino acid sequences represented by SEQ ID NOs: 1 to 10 in a sample of a subject.
項２、配列番号１〜１０で示されるアミノ酸配列のタンパク質から選択される少なくとも１種からなる、特発性間質性肺炎を検出に用いるためのマーカー。 Item 2. A marker for detecting idiopathic interstitial pneumonia, comprising at least one selected from proteins having the amino acid sequences represented by SEQ ID NOs: 1 to 10.
項３、配列番号１〜１０で示されるアミノ酸配列のタンパク質から選択される少なくとも１種に対する抗体を検出する手段を含む、特発性間質性肺炎を検出するためのキット。 Item 3. A kit for detecting idiopathic interstitial pneumonia, comprising means for detecting an antibody against at least one selected from the proteins having the amino acid sequences represented by SEQ ID NOs: 1 to 10.
本発明により、簡便に、かつ、高い陽性率及び特異性をもって特発性間質性肺炎の診断が可能となる。また、本発明により、特発性間質性肺炎の早期の診断が可能となり、早期の治療開始が可能となり、適切な処置を施すことで、患者のQOLの向上が期待できる。 According to the present invention, idiopathic interstitial pneumonia can be diagnosed easily and with a high positive rate and specificity. In addition, according to the present invention, early diagnosis of idiopathic interstitial pneumonia is possible, early treatment can be started, and improvement of the patient's QOL can be expected by taking appropriate measures.
本発明で見出した抗体を標的とした特発性間質性肺炎の治療薬の開発も期待される。 Development of a therapeutic agent for idiopathic interstitial pneumonia targeting the antibodies found in the present invention is also expected.
以下、本発明を詳細に説明する。 Hereinafter, the present invention will be described in detail.
１．対象疾患
本発明が対象とする疾患は、特発性間質性肺炎である。特発性間質性肺炎の病態は、例えば非特許文献１などにより公知である。肺において肺胞間の隔壁である、肺の間質組織における炎症性疾患である間質性肺炎（interstitial pneumonia）のうち、原因が不明なものを主に指す。
1. Target Disease The disease targeted by the present invention is idiopathic interstitial pneumonia. The pathology of idiopathic interstitial pneumonia is known, for example, from Non-Patent Document 1. Interstitial pneumonia, which is an inflammatory disease in the interstitial tissue of the lung, which is the septum between alveoli in the lung, mainly refers to those whose cause is unknown.
特発性間質性肺炎は、病理組織学的に主として７パターンに分類され得る。これらのパターンとして、特発性肺線維症（idiopathic pulmonary fibrosis、IPF；通常型間質性肺炎（usual interstitial pneumonia、UIP）ともいう。）、非特異性間質性肺炎（nonspecific interstitial pneumonia、NSIP）（線維化型非特異型間質性肺炎（fibroic NSIP、fNSIP)を含む。）、特発性基質化肺炎（cryptogenic organizing pneumonia、COP）、急性間質性肺炎（respiratory bronchiolitis-associated interstitial lung disease：RB-ILD）、剥離性間質性肺炎（desquamative interstitial pneumonia、DIP）、呼吸細気管支炎に伴う間質性肺疾患（lymphocytic interstitial pneumonia、LIP）、リンパ球性間質性肺炎（acute interstitial pneumonia、AIP）が挙げられる。これらの疾患それぞれの具体的病態は、公知である。例えば、日本呼吸器学会による診断ガイドライン、あるいは、アメリカ胸部医学会（American Thoracic Society、ATS）及びヨーロッパ胸部疾患学会（European Respiratory Society、ERS）による分類が挙げられる。 Idiopathic interstitial pneumonia can be classified into seven patterns in histopathology. These patterns include idiopathic pulmonary fibrosis (IPF; also known as normal interstitial pneumonia, UIP), nonspecific interstitial pneumonia (NSIP) ( Non-fibrotic interstitial pneumonia (including fibroic NSIP, fNSIP)), idiopathic matrixizing pneumonia (COP), respiratory bronchiolitis-associated interstitial lung disease: RB- ILD), desquamative interstitial pneumonia (DIP), interstitial lung disease associated with respiratory bronchiolitis (LIP), acute interstitial pneumonia (AIP) Is mentioned. The specific pathology of each of these diseases is known. Examples include diagnostic guidelines by the Japanese Respiratory Society, or classification by the American Thoracic Society (ATS) and the European Respiratory Society (ERS).
