JP6744544B2 - How to distinguish nephritis - Google Patents
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本発明は、種々の腎炎のうち、ＩｇＡ腎症と紫斑病性腎炎と他の腎炎とを区別して鑑別する方法に関する。 The present invention relates to a method for distinguishing and distinguishing IgA nephropathy, purpura nephritis, and other nephritis among various nephritis.
ＩｇＡ腎症は、世界で最も頻度の高い原発性糸球体腎炎で、約３０〜４０％は末期腎不全に至る予後不良の疾患である。ＩｇＡ腎症は、このように予後不良であることから、確定診断及び定義は極めて重要である。最近、ＩｇＡ腎症は、血尿、蛋白尿等の尿所見を呈し、優位なＩｇＡ沈着を糸球体に認め、その原因となり得る基礎疾患が認められないものである、と定義されるようになった（非特許文献１）。 IgA nephropathy is the most frequent primary glomerulonephritis in the world, and about 30-40% is a disease with a poor prognosis leading to end-stage renal failure. Since IgA nephropathy has such a poor prognosis, definitive diagnosis and definition are extremely important. Recently, IgA nephropathy has come to be defined as urinary findings such as hematuria and proteinuria, with predominant IgA deposits in the glomerulus and no underlying disease that can cause them. (Non-patent document 1).
このように定義されていることからもわかるように、ＩｇＡ腎症の診断には腎組織所見が必須である。糸球体のＩｇＡ沈着部位は主にメサンギウム領域で、多くはＣ３の沈着を同時に認める。一方で、ＩｇＡ腎症では、腎糸球体にＩｇＡが優位に沈着することが定義とされているものの、ＩｇＧやＩｇＭ、あるいは両者が沈着するケースなど、多様性に富む疾患であることも知られている。 As can be seen from this definition, renal tissue findings are essential for the diagnosis of IgA nephropathy. The site of IgA deposition in the glomerulus is mainly in the mesangial region, and in many cases, C3 deposition is observed simultaneously. On the other hand, IgA nephropathy is defined as a predominant IgA deposition in the renal glomerulus, but it is also known to be a disease with a great variety of cases in which IgG, IgM, or both are deposited. ing.
近年、腎生検をすることなくＩｇＡ腎症を診断する試みが検討され、免疫グロブリンＡ１の重鎖遺伝子によってコードされるポリペプチドのヒンジ領域におけるガラクトースが結合していないセリン／スレオニン結合型糖鎖（以下、糖鎖異常ＩｇＡ１）を特異的に認識し、当該糖鎖異常ＩｇＡ１と結合するモノクローナル抗体を用いて、血中の糖鎖異常ＩｇＡ１を測定することが可能となった。血中糖鎖異常ＩｇＡ１、また血中糖鎖異常ＩｇＡ１に対する自己抗体、免疫複合体などを組み合わせてＩｇＡ腎症を診断する方法が報告された（特許文献１）。 In recent years, attempts to diagnose IgA nephropathy without renal biopsy have been studied, and serine/threonine-linked sugar chains in which galactose in the hinge region of the polypeptide encoded by the heavy chain gene of immunoglobulin A1 is not bound. It has become possible to measure blood sugar chain abnormal IgA1 using a monoclonal antibody that specifically recognizes (hereinafter, sugar chain abnormal IgA1) and binds to the sugar chain abnormal IgA1. A method for diagnosing IgA nephropathy by combining blood sugar chain abnormal IgA1, autoantibodies against blood sugar chain abnormal IgA1, immune complexes and the like has been reported (Patent Document 1).
