KR20190129004A - Diagnosis of Systemic Lupus Erythematosus Using TCP1 Autoantibodies - Google Patents
Diagnosis of Systemic Lupus Erythematosus Using TCP1 Autoantibodies Download PDFInfo
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- KR20190129004A KR20190129004A KR1020190053056A KR20190053056A KR20190129004A KR 20190129004 A KR20190129004 A KR 20190129004A KR 1020190053056 A KR1020190053056 A KR 1020190053056A KR 20190053056 A KR20190053056 A KR 20190053056A KR 20190129004 A KR20190129004 A KR 20190129004A
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- KR
- South Korea
- Prior art keywords
- lupus erythematosus
- systemic lupus
- tcp1
- autoantibodies
- ala
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
본 발명은 전신홍반성루푸스 환자의 혈액 내 존재하는 TCP1 자가항체와 특이적으로 결합하는 항원 단백질을 이용하여 전신홍반성루푸스를 진단하는 방법에 관한 것이다. 본 발명의 진단 방법은 혈액과 같은 비침습적 생물학적 시료를 사용하기 때문에 기존의 진단방법과는 달리 환자에게 부담을 주지 않고 매우 간편하게 전신홍반성루푸스를 진단할 수 있을 뿐만 아니라 특이도 및 민감도가 높아 전신홍반성루푸스의 조기 진단에 유용하게 사용될 수 있다.The present invention relates to a method for diagnosing systemic lupus erythematosus using antigenic proteins that specifically bind to TCP1 autoantibodies present in the blood of patients with systemic lupus erythematosus. Since the diagnostic method of the present invention uses a non-invasive biological sample such as blood, it is very easy to diagnose systemic lupus erythematosus without burdening the patient, unlike conventional diagnostic methods, and also has high specificity and sensitivity. It can be useful for early diagnosis of lupus.
Description
본 발명은 TCP1 (T-complex polypeptide 1) 자가항체를 이용한 전신홍반성루푸스 (Systemic lupus erythematosus; SLE) 진단에 관한 것으로, 더욱 자세하게는 전신홍반성루푸스 환자의 혈액 내 존재하는 TCP1 자가항체와 특이적으로 결합하는 항원 단백질을 이용하여 전신홍반성루푸스를 진단하는 방법에 관한 것이다.The present invention relates to the diagnosis of systemic lupus erythematosus (SLE) using TCP1 (T-complex polypeptide 1) autoantibodies, and more specifically to specific binding to TCP1 autoantibodies present in the blood of patients with systemic lupus erythematosus. It relates to a method for diagnosing systemic lupus erythematosus using an antigenic protein.
전신홍반루푸스 (Systemic lupus erythematosus; SLE)란 전신의 다양한 조직에 자가면역으로 인한 염증반응이 발생하는 질환으로 침범 조직에 따라 피부발진, 광과민성, 관절염, 구강궤양, 신장염, 혈구감소증, 혈관염, 장막염 등 다양한 증상을 나타낸다. 전신홍반루푸스는 유전적인 소인을 가진 사람에게서 특정 바이러스 감염이나 자외선, 흡연 등의 환경적인 노출에 의하여 발병한다고 알려져 있다 (Paula S et al., Semin Nephrol. 30(2):164-176, 2010; James JA et al., Opin Rheumatol. 8:462-467, 2006).Systemic lupus erythematosus (SLE) is an inflammatory reaction caused by autoimmunity in various tissues of the whole body. Skin rash, photosensitivity, arthritis, mouth ulcers, nephritis, cytopenia, vasculitis, and meningitis depending on the invading tissue And various symptoms. Systemic lupus erythematosus is known to be caused by certain viral infections or environmental exposures such as ultraviolet rays and smoking in people with genetic predisposition (Paula S et al., Semin Nephrol . 30 (2): 164-176, 2010; James JA et al., Opin Rheumatol . 8: 462-467, 2006).
전신홍반루푸스의 진단은 1997년 개정된 미국류마티스학회의 진단기준이 주로 사용되며 이는 총 11가지 임상적 기준과 항핵항체의 양성을 포함한 면역학적 기준에서 4개 이상에 해당되는 경우로 정의하며 전신홍반루푸스에 특이적인 바이오마커는 아직 없다고 알려져 있다 (Ahn JK et al., Korean J of Med , 78(4):409-415, 2010). The diagnosis of systemic lupus erythematosus is mainly based on the diagnostic criteria of the American Society of Rheumatology revised in 1997, which is defined as four or more cases out of 11 clinical criteria and immunological criteria including positive antinuclear antibody. There are no known biomarkers specific for lupus (Ahn JK et al., Korean J of Med , 78 (4): 409-415, 2010).
전신홍반루푸스의 치료는 1990년대까지는 비특이적 약제가 사용되기 시작하였고, 최근에는 싸이클로포스파마이드가 가장 강력한 약제로 신장염, 혈관염과 같은 위급하거나 심한 염증 반응에서 사용되고 있으나 때때로 불임, 중증감염, 출혈성 방광염 등의 심각한 합병증이 발생한다 (M Petri et al., Lupus, 13:366-371, 2004). 또한, 스테로이드는 전신홍반루푸스가 활성화되었을 때 가장 빠르고 강력하게 염증을 조절하는 약제로 치료에 사용되고 있으나, 젊은 연령에 루푸스 진단받는 환자가 많고 반복적 악화에 따른 스테로이드의 지속적 투여로 인한 부작용의 발생이 증가된다 (Susan D et al., Health and Quality of Life Outcomes, 15:43, 2017). 아직까지 전신홍반루푸스는 완치를 할 수 있는 방법이 없으며, 환자에 따라 매우 다양한 임상 소견과 경과를 보이므로 질병의 활동성을 판정하고 감염성 질환과 같은 동반된 다른 질환의 유무를 정확히 파악하여 각 환자의 질병 상태에 합당한 치료 방침을 결정해야 한다.In the treatment of systemic lupus erythematosus, nonspecific drugs began to be used until the 1990s, and recently, cyclophosphamide is the most powerful drug used in urgent or severe inflammatory reactions such as nephritis and vasculitis, but sometimes infertility, severe infections, and hemorrhagic cystitis. Serious complications occur (M Petri et al., Lupus, 13: 366-371, 2004). In addition, steroids are the most rapid and potent inflammation-controlling agents when systemic lupus erythematosus is activated, but many patients are diagnosed with lupus at a young age, and the incidence of side effects from continuous administration of steroids due to repeated exacerbations is increased. (Susan D et al., Health and Quality of Life Outcomes, 15:43, 2017). There is no method for complete systemic lupus erythematosus yet, and there are various clinical findings and progression according to the patients. Therefore, the activity of the disease is judged and the presence or absence of other diseases such as infectious diseases is accurately determined. The appropriate treatment policy should be determined for the disease state.