本発明は、中でも、特発性肺線維症を対象とすることが好適である。 The present invention is particularly suitable for idiopathic pulmonary fibrosis.
なお、サルコイドーシス、過敏性肺臓炎（Hypersensitivity Pneumonitis、HP）などの疾患に伴う原因や病態が明らかな間質性肺炎は、特発性間質性肺炎に含まれないと理解される。 In addition, it is understood that interstitial pneumonia whose cause and pathology associated with diseases such as sarcoidosis and hypersensitivity pneumonitis (HP) are not included in idiopathic interstitial pneumonia.
２．被験者
本発明が対象とする被験者（被験対象）は、特に限定されるものではない。特発性間質性肺炎を発症する可能性がある、ヒト、並びに、マウス、ラット、ウサギ、イヌ、ネコ、ウシ、ウマ等の非ヒト哺乳類が例示され、特にヒトが好適である。被験者がヒトである場合、例えば、間質性肺炎を含む間質性肺疾患の患者、又は、間質性肺疾患が疑われる被験者が特に好適な例として挙げられる。
2. Subject The subject (test subject) targeted by the present invention is not particularly limited. Examples include humans and non-human mammals such as mice, rats, rabbits, dogs, cats, cows, horses, etc., who are likely to develop idiopathic interstitial pneumonia, and humans are particularly preferred. When the subject is a human, for example, a patient with interstitial lung disease including interstitial pneumonia or a subject suspected of having interstitial lung disease is particularly preferable.
被験者がヒトである場合、性別、年齢、人種は特に限定されるものではない。 When the subject is a human, the sex, age, and race are not particularly limited.
３．サンプル
本発明の被験者のサンプルは、被験者の血液（全血）、血清、血漿、リンパ液などが挙げられる。サンプルとして、血液、血清、血漿が好ましく、特に血清が好ましく使用される。
3. Sample The subject's sample of the present invention includes subject's blood (whole blood), serum, plasma, lymph, and the like. As a sample, blood, serum and plasma are preferable, and serum is particularly preferably used.
サンプルは、当業者に公知の方法で採取することができる。例えば、血液は、注射器などを用いた採血によって採取することができる。なお、採血は、医師、看護師などの医療従事者が行うことが望ましい。血清は、血液から血球及び特定の血液凝固因子を除去した部分であり、例えば、血液を凝固させた後の上澄みとして得ることができる。血漿は、血液から血球を除去した部分であり、例えば、血液を凝固させない条件下で遠心分離に供した際の上澄みとして得ることができる。検体は、被験対象の動脈由来、静脈由来、末梢血管由来のいずれであってもよい。 The sample can be collected by methods known to those skilled in the art. For example, blood can be collected by blood collection using a syringe or the like. Note that blood collection is preferably performed by medical personnel such as doctors and nurses. Serum is a part obtained by removing blood cells and a specific blood coagulation factor from blood, and can be obtained, for example, as a supernatant after coagulating the blood. Plasma is a portion obtained by removing blood cells from blood, and can be obtained, for example, as a supernatant when subjected to centrifugation under conditions that do not coagulate blood. The specimen may be derived from the subject's arteries, veins, or peripheral blood vessels.
４．抗体
本発明は、配列番号１〜１０で示されるアミノ酸配列のタンパク質から選択される少なくとも１種もしくはその断片に対する抗体を指標とすることを特徴とする。
4). Antibody The present invention is characterized by using as an index an antibody to at least one selected from the proteins having the amino acid sequences represented by SEQ ID NOs: 1 to 10 or fragments thereof.