血中の糖鎖異常ＩｇＡ１は、ＩｇＡ腎症だけでなく紫斑病性腎炎（ＨＳＰＮ）でも有意に高値を示すが、その他の腎炎患者や健常者と同等の値を示す症例もある（非特許文献２、３）。紫斑病性腎炎は、ＩｇＡ腎症と同様に腎糸球体メサンギウム領域にＩｇＡ優位の沈着が認められ、組織学的にはＩｇＡ腎症と鑑別が困難であるだけではなく、感染を契機に尿所見異常が悪化すること、糖鎖異常ＩｇＡ１の産生亢進など、病態もＩｇＡ腎症と極めて類似している。しかし、ＨＳＰＮは紫斑を先行所見とすることから、臨床上ＨＳＰＮとＩｇＡ腎症の鑑別は可能である。腎生検組織上、ＩｇＡ腎症と鑑別が困難な疾患として、ループス腎炎、関節リウマチ、セリアック病、肝硬変に伴うもの、HCV関連腎炎、HIV腎症などが挙げられる。 Abnormal sugar chain in blood IgA1 shows a significantly high value not only in IgA nephropathy but also in purpura nephritis (HSPN), but there are cases showing the same value as other nephritis patients and healthy persons (Non-patent document) 2, 3). Purpura nephritis has IgA-predominant deposits in the glomerular mesangial region, similar to IgA nephropathy. Not only is histologically difficult to distinguish from IgA nephropathy, but urinary findings are also triggered by infection. The pathological conditions are extremely similar to those of IgA nephropathy, such as aggravation of abnormalities and increased production of sugar chain abnormal IgA1. However, since HSPN has purpura as a preceding finding, it is possible to clinically distinguish between HSPN and IgA nephropathy. Diseases that are difficult to distinguish from IgA nephropathy on renal biopsy tissues include lupus nephritis, rheumatoid arthritis, celiac disease, those associated with cirrhosis, HCV-related nephritis, and HIV nephropathy.
従って、本発明の課題は、ＩｇＡ腎症及び紫斑病性腎炎と他の腎炎との新たな鑑別方法を提供することにある。 Therefore, an object of the present invention is to provide a new method for differentiating IgA nephropathy and purpura nephritis from other nephritis.
そこで本発明者は、ＩｇＡ腎症及び紫斑病性腎炎と他の類似する腎炎とを明確に鑑別する手法を見出すべく検討した結果、糖鎖異常ＩｇＡ１に特異的なモノクローナル抗体を用いて、血中でなく、腎炎患者の腎組織に沈着する糖鎖異常ＩｇＡ１を検出すれば、ＩｇＡ腎症及び紫斑病性腎炎と他の腎炎とが明確に区別できることを見出し、本発明を完成した。 Therefore, the present inventor has conducted studies to find out a method for clearly distinguishing IgA nephropathy and purpura nephritis from other similar nephritis, and as a result, using a monoclonal antibody specific for a sugar chain abnormality IgA1 in blood, However, it was found that IgA nephropathy and purpura nephritis can be clearly distinguished from other nephritis by detecting IgA1 with abnormal sugar chain deposited in renal tissue of patients with nephritis.
すなわち、本発明は、次の〔１〕及び〔２〕を提供するものである。 That is, the present invention provides the following [1] and [2].
〔１〕糖鎖異常ＩｇＡ１を特異的に認識し、当該糖鎖異常ＩｇＡ１と結合するモノクローナル抗体又はその断片を用いて、腎炎患者由来の腎組織に沈着する糖鎖異常ＩｇＡ１を検出することを特徴とする、ＩｇＡ腎症及び紫斑病性腎炎と他の腎炎との鑑別方法。
〔２〕腎炎患者由来の腎組織に沈着する糖鎖異常ＩｇＡ１の検出が、抗体組織染色である〔１〕記載の鑑別方法。
[1] Characteristic of specifically recognizing abnormal sugar chain IgA1 and detecting abnormal sugar chain IgA1 deposited in renal tissue derived from a patient with nephritis using a monoclonal antibody or a fragment thereof that binds to the abnormal sugar chain IgA1 And a method for differentiating IgA nephropathy and purpura nephritis from other nephritis.
[2] The identification method according to [1], wherein the detection of the abnormal sugar chain IgA1 deposited in the renal tissue derived from a patient with nephritis is antibody tissue staining.
