免疫相关性全血细胞减少症患者骨髓造血细胞膜靶抗原的初步研究
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摘要
目的：检测免疫相关性全血细胞减少(immuno-related pancytopenia, IRP)患者自身抗体(IgG／IgM)在骨髓红系造血细胞及其他造血细胞膜上的作用靶点,探索IRP患者造血细胞膜上可能的靶抗原成分,为进一步纯化和克隆IRP患者自身抗原提供依据。
方法：研究对象为66例初治IRP患者及28名正常对照。应用流式细胞术(FACS)检测骨髓红系造血细胞膜表面自身抗体与促红细胞生成素受体(EPOR)的数量,观察有核红细胞自身抗体阳性组与自身抗体阴性组IRP患者EPOR的表达水平；RT-PCR检测EPOR mRNA的表达水平；FACS分选骨髓红系造血细胞后,免疫印迹法检测Stat5及P-Stat5蛋白表达水平以观察EPO／EPOR信号通路是否受抑；利用甘氨酸缓冲液洗脱骨髓红系造血细胞膜上结合的自身抗体,重新标记后再次检测EPOR的表达水平；FACS检测骨髓造血细胞膜抗体,提取细胞膜蛋白,免疫印迹法检测IRP患者骨髓上清液中自身抗体IgG的阳性率,进而应用聚丙烯酰胺凝胶电泳结合免疫印迹法分离和鉴定IRP患者自身抗体IgG在细胞膜上的靶抗原,并与正常对照及病例对照组进行对比；选取目标蛋白条带进行高压液相串联质谱(LC-MS／MS)分析以确定靶抗原成分。
结果：
1.(1)有核红细胞自身抗体阳性组IRP患者有核红细胞膜EPOR表达量为(1.59±0.87)%,明显低于自身抗体阴性组(4.58±4.09)%(P<0.01),后者则明显高于正常对照组(2.27±1.76)%(P<0.05)；IRP患者有核红细胞膜上EPOR表达水平与自身抗体呈显著负相关(r=-0.543,p=0.000),EPOR(Y)与自身抗体(X)的直线回归方程为Y=0.040-0.335X；有核红细胞自身抗体阳性组网织红细胞百分率为(1.55±0.64)%,显著低于自身抗体阴性组(2.41±1.42)%(P<0.05)；IRP患者有核红细胞膜上EPOR表达水平与其网织红细胞百分率呈显著正相关(r=0.346,p=0.029)；(2)有核红细胞自身抗体阳性组EPOR mRNA表达水平为(0.685±0.136),明显高于自身抗体阴性组(0.554±0.116)(P<0.01)和正常对照组(0.580±0.119)(P<0.05)；(3)有核红细胞自身抗体阳性组Stat5蛋白表达水平为(1.45±0.94),明显高于正常对照组(0.54±0.36)(P<0.05),而自身抗体阴性组Stat5蛋白表达水平为(0.75+0.69),与正常对照组无统计学差异(P>0.05)；自身抗体阳性组P-Stat5蛋白表达水平为(0.42±0.18),明显低于正常对照组(0.85±0.38)(P<0.05),而自身抗体阴性组P-Stat5蛋白表达水平为(0.70±0.18),与正常对照组无统计学差异(P>0.05)；(4)应用甘氨酸洗脱液洗脱抗体后自身抗体数量明显减少,而EPOR表达水平明显增高,提示部分自身抗体洗脱前封闭EPOR。
2.IRP组骨髓上清液中IgG的阳性率为75%(15／20),明显高于病例对照组(0%)和正常对照组(10%,1／10)(均P<0.01)。在20例初治IRP患者中,其骨髓造血细胞膜上共有五种蛋白成分可被自身抗体IgG识别,其相对分子量分别为25-30kDa、47.5kDa、60-65 kDa、73 kDa和83 kDa,其阳性率分别为35%(7／20)、10%(2／20)、50%(10／20)、20%(4／20)、10%(2／20)。6例再生障碍性贫血(AA)患者及4例骨髓增生异常综合征(MDS)患者经免疫印迹法鉴定后均未发现细胞膜上有蛋白被自身抗体IgG识别。正常对照组可见相对分子量为90kDa和150kDa的蛋白被识别,其阳性率均为10%(1／10)。选取25kDa、30kDa和47.5 kDa蛋白条带进行高压液相串联质谱分析,发现G蛋白偶联受体156变异体及人红细胞带3蛋白胞内区域结晶体,P链两种膜蛋白成分。
结论：部分IRP患者自身抗体可作用于骨髓红系造血细胞膜上的EPOR,封闭EPOR信号转导,导致红系较早阶段增殖和分化受到抑制。EPOR为自身抗体作用的靶点之一；IRP患者骨髓上清液中存在自身抗体IgG,可作用于骨髓细胞膜上多个靶抗原成分,质谱鉴定结果含G蛋白偶联受体156变异体及人红细胞带3蛋白胞内区域结晶体,P链两种膜蛋白成分。
Objective:To investigate the autoantigens targeted by autoantibodies(IgG/IgM) on the membrane of erythropoietic cells and other bone marrow cells of the patients with immuno-related pancytopenia(IRP),for further purifying and cloning them.
Methods:66 newly diagnosed IRP patients and 28 healthy donors as controls were enrolled in this study. EPOR expression on their nucleared erythrocytes were tested by flow cytometry to observe the relationship between EPOR and autoantibodies; EPOR mRNA were tested by RT-PCR to observe the production of EPOR; Stat5 and P-Stat5 proteins in nucleared erythrocytes were measured by Western blot to observe EPO/EPOR signal transduction; EPOR expression on the nucleared erythrocyte membrane were tested again after stripping autoantibodies with glycine buffer to see if autoantibodies had covered EPOR;Autoantibody IgG in bone marrow supernatant was measured by Western blot;The bone marrow cell membrane autoantigens targeted by IgG in IRP were identified from membrane protein extracts by SDS-PAGE, Western blot and liquid chromatography-mass spectrography/mass spectrography.
Results:
1. (1) EPOR on nucleared erythrocytes of the IRP patients with detected erythrocyte autoantibodies (auto-Ab (+) arm) (1.59±0.87)% was significiantly lower than that of auto-Ab (-) arm (4.58±4.09)%(P<0.01), and the latter was significiantly higher than that of normal controls (2.27±1.76)%(P<0.05); EPOR of IRP patients was inversely correlated with their autoantibodies on erythrocytes (r=-0.543,P=0.000) and its regression equation was Y(EPOR)=0.040-0.335X(auto-Ab);(2) EPOR mRNA of auto-Ab (+) arm (0.685±0.136) was significiantly higher than those of auto-Ab (-) arm (0.554±0.116) (P<0.01) and normal controls (0.580±0.119) (P<0.05);(3) Stat5 protein of auto-Ab (+) arm (1.45±0.94) was significiantly higher than that of normal controls(0.54±0.36)(P<0.05);While P-Stat5 protein of auto-Ab (+) arm(0.42±0.18) was significiantly lower than that of normal controls(0.85±0.38)(P<0.05); (4) EPOR expression increased significantly after stripping the auto-Ab from nucleared erythrocytes with glycine buffer.