配列番号１で示されるアミノ酸配列は、ユビキチン結合酵素（Ubiquitin-conjugating enzyme、E2）であるヒトUBE2Tタンパク質をコードする。当該アミノ酸配列は、GenBankアクセッション番号NM_014176により表される塩基配列の翻訳産物であり、GenBankアクセッション番号NP_054895により表される。 The amino acid sequence represented by SEQ ID NO: 1 encodes human UBE2T protein which is a ubiquitin-conjugating enzyme (E2). The amino acid sequence is a translation product of the base sequence represented by GenBank accession number NM_014176, and is represented by GenBank accession number NP_054895.
配列番号２で示されるアミノ酸配列は、ヒトヘキソキナーゼ１（hexokinase 1）タンパク質をコードする。当該アミノ酸配列は、GenBankアクセッション番号BC008730により表される塩基配列の転写産物であり、GenBankアクセッション番号AAH08730により表される。 The amino acid sequence shown in SEQ ID NO: 2 encodes human hexokinase 1 protein. The amino acid sequence is a transcription product of the base sequence represented by GenBank accession number BC008730, and is represented by GenBank accession number AAH08730.
配列番号３で示されるアミノ酸配列は、ヒトプロテアソーム（proteasome、別名prosome,又はmacropain）活性化サブユニット（activator subunit）１タンパク質（PSME1）（別名、PA28 alpha）をコードする。当該アミノ酸配列は、GenBankアクセッション番号NM_176783により表される塩基配列の転写産物であり、GenBankアクセッション番号NP_788955により表される。 The amino acid sequence shown in SEQ ID NO: 3 encodes the human proteasome (proteasome, also known as prosome, or macroain) activation subunit 1 protein (PSME1) (also known as PA28 alpha). The amino acid sequence is a transcription product of the base sequence represented by GenBank accession number NM_176783, and is represented by GenBank accession number NP_788955.
配列番号４で示されるアミノ酸配列は、酵母の小胞ドッキングタンパク質（vesicle docking protein）であるUSO1タンパク質のヒトホモログタンパク質をコードする。当該アミノ酸配列は、GenBankアクセッション番号BC032654により表される塩基配列の転写産物であり、GenBankアクセッション番号AAH32654により表される。 The amino acid sequence shown in SEQ ID NO: 4 encodes a human homologue protein of USO1 protein, which is a yeast vesicle docking protein. The amino acid sequence is a transcription product of the base sequence represented by GenBank accession number BC032654, and is represented by GenBank accession number AAH32654.
配列番号５で示されるアミノ酸配列は、ヒトインターフェロンγ誘導性タンパク質１６（interferon-gamma-inducible protein 16、IFI16）（別名IFNGIP1、PYHIN2）をコードする。当該アミノ酸配列は、GenBankアクセッション番号BC017059により表される塩基配列の転写産物であり、GenBankアクセッション番号AAH17059により表される。 The amino acid sequence shown in SEQ ID NO: 5 encodes human interferon-gamma-inducible protein 16, IFI16 (also known as IFNGIP1, PYHIN2). The amino acid sequence is a transcription product of the base sequence represented by GenBank accession number BC017059, and is represented by GenBank accession number AAH17059.
配列番号６で示されるアミノ酸配列は、ヒトGLTP（Glycolipid Transfer Protein）タンパク質をコードする。当該アミノ酸配列は、GenBankアクセッション番号NM_016433により表される塩基配列の転写産物であり、GenBankアクセッション番号NP_057517により表される。 The amino acid sequence shown by SEQ ID NO: 6 encodes human GLTP (Glycolipid Transfer Protein) protein. The amino acid sequence is a transcription product of the base sequence represented by GenBank accession number NM_016433, and is represented by GenBank accession number NP_057517.