전신홍반루푸스와 같은 자가면역질환은 현재까지 특이적 치료제가 없고, 특정 약제로 제거할 수 있는 다른 질병과 달리 활성화된 자가면역세포를 완벽하게 억제할 수만은 없기 때문에 치료에 많은 어려움이 있다. 따라서, 전신홍반루푸스의 초기 진단, 중증도 판별, 약제의 효용성 확인을 위한 바이오마커 연구는 매우 중요하며 꾸준한 기초 및 임상연구를 통하여 루푸스의 바이오마커를 찾아내는 것이 매우 시급하다.Autoimmune diseases such as systemic lupus erythematosus are difficult to treat because there are no specific therapeutic agents to date, and unlike other diseases that can be eliminated with specific drugs, they cannot completely inhibit activated autoimmune cells. Therefore, biomarker research for early diagnosis, severity determination, and drug efficacy of systemic lupus erythematosus is very important, and it is very urgent to find biomarker of lupus through steady basic and clinical studies.
이에, 본 발명자들은 조직검사 또는 영상촬영 기술을 사용하지 않고도 초기에 간편하게 전신홍반루푸스를 진단할 수 있는 바이오마커를 찾고자 예의 노력한 결과, TCP1 (T-complex polypeptide 1) 자가항체가 전신홍반루푸스 특이적으로 발현하여 혈액 내 존재하는 것을 확인하고, 본 발명을 완성하게 되었다.Accordingly, the present inventors have made efforts to find a biomarker that can easily diagnose systemic lupus erythematosus at an early stage without using biopsy or imaging technique. As a result, TCP1 (T-complex polypeptide 1) autoantibodies are specific for systemic lupus erythematosus. It was confirmed that the present in the blood, and completed the present invention.
본 발명의 목적은 전신홍반성루푸스 환자의 혈액 내에 존재하는 TCP1 자가항체를 이용하여 간편하게 전신홍반성루푸스를 진단하고자, TCP1 자가항체 인지 항원 단백질을 포함하는 전신홍반성루푸스 진단용 조성물 및 상기 조성물을 포함하는 전신홍반성루푸스 진단용 키트를 제공하는데 있다.An object of the present invention is to easily diagnose systemic lupus erythematosus using TCP1 autoantibodies present in the blood of patients with systemic lupus erythematosus, systemic lupus erythematosus comprising a composition for diagnosing systemic lupus erythematosus comprising TCP1 autoantibodies It is to provide a lupus diagnostic kit.
본 발명의 다른 목적은 전신홍반성루푸스 환자의 혈액에서 TCP1 자가항체를 검출하고, TCP1 자가항체 수준을 대조군과 비교하는 전신홍반성루푸스 진단을 위한 정보제공 방법을 제공하는데 있다.Another object of the present invention is to provide a method for detecting TCP1 autoantibodies in blood of a systemic lupus erythematosus patient and for diagnosing systemic lupus erythematosus by comparing TCP1 autoantibody levels with a control group.
상기 목적을 달성하기 위해, 본 발명은 TCP1 (T-complex polypeptide 1) 자가항체와 특이적으로 결합하는 항원 단백질을 포함하는 전신홍반성루푸스 (Systemic lupus erythematosus; SLE) 진단용 조성물을 제공한다.In order to achieve the above object, the present invention provides a systemic lupus erythematosus (SLE) diagnostic composition comprising an antigen protein that specifically binds to TCP-T (complex polypeptide 1) autoantibodies.
본 발명은 또한, 상기 조성물을 포함하는 전신홍반성루푸스 (Systemic lupus erythematosus; SLE) 진단용 키트를 제공한다.The present invention also provides a kit for diagnosing systemic lupus erythematosus (SLE) comprising the composition.
본 발명은 또한, (a) 대상체 (subject)로부터 분리된 생물학적 시료에서 TCP1 (T-complex polypeptide 1) 자가항체를 검출하는 단계; 및 (b) 상기 검출된 TCP1 자가항체 수준을 대조군과 비교하는 단계를 포함하는 전신홍반성루푸스 (Systemic lupus erythematosus; SLE) 진단을 위한 정보제공 방법을 제공한다.The present invention also includes the steps of (a) detecting a TCP- (T-complex polypeptide 1) autoantibody in a biological sample isolated from the subject; And (b) provides a method for providing information for diagnosing systemic lupus erythematosus (SLE) comprising the step of comparing the detected TCP1 autoantibody level with the control.
본 발명의 TCP1 자가항체와 특이적으로 결합하는 항원 단백질을 이용한 전신홍반성루푸스 진단 방법은 혈액과 같은 비침습적 생물학적 시료를 사용하기 때문에 기존의 방법과는 달리 환자에게 부담을 주지 않고 매우 간편하게 전신홍반성루푸스를 진단할 수 있을 뿐만 아니라 특이도 및 민감도가 높아 전신홍반성루푸스의 조기 진단에 유용하게 사용될 수 있다.Systemic lupus erythematosus diagnosis method using an antigen protein specifically binding to the TCP1 autoantibody of the present invention, because it uses a non-invasive biological sample such as blood, unlike the conventional method, very simple systemic lupus erythematosus Not only can be diagnosed but also high specificity and sensitivity can be useful for early diagnosis of systemic lupus erythematosus.
도 1은 22K 단백질 마이크로어레이를 활용하여 전신홍반루푸스 특이적 자가항체를 동정한 것이다.
도 2는 TCP1 재조합 단백질 발현 벡터 제작을 위한 pCR8GW-TCP1 벡터를 나타낸 것이다.
도 3은 TCP1 재조합 단백질 발현 벡터 제작을 위한 pCR8GW-TCP1 벡터의 클로닝 결과를 보여주는 것이다.
도 4는 TCP1 재조합 단백질의 정제를 위한 pDEST20-TCP1 벡터를 나타낸 것이다.
도 5는 TCP1 재조합 단백질의 정제를 위한 pDEST20-TCP1 벡터의 클로닝 결과를 보여주는 것이다.
도 6은 GST-TCP1 재조합 단백질의 발현을 확인한 것이다.
도 7은 정제된 GST-TCP1 재조합 단백질의 SDS-PAGE 분석 결과를 보여주는 것이다.
도 8은 TCP1 재조합 단백질 및 전신홍반루푸스 임상시료를 이용하여 전신홍반루푸스 특이적 자가항체를 검증한 것이다.
도 9는 TCP1 재조합 단백질 및 전신홍반루푸스 임상시료를 이용하여 전신홍반루푸스 마커의 특이도를 분석한 것이다.
도 10은 TCP1 재조합 단백질 및 전신홍반루푸스 임상시료를 이용한 특이도에 대한 Dot-blot assay 결과를 imageJ 프로그램으로 분석한 것이다.
도 11은 대조군인 정제된 CTT3 단백질 및 정제된 TCP1 재조합 단백질을 이용하여 전신홍반루푸스 임상시료에서 Dot-blot assay를 수행하여 자가항체 검출 특이도를 비교한 것이다.Figure 1 shows the systemic lupus erythematosus specific autoantibodies using 22K protein microarray.
Figure 2 shows the pCR8GW-TCP1 vector for the production of TCP1 recombinant protein expression vector.
Figure 3 shows the cloning results of the pCR8GW-TCP1 vector for the production of TCP1 recombinant protein expression vector.
4 shows the pDEST20-TCP1 vector for purification of TCP1 recombinant protein.
5 shows the cloning results of the pDEST20-TCP1 vector for purification of TCP1 recombinant protein.
Figure 6 confirms the expression of the GST-TCP1 recombinant protein.
Figure 7 shows the results of SDS-PAGE analysis of the purified GST-TCP1 recombinant protein.