2. Autoantibody IgG reacting with bone marrow cell membrane antigens could be found in bone marrow supernatant of IRP patients in a positive rate of 75%(15/20), which was significantly higher than those of aplastic anemia(AA) or myelodysplastic syndrome (MDS) patients(0%) and normal controls(10%) (P<0.01).Autoantibody IgG in IRP could react with several autoantigens with approximate MWs of 25-30kDa,47.5 kDa,60-65 kDa,73 kDa and 83 kDa.Positive retes of individual autoantigens were 35%,10%,50%,20% and 10%,respectively.25kDa、30kDa and 47.5 kDa were identified by liquid chromatography-mass spectrography/mass spectrography as G protein coupled receptor 156 variant and chain P, crystal structure of the cytoplasmic domain of human erythrocyte band-3 protein.
Conclusions:The autoantibody of some IRP patients might block or competitively inhibit the EPOR on the membrane of erythropoietic cells. EPOR was one of autoantigens in IRP. Autoantibody IgG could be found in bone marrow supernatant in IRP.The molecular weights of the autoantigens targeted by IgG were mainly 25-30kDa,47.5kDa,60-65 kDa,73 kDa and 83 kDa. Autoantigens in 25kDa protein were identified as G protein coupled receptor 156 variant and chain P, crystal structure of the cytoplasmic domain of human erythrocyte band-3 protein.
方法：研究对象为66例初治IRP患者及28名正常对照。应用流式细胞术(FACS)检测骨髓红系造血细胞膜表面自身抗体与促红细胞生成素受体(EPOR)的数量,观察有核红细胞自身抗体阳性组与自身抗体阴性组IRP患者EPOR的表达水平；RT-PCR检测EPOR mRNA的表达水平；FACS分选骨髓红系造血细胞后,免疫印迹法检测Stat5及P-Stat5蛋白表达水平以观察EPO／EPOR信号通路是否受抑；利用甘氨酸缓冲液洗脱骨髓红系造血细胞膜上结合的自身抗体,重新标记后再次检测EPOR的表达水平；FACS检测骨髓造血细胞膜抗体,提取细胞膜蛋白,免疫印迹法检测IRP患者骨髓上清液中自身抗体IgG的阳性率,进而应用聚丙烯酰胺凝胶电泳结合免疫印迹法分离和鉴定IRP患者自身抗体IgG在细胞膜上的靶抗原,并与正常对照及病例对照组进行对比；选取目标蛋白条带进行高压液相串联质谱(LC-MS／MS)分析以确定靶抗原成分。
结果：
1.(1)有核红细胞自身抗体阳性组IRP患者有核红细胞膜EPOR表达量为(1.59±0.87)%,明显低于自身抗体阴性组(4.58±4.09)%(P<0.01),后者则明显高于正常对照组(2.27±1.76)%(P<0.05)；IRP患者有核红细胞膜上EPOR表达水平与自身抗体呈显著负相关(r=-0.543,p=0.000),EPOR(Y)与自身抗体(X)的直线回归方程为Y=0.040-0.335X；有核红细胞自身抗体阳性组网织红细胞百分率为(1.55±0.64)%,显著低于自身抗体阴性组(2.41±1.42)%(P<0.05)；IRP患者有核红细胞膜上EPOR表达水平与其网织红细胞百分率呈显著正相关(r=0.346,p=0.029)；(2)有核红细胞自身抗体阳性组EPOR mRNA表达水平为(0.685±0.136),明显高于自身抗体阴性组(0.554±0.116)(P<0.01)和正常对照组(0.580±0.119)(P<0.05)；(3)有核红细胞自身抗体阳性组Stat5蛋白表达水平为(1.45±0.94),明显高于正常对照组(0.54±0.36)(P<0.05),而自身抗体阴性组Stat5蛋白表达水平为(0.75+0.69),与正常对照组无统计学差异(P>0.05)；自身抗体阳性组P-Stat5蛋白表达水平为(0.42±0.18),明显低于正常对照组(0.85±0.38)(P<0.05),而自身抗体阴性组P-Stat5蛋白表达水平为(0.70±0.18),与正常对照组无统计学差异(P>0.05)；(4)应用甘氨酸洗脱液洗脱抗体后自身抗体数量明显减少,而EPOR表达水平明显增高,提示部分自身抗体洗脱前封闭EPOR。
2.IRP组骨髓上清液中IgG的阳性率为75%(15／20),明显高于病例对照组(0%)和正常对照组(10%,1／10)(均P<0.01)。在20例初治IRP患者中,其骨髓造血细胞膜上共有五种蛋白成分可被自身抗体IgG识别,其相对分子量分别为25-30kDa、47.5kDa、60-65 kDa、73 kDa和83 kDa,其阳性率分别为35%(7／20)、10%(2／20)、50%(10／20)、20%(4／20)、10%(2／20)。6例再生障碍性贫血(AA)患者及4例骨髓增生异常综合征(MDS)患者经免疫印迹法鉴定后均未发现细胞膜上有蛋白被自身抗体IgG识别。正常对照组可见相对分子量为90kDa和150kDa的蛋白被识别,其阳性率均为10%(1／10)。选取25kDa、30kDa和47.5 kDa蛋白条带进行高压液相串联质谱分析,发现G蛋白偶联受体156变异体及人红细胞带3蛋白胞内区域结晶体,P链两种膜蛋白成分。
结论：部分IRP患者自身抗体可作用于骨髓红系造血细胞膜上的EPOR,封闭EPOR信号转导,导致红系较早阶段增殖和分化受到抑制。EPOR为自身抗体作用的靶点之一；IRP患者骨髓上清液中存在自身抗体IgG,可作用于骨髓细胞膜上多个靶抗原成分,质谱鉴定结果含G蛋白偶联受体156变异体及人红细胞带3蛋白胞内区域结晶体,P链两种膜蛋白成分。
Objective:To investigate the autoantigens targeted by autoantibodies(IgG/IgM) on the membrane of erythropoietic cells and other bone marrow cells of the patients with immuno-related pancytopenia(IRP),for further purifying and cloning them.