配列番号７で示されるアミノ酸配列は、ヒトPRC1（Protein Regulator of Cytokinesis 1）をコードする。当該アミノ酸配列は、GenBankアクセッション番号NM_003981により表される塩基配列の転写産物であり、GenBankアクセッション番号NP_003972により表される。 The amino acid sequence shown in SEQ ID NO: 7 encodes human PRC1 (Protein Regulator of Cytokinesis 1). The amino acid sequence is a transcription product of the base sequence represented by GenBank accession number NM_003981, and is represented by GenBank accession number NP_003972.
配列番号８で示されるアミノ酸配列は、ヒトTFE3（transcription factor binding to IGHM enhancer 3、別名bHLHe33; RCCP2; TFEA）タンパク質をコードする。当該アミノ酸配列は、GenBankアクセッション番号NM_00652により表される塩基配列の転写産物であり、GenBankアクセッション番号NP_006512により表される。 The amino acid sequence represented by SEQ ID NO: 8 encodes human TFE3 (transcription factor binding to IGHM enhancer 3, also known as bHLHe33; RCCP2; TFEA) protein. The amino acid sequence is a transcription product of the base sequence represented by GenBank accession number NM_00652, and is represented by GenBank accession number NP_006512.
配列番号９で示されるアミノ酸配列は、ヒトWHSC1（Wolf-Hirschhorn syndrome candidate 1、別名FLJ23286;、KIAA1090、MMSET、NSD2、REIIBP、TRX5）タンパク質をコードする。当該アミノ酸配列は、GenBankアクセッション番号NM_133336により表される塩基配列の転写産物であり、GenBankアクセッション番号NP_006512により表される。 The amino acid sequence shown by SEQ ID NO: 9 encodes human WHSC1 (Wolf-Hirschhorn syndrome candidate 1, also known as FLJ23286; KIAA1090, MMSET, NSD2, REIIBP, TRX5) protein. The amino acid sequence is a transcription product of the base sequence represented by GenBank accession number NM_133336, and is represented by GenBank accession number NP_006512.
配列番号１０で示されるアミノ酸配列は、DNA修復タンパク質であるヒトXRCC4タンパク質をコードする。当該アミノ酸配列は、GenBankアクセッション番号NM_022406により表される塩基配列の転写産物であり、GenBankアクセッション番号NP_071801により表される。 The amino acid sequence shown in SEQ ID NO: 10 encodes human XRCC4 protein which is a DNA repair protein. The amino acid sequence is a transcription product of the base sequence represented by GenBank accession number NM_022406, and is represented by GenBank accession number NP_071801.
配列番号１〜１０で示されるアミノ酸配列を、下記表に示す。 The amino acid sequences shown in SEQ ID NOs: 1 to 10 are shown in the following table.
上記タンパク質のうち、特に配列番号１〜６で示されるアミノ酸配列のタンパク質を用いることが好ましく、配列番号１〜３で示されるアミノ酸配列のタンパク質が特に好ましい。 Among the above proteins, it is particularly preferable to use a protein having an amino acid sequence represented by SEQ ID NOs: 1 to 6, and particularly preferably a protein having an amino acid sequence represented by SEQ ID NOs: 1 to 3.
配列番号１〜１０は、各々のタンパク質の全長アミノ酸配列を示す。本発明において用いられるタンパク質は、配列番号１〜１０に示すアミノ酸配列からなるタンパク質であっても、本発明の実施ができる限度において、配列番号１〜１０が示す各々のアミノ酸配列の一部分であってもよい。 SEQ ID NOs: 1 to 10 show the full-length amino acid sequences of the respective proteins. Even if the protein used in the present invention is a protein consisting of the amino acid sequences shown in SEQ ID NOs: 1 to 10, it is a part of each amino acid sequence shown in SEQ ID NOs: 1 to 10 as long as the present invention can be carried out. Also good.