Figure 8 shows the systemic lupus erythematosus specific autoantibodies using TCP1 recombinant protein and systemic lupus erythematosus clinical sample.
Figure 9 analyzes the specificity of systemic lupus erythematosus markers using TCP1 recombinant protein and systemic lupus erythematosus clinical sample.
Figure 10 is the analysis of the dot-blot assay results for specificity using the TCP1 recombinant protein and systemic lupus erythematosus clinical sample with the imageJ program.
FIG. 11 compares autoantibody detection specificity by performing a dot-blot assay in a systemic lupus erythematosus clinical sample using purified CTT3 protein and purified TCP1 recombinant protein as controls.
다른 식으로 정의되지 않는 한, 본 명세서에서 사용된 모든 기술적 및 과학적 용어들은 본 발명이 속하는 기술분야에서 숙련된 전문가에 의해서 통상적으로 이해되는 것과 동일한 의미를 갖는다. 일반적으로 본 명세서에서 사용된 명명법은 본 기술분야에서 잘 알려져 있고 통상적으로 사용되는 것이다.Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In general, the nomenclature used herein is well known and commonly used in the art.
본 발명에서는 전신홍반성루푸스를 특이적으로 진단하고자 자가항체에 주목하고, 이를 발굴하고 검증하였다. 이에, 인간 항원이 집적된 단백질 칩을 활용하여 전신홍반루푸스 환자 특이적인 자가항체들을 동정하였으며, 이중 TCP1 자가항체와 특이적으로 결합할 수 있는 TCP1 단백질 항원을 제조하였다. 제조한 TCP1 단백질 항원을 이용하여 전신홍반성루푸스 환자의 혈청에서 검증한 결과, TCP1 자가항체가 정상군에 비해 전신홍반루푸스 환자의 혈청에 다량 존재하고 있음을 확인할 수 있었다.In the present invention, in order to specifically diagnose systemic lupus erythematosus, attention was paid to autoantibodies, and the findings were verified. Accordingly, specific autoantibodies specific to systemic lupus erythematosus were identified using protein chips in which human antigens were integrated, and a TCP1 protein antigen capable of specifically binding to TCP1 autoantibodies was prepared. As a result of verifying the serum of systemic lupus erythematosus using the prepared TCP1 protein antigen, it was confirmed that the amount of TCP1 autoantibodies was present in the serum of systemic lupus erythematosus patients compared to the normal group.
따라서, 본 발명은 일 관점에서 TCP1 자가항체와 특이적으로 결합하는 항원 단백질을 포함하는 전신홍반성루푸스 진단용 조성물에 관한 것이다.Accordingly, the present invention relates to a composition for diagnosing systemic lupus erythematosus comprising an antigen protein that specifically binds to TCP1 autoantibodies in one aspect.
본 발명에 있어서, 상기 TCP1는 서열번호 1의 아미노산 서열로 표시되는 것을 특징으로 할 수 있다. TCP1은 GenBank Accession No. NM_030752.2에 기재된 서열인 것이 바람직하다.In the present invention, the TCP1 may be represented by the amino acid sequence of SEQ ID NO: 1. TCP1 is GenBank Accession No. It is preferable that it is the sequence of NM_030752.2.
본 발명의 용어 "자가항체(autoantibodies, AAb)"란, 체내에서 발현되어 생체내 성분과 특이적으로 반응하는 항체를 의미한다As used herein, the term "autoantibodies (AAb)" refers to antibodies that are expressed in the body and specifically react with components in vivo.
본 발명에 있어서, 상기 자가항체는 전신홍반성루푸스의 발병 시에 생성되는 TCP1에 대한 자가항체가 될 수 있다.In the present invention, the autoantibody may be an autoantibody against TCP1 produced at the onset of systemic lupus erythematosus.
본 발명의 용어 "전신홍반성루푸스 (Systemic lupus erythematosus; SLE)" 란, 외부로부터 인체를 방어하는 면역계의 이상으로 인해 피부, 관절, 신장, 폐, 신경 등 여러 장기에 염증을 일으키는 만성 자가 면역 질환이다.The term "systemic lupus erythematosus (SLE)" of the present invention is a chronic autoimmune disease that causes inflammation of various organs such as skin, joints, kidneys, lungs and nerves due to abnormalities of the immune system that protects the human body from the outside. .
본 발명은 다른 관점에서, 상기의 조성물을 포함하는 전신홍반성루푸스 진단용 키트에 관한 것이다.In another aspect, the present invention relates to a kit for diagnosing systemic lupus erythematosus comprising the above composition.
본 발명에 있어서, 상기 키트는 항원-항체 결합반응을 통해 체액 시료내 TCP1 자가항체를 검출하여 전신홍반성루푸스를 진단하는 것을 특징으로 할 수 있다. 즉, 상기 전신홍반성루푸스는 환자의 혈액 내에서 TCP1에 대한 자가항체를 검출함에 의하여 그의 발병여부를 진단할 수 있다.In the present invention, the kit may be characterized by diagnosing systemic lupus erythematosus by detecting TCP1 autoantibodies in a bodily fluid sample through an antigen-antibody binding reaction. That is, the systemic lupus erythematosus can diagnose its onset by detecting autoantibodies against TCP1 in the blood of the patient.
본 발명의 용어 "진단"이란, 병리 상태의 존재 또는 특징을 확인하는 것을 의미한다 본 발명에 있어서, 상기 진단은 전신홍반성루푸스의 발병 여부를 확인하는 것으로 해석될 수 있다.The term "diagnosis" of the present invention means confirming the presence or characteristic of a pathological condition. In the present invention, the diagnosis may be interpreted as confirming the development of systemic lupus erythematosus.
본 발명의 용어 "항원"이란, 항체와 항원-항체 결합을 수행할 수 있는 단백질성 면역원을 의미하는데, 이러한 항원은 각 유전자를 통상적인 방법에 따라 발현벡터에 클로닝하여 상기 마커 유전자에 의해 코딩되는 단백질을 얻고, 얻어진 단백질로부터 통상적인 방법에 의해 제조될 수 있다As used herein, the term “antigen” refers to a proteinaceous immunogen capable of performing antigen-antibody binding with an antibody, which is encoded by the marker gene by cloning each gene into an expression vector according to a conventional method. Proteins can be obtained and prepared from conventional proteins by conventional methods.
본 발명에서 사용된 항원은 상술한 TCP1가 될 수 있다.The antigen used in the present invention may be TCP1 described above.
본 발명의 키트는 전신홍반성루푸스가 발병된 개체에서 유래된 시료로부터 TCP1에 대한 자가항체의 수준을 측정하여 전신홍반성루푸스의 발병여부를 진단하는데 사용될 수 있는데, 특별히 이에 제한되지 않으나, 상기 단백질의 수준을 측정하기 위한 항원, 항체, 앱타머 뿐만 아니라 분석 방법에 적합한 한 종류 또는 그 이상의 다른 구성 성분 조성물, 용액 또는 장치가 포함될 수도 있다The kit of the present invention can be used to diagnose the onset of systemic lupus erythematosus by measuring the level of autoantibodies against TCP1 from a sample derived from an individual suffering from systemic lupus erythematosus, but is not particularly limited thereto. Antigens, antibodies, aptamers, as well as one or more other constituent compositions, solutions or devices suitable for assays may be included for measuring
본 발명의 용어 "시료"란, 전신홍반성루푸스가 발병된 개체에서 분리되어 TCP1에 대한 자가항체의 발현수준을 측정하는 직접적인 대상을 의미하고, 바람직하게는 전신홍반성루푸스가 발병된 환자의 혈액, 혈청, 혈장인 것이나, 이에 한정되는 것은 아니다.As used herein, the term "sample" refers to a direct subject which is isolated from an individual suffering from systemic lupus erythematosus and measures the level of expression of autoantibodies against TCP1, and preferably blood and serum of a patient suffering from systemic lupus erythematosus. , But is not limited to plasma.