Methods:66 newly diagnosed IRP patients and 28 healthy donors as controls were enrolled in this study. EPOR expression on their nucleared erythrocytes were tested by flow cytometry to observe the relationship between EPOR and autoantibodies; EPOR mRNA were tested by RT-PCR to observe the production of EPOR; Stat5 and P-Stat5 proteins in nucleared erythrocytes were measured by Western blot to observe EPO/EPOR signal transduction; EPOR expression on the nucleared erythrocyte membrane were tested again after stripping autoantibodies with glycine buffer to see if autoantibodies had covered EPOR;Autoantibody IgG in bone marrow supernatant was measured by Western blot;The bone marrow cell membrane autoantigens targeted by IgG in IRP were identified from membrane protein extracts by SDS-PAGE, Western blot and liquid chromatography-mass spectrography/mass spectrography.
Results:
1. (1) EPOR on nucleared erythrocytes of the IRP patients with detected erythrocyte autoantibodies (auto-Ab (+) arm) (1.59±0.87)% was significiantly lower than that of auto-Ab (-) arm (4.58±4.09)%(P<0.01), and the latter was significiantly higher than that of normal controls (2.27±1.76)%(P<0.05); EPOR of IRP patients was inversely correlated with their autoantibodies on erythrocytes (r=-0.543,P=0.000) and its regression equation was Y(EPOR)=0.040-0.335X(auto-Ab);(2) EPOR mRNA of auto-Ab (+) arm (0.685±0.136) was significiantly higher than those of auto-Ab (-) arm (0.554±0.116) (P<0.01) and normal controls (0.580±0.119) (P<0.05);(3) Stat5 protein of auto-Ab (+) arm (1.45±0.94) was significiantly higher than that of normal controls(0.54±0.36)(P<0.05);While P-Stat5 protein of auto-Ab (+) arm(0.42±0.18) was significiantly lower than that of normal controls(0.85±0.38)(P<0.05); (4) EPOR expression increased significantly after stripping the auto-Ab from nucleared erythrocytes with glycine buffer.
2. Autoantibody IgG reacting with bone marrow cell membrane antigens could be found in bone marrow supernatant of IRP patients in a positive rate of 75%(15/20), which was significantly higher than those of aplastic anemia(AA) or myelodysplastic syndrome (MDS) patients(0%) and normal controls(10%) (P<0.01).Autoantibody IgG in IRP could react with several autoantigens with approximate MWs of 25-30kDa,47.5 kDa,60-65 kDa,73 kDa and 83 kDa.Positive retes of individual autoantigens were 35%,10%,50%,20% and 10%,respectively.25kDa、30kDa and 47.5 kDa were identified by liquid chromatography-mass spectrography/mass spectrography as G protein coupled receptor 156 variant and chain P, crystal structure of the cytoplasmic domain of human erythrocyte band-3 protein.
Conclusions:The autoantibody of some IRP patients might block or competitively inhibit the EPOR on the membrane of erythropoietic cells. EPOR was one of autoantigens in IRP. Autoantibody IgG could be found in bone marrow supernatant in IRP.The molecular weights of the autoantigens targeted by IgG were mainly 25-30kDa,47.5kDa,60-65 kDa,73 kDa and 83 kDa. Autoantigens in 25kDa protein were identified as G protein coupled receptor 156 variant and chain P, crystal structure of the cytoplasmic domain of human erythrocyte band-3 protein.
引文
[1]付蓉,邵宗鸿,刘鸿,等.与免疫相关的血细胞减少患者骨髓造血细胞自身抗体的研究[J].中华血液学杂志,2003,24：177-180.
[2]和虹,邵宗鸿,刘鸿,等.与异常免疫相关的全血细胞减少症[J].中华血液学杂志,2001,22：79-82.
[3]邵宗鸿.免疫性血细胞减少症的分类及治疗原则.中国实用内科杂志,2006,26(7)：481-482.
[4]付蓉.免疫相关性全血细胞减少症的诊断和治疗.中国实用内科杂志.2006；26(7)：492-495.
[5]Valent P,Horny HP,Bennett JM,et al.Definitions and standards in the diagnosis and treatment of the myelodysplastic syndromes:consensus statements and report from a working conference.Leuk Res,2007,31:727-736.
[6]Wimazal F,Fonatsch C,Thalhammer R,et al.Idiopathic cytopenia of undetermined significance (ICUS) versus low risk MDS:the diagnostic interface.Leuk Res,2007,31:1461-1468.
[7]Hong He,Zonghong Shao, Rong Fu. Hemocytopenia related to immunity detected by modified Coombs test for measuring autoantibody of bone marrow mononuclear cells.BLOOD,2002,100:136b.
[8]Rong Fu, Zonghong Shao, HongLiu. Type, Distribution, and Clinical Significance of Auto-antibody on Bone Marrow Hematopoietic Cells in Patients with Immuno-Related Pancytopenia.BLOOD,2002,100:136b.
[9]Rong Fu, Zonghong Shao, Hong he, et al. The quantities and apoptosis Related protein levels of B lymphocytes in patients with immunorelated pancytopenia. BLOOD,2002,100:171b.
[10]Fu R, Shao ZH, Liu H,et al.Role of B lymphocyte and its subpopulations in pathogenesis of immunorelated pancytopenia.Chin Med Sci J,2007,22(3):199-202.
[11]Xing LM, Shao ZH, Fu R, et al.Subtypes of B lymphocytes in patients with autoimmune hemocytopenia. Chin Med Sci J,2007,22(2):128-131.
[12]陈瑾,付蓉,李丽娟等.骨髓单个核细胞Coomb's试验阳性的血细胞减少患者骨髓液补体水平变化及其意义.中华血液学杂志,2009,30(7)：544-547.
[13]王一浩,付蓉,邵宗鸿等.骨髓单个核细胞Coombs实验+血细胞减少患者骨髓巨噬细胞数量及功能的研究.中华血液学杂志,200930(8)：538-542.
[14]Fu R, Wang Y H, Shao Z H et al. Study on the Ratio and Function of nacrophages in the Patients with BMMNC Test(+) Hematocytopenia[J]. Blood(ASH Annual Meeting Abstracts),2008; 112:4656.
[15]Fu R, Wang Y H, Shan Z H et al. Study on the mechanism of'ei'formationin the bone nlal'l'ow snxXIm of the patients with BMMNC—Coombs test(+) Hematoeytepenia[J]. Blood(ASH Annual Meeting Al,8tmcts),2008; 112:4753.
[16]Leeuwen EF,van JT,Engelfriet CP,et al.Specificity of autoantibodies in autoimmune thrombocytopenia.Blood,1982 59:23-26.
[17]William C,Paul H,Haering P,Beat S.Conformational modulation of purified Glycoprotein (GP) Ⅱb-Ⅲa allows proteolytic generation of active fragments from either active or inactive GP Ⅱb-IIIa. J Biol Chem,1992267:18844-51.