上記のタンパク質に対する抗体は、当該タンパク質に特異的に結合する抗体が主に意図される。本発明において、「抗体」の好ましい具体例は自己抗体である。「自己抗体」とは、自己の細胞又は組織に対して産生される抗体を意味する。 An antibody against the above protein is mainly intended to be an antibody that specifically binds to the protein. In the present invention, a preferred specific example of “antibody” is an autoantibody. “Autoantibody” means an antibody produced against an autologous cell or tissue.
「抗体」は、「免疫グロブリンタンパク質」と交換可能に用いられる。抗体のアイソタイプは、IgG（IgG1、IgG2、IgG3、IgG4）、IgM、IgA、IgDなどがあるが、特に限定されるものではない。抗体のアイソタイプは、好適にはIgGである。 “Antibody” is used interchangeably with “immunoglobulin protein”. Antibody isotypes include, but are not limited to, IgG (IgG1, IgG2, IgG3, IgG4), IgM, IgA, and IgD. The isotype of the antibody is preferably IgG.
５．抗体の検出
被験者のサンプルにおいて、上記抗体を検出する手段は、適宜公知の手法を用いることができる。具体的には、ELISA法（Enzyme-Linked ImmunoSorbent Assay）、ラジオイムノアッセイ法(RIA）などの免疫学的測定方法が好適な例として挙げられる。簡便性と正確性の観点から、特に好ましい抗体を検出する手段としてELISAが挙げられる。
5. Antibody Detection In the subject's sample, the means for detecting the antibody may appropriately use known techniques. Specifically, immunological measurement methods such as ELISA (Enzyme-Linked ImmunoSorbent Assay) and radioimmunoassay (RIA) are preferable examples. From the viewpoint of simplicity and accuracy, ELISA is an especially preferable means for detecting an antibody.
ELISA法の具体的な実施態様として、競合イムノアッセイ、サンドイッチイムノアッセイが挙げられる。 Specific embodiments of the ELISA method include competitive immunoassay and sandwich immunoassay.
６．特発性間質性肺炎の検出
本発明において、被験者のサンプル中における、上記タンパク質から選択される少なくとも１種もしくはその断片に対する抗体を指標として、特発性間質性肺炎の検出または診断を行う。従って、本発明は、上記タンパク質を、特発性間質性肺炎の検出または診断に用いるためのマーカーとして使用することをも提供する。
6). Detection of idiopathic interstitial pneumonia In the present invention, idiopathic interstitial pneumonia is detected or diagnosed using, as an index, an antibody against at least one selected from the above proteins or a fragment thereof in a sample of a subject. Therefore, the present invention also provides the use of the above protein as a marker for use in the detection or diagnosis of idiopathic interstitial pneumonia.
本明細書において、「検出」は、「診断」または「判定」と交換可能に用いることができる。「特発性間質性肺炎の検出」とは、被験者が、特発性間質性肺炎を発症していることの検出を主に指す。さらに、「特発性間質性肺炎の検出」は、特発性間質性肺炎を将来発症する可能性があることの検出であってもよい。あるいは、「特発性間質性肺炎の検出又は診断」は、過去に特発性間質性肺炎であると診断された被験者の、病態の変化（治療効果、重症度等）の検出であってもよい。 In this specification, “detection” can be used interchangeably with “diagnosis” or “determination”. “Detection of idiopathic interstitial pneumonia” mainly refers to detection of the subject developing idiopathic interstitial pneumonia. Furthermore, “detection of idiopathic interstitial pneumonia” may be detection of the possibility of developing idiopathic interstitial pneumonia in the future. Alternatively, “detection or diagnosis of idiopathic interstitial pneumonia” may be detection of a change in pathological condition (therapeutic effect, severity, etc.) of a subject previously diagnosed with idiopathic interstitial pneumonia. Good.