본 발명에 있어서, 상기 키트는 효소면역측정법 (ELISA), 닷 블랏 분석 (dot blot assay) 또는 웨스턴 블랏 분석 (western blot assay) 키트인 것이 바람직하며, 상기 키트는 특별히 이에 제한되지 않으나, 항체의 면역학적 검출을 위하여 기재, 적당한 완충용액, 발색 효소 또는 형광물질로 표지된 2차 항체, 발색 기질 등을 포함할 수 있다 상기 기재는 특별히 이에 제한되지 않으나 니트로셀룰로오스 막, 폴리비닐 수지로 합성된 96 웰 플레이트, 폴리스티렌 수지로 합성된 96 웰 플레이트 및 유리로 된 슬라이드글라스 등이 이용될 수 있고, 발색효소는 특별히 이에 제한되지 않으나 퍼옥시다아제(peroxidase), 알칼라인 포스파타아제(Alkaline Phosphatase)가 사용될 수 있으며, 형광물질은 특별히 이에 제한되지 않으나 FITC, RITC 등이 될 수 있고, 발색 기질액은 특별히 이에 제한되지 않으나 ABTS(2,2'-아지노-비스(3-에틸벤조티아졸린-6-설폰산)) 또는 OPD(o-페닐렌디아민), TMB(테트라메틸 벤지딘)가 될 수 있다.In the present invention, the kit is preferably an enzyme immunoassay (ELISA), dot blot assay, or western blot assay kit, and the kit is not particularly limited, but is not particularly limited thereto. Substrates, suitable buffers, secondary antibodies labeled with chromophores or fluorophores, chromogenic substrates, and the like for physiological detection. The substrates are not particularly limited to 96 wells synthesized with nitrocellulose membranes and polyvinyl resins. Plates, 96-well plates synthesized with polystyrene resin, glass slides, etc. may be used, and chromase is not particularly limited, but peroxidase, alkaline phosphatase may be used, The fluorescent material is not particularly limited, but may be FITC, RITC, and the like, and the coloring substrate liquid is particularly limited thereto. Although not ABTS (2,2'- ahjino-bis (3-ethyl-benzothiazole-6-sulfonic acid sleepy)) can be a or OPD (o- phenylenediamine), TMB (tetramethylbenzidine).
본 발명의 키트는 음성 및 양성 대조군 반응을 수행하는데 필요한 시약 또는 혼성화 반응에 필요한 완충액과 같은 시약을 포함할 수 있다 특정 반응에서 이용되는 시약의 최적량은 본 명세서의 내용을 파악한 당업자에 의해 용이하게 결정될 수 있다 예를 들어, 본 발명의 키트는 분리된 패키지 또는 컴파트먼트에 상술한 성분들을 포함할 수 있다.Kits of the invention may include reagents, such as the reagents required to perform negative and positive control reactions or the buffers required for hybridization reactions. The optimal amount of reagent used in a particular reaction is readily available to those of ordinary skill in the art having read the disclosure. For example, the kit of the present invention may include the above-mentioned components in a separate package or compartment.
본 발명은 또 다른 관점에서, (a) 대상체 (subject)로부터 분리된 생물학적 시료에서 TCP1 (T-complex polypeptide 1) 자가항체를 검출하는 단계; 및 (b) 상기 검출된 TCP1 자가항체 수준을 대조군과 비교하는 단계를 포함하는 전신홍반성루푸스 (Systemic lupus erythematosus; SLE) 진단을 위한 정보제공 방법에 관한 것이다.In still another aspect, the present invention provides a method for detecting a T-complex polypeptide 1 (TCP1) autoantibody in a biological sample isolated from a subject; And (b) relates to a method for providing information for diagnosing Systemic lupus erythematosus (SLE) comprising the step of comparing the detected TCP1 autoantibody level with the control.
본 발명에 있어서, 상기 생물학적 시료는 특별히 이에 제한되지 않으나, 바람직하게는 혈액, 혈청 또는 혈장인 것을 특징으로 할 수 있다.In the present invention, the biological sample is not particularly limited thereto, and may be preferably blood, serum or plasma.
본 발명에 있어서, 용어, "검출"이란 항원-항체 결합반응을 통해 생물학적 시료에서 SMYD3 자가항체를 검출하여 확인하는 과정으로, 상기 SMYD3 자가항체에 대하여 특이적으로 결합하는 항원 단백질을 이용하여 전신홍반성루푸스를 진단할 수 있다. 이를 위한 분석방법으로는 웨스턴블랏(western blotting), ELISA(enzyme linked immunosorbent assay), 방사선면역분석법(Radioimmunoassay), 방사면역확산법(Radioimmunodiffusion), 오우크레로니 (Ouchterlony) 면역 확산법, 로케트(Rocket) 면역전기영동, 조직면역 염색, 면역침전분석법(immunoprecipitation assay), 보체 고정 분석법(complete fixation assay), FACS, 단백질 칩(protein chip) 등이 있으나, 이에 제한되는 것은 아니다In the present invention, the term "detection" refers to a process of detecting and confirming an SMYD3 autoantibody in a biological sample through an antigen-antibody-binding reaction, using systemic leukemia using an antigen protein that specifically binds to the SMYD3 autoantibody. Lupus can be diagnosed. Western blotting, ELISA (enzyme linked immunosorbent assay), radioimmunoassay, radioimmunodiffusion, Ouchterlony immunodiffusion, and rocket immunoelectrolysis Electrophoresis, tissue immunostaining, immunoprecipitation assay, complement fixation assay, FACS, protein chip, etc., but are not limited thereto.
본 발명에 있어서, 상기 TCP1은 서열번호 1의 아미노산 서열로 표시되는 것을 특징으로 할 수 있다.In the present invention, the TCP1 may be represented by the amino acid sequence of SEQ ID NO: 1.
상기 방법에 있어서, 상기 생물학적 시료에서 측정된 TCP1에 대한 자가항체의 수준이 정상 개체의 생물학적 시료로부터 측정된 수준과 비교하여 유의하게 증가하는 경우에는 상기 검사대상 개체에서 전신홍반성루푸스가 발병하였다고 판정할 수 있고, 유의하게 증가하지 않는 경우에는 상기 개체에서 전신홍반성루푸스가 발병하지 않았다고 판정할 수 있다 이때, 상기 TCP1에 대한 자가항체의 수준을 측정하는 방법은 상술한 바와 동일하다.In the method, if the level of autoantibody against TCP1 measured in the biological sample is significantly increased compared to the level measured from the biological sample in normal subjects, it may be determined that systemic lupus erythematosus occurs in the subject under test. If it does not increase significantly, it may be determined that systemic lupus erythematosus does not develop in the subject. In this case, the method for measuring the level of autoantibodies to TCP1 is the same as described above.