[18]Joel S,Bennett F,Gaston V,Douglas B.Identification of the fibrinogen receptor on human platelets by photoaffinity labeling J Biol Chem,1982;257;8049-54.
[19]Szatkowski NS,Kunicki TJ,Aster RH.Identification of glycoprotein Ib as a target for autoantibody in idiopathic(autoimmune) thrombocytopenic purpuraBlood,1986 67:310-315.
[20]Pedersen SK,Sloane AJ,Prasad SS,et al.An immunoproteomic approach for identification of clinical biomarkers for monitoring disease.Mol Cell Proteomics,2005, 4:1052-1060.
[21]Khole V, Wakle M.A testis specific auto-antigen TSA70 belongs to Odf2/Cenexin family. Soc Reprod Fertil Suppl,2007,63:159-171.
[22]Bohring C,Krause E,Habermannn B,et al.Isolation and identification of sperm membrane antigens recognized by antisperm antibodies,and their possible role in immunological infertility disease.Mol Hum Reprod,2001,7:113-118.
[23]Nahm DH, Lee KH, Shin JY, Ye YM, Kang Y, Park HS.Identification of alpha-enolase as an autoantigen associated with severe asthma.J Allergy Clin Immunol,2006,118(2):376-381.
[24]Lupi I, Broman KW, Tzou SC, Gutenberg A, Martino E, Caturegli P.Novel autoantigens in autoimmune hypophysitis. Clin Endocrinol (Oxf),2008,10
[25]Nakamura M,Tsutsumi K,Ooka S,et al.Identification of b-tubulin isoform V as an autoantigen in allergic rhinitis by a proteomic approach.Microbiol Immunol.2004 48(5):427-34.
[26]Chen M, Zhao MH, Zhang YK, Wang HY.Antineutrophil cytoplasmic autoantibodies in patients with systemic lupus erythematosus recognize a novel 69 kDa target antigen of neutrophil granules.Nephrology (Carlton),2005,10(5):491-495.
[27]Leddy JP,Wikinson SL,et al.Erythrocyto membrance proteins reactive with IgG anti-red blood cell autoantibodies:II.antibodies coprecipitating band 3 and glycophorin A.Blood,1994,84(2):650-6.
[28]Barker RN, Casswell KM, Reid ME, Sokol RJ, Elson CJ.Identification of autoantigens in autoimmune haemolytic anaemia by a non-radioisotope immunoprecipit-ation method. Br J Haematol,1992,82(1):126-132.
[29]Uchida K,Akita Y,Matsuo K,Identification of autoantigens in sjogren's syndrome by SEREX. Immunology,2005,116:53-63.
[30]Robert J,Oliver W,Autoantibody microarrays for biomarker discovery.Expert Rev.Proteomics,2007,4:261-272.
[31]Oliver W,Robert J Joshua R,et al.Identifying autoantigens as theranostic targets:antigen arrays and immunoproteomics approaches.Molecular Therapeutics 2008,10(2):107-15.
[32]和虹,邵宗鸿,曹增等.骨髓单个核细胞抗人球蛋白分型试验[J].中华血液学杂志,2000,21：550-551.
[33]和虹,邵宗鸿.改良直接抗人球蛋白试验的进展.中华检验医学杂志.2001,24(5)：313-315.
[34]邵宗鸿,付蓉.免疫相关性血细胞减少症—一种新认知的疾病(上).中国医刊,2005,40：5-8.
[35]邵宗鸿,付蓉.免疫相关性血细胞减少症—一种新认知的疾病(下).中国医刊,2005,41：6-9.
[36]邵宗鸿,付蓉,王化泉。免疫相关性血细胞减少症发病机制研究.中国免疫学杂志,2009,25(7)：587-590.
[37]付蓉,邵宗鸿,和虹等.免疫相关性会血细胞减少患者骨髓B淋巴细胞数量及凋亡相关蛋白水平[J].中华血液学杂志,2002；23(5)：236-240.
[38]付蓉,邵宗鸿,刘鸿等.免疫相关全血细胞减少患者骨髓造血祖细胞增殖功能及Th细胞功能观察[J].中华血液学杂志,2004；25(4)：213—216
[39]郑文洁,唐福林,赵岩等.系统性血管炎中抗内皮细胞抗体的检测及其靶抗原研究,中华医学杂志,2005,85(46)：3272-76.
[40]Jia X,Li QChen Z,et al. Expression and identification of type 1 diabetes associated autoantigen IA-2,Chin Med J,2003,116(4):524-8.
[41]Oliver W,Robert J,Joshua R,et al.Identifying autoantigens as theranostic targets:antigen arrays and immunoproteomics approaches.Molecular Therapeutics 2008,10(2):107-115.
[42]Catherine L,Patrick M.Biology of erythropoietin.Haematologica,1998;83:724-732.
[43]Marc A.Kerenyi,Florian Grebien,Helmuth Gehart,et al.Stat5 regulates cellular iron uptake of erythroid cells via IRP-2 and TfR-l.Blood,2008 112:3878-88.
[44]Madhu P.Menon,Jing Fang,Don M.Wojchowski.Core erythropoietin receptor signals for late erythroblast development.Blood,2006 107:2662-72.
[45]Florian Grebien,Marc A,Kerenyi,et al.Stat5 activation enables etythropoiesis in the absence of EpoR and Jak2.Blood,2008 111:4511-22.
[46]Berg CP,Stein GM,Keppeler H,Gregor M,Wesselborg S,Lauber K.Apoptosis-associated antigens recognized by autoantibodies in patients with the autoimmune liver disease primary biliary cirrhosis. Apoptosis,2007,30.
[47]McMillan R.Autoantibodies and autoantigens in chronic immune thrombo-Cytopenic purpura.J Semin Hemotol,2000;37:239-48.
[48]Huang Y, Cai J, Ji L, Li Y.Classifying G-protein Coupled receptors with baggingclassification tree. Computational Biology and Chemistry,2004 28,275-280.
[49]Ji, T.H., Grossmann, M. and Ji,1. (1998) G protein-coupled receptors. I. Diversit-y of receptor-ligand interactions. J Biol C hem 273:17299-17302.
[50]Gether, U. and Kobilka, B.K. (1998) G protein-coupled receptors.11. Mechanism of agonist activation. J Biol Chem 273:1 7979-1 7982.
[51]Milligan G.Constitutive activity and inverse agonises of G protein-coupled receptors:a current perspective.Mol Pharmacol,2003,64(6):1271-1276.
[52]Levin MC,Marullo S,Muntaner O,et al.The myocardium-protective Gly-49 variant of the beta 1-adrenergic receptor exhibits constitutive activity and increased desensitization and down-regulation.J Biol Chem,2002,277(34):30429-30435.