本発明の好ましい態様の1つにおいては、上記タンパク質に対する抗体が、予め設定されたカットオフ値よりも多く存在する場合、被験者は特発性間質性肺炎であると判定することができる。上記予め設定するカットオフ値は、当業者が適宜設定することができる。例えば、特発性間質性肺炎を発症していない健常者の平均値又は中央値と比べて統計的に有意に高い値とすることができる。 In one preferred embodiment of the present invention, when the antibody against the protein is present in a larger amount than a preset cutoff value, the subject can be determined to have idiopathic interstitial pneumonia. A person skilled in the art can appropriately set the cutoff value set in advance. For example, the value can be statistically significantly higher than the average value or median value of healthy subjects who do not develop idiopathic interstitial pneumonia.
７．キット
本発明は、特発性間質性肺炎を検出するためのキットをも提供する。本発明のキットは、配列番号１〜１０で示されるアミノ酸配列のタンパク質から選択される少なくとも１種に対する抗体を検出する手段を含むものであれば特に限定されない。
7). Kit The present invention also provides a kit for detecting idiopathic interstitial pneumonia. The kit of the present invention is not particularly limited as long as it includes a means for detecting an antibody against at least one selected from proteins having amino acid sequences represented by SEQ ID NOs: 1 to 10.
例えば、配列番号１〜１０で示されるアミノ酸配列のタンパク質から選択される少なくとも１種に対する抗体を検出する手段は、当該タンパク質が固相に結合された、ELISA法を実施するための器具であってもよい。固相の具体例としては、試験管、マイクロタイタープレートのウェル、アガロース粒子、ラテックス粒子などが挙げられる。 For example, the means for detecting an antibody against at least one selected from proteins having the amino acid sequences represented by SEQ ID NOs: 1 to 10 is an instrument for performing an ELISA method in which the protein is bound to a solid phase. Also good. Specific examples of the solid phase include test tubes, microtiter plate wells, agarose particles, latex particles, and the like.
また、本発明のキットには、必要に応じて他の成分を含めることができる。他の成分は、例えばサンプルを採取するための道具（例えば、注射器等）、ポジティブコントロール試料及びネガティブコントロール試料などが挙げられるが、これに限定されない。本発明の検出方法を行うための手順を書き記した書面等を含むこともできる。 The kit of the present invention can contain other components as necessary. Examples of other components include, but are not limited to, a tool for collecting a sample (for example, a syringe), a positive control sample, and a negative control sample. The document etc. which wrote down the procedure for performing the detection method of this invention can also be included.
［実施例１］
サンプル
日本呼吸器学会による診断ガイドライン（非特許文献１）及びATS/ERS/JRS/ALAT Statement（非特許文献２）に基づき特発性肺線維症 (idiopathic pulmonary fibrosis; IPF)と診断したIPF9症例から血液を採取し血清を分離した。対象をIPFに罹患していない健常者とし採血後血清を分離した。
[Example 1]
Sample Japanese Respiratory Society by the diagnostic guidelines (Non-Patent Document 1) and ATS / ERS / JRS / ALAT Statement ( Non-Patent Document 2) based idiopathic pulmonary fibrosis (idiopathic pulmonary fibrosis; IPF) blood from IPF9 cases diagnosed with Were collected and serum was separated. The subjects were healthy individuals who did not suffer from IPF, and serum was isolated after blood collection.
ProtoArray
上記患者群の血清及び対照群の血清について、ライフテクノロジーズ社が提供するProtoArrayヒトタンパク質マイクロアレイを用いて、血清中に存在する自己抗体のプロファイルを求めた。具体的手法は、製造者が提供するプロトコールに従った。
ProtoArray
Using the ProtoArray human protein microarray provided by Life Technologies, the profiles of autoantibodies present in the sera of the patient group and the control group were determined. The specific procedure followed the protocol provided by the manufacturer.
得られた結果を解析し、患者群の血清中に、対照群と比して、自己抗体が多く存在する抗原タンパク質を抽出し、配列番号１〜１０のアミノ酸配列のタンパク質が得られた。 The obtained results were analyzed, and an antigen protein in which more autoantibodies were present in the serum of the patient group than in the control group was extracted, and a protein having an amino acid sequence of SEQ ID NOs: 1 to 10 was obtained.