本発明方法によれば、腎生検組織にてＩｇＡ腎症と鑑別が困難であった、ループス腎炎、関節リウマチ、セリアック病、肝硬変に伴うもの、HCV関連腎炎、HIV腎症等が、ＩｇＡ腎症及び紫斑病性腎炎と明確に鑑別できる。従って、早期に正確な治療計画を立てることができる。 According to the method of the present invention, it was difficult to distinguish IgA nephropathy from renal biopsy tissue, lupus nephritis, rheumatoid arthritis, celiac disease, those associated with cirrhosis, HCV-related nephritis, HIV nephropathy, etc. Can be clearly differentiated from the disease and purpura nephritis. Therefore, an accurate treatment plan can be established early.
本発明方法に用いられるモノクローナル抗体は、免疫グロブリンＡ１の重鎖遺伝子によってコードされるポリペプチド（ＩｇＡ１重鎖）のヒンジ領域におけるガラクトースが結合していないセリン／スレオニン結合型糖鎖（糖鎖異常ＩｇＡ１）を特異的に認識し、当該糖鎖異常ＩｇＡ１と結合するモノクローナル抗体である。このようなモノクローナル抗体の例としては、ＷＯ２０１１／０８１１８９に記載のモノクローナル抗体が挙げられる。 The monoclonal antibody used in the method of the present invention is a serine/threonine-linked sugar chain (glycan abnormal IgA1) to which galactose in the hinge region of a polypeptide (IgA1 heavy chain) encoded by the heavy chain gene of immunoglobulin A1 is not bound. ) Is specifically recognized and binds to the abnormal sugar chain IgA1. Examples of such monoclonal antibodies include the monoclonal antibodies described in WO2011/081189.
前記糖鎖異常ＩｇＡ１が、α−Ｎ−アセチルガラクトサミン−セリン／スレオニン（以下、Ｔｎ抗原）又はシアリルＴｎ抗原から選ばれる糖鎖異常ＩｇＡ１であるのが好ましい。 The abnormal sugar chain IgA1 is preferably an abnormal sugar chain IgA1 selected from α-N-acetylgalactosamine-serine/threonine (hereinafter, Tn antigen) or sialyl Tn antigen.
ＩｇＡ１重鎖のアミノ酸配列を配列番号１に示す。ヒンジ領域は、配列番号１のVPSTPPTPSPSTPPTPSPSである（Mol Cell Proteomics 9: 2545-2557, 2010）。 The amino acid sequence of the IgA1 heavy chain is shown in SEQ ID NO:1. The hinge region is VPSTPPTPSPSTPPTPSPS of SEQ ID NO: 1 (Mol Cell Proteomics 9: 2545-2557, 2010).
さらに具体的には、ハイブリドーマＫＭ４１３７（ＦＥＲＭ ＢＰ−１１２１４）、ＫＭ４１４０（ＦＥＲＭ ＢＰ−１１２１５）、ＫＭ４１４４（ＦＥＲＭ ＢＰ−１１２１６）及びＫＭ５５から選ばれるハイブリドーマが産生するモノクローナル抗体が好ましい。 More specifically, a monoclonal antibody produced by a hybridoma selected from hybridomas KM4137 (FERM BP-11214), KM4140 (FERM BP-11215), KM4144 (FERM BP-11216) and KM55 is preferable.
これらのモノクローナル抗体は、ＷＯ２０１１／０８１１８９に記載の方法により製造することができる。 These monoclonal antibodies can be produced by the method described in WO2011/081189.
前記モノクローナル抗体は、遺伝子組み換え抗体であってもよく、さらにヒト型キメラ抗体、ヒト化抗体及びヒト抗体から選ばれる抗体であってもよい。 The monoclonal antibody may be a recombinant antibody, or may be an antibody selected from human chimeric antibodies, humanized antibodies and human antibodies.
前記モノクローナル抗体の断片としては、Ｆａｂ、Ｆａｂ’、Ｆ（ａｂ’）2、一本鎖抗体（ｓｃＦｖ）、二量化Ｖ領域（Ｄｉａｂｏｄｙ）、ジスルフィド安定化Ｖ領域（ｄｓＦｖ）及びＣＤＲを含むペプチドから選ばれる抗体断片が挙げられる。 Examples of the fragment of the monoclonal antibody include peptides containing Fab, Fab′, F(ab′) 2 , single chain antibody (scFv), dimerized V region (Diabody), disulfide-stabilized V region (dsFv) and CDR. The selected antibody fragment may be mentioned.