[53]Costa T,Hertz A.Antagonists with negative intrinsic activity at delta opiod receptors coupled to GTP-binding proteins.Proc Natl Acad Sci USA,1989,86(19): 7321-7325.
[54]Zdebska E,Wozniewicz B,Adamowicz A,et al.Short report:erythrocyte membranes from a patient with congenital dyserythropoietic anemia type I (CDA I) show identical,although less pronounced,glycoconjugate abnoralities to those from patients with CDAⅡ (HEMPAS).Br J Haematol,2000,110(4):998-1001.
[55]Kameh H,Landolt C,Charuk J H,et al.Structural and functional consequences of an N-glycosylation mutation (HEMPAS) affecting human eruthrocyte membrane glycoproteins.Biochem Cell Biol,1998,76(9):823-835.
[56]Liu DN, He ZY, Li JS. Relationship between Helicobacter pylori infection, virulence of Hp and myocardial infarction.Zhongguo Weixunhuan Zazhi 2004; 8: 26-29.
[57]Feng-hua Guo,Xiao-mei Yan,Chun-xiang Fan,et al.Cross-reactivity of anti-H pylori antibodies with membrane antigens of human erythrocytes.World J Gastroenterol 2007;13(27):3742-3746.
[58]S anchez L, Calvo M, Brock JH:Biological role of lactoferrin. Arch Dis Child 67:657,1992.
[59]Headon DR:Human Lactoferrin:Production at large scale, characterization and applications. Lactoferrin Structure, Function and Applications, Wiley Publ,2000, p415.
[60]Crouch SP, Slater KJ, Fletcher J:Regulation of cytokine release from mononuclear cells by the iron-binding protein lactoferrin.Blood 80:235,1992.
[61]Machnicki M, Zimecki M, Zagulski T:Lactoferrin regulates the release of tumour necrosis factor alpha and interleukin 6 in vivo.Int J Exp Pathol 74:433,1993.
[62]Mazurier J, Legrand D, Hu WL, Montreuil J, Spik G:Expression of human lactotransferrin receptors in hytohemagglutininstimulated human peripheral blood lymphocytes. Isolation of the receptors by antiligand-affinity chromatography. Eur J Biochem 179:481,1989.
[63]Iyer S, Lonnerdal B:Lactoferrin, lactoferrin receptors and iron metabolism. Eur J Clin Nutr 47:232,1993.
[64]张之南,沈悌主编.血液病诊断及疗效标准.第三版,北京：科学技术出版社,2007.
[I]Kurien BT,Scofield RH.Autoimmunity and oxidatively modified autoantigens. Autoimmune Rev,2008,7:567-573.
[2]Scofield RH,Kurien BT,Ganick S, et al.Modification of lupus-associated 60-kDa Ro protern with the lipid oxidation product 4-hydroxy-2-nonenal increases antigenicity and facilitates epitope spreading.Free Radic Biol Med,2005,38:719-728.
[3]Barzilai O,Ram M,Shoenfeld Y.Viral infection can induce the production of autoantibodies.Curr Opin Rheumatol,2007,19:636-643.
[4]Leeuwen EF,van JT,Engelfriet CP,et al.Specificity of autoantibodies in autoimmune thrombocytopenia.Blood,1982 59:23-26.
[5]Szatkowski NS,Kunicki TJ,Aster RH.Identification of glycoprotein Ib as a target for autoantibody in idiopathic(autoimmune) thrombocytopenic purpuraBlood,1986 67:310-315.
[6]William C,Paul H,Haering P,Beat S.Conformational modulation of purified Glycoprotein (GP) Ⅱb-Ⅲa allows proteolytic generation of active fragments from either active or inactive GP Ⅱb-Ⅲa. J Biol Chem,1992267:18844-51.
[7]Joel S,Bennett F,Gaston V,Douglas B.Identification of the fibrinogen receptor on human platelets by photoaffinity labeling.J Biol Chem,1982;257;8049-54.
[8]Inogradova O,Velyvis A,Velyviene A,et al.A structural mechanism of integrin alpha(IIb)beta(3)'inside-out'activation as regulated by its cytoplasmic face.Cell,2002, 110:587.
[9]Kyra C,Debbie L,David P.Identification of Shc as the primary protein bingding to the tyrosine-phosphorylated β3 subunit of αⅡbβ3 during outside-in integrin platelet signaling.J Bio Chemistry,2000,275:36423-36429.
[10]Collet JP,Montalescot G,Lesty C,et al.A structural and dynamic investigation of the facilitating effect of glycoprotein Ⅱb/Ⅲa inhibitors in dissolving platelet rich clots.Circ Res,2002,90:428-434.
[11]Rocha-Singh KI,Trokey J.Combined glycoprotein Ⅱb/Ⅲa receptor inhibition and loe-dose fibrinolysis for peripheral arterial thrombosis.Catheter Cardiovasc Interv,2002,55:457-460.
[12]Pedersen SK,Sloane AJ,Prasad SS,et al.An immunoproteomic approach for identification of clinical biomarkers for monitoring disease.Mol Cell Proteomics,2005, 4:1052-1060.
[13]Frampton QMoriya S,Pearson JD,et al.Identification of candidate endothelial cell autoantigens in systemic lupus erythematosus using a molecular cloning strategy:a role for ribosomal P protein P0 as an endothelial cell autoantigen.Rheuatlolgy,2000,39:1114-1120.
[14]Guilpain P,Servettaz A,Tamby MC,et al.a combined SDS-PAGE and proteomics approach to identify target autoantigens in healthy individuals and patients with autoimmune diseases.Ann N Y Acad Sci,2007,1109:538-549.
[15]Berg CP,Stein GM,Keppeler H,et al.Apoptosis-associated antigens recognized by autoantibodies in patients with the autoimmune liver disease primary biliaty cirrhosis.Apoptosis,2008,13:63-75.
[16]Lunardi C,Bason C,Dolcino M,et al.Antiflagellin antibodies recognize the autoantigens Toll-like Receptor 5 and Pals 1-associated tight junction protein and induce monocytes activation and increased intestinal permeability in Crohn's disease.J Intern Med,2009,265:250-265.
[17]Jadali Z,Sanati MH.The autoimmune diseases manifested by production of autoantibodies:the autoantigens identified by random peptide library.Asthma Immunol,2008,7:115-131.
[18]裴斐,赵明辉,汪莺昱等.狼疮肾炎中新发现的抗肾小球系膜细胞抗体靶抗原的鉴定.中华医学杂志,2004,84：194-198.
[19]郑文洁,唐福林,赵岩等.系统性血管炎中抗内皮细胞抗体的检测及其靶抗原研究.中华医学杂志,2005,85：3272-3276.