[실시예]EXAMPLE
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 예시하기 위한 것으로, 본 발명의 범위가 이들 실시예에 의해 제한되는 것으로 해석되지 않는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention, and it will be apparent to those skilled in the art that the scope of the present invention is not to be construed as being limited by these examples.
실시예Example 1: 22K1: 22 K 단백질 protein 마이크로어레이를Microarray 활용한 Utilized 전신홍반루푸스Systemic lupus erythematosus 자가항체Autoantibodies 동정 Sympathy
전신홍반루푸스 특이적 자가항체를 검출하기 위해 22,000 (22K)개의 인간 항원이 집적된 단백질 칩을 활용하여 5명의 정상군과 10명의 전신홍반루푸스 환자의 혈청샘플에 대하여 실험한 결과, 총 63개의 자가항체들이 동정되었다 (도 1). In order to detect systemic lupus erythematosus specific autoantibodies, serum samples of 5 normal and 10 systemic lupus erythematosus patients were tested using protein chips containing 22,000 (22K) human antigens. Antibodies were identified (FIG. 1).
이 중 29개의 자가항체들은 4명의 환자로부터, 10개의 자가항체들은 5명의 환자로부터, 7개의 자가항체들은 6명의 환자로부터, 6개의 자가항체들은 7명의 환자로부터, 8개의 자가항체들은 8명의 환자로부터 중복 검출되었다. 특히, 3종의 자가 항체들은 9명의 전신홍반루푸스 환자 혈액으로부터 모두 중복 검출되었다.Of these, 29 autoantibodies were from 4 patients, 10 autoantibodies were from 5 patients, 7 autoantibodies were from 6 patients, 6 autoantibodies were from 7 patients, 8 autoantibodies were from 8 patients Duplicates were detected from In particular, all three autoantibodies were detected in duplicate from the blood of nine systemic lupus erythematosus patients.
이는 하기 표 1의 전신홍반루푸스 특이적 바이오마커로 나타냈다.This is indicated by the systemic lupus erythematosus specific biomarker in Table 1 below.
실시예 2: 전신홍반루푸스 바이오마커 단백질 발현 벡터 제작Example 2: Preparation of systemic lupus erythematosus biomarker protein expression vector
전신홍반루푸스 바이오마커의 후보물질 TCP1의 전체 도메인을 포함하여 ENTRY 벡터를 제작하고 이를 pCR8GW-TCP1로 명명하였다.An ENTRY vector was constructed containing the full domain of candidate TCP1 of systemic lupus erythematosus biomarker and named pCR8GW-TCP1.
pCR8GW-TCP1 컨스트럭트를 제작하기 위해 Full-length TCP1 DNA 서열 (1671 bp)을 바탕으로 프라이머 (primer)를 디자인한 후, 마크로젠에 의뢰하여 제작하였다 (표 2). In order to construct a pCR8GW-TCP1 construct, a primer was designed based on the full-length TCP1 DNA sequence (1671 bp), and then prepared by requesting macrogen (Table 2).
Full-length TCP1의 아미노산 서열 (aa 1-556)은 서열번호 1로 나타냈으며, 하기 표 2의 TCP1 WT forward 프라이머는 서열번호 2, TCP1 WT reverse 프라이머는 서열번호 3으로 나타냈다.The amino acid sequence of the full-length TCP1 (aa 1-556) is shown in SEQ ID NO: 1, the TCP1 WT forward primer in Table 2 is shown in SEQ ID NO: 2, TCP1 WT reverse primer in SEQ ID NO: 3.
Human cDNA를 템플레이트 (Template)로하고 상기 제작된 프라이머를 활용하여 PCR을 수행하였다. 합성된 PCR product를 pCR8GW 벡터에 클로닝하였다 (도 2 및 도 3).Human cDNA was used as a template and PCR was performed using the prepared primers. The synthesized PCR product was cloned into pCR8GW vector (FIGS. 2 and 3).
그 다음, TCP1 N-말단에 GST-Tag을 접합하기 위하여 상기 제작된 벡터와 gateway cloning을 통해 pDEST20-TCP1 컨스트럭트를 제작하였다 (도 4 및 5). 서열번호 1로 표시되는 상기 아미노산 서열로 제작된 벡터를 이용하여 insect 세포에서 재조합 단백질 발현이 가능한 TCP1-Bacmid를 제작하였다. Then, the pDEST20-TCP1 construct was constructed by gateway cloning with the prepared vector to conjugate the GST-Tag to the TCP1 N-terminus (FIGS. 4 and 5). Using the vector produced by the amino acid sequence represented by SEQ ID NO: 1 was prepared TCP1-Bacmid capable of recombinant protein expression in insect cells.
실시예Example 3: Insect 세포에서 3: in Insect cells 전신홍반루푸스Systemic lupus erythematosus 바이오마커Biomarker 재조합 단백질의 발현 Expression of Recombinant Protein
실시예 2에서 제작한 전신홍반루푸스 바이오마커 TCP1의 재조합 단백질의 발현을 위해 제작된 TCP1-Bacmid를 SF9 insect 세포에 형질주입하였다. 형질주입된 세포에서 TCP1 재조합 단백질의 발현을 유도하는 Baculovirus를 생산하였다. 세포내 재조합 단백질의 발현은 웨스턴블랏으로 확인하였다 (도 6). TCP1-Bacmid prepared for expression of the recombinant protein of systemic lupus erythematosus biomarker TCP1 prepared in Example 2 was transfected into SF9 insect cells. Baculovirus was produced to induce the expression of TCP1 recombinant protein in transfected cells. Expression of recombinant protein in cells was confirmed by Western blot (FIG. 6).
그 결과, 도 6에 나타낸 바와 같이, 상기 전신홍반루푸스 바이오마커 TCP1의 발현이 잘 유도된 것을 확인할 수 있었다.As a result, as shown in Figure 6, it was confirmed that the expression of the systemic lupus erythematosus biomarker TCP1 was well induced.
실시예Example 4: 4: 전신홍반루푸스Systemic lupus erythematosus 바이오마커의Biomarker 정제 refine
전신홍반루푸스 바이오마커 단백질의 대규모 정제를 위해 제작된 TCP1 Baculovirus를 SF9 insect 숙주세포에 2차 감염시켰다. 상기 제작된 bacmid에 포함되어있는 GST-tag을 이용하여 정제할 수 있도록 TCP1 재조합 단백질의 발현을 유도하였다. TCP1 Baculovirus prepared for large-scale purification of systemic lupus erythematosus biomarker protein was secondaryly infected with SF9 insect host cells. Expression of TCP1 recombinant protein was induced to be purified using GST-tag contained in the bacmid.