本発明においては、前記のモノクローナル抗体を用いて、腎炎患者由来の腎組織に沈着する糖鎖異常ＩｇＡ１を検出する。腎炎患者としては、ＩｇＡ腎症や紫斑病性腎炎を含む急性又は慢性の糸球体腎炎、すなわち溶連菌感染後糸球体腎炎、膜性腎症、膜性増殖性糸球体腎炎、ANCA関連腎炎、ループス腎炎、関節リウマチ、セリアック病、肝硬変に伴うもの、HCV関連腎炎、HIV腎症等が挙げられる。腎炎患者由来の腎組織としては、腎炎患者の腎臓から採取した組織が用いられる。 In the present invention, the above-mentioned monoclonal antibody is used to detect abnormal IgA1 of a sugar chain deposited in renal tissue derived from a patient with nephritis. Patients with nephritis include acute or chronic glomerulonephritis including IgA nephropathy and purpura nephritis, ie post streptococcal glomerulonephritis, membranous nephropathy, membranous proliferative glomerulonephritis, ANCA-related nephritis, lupus nephritis. , Rheumatoid arthritis, celiac disease, those associated with cirrhosis, HCV-related nephritis, HIV nephropathy and the like. As the renal tissue derived from the nephritis patient, a tissue collected from the kidney of the nephritis patient is used.
腎炎患者由来の腎組織に沈着する糖鎖異常ＩｇＡ１を検出する手段としては、前記モノクローナル抗体を用いる抗体組織染色法が好ましい。より具体的には、腎組織と前記モノクローナル抗体を反応させた後、ＦＩＴＣなどの蛍光標識、ペルオキシダーゼなどの酵素標識、ビオチン標識などを施した抗イムノグロブリン抗体又は結合断片を反応させた後、該標識を可視化し、顕微鏡にて顕鏡する方法が挙げられる。 As a means for detecting the abnormal sugar chain IgA1 deposited in the renal tissue derived from a nephritis patient, the antibody tissue staining method using the above-mentioned monoclonal antibody is preferable. More specifically, after the renal tissue is reacted with the monoclonal antibody, an anti-immunoglobulin antibody or binding fragment labeled with a fluorescent label such as FITC, an enzyme label such as peroxidase, or a biotin label is reacted, Examples include a method of visualizing the label and microscopic observation with a microscope.
腎組織に糖鎖異常ＩｇＡ１の沈着が認められる場合には、ＩｇＡ腎症又は紫斑病性腎炎と鑑別できる。一方、腎組織に糖鎖異常ＩｇＡ１の沈着が認められない場合には、ＩｇＡ腎症及び紫斑病性腎炎以外の腎炎と鑑別できる。
従来の腎組織へのＩｇＡの沈着では、ＩｇＡ腎症及び紫斑病性腎炎以外の腎炎、例えば、ループス腎炎、関節リウマチ、セリアック病、肝硬変に伴うもの、ＨＣＶ関連腎炎、ＨＩＶ腎症等も陽性になるが、本発明によればＩｇＡ腎症及び紫斑病性腎炎と他の腎炎とが正確に鑑別できる。
When deposition of abnormal IgA1 sugar chain is found in renal tissue, it can be distinguished from IgA nephropathy or purpura nephritis. On the other hand, in the case where no abnormal sugar chain deposition of IgA1 is found in renal tissue, it can be distinguished from nephritis other than IgA nephropathy and purpura nephritis.
With conventional IgA deposition in renal tissue, nephritis other than IgA nephropathy and purpura nephritis, for example, lupus nephritis, rheumatoid arthritis, celiac disease, those associated with cirrhosis, HCV-related nephritis, HIV nephropathy, etc. were also positive. However, according to the present invention, IgA nephropathy and purpura nephritis can be accurately distinguished from other nephritis.
次に実施例を挙げて本発明を更に詳細に説明する。 Next, the present invention will be described in more detail with reference to examples.