[20]Gajbhiye R,Suryawanshi A,Khan S, et al.Multipe endometrial antigens are targeted in autoimmune endometriosis.Reprod Biomed Online,2008,16:817-824.
[21]Nakamura M,Tsutsumi K,Ooka S,et al.Identification of β-tubulin isoform V as an autoantigen in allergic rhinitis by a proteomic approach.Microbiol Immunol,2004, 48:427-434.
[22]Berg CP,Stein GM,Keppeler H,et al,Apoptosis-associated antigens recognized by autoantibodies in patients with the autoimmune liver disease primary biliaty cirrhosis.Apoptosis,2008,13:63-75.
[23]Lupi I,Broman KW,Tzou SC,et al.Novel autoantigens in autoimmune hypophysitis.Clin Endocrinol (Oxf),2008,69:269-278.
[24]Chen M,Zhao MH,Zhang Y,et al.Antineutrophil cytoplasmic autoantibodies in patients with systemic lupus erythematosus recognize a novel 69kDa target antigen of neutrophil gtanules.Nephrology(Carlton) 2005,10:491-495.
[25]Nahm DH,Lee KH,Shin JY,et al.Identification of alpha-enolase as an autoantigen associated with severe asthma.J Allergy Clin Immunol,2006,118:376-381.
[26]Bohring C,Krause E,Habermannn B,et al.Isolation and identification of sperm membrane antigens recognized by antisperm antibodies,and their possible role in immunological infertility disease.Mol Hum Reprod,2001,7:113-118.
[27]Jia X,Li G,Chen Z,et al. Expression and identification of type 1 diabetes associated autoantigen IA-2.Chin Med J,2003,116:524-528.
[28]Oliver W,Robert J,Joshua R,et al.Identifying autoantigens as theranostic targets:antigen arrays and immunoproteomics approaches.Molecular Therapeutics, 2008,10:107-115.
[29]Uchida K,Akita Y,Matsuo K,Identification of autoantigens in sjogren's syndrome by SEREX. Immunology,2005,116:53-63.
[30]Robert J,Oliver W,Autoantibody microarrays for biomarker discovery.Expert Rev.Proteomics,2007,4:261-272.
[31]Zhang ZJ, Lee CSY, Lider O, et al. Suppression of adjuvant arthritis in lewis rats by oral administration of type Ⅱ collegen. J Immunol,1990,145:2489-2493.
[32]Nussenblatt RB, Caspi RR, Mahdi R, et al. Inhibition. of S-antigen induced experimental autoimmune uveoretinitis by oral induction of tolerance with S-antigen. J Immunol,1990,144:1689-1695.
[33]Wang ZY, He B, Qiao J, et al. Suppression of experimental autoimmune myasthenia gravis and experimental allergic encephalomyelitis by oral administration of acetycholine receptor and myelin basic protein:double tolerance. J Neuroimmunol, 1995,63:79-86.
[34]Zhang ZJ, Davidson L, Eisenbarth G, et al. Suppression of diabetes in the NOD mouse by oral administration of porcine insulin. Proc Natl Acad Sci USA,1991, 88:10252-10256.
[35]Higgins PJ, Weiner HL. Suppression of experimental autoimmune encephalomyelitis by oral administration of myelin basic protein and its fragments. J Immunol,1988,140:440-445.
[36]Meyer Al, Benson JM, Gienapp LE, et al. Suppression of murine chronic relapsing experimental autoimmune encephalomyelitis by the oral administration of myelin basic protein. J Immunol,1996,157:4230-4238.
[37]Miller A, Lider O, Al-Sabbagh A, et al. Suppression of experimental autoimmune encephalomyelitis by oral administration of myelin basic protein. V. hierarchy of suppressionby myelin basic protein from different species. J neuroimmunol,1992,39:243-250.
[38]Whitacre CC, Gienapp IE, Meyer A, et al. Treatment of autoimmune diseases by oral tolerance to autoantigens. Clin Immunol Immunopathol,&nbs p;1996,80:31-37.
[39]Shi FD, Bai XF, Li HL, et al. Nasal tolerance in experimental autoimmune myasthenia gravis (EAMG):induction of protective tolerance in primed animals. clin Exp Immunol,1998,111:506-512.
[40]Whitacre CC, Gienapp IE, Orosz CG, et al. Oral tolerance in experimental autoimmune encephalomyelitis. J Immunol,1991,147:2155-2163.
[41]Johnson JG, Jenkins MK. The role of anergy in peripheral T cell unresponsiveness.Life Sci.1994,55:1767-1780.
[42]Evavold BD, Sloan-Lancaster J, Allen PM. Tickling the TCR:Selective T-cellfunctions stimulated by altered peptide ligands.Immunol. Todayl993,14: 602-609.
[43]Miller A, Lider O, Weiner HL. Antigen-driven bystander suppression after oral administration of antigens. J Exp Med,1991,174:791-798.
[44]Tisch R, Yang X-D, Singer SM, et al. Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice. Nature 1993,366: 72-75.
[45]Kaufman DL, Clare-Salzler M, Tian J, et al.Spontaneous loss of T-cell toleranceto glutamic acid decarboxylase in murine insulin-dependent diabetes. Nature 1993,366:69-72.
[46]Weiner HL, Zhang ZJ, Khoury SJ, et al. Antigen-driven peripheral immune tolerance. Ann NY Acad Sci,1991,636:227-232.
[47]Ma CG, Zhang GX, Xiao BG, et al. Suppression of experimental autoimmune myasthenia gravis by nasal administration of acaetylcholine receptor. J neuroimmunol, 1995,58:51-60.
[48]Ma CG, Zhang GX, Xiao BG, et al. Cellular mRNA expression of IFN-γ IL-4 and TGF-β in rat nasally tolerized against experimental autoimmune myasthenia gravis. Clin Exp Immunol,1996,104:509-517.
[49]Weiner HL, Mackin GA, Matsui M, et al. Double-blind pilot trial of tolerization with myelin antigens in multiple sclerosis. Science.1993,259:1321-1324.
[50]Weiner HL, Friedman A, Miller A, et al. Oral tolerance:Immunologic mechanisms and treatment of murine and human organ-specific autoimmune diseases by oral administration of autoantigens. Ann Rev Immunol,1994,12:809-837.
[51]Weiner HL. Oral tolerance:immune mechanisms and treatment of autoimmune diseases. Immunology Today,1997,18:335-343.
[52]Trentham DE, Dynesium-Trentham A, Orav EJ, et al. Effects of oral administratiion of type II collagen on rheumatoid arthritis. Science, 1993,261:1727-1730.
[53]Chatenoud L.Immune therapies of autoimmune diseases:are we approaching a real cure?Curr Opin Immunol.2006 10; 18(6):710-717.