Baculovirus에 의해 2차 감염된 SF9 insect 세포는 3일간 28℃에서 배양하였다. 이후, 바이러스가 포함된 배지는 1500 rpm으로 원심분리하여 4℃에 보관하고 재조합 단백질이 과발현된 세포는 잔여배지를 제거하기 위하여 PBS로 1회 세척하였다. 1500 rpm에서 1분간 원심분리하여 세포를 회수하고, 세포에 75T flask 1개당 5 ml의 세포 용해 버퍼 (25 mM Tris-Cl (pH7.4), 150 mM NaCl, 1mM EDTA, 1 mM DTT, 1% NP-40, 0.1% Triton X-100, 1mM PMSF, 1X protease inhibitor cocktail)를 넣어 혼합한 후, 4℃에서 30분간 반응하였다. 용해물은 14000 rpm에서 10분간 원심분리하여 상층액만을 회수하였다. 수용액으로부터 GST-TCP1 만을 정제하기 위하여 glutathione Sepharose 4B (GEHealthcare Life Science, USA)와 반응시켰으며. 이후, 크로마토그래피 방법을 이용하여 재조합 단백질과 결합한 glutathione Sepharose 4B를 분리하였다. 비특이적으로 결합한 단백질들의 제거를 위해 세포 용해버퍼로 3회 세척하였다. pH 7.5의 50 mM HEPES, 100mM NaCL, 30% Glycerol과 40 mM GSH가 포함된 용액을 사용하여 재조합 단백질들을 glutathione Sepharose 4B로부터 용리하였다. SF9 insect cells secondarily infected with Baculovirus were incubated at 28 ° C. for 3 days. Afterwards, the virus-containing medium was centrifuged at 1500 rpm, stored at 4 ° C., and cells overexpressed with recombinant protein were washed once with PBS to remove residual medium. Cells were harvested by centrifugation at 1500 rpm for 1 minute, and 5 ml of cell lysis buffer (25 mM Tris-Cl (pH7.4), 150 mM NaCl, 1 mM EDTA, 1 mM DTT, 1% per 75T flask) into cells. NP-40, 0.1% Triton X-100, 1 mM PMSF, 1X protease inhibitor cocktail) were mixed and reacted at 4 ° C. for 30 minutes. The lysate was centrifuged at 14000 rpm for 10 minutes to recover only the supernatant. In order to purify only GST-TCP1 from aqueous solution, it was reacted with glutathione Sepharose 4B (GEHealthcare Life Science, USA). Thereafter, glutathione Sepharose 4B bound to the recombinant protein was isolated using a chromatography method. Wash three times with cell lysis buffer for removal of nonspecifically bound proteins. Recombinant proteins were eluted from glutathione Sepharose 4B using a solution containing 50 mM HEPES, 100 mM NaCL, 30% Glycerol and 40 mM GSH at pH 7.5.
SDS-PAGE로 분석한 결과, 약 70 kDa의 GST-TCP1 재조합 단백질이 정제되었음을 확인하였다 (도 7).Analysis by SDS-PAGE confirmed that about 70 kDa GST-TCP1 recombinant protein was purified (FIG. 7).
실시예 5: 전신홍반성 루푸스 특이적 자가항체의 검증Example 5: Verification of Systemic Lupus Erythematosus
전신홍반루푸스 환자의 혈청 내에 단백질 마이크로어레이 기법을 통하여 신규 발굴된 TCP1 자가항체가 다량 존재하는지 검증하기 위하여 정제된 GST-TCP1 재조합 단백질을 활용하여 dot blot assay를 수행하였다. 1㎍의 GST-TCP1 단백질을 NC membrane 위에 집적하고, 50명의 정상인 및 48명의 전신홍반루푸스 환자의 혈청과 반응시켜 dot blot assay를 수행하였다.Dot blot assay was performed using purified GST-TCP1 recombinant protein to verify the presence of a large amount of newly discovered TCP1 autoantibodies in the serum of systemic lupus erythematosus patients. 1 μg of GST-TCP1 protein was accumulated on the NC membrane, and a dot blot assay was performed by reacting with serum of 50 normal and 48 systemic lupus erythematosus patients.
그 결과, 27명의 환자 혈청에 TCP1 자가항원을 인지하는 TCP1 자가항체가 정상군에 비해 과발현 되어 있음을 확인하였다 (도 8). 이러한 단백질 마이크로어레이 결과와 동일한 결과에 의해 TCP1 자가항체가 정상군에 비해 전신홍반루푸스 환자의 혈청에 다량 존재하고 있음이 검증되었다.As a result, it was confirmed that TCP1 autoantibodies recognizing TCP1 autoantigens in serum of 27 patients were overexpressed compared to the normal group (FIG. 8). By the same results as the protein microarray results, it was verified that TCP1 autoantibodies were present in the serum of systemic lupus erythematosus patients more than the normal group.
실시예 6: 임상시료에 대한 전신홍반루푸스 바이오마커의 특이도 분석Example 6: Specificity Analysis of Systemic Lupus Erythematosus Biomarkers for Clinical Samples
전신홍반루푸스 환자 혈청내 존재하는 TCP1 자가항체가 전신홍반루푸스 특이적인지 검증하기 위하여 정제된 GST-TCP1 재조합 단백질을 활용하여 Dot blot assay를 수행하였다. 1㎍의 GST-TCP1 단백질을 NC membrane 위에 집적하고, 25명의 류마티스 관절염(Rheumatoid arthritis) 환자, 30명의 경피증(Systemic sclerosis) 환자 및 15명의 베체트증후군(Behcet's disease) 환자의 혈청과 각각 반응시켜 Dot blot assay를 수행하였다.To verify whether TCP1 autoantibodies in serum of systemic lupus erythematosus are specific for systemic lupus erythematosus Dot blot assay was performed using purified GST-TCP1 recombinant protein. 1 μg of GST-TCP1 protein was accumulated on NC membrane and reacted with serum from 25 patients with Rheumatoid arthritis, 30 patients with Systemic sclerosis and 15 patients with Behcet's disease. The assay was performed.
그 결과, 25명의 류마티스 관절염 (Rheumatoid arthritis) 환자, 26명의 경피증 (Systemic sclerosis) 환자 및 11명의 베체트증후군 (Behcet's disease) 환자에서 TCP1 자가항체가 검출되지 않음을 확인하였다 (도 9). 즉, 환자의 혈청 내에 존재하는 TCP1 자가항체가 전신홍반루푸스 특이적임을 검증하였다. As a result, it was confirmed that TCP1 autoantibodies were not detected in 25 patients with Rheumatoid arthritis, 26 patients with Systemic sclerosis, and 11 patients with Behcet's disease (FIG. 9). That is, it was verified that TCP1 autoantibodies present in the serum of the patient were systemic lupus erythematosus specific.
실시예 5 및 실시예 6에서 수행한 Dot blot assay의 결과를 imageJ 프로그램을 활용하여 분석한 후 그래프로 나타내었다 (도 10).The results of the Dot blot assay performed in Example 5 and Example 6 were analyzed using the imageJ program and then graphically shown (FIG. 10).