参考例１
（血中の糖鎖異常ＩｇＡ１測定）
血中糖鎖異常ＩｇＡ１値は、ＫＭ５５を用いたＥＬＩＳＡ法により測定する。まず９６ｗｅｌｌのＥＬＩＳＡプレートにＫＭ５５を固相化する。１％のBovine serum albumin（ＢＳＡ）ＰＢＳ溶液にてブロッキング後に、血清サンプルを反応させる。ペルオキシダーゼ標識の抗ヒトＩｇＡ１抗体で同定する（Nephrol Dial Transplant. 30: 1315-1321, 2015）。
Reference example 1
(Measurement of abnormal sugar chain IgA1 in blood)
The blood sugar chain abnormal IgA1 value is measured by an ELISA method using KM55. First, KM55 is immobilized on a 96-well ELISA plate. After blocking with a 1% Bovine serum albumin (BSA) PBS solution, a serum sample is reacted. It is identified by a peroxidase-labeled anti-human IgA1 antibody (Nephrol Dial Transplant. 30: 1315-1321, 2015).
その結果を図１に示す。図１の結果から、ＩｇＡ腎症であっても血中の糖鎖異常ＩｇＡ１陰性の患者もあり、一方血中の糖鎖異常ＩｇＡ１陽性であっても他の腎炎患者である例も存在する。 The result is shown in FIG. From the results of FIG. 1, there are patients with IgA nephropathy who have negative IgA1 abnormalities in blood sugar chains, while there are also cases with other nephritis patients who have positive IgA1 abnormal sugar chains in blood.
実施例１
（腎組織の糖鎖ＩｇＡ１沈着の測定）
パラフィンブロックの腎生検組織を３μｍに薄切し、プレパラートにサンプルをのせ、脱パラフィンを行う。５分間、流水洗浄後、プロテアーゼ溶液：Protease from Bacillus licheniformis（ＳＩＧＭＡ Ｐ５３８０）を用いて室温２時間で抗原賦活処理を行う。５分間、流水洗浄後、Protein Block Serum Free(Dako X090930)を用いて室温３０分でブロッキングする。ＫＭ５５抗体を抗体希釈液：REAL Antibody Diluent（Dako S2022）を用いて１００μｇ／ｍｌに希釈して反応させる（３７℃、３０分）。０．０５％Ｔｗｅｅｎ＋ＰＢＳ溶液（ＰＢＳ−Ｔ）にて３回洗浄後、Alexa Fluor 555 Goat anti-Rat IgG (Invitrogen A21434)を１０００倍希釈で反応させる（３７℃、３０分）。ＰＢＳ−Ｔにて３回洗浄後、プレパラートに封入剤を用いてカバーガラスをかける。
Example 1
(Measurement of sugar chain IgA1 deposition in renal tissue)
The paraffin block kidney biopsy tissue is sliced into 3 μm slices, the sample is placed on the preparation, and deparaffinization is performed. After washing with running water for 5 minutes, antigen activation treatment is performed at room temperature for 2 hours using a protease solution: Protease from Bacillus licheniformis (SIGMA P5380). After washing with running water for 5 minutes, blocking is performed at room temperature for 30 minutes using Protein Block Serum Free (Dako X090930). The KM55 antibody is diluted to 100 μg/ml with an antibody diluent: REAL Antibody Diluent (Dako S2022) and reacted (37° C., 30 minutes). After washing three times with 0.05% Tween+PBS solution (PBS-T), Alexa Fluor 555 Goat anti-Rat IgG (Invitrogen A21434) is reacted with 1000-fold dilution (37° C., 30 minutes). After washing three times with PBS-T, a cover glass is applied to the preparation using the mounting medium.
その結果を図２〜図４に示す。図２〜図４から明らかなように、本発明のモノクローナル抗体を用いて腎組織への糖鎖異常ＩｇＡ１の沈着を検出すれば、ＩｇＡ腎症と紫斑病性腎炎と他の腎炎が正確に鑑別できる。 The results are shown in FIGS. As is clear from FIGS. 2 to 4, if the deposition of abnormal sugar chain IgA1 in renal tissue is detected using the monoclonal antibody of the present invention, IgA nephropathy, purpura nephritis and other nephritis can be accurately distinguished. it can.
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