[54]Snowden JA,Passweg J,Moore JJ,et al.Autologous hemopoietic stem cell transplantation in severe rheumatoid arthritis:a report from th EBMT and ABMTR.J Rheumatlo 2004,31:482-488.
[55]Fassas A,Passweg JR,Anagnostopoulos A,et al.Hematopoietic stem cell transplantation for ultiple sclerosis.A retrospective multicenter study.J Neurol 2002.249:1088-1097.
[56]Brennan FM,Chantry D,Jackson A,et al.Inhibitory effect of TNG Alpha antibodies on synovial cell interleukin-1 production in rheumatoid arthritis.Lancet 1989,2:244-247.
[57]Feldmann M.Development of anti-TNF Therapy for rheumatoid arthritis.Nat Rev Imunol 20002,2:364-371.
[58]Williams RO,feldmann M,Maini RN.Anti-tumor necrosis factor ameliorates joint disease in murine collagen-induced arthritis.Proc Natl Acad Sci USA 1992,89:9784-9788.
[59]Elliott MJ,Maini RN,Feldmann M,et al. Treatment of rheumatoid arthritis with chinmeric monoclonal antibodies to tumor necrosis factor alpha.Arhtritis Rheum 1993,36:1681-1690.
[60]Elliott MJ, Maini RN,Feldmann M,et al.Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis.Lancet 1994,344:1105-1110.
[61]Maini RN,St Clari EW,Breedveld F,et al.Infliximab (chimeric anti-tumor necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate:a randomized phase III trial.ATTRACT Study Group.Lancet 1999,354:1932-1939.
[62]Lipsky PE,van der Heijde D,St clair EW,et al.Infliximab and methotrexate in the treatment of rheumatoid arthritis.anti-tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study group.Rheumatoid Arthritis with therapy study group.N Engl J Med 2000,343:1594-1602.
[63]Boye J, Elter T, Engert A:An overview of the current clinical use of the anti-CD20 monoclonal antibody rituximab. Ann Oncol 2003,14:520-535.
[64]Riley JK, Sliwkowski MX:CD20:a gene in search of a function. Semin Oncol 2000, Suppl 12:17-24.
[65]Lonberg N, Huszar D:Human antibodies from transgenic mice.Int Rev Immunol 1995,13:65-93.
[66]Tedder TF, Isaacs CM:Isolation of cDNAs encoding the CD 19 antigen of human and mouse B lymphocytes. A new member of the immunoglobulin superfamily. J Immunol 1989,143:712-717.
[67]Loffler A, Kufer P, Lutterbuse R, et al.A recombinant bispecific single-chain antibody, CD19 x CD3, induces rapid and high lymphoma-directed cytotoxicity by unstimulated T lymphocytes. Blood 2000,95:2098-2103.
[68]Loffler A, Gruen M, Wuchter C, Schriever F, et al.Efficient elimination of chronic lymphocytic leukaemia B cells by autologous T cells with a bispecific anti-CD 19/anti-CD3 single-chain antibody construct. Leukemia 2003,17:900-909.
[69]Satterthwaite AB, Witte ON:The role of Bruton's tyrosine kinase in B-cell development and function:a genetic perspective.Immunol Rev 2000,175:120-127.
[70]Gold MR:To make antibodies or not:signaling by the B-cell antigen receptor. Trends Pharmacol Sci 2002,23:316-324.
[71]Niiro H, Clark EA:Regulation of B-cell fate by antigen-receptor signals. Nat Rev Immunol 2002,2:945-956.
[72]Tsukada S, Saffran DC, Rawlings DJ, Parolini O, Allen RC, KlisakI, Sparkes RS, Kubagawa H, Mohandas T, Quan S, Belmont W,Cooper MD, Conley ME, Witte ON: Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia.Cell 1993,72:279-290.
[73]Sato S, Ono N, Steeber DA, Pisetsky DS, Tedder TF:CD19 regulates B lymphocyte signaling thresholds critical for the development of B-1 lineage cells and autoimmunity. J Immunol 1996,157:4371-4378.
[74]Sato S, Hasegawa M, Fujimoto M, Tedder TF, Takehara K:Quantitative genetic variation in CD19 expression correlates with autoimmunity. J Immunol 2000, 165:6635-6643.
[75]Mackay F, Browning JL:BAFF:a fundamental survival factor for B cells. Nat Rev Immunol 2002,2:465-475.
[76]Mackay F, Mackay CR:The role of BAFF in B-cell maturation,T-cell activation and autoimmunity. Trend Immunol 2002,23:113-115.
[77]Mackay F, Woodcock SA, Lawton P, et al.Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations.J Exp Med 1999, 190:1697-1710.
[78]Khare SD, Sarosi I, Xia XZ, et al.Severe B cell hyperplasia and autoimmune disease in TALL-1 transgenic mice. Proc Natl Acad Sci USA 2000,97:3370-3375.
[79]Do RK, Hatada E, Lee H, Tourigny MR, Hilbert D, Chen-Kiang S:Attenuation of apoptosis underlies B lymphocyte stimulator enhancement of humoral immune response. J Exp Med 2000,192:953-964.
[80]Chaillous L, Lefevre H, Thivolet C, et al.Oral insulin administration and residual beta-cell function inrecent-onset type 1 diabetes:a multicentre randomized controlled trial. Diabete Insuline Orale group.Lancet 2000,356:545-549.
[81]Ergun-Longmire B, Marker J, Zeidler A, et al.Oral insulin therapy to prevent progression of immune-mediated(type 1) diabetes. Ann N Y Acad Sci 2004, 1029:260-277.
[82]Chatenoud L:CD3-specific antibody-induced active tolerance:from bench to bedside. Nat Rev Immunol 2003,3:123-132.
[83]Chatenoud L, Baudrihaye MF, Chkoff N, Kreis H, Goldstein G,Bach JF: Restriction of the human in vivo immune response against the mouse monoclonal antibody OKT3.J Immunol 1986,137:830-838.
[84]Abramowicz D, Schandene L, Goldman M, et al.Release of tumor necrosis factor, interleukin-2,and gamma-interferon in serum after injection of OKT3 monoclonal antibody in kidney transplant recipients.Transplantation 1989, 47:606-608.
[85]Alegre ML, Peterson LJ, Xu D, et al.A non-activating "humanized" anti-CD3 monoclonal antibody retains immunosuppressive properties in vivo. Transplantation 1994,57:1537-1543.
[86]Bolt S, Routledge E, Lloyd I, et al.The generation of a humanized, nonmitogenic CD3 monoclonal antibody which retains in vitro immunosuppressive properties. Eur J Immunol 1993,23:403-411.
[87]Chatenoud L:CD3-specific antibodies restore self-tolerance:mechanisms and clinical applications. Curr Opin Immunol 2005,17:632-637.