실시예 7: 전신홍반루푸스 임상시료에 대한 CCT3와 TCP1의 검출 특이도 비교Example 7 Comparison of Detection Specificity of CCT3 and TCP1 for Systemic Lupus Erythematosus Samples
기존에 보고된 전신홍반루푸스 특이적 자가항체인 CCT3와 TCP1과의 비교분석을 위해 재조합 단백질 CCT3 (NM_005998, human recmbinant protein, cat#TP321229, Origene, USA) 및 실시예 4에서 정제한 TCP1을 활용하여 전신홍반루푸스 특이적 자가항체의 검출빈도를 비교 분석하였다.For comparative analysis of the previously reported systemic lupus erythematosus specific autoantibody with CCT3 and TCP1, recombinant protein CCT3 (NM_005998, human recmbinant protein, cat # TP321229, Origene, USA) and TCP1 purified in Example 4 were used. The frequency of detection of systemic lupus erythematosus-specific autoantibodies was compared and analyzed.
그 결과, 전신홍반루푸스 혈액내에 TCP1 재조합 단백질에 의한 TCP1의 자가항체 검출률은 CCT3 재조합 단백질에 의한 CCT3 자가항체 검출률보다 현저히 우수하였다 (도 11). 이는 TCP1과 CCT3는 같은 복합체에 존재하지만 서로 다른 항원으로 작용하고 있는 것을 의미하며, TCP1의 자가항체 발현빈도가 CCT3 자가항체에 비해 상대적으로 높다는 것을 나타낸다. 즉, 전신홍반루푸스 특이적인 바이오마커로 본 발명의 TCP1이 매우 우수한 것을 알 수 있다.As a result, the autoantibody detection rate of TCP1 by TCP1 recombinant protein in systemic lupus erythematosus blood was remarkably superior to that of CCT3 autoantibodies by CCT3 recombinant protein (FIG. 11). This means that TCP1 and CCT3 are present in the same complex but act as different antigens, indicating that the expression level of TCP1 autoantibodies is relatively higher than that of CCT3 autoantibodies. That is, it can be seen that TCP1 of the present invention is very excellent as a systemic lupus erythematosus specific biomarker.
이상으로 본 발명의 내용의 특정한 부분을 상세히 기술하였는바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.As described above in detail a specific part of the content of the present invention, for those skilled in the art, such a specific description is only a preferred embodiment, which is not limited by the scope of the present invention Will be obvious. Thus, the substantial scope of the present invention will be defined by the appended claims and their equivalents.
<110> AJOU UNIVERSITY INDUSTRY-ACADEMIC COOPERATION FOUNDATION <120> Diagnosis of Systemic Lupus Erythematosus Using TCP1 Autoantibodies <130> P19-B113 <150> KR 10-2018-0053278 <151> 2018-05-09 <160> 3 <170> KoPatentIn 3.0 <210> 1 <211> 556 <212> PRT <213> Artificial Sequence <220> <223> TCP1 <400> 1 Met Glu Gly Pro Leu Ser Val Phe Gly Asp Arg Ser Thr Gly Glu Thr 1 5 10 15 Ile Arg Ser Gln Asn Val Met Ala Ala Ala Ser Ile Ala Asn Ile Val 20 25 30 Lys Ser Ser Leu Gly Pro Val Gly Leu Asp Lys Met Leu Val Asp Asp 35 40 45 Ile Gly Asp Val Thr Ile Thr Asn Asp Gly Ala Thr Ile Leu Lys Leu 50 55 60 Leu Glu Val Glu His Pro Ala Ala Lys Val Leu Cys Glu Leu Ala Asp 65 70 75 80 Leu Gln Asp Lys Glu Val Gly Asp Gly Thr Thr Ser Val Val Ile Ile 85 90 95 Ala Ala Glu Leu Leu Lys Asn Ala Asp Glu Leu Val Lys Gln Lys Ile 100 105 110 His Pro Thr Ser Val Ile Ser Gly Tyr Arg Leu Ala Cys Lys Glu Ala 115 120 125 Val Arg Tyr Ile Asn Glu Asn Leu Ile Val Asn Thr Asp Glu Leu Gly 130 135 140 Arg Asp Cys Leu Ile Asn Ala Ala Lys Thr Ser Met Ser Ser Lys Ile 145 150 155 160 Ile Gly Ile Asn Gly Asp Phe Phe Ala Asn Met Val Val Asp Ala Val 165 170 175 Leu Ala Ile Lys Tyr Thr Asp Ile Arg Gly Gln Pro Arg Tyr Pro Val 180 185 190 Asn Ser Val Asn Ile Leu Lys Ala His Gly Arg Ser Gln Met Glu Ser 195 200 205 Met Leu Ile Ser Gly Tyr Ala Leu Asn Cys Val Val Gly Ser Gln Gly 210 215 220 Met Pro Lys Arg Ile Val Asn Ala Lys Ile Ala Cys Leu Asp Phe Ser 225 230 235 240 Leu Gln Lys Thr Lys Met Lys Leu Gly Val Gln Val Val Ile Thr Asp 245 250 255 Pro Glu Lys Leu Asp Gln Ile Arg Gln Arg Glu Ser Asp Ile Thr Lys 260 265 270 Glu Arg Ile Gln Lys Ile Leu Ala Thr Gly Ala Asn Val Ile Leu Thr 275 280 285 Thr Gly Gly Ile Asp Asp Met Cys Leu Lys Tyr Phe Val Glu Ala Gly 290 295 300 Ala Met Ala Val Arg Arg Val Leu Lys Arg Asp Leu Lys Arg Ile Ala 305 310 315 320 Lys Ala Ser Gly Ala Thr Ile Leu Ser Thr Leu Ala Asn Leu Glu Gly 325 330 335 Glu Glu Thr Phe Glu Ala Ala Met Leu Gly Gln Ala Glu Glu Val Val 340 345 350 Gln Glu Arg Ile Cys Asp Asp Glu Leu Ile Leu Ile Lys Asn Thr Lys 355 360 365 Ala Arg Thr Ser Ala Ser Ile Ile Leu Arg Gly Ala Asn Asp Phe Met 370 375 380 Cys Asp Glu Met Glu Arg Ser Leu His Asp Ala Leu Cys Val Val Lys 385 390 395 400 Arg Val Leu Glu Ser Lys Ser Val Val Pro Gly Gly Gly Ala Val Glu 405 410 415 Ala Ala Leu Ser Ile Tyr Leu Glu Asn Tyr Ala Thr Ser Met Gly Ser 420 425 430 Arg Glu Gln Leu Ala Ile Ala Glu Phe Ala Arg Ser Leu Leu Val Ile 435 440 445 Pro Asn Thr Leu Ala Val Asn Ala Ala Gln Asp Ser Thr Asp Leu Val 450 455 460 Ala Lys Leu Arg Ala Phe His Asn Glu Ala Gln Val Asn Pro Glu Arg 465 470 475 480 Lys Asn Leu Lys Trp Ile Gly Leu Asp Leu Ser Asn Gly Lys Pro Arg 485 490 495 Asp Asn Lys Gln Ala Gly Val Phe Glu Pro Thr Ile Val Lys Val Lys 500 505 510 Ser Leu Lys Phe Ala Thr Glu Ala Ala Ile Thr Ile Leu Arg Ile Asp 515 520 525 Asp Leu Ile Lys Leu His Pro Glu Ser Lys Asp Asp Lys His Gly Ser 530 535 540 Tyr Glu Asp Ala Val His Ser Gly Ala Leu Asn Asp 545 550 555 <210> 2 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> TCP1 WT F <400> 2 atggaggggc ctttgtccgt gttc 24 <210> 3 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> TCP1 WT R <400> 