なお、ProtoArrayヒトタンパク質マイクロアレイには、9000種以上の完全長ヒトタンパク質が２スポット搭載されている、タンパク質マイクロアレイである。 The ProtoArray human protein microarray is a protein microarray on which two spots of 9000 or more full-length human proteins are mounted.
［実施例２］
サンプル
日本呼吸器学会による診断ガイドライン（非特許文献１）及びATS/ERS/JRS/ALAT Statement（非特許文献２）に基づき特発性肺線維症 (idiopathic pulmonary fibrosis; IPF)と診断したIPF16症例から血液を採取し血清を分離した（図中、「Group 2 Patient」）。対象をIPFに罹患していない健常者とし採血後血清を分離した（図中、「Group 1 Control」）。
[Example 2]
Sample Japanese Respiratory Society by the diagnostic guidelines (Non-Patent Document 1) and ATS / ERS / JRS / ALAT Statement ( Non-Patent Document 2) based idiopathic pulmonary fibrosis (idiopathic pulmonary fibrosis; IPF) blood from IPF16 cases diagnosed with And serum was separated ("Group 2 Patient" in the figure). The subject was a healthy person who did not suffer from IPF, and serum was separated after blood collection ("Group 1 Control" in the figure).
ProtoPlex
ライフテクノロジーズ社が提供するProtoPlex免疫応答アッセイサービスにより、実施例１で選択した上記配列番号１〜１０のアミノ酸配列のタンパク質について、患者群及び対照群の血清中に存在する自己抗体の量を測定した。具体的手法は、製造者が提供するプロトコールに従った。
ProtoPlex
With the ProtoPlex immune response assay service provided by Life Technologies, the amount of autoantibodies present in the serum of the patient group and the control group was measured for the protein having the amino acid sequence of SEQ ID NO: 1 to 10 selected in Example 1. . The specific procedure followed the protocol provided by the manufacturer.
結果を、図１〜６に示す。また、図７に統計解析の結果を示す。 The results are shown in FIGS. FIG. 7 shows the results of statistical analysis.
以上の結果は、本発明のタンパク質が、特発性間質性肺炎の検出に有用であることを示している。 The above results indicate that the protein of the present invention is useful for detection of idiopathic interstitial pneumonia.
［実施例３］
配列番号１のアミノ酸配列のタンパク質（ヒトUBE2Tタンパク質）について、ELISA法により、各種間質性肺炎の患者由来の血清に存在する自己抗体の量を定量した。対照として、血清中のKL-6値の測定をした。
[Example 3]
For the protein having the amino acid sequence of SEQ ID NO: 1 (human UBE2T protein), the amount of autoantibodies present in sera from patients with various interstitial pneumonia was quantified by ELISA. As a control, serum KL-6 levels were measured.
サンプル
日本呼吸器学会による診断ガイドライン及びATS/ERS/JRS/ALAT Statement参考文献１）に基づき特発性肺線維症(idiopathic pulmonary fibrosis; IPF)に基づいてIPFと診断したIPF 26症例、過敏性肺臓炎及びサルコイドーシス各２症例から血液を採取し血清を分離した。対象をIPFに罹患していない健常者とし採血後血清を分離した。
Sample Japanese Respiratory Society by the diagnostic guidelines and ATS / ERS / JRS / ALAT Statement References 1) based idiopathic pulmonary fibrosis (idiopathic pulmonary fibrosis; IPF) IPF 26 were diagnosed as IPF based on cases, hypersensitivity pneumonitis And blood was collected from 2 cases each of sarcoidosis and serum was separated. The subjects were healthy individuals who did not suffer from IPF, and serum was isolated after blood collection.