3 tcacaaatcg ttaagggctc cagagtg 27 <110> AJOU UNIVERSITY INDUSTRY-ACADEMIC COOPERATION FOUNDATION <120> Diagnosis of Systemic Lupus Erythematosus Using TCP1 Autoantibodies <130> P19-B113 <150> KR 10-2018-0053278 <151> 2018-05-09 <160> 3 <170> KoPatentIn 3.0 <210> 1 <211> 556 <212> PRT <213> Artificial Sequence <220> TCP1 <400> 1 Met Glu Gly Pro Leu Ser Val Phe Gly Asp Arg Ser Thr Gly Glu Thr 1 5 10 15 Ile Arg Ser Gln Asn Val Met Ala Ala Ala Ser Ile Ala Asn Ile Val 20 25 30 Lys Ser Ser Leu Gly Pro Val Gly Leu Asp Lys Met Leu Val Asp Asp 35 40 45 Ile Gly Asp Val Thr Ile Thr Asn Asp Gly Ala Thr Ile Leu Lys Leu 50 55 60 Leu Glu Val Glu His Pro Ala Ala Lys Val Leu Cys Glu Leu Ala Asp 65 70 75 80 Leu Gln Asp Lys Glu Val Gly Asp Gly Thr Thr Ser Val Val Ile Ile 85 90 95 Ala Ala Glu Leu Leu Lys Asn Ala Asp Glu Leu Val Lys Gln Lys Ile 100 105 110 His Pro Thr Ser Val Ile Ser Gly Tyr Arg Leu Ala Cys Lys Glu Ala 115 120 125 Val Arg Tyr Ile Asn Glu Asn Leu Ile Val Asn Thr Asp Glu Leu Gly 130 135 140 Arg Asp Cys Leu Ile Asn Ala Ala Lys Thr Ser Met Ser Ser Lys Ile 145 150 155 160 Ile Gly Ile Asn Gly Asp Phe Phe Ala Asn Met Val Val Asp Ala Val 165 170 175 Leu Ala Ile Lys Tyr Thr Asp Ile Arg Gly Gln Pro Arg Tyr Pro Val 180 185 190 Asn Ser Val Asn Ile Leu Lys Ala His Gly Arg Ser Gln Met Glu Ser 195 200 205 Met Leu Ile Ser Gly Tyr Ala Leu Asn Cys Val Val Gly Ser Gln Gly 210 215 220 Met Pro Lys Arg Ile Val Asn Ala Lys Ile Ala Cys Leu Asp Phe Ser 225 230 235 240 Leu Gln Lys Thr Lys Met Lys Leu Gly Val Gln Val Val Ile Thr Asp 245 250 255 Pro Glu Lys Leu Asp Gln Ile Arg Gln Arg Glu Ser Asp Ile Thr Lys 260 265 270 Glu Arg Ile Gln Lys Ile Leu Ala Thr Gly Ala Asn Val Ile Leu Thr 275 280 285 Thr Gly Gly Ile Asp Asp Met Cys Leu Lys Tyr Phe Val Glu Ala Gly 290 295 300 Ala Met Ala Val Arg Arg Val Leu Lys Arg Asp Leu Lys Arg Ile Ala 305 310 315 320 Lys Ala Ser Gly Ala Thr Ile Leu Ser Thr Leu Ala Asn Leu Glu Gly 325 330 335 Glu Glu Thr Phe Glu Ala Ala Met Leu Gly Gln Ala Glu Glu Val Val 340 345 350 Gln Glu Arg Ile Cys Asp Asp Glu Leu Ile Leu Ile Lys Asn Thr Lys 355 360 365 Ala Arg Thr Ser Ala Ser Ile Ile Leu Arg Gly Ala Asn Asp Phe Met 370 375 380 Cys Asp Glu Met Glu Arg Ser Leu His Asp Ala Leu Cys Val Val Lys 385 390 395 400 Arg Val Leu Glu Ser Lys Ser Val Val Pro Gly Gly Gly Ala Val Glu 405 410 415 Ala Ala Leu Ser Ile Tyr Leu Glu Asn Tyr Ala Thr Ser Met Gly Ser 420 425 430 Arg Glu Gln Leu Ala Ile Ala Glu Phe Ala Arg Ser Leu Leu Val Ile 435 440 445 Pro Asn Thr Leu Ala Val Asn Ala Ala Gln Asp Ser Thr Asp Leu Val 450 455 460 Ala Lys Leu Arg Ala Phe His Asn Glu Ala Gln Val Asn Pro Glu Arg 465 470 475 480 Lys Asn Leu Lys Trp Ile Gly Leu Asp Leu Ser Asn Gly Lys Pro Arg 485 490 495 Asp Asn Lys Gln Ala Gly Val Phe Glu Pro Thr Ile Val Lys Val Lys 500 505 510 Ser Leu Lys Phe Ala Thr Glu Ala Ala Ile Thr Ile Leu Arg Ile Asp 515 520 525 Asp Leu Ile Lys Leu His Pro Glu Ser Lys Asp Asp Lys His Gly Ser 530 535 540 Tyr Glu Asp Ala Val His Ser Gly Ala Leu Asn Asp 545 550 555 <210> 2 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> TCP1 WT F <400> 2 atggaggggc ctttgtccgt gttc 24 <210> 3 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> TCP1 WT R <400> 3 tcacaaatcg ttaagggctc cagagtg 27
Claims (9)
Systemic lupus erythematosus (SLE) diagnostic composition comprising an antigen protein that specifically binds to TCP1 (T-complex polypeptide 1) autoantibodies.
According to claim 1, The TCP1 systemic lupus erythematosus diagnostic composition, characterized in that represented by the amino acid sequence of SEQ ID NO: 1.
Systemic lupus erythematosus (SLE) diagnostic kit comprising the composition of claim 1 or 2.
The kit for diagnosing systemic lupus erythematosus according to claim 3, wherein the kit diagnoses systemic lupus erythematosus by detecting TCP1 autoantibodies in a bodily fluid sample through an antigen-antibody binding reaction.
The systemic lupus erythematosus diagnostic kit according to claim 4, wherein the body fluid is blood, serum or plasma.
4. The kit for diagnosing systemic lupus erythematosus according to claim 3, which is an enzyme immunoassay (ELISA), dot blot assay or western blot assay kit.
(a) 대상체 (subject)로부터 분리된 생물학적 시료에서 TCP1 (T-complex polypeptide 1) 자가항체를 검출하는 단계; 및
(b) 상기 검출된 TCP1 자가항체 수준을 대조군과 비교하는 단계.
Informational methods for diagnosing systemic lupus erythematosus (SLE), including the following steps:
(a) detecting a T-complex polypeptide 1 (TCP1) autoantibody in a biological sample isolated from the subject; And
(b) comparing the detected TCP1 autoantibody levels with a control.
8. The method of claim 7, wherein the biological sample is blood, serum or plasma.
The method of claim 7, wherein the TCP1 is an information providing method for diagnosing systemic lupus erythematosus, characterized in that represented by the amino acid sequence of SEQ ID NO: 1.
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| US20100273671A1 (en) * | 2007-03-01 | 2010-10-28 | Universite Catholique De Louvain | Method for the determination and the classification of rheumatic conditions |
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