測定
ヒトUBE2T（1-197aa Human, His-tagged, Recombimamt, E.coli （ATGEN 社: #ATGP0529））をマイクロプレート上に固相化し洗浄後、6 x His antibody(rabbit polyclonal)（Gene Tex社：#GTX30501）を10,000 - 156.25 pg/mlまでサンプルバッファーにより７段階に希釈した標準サンプルと、サンプルバッファーで200倍に希釈した血清をウェルに加え、室温で２時間インキュベーションした。洗浄バッファーで３回洗浄後、Biotin anti-Human IgG(Fc)（BioLegend 社）を検出抗体とし１時間室温でインキュベーションし、洗浄バッファーで５回洗浄した。TMB （Kirkegaard & Perry Laboratories,Inc 社）で発色し、1N 塩酸で発色を停止後、吸光高度計Multiskan GO (Thermo)で450nmの吸光度を測定した。標準サンプルの吸光度からSkanIt 3.2 software （Thermo）を用いて検量線を作成し、4パラメーターロジティックモデルy=(A-D)/(1+(x/C)＾B)+D, R2を用いて濃度を算出した。
Measurement Human UBE2T (1-197aa Human, His-tagged, Recombimamt, E.coli (ATGEN: # ATGP0529)) was immobilized on a microplate and washed, then 6 x His antibody (rabbit polyclonal) (Gene Tex: # GTX30501) was diluted in 7 steps with sample buffer to 10,000-156.25 pg / ml and serum diluted 200-fold with sample buffer was added to the wells and incubated at room temperature for 2 hours. After washing 3 times with the washing buffer, Biotin anti-Human IgG (Fc) (BioLegend) was incubated as a detection antibody for 1 hour at room temperature and washed 5 times with the washing buffer. The color was developed with TMB (Kirkegaard & Perry Laboratories, Inc.), the color development was stopped with 1N hydrochloric acid, and the absorbance at 450 nm was measured with an absorption altimeter Multiskan GO (Thermo). Create a calibration curve from the absorbance of the standard sample using SkanIt 3.2 software (Thermo), and use the 4-parameter logistic model y = (AD) / (1+ (x / C) ^ B) + D, R 2 Concentration was calculated.
KL-6値の測定は、製造者が提供する指示書に従った。 The measurement of the KL-6 value was according to the instructions provided by the manufacturer.
結果
結果を図８及び図９に示す。図８に示すように、特発性肺線維症（IPF）の患者において、健常者と比較して、有意にUBE2Tタンパク質に対する自己抗体の血中濃度が高いことが確認できた（P＜0.05、IPF vs normal、Mann-Whitney U test）。一方、図９に示すように、KL-6値については、有意差は見られなかった。
The results are shown in FIG. 8 and FIG. As shown in FIG. 8, in patients with idiopathic pulmonary fibrosis (IPF), it was confirmed that the blood concentration of autoantibodies against UBE2T protein was significantly higher than that in healthy subjects (P <0.05, IPF). vs normal, Mann-Whitney U test). On the other hand, as shown in FIG. 9, no significant difference was observed for the KL-6 value.
ROC曲線解析
次いで、配列番号１のアミノ酸配列のタンパク質（ヒトUBE2Tタンパク質）を特発性肺線維症のマーカーとして用いることのモデル性能の評価をするために、ROC曲線を作成した。ROC曲線を図１０に示す。また、解析結果を図１１に示す。血清抗UBE2T抗体の濃度のカットオフ値を219ng/mlとした場合、IPFの診断における感度は92.9％、特異度は80.8％で、感度、特異度ともにIPFの診断において血清抗UBE2T抗体の測定が有効であることが示された。
ROC curve analysis Next, in order to evaluate the model performance of using the protein having the amino acid sequence of SEQ ID NO: 1 (human UBE2T protein) as a marker of idiopathic pulmonary fibrosis, an ROC curve was prepared. The ROC curve is shown in FIG. The analysis results are shown in FIG. When the cutoff value of the serum anti-UBE2T antibody concentration is 219 ng / ml, the sensitivity in IPF diagnosis is 92.9% and the specificity is 80.8%. It was shown to be effective.
Claims (3)
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| JP2013230423A JP6312054B2 (en) | 2013-11-06 | 2013-11-06 | Biomarker for interstitial pneumonia |
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