[88]Plain KM, Chen J, Merten S, He XY, Hall BM:Induction of specific tolerance to allografts in rats by therapy with non-mitogenic,non-depleting anti-CD3 monoclonal antibody:association with TH2 cytokines not anergy. Transplantation 1999,67:605-613.
[89]Belghith M, Bluestone JA, Barriot S, Megret J, Bach JF,Chatenoud L: TGF-beta-dependent mechanisms mediate restoration of self-tolerance induced by antibodies to CD3 in overt autoimmune diabetes. Nat Med 2003,9:1202-1208.
[90]Chatenoud L, Primo J, Bach JF:CD3 antibody-induced dominant self tolerance in overtly diabetic NOD mice.J Immunol 1997,158:2947-2954.
[91]Kohm AP, Williams JS, Bickford AL, et al.Treatment with non mitogenic anti-CD3 monoclonal antibody induces CD4+ T cell unresponsiveness and functional reversal of established experimental autoimmune encephalomyelitis. J Immunol 2005,174:4525-4534.
[92]Herold KC, Hagopian W, Auger JA, et al.Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med 2002,346:1692-1698.
[93]Herold KC, Gitelman SE, Masharani U, et al.A single course of anti-CD3 monoclonal antibody hOKT3g1 (Ala-Ala) results in improvement in C-peptide responses and clinical parameters for at least 2 years after onset of type 1 diabetes. Diabetes 2005,54:1763-1769.
[94]Keymeulen B, Vandemeulebroucke E, Ziegler AG, et al.Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med 2005, 352:2598-2608.
[95]Chatenoud L, Salomon B, Bluestone JA:Suppressor T cells —they're back and critical for regulation of autoimmunity!Immunol Rev 2001,182:149-163.
[96]Ochi H, Abraham M, Ishikawa H, et al.Oral CD3-specific antibody suppresses autoimmune encephalomyelitis by inducing CD4+CD25SLAP+ T cells. Nat Med 2006,12:627-635.
[97]Moreau T, Thorpe J, Miller D, et al.Preliminary evidence from magnetic resonance imaging for reduction in disease activity after lymphocyte depletion in multiple sclerosis Lancet 1994,344:298-301.
[98]Coles AJ, Wing MG, Smith S, et al.Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis. Lancet 1999,354:1691-1695.
[99]Miller DH, Khan OA, Sheremata WA, et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2003,348:15-23.
[100]Polman CH, O'Connor PW, Havrdova E, et al.A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006,354:899-910.
[101]Furst DE, Weisman M, Paulus HE, et al.Intravenous human recombinant tumor necrosis factor receptor p55-Fc IgGl fusion protein, Ro 45-2081 (lenercept):results of a dose-finding study in rheumatoid arthritis.J Rheumatol 2003,30:2123-2126.
[102]Moreland LW, Baumgartner SW, Schiff MH, et al.Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. N Engl J Med 1997,337:141-147.
[103]Klareskog L, Gaubitz M, Rodriguez-Valverde V, Malaise M,Dougados M, Wajdula J:A long-term, open-label trial of the safety and efficacy of etanercept (ENBREL(R)) in patients with rheumatoid arthritis not treated with other DMARDs (3-yearinterim report). Ann Rheum Dis 2006.
[104]den Broeder A, van de Putte L, Rau R, Set al.A single dose, placebo controlled study of the fully human anti-tumor necrosis factor-alpha antibody adalimumab (D2E7) in patients with rheumatoid arthritis.J Rheumatol 2002,29:2288-2298.
[105]Schiff MH, Burmester GR, Kent JD, Pangan AL, Kupper H,Fitzpatrick SB, Donovan C:Safety analyses of adalimumab (HUMIRA) in global clinical trials and US postmarketing surveillance of patients with rheumatoid arthritis. Ann Rheum Dis 2006,65:889-894.
[106]Isaacs JD, Watts RA, Hazleman BL, et al.Humanised monoclonal antibody therapy for rheumatoid arthritis. Lancet 1992,340:748-752.
[107]Kremer JM, Westhovens R, Leon M, et al.Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig.N Engl J Med 2003,349:1907-1915.
[108]Genovese MC, Becker JC, Schiff M, et al.Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med 2005,353:1114-1123.
[109]Moreland LW, Alten R, Van den Bosch F, et al.Costimulatory blockade in patients with rheumatoid arthritis:a pilot, dose-finding, double-blind, placebo-controlled clinical trial evaluating CTLA-4Ig and LEA29Y eighty-five days afterthe first infusion. Arthritis Rheum 2002,46:1470-1479.
[110]Fleischmann RM, Schechtman J, Bennett R, et al.Anakinra, a recombinant human interleukin-1 receptorantagonist (r-metHuIL-1ra), in patients with rheumatoid arthritis:a large, international, multicenter,placebo-controlled trial. Arthritis Rheum 2003,48:927-934.
[111]Fleischmann RM, Tesser J, Schiff M, et al.Safety of extended treatment with anakinra in patients with rheumatoid arthritis. Ann Rheum Dis 2006,65:1006-1012.
[112]Edwards JC, Szczepanski L, Szechinski J, et al.Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 2004, 350:2572-2581.
[113]Emery P, Fleischmann R, Filipowicz-Sosnowska A, et al.The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment:results of a phase ⅡB randomized, double-blind,placebo-controlled, dose-ranging trial. Arthritis Rheum 2006,54:1390-1400.
[114]Sigidin YA, Loukina GV, Skurkovich B, Skurkovich S:Randomized, double-blind trial of anti-interferon-gamma antibodies in rheumatoid arthritis. Scand J Rheumatol 2001,30:203-207.
[115]Lovell DJ, Giannini EH, Reiff A, Cawkwell GD, et al.Etanercept in children with polyarticular juvenile rheumatoid arthritis. Pediatric Rheumatology Collaborative Study Group.N Engl J Med 2000,342:763-769.
[116]Verbsky JW, White AJ:Effective use of the recombinant interleukin 1 receptor antagonist anakinra in therapy resistant systemic onset juvenile rheumatoid arthritis.J Rheumatol 2004,31:2071-2075.
[117]Leandro MJ, Cambridge G, Edwards JC, Ehrenstein MR,Isenberg DA:B-cell depletion in the treatment of patients with systemic lupus erythematosus:a longitudinal analysis of 24 patients. Rheumatology (Oxford) 2005,44:1542-1545.
[118]Looney RJ, Anolik J, Sanz I:B lymphocytes in systemic lupuserythematosus: lessons from therapy targeting B cells.Lupus 2004,13:381-390.
[119]Ostendorf B, Iking-Konert C, Kurz K, Jung G, Sander O,Schneider M: Preliminary results of safety and efficacy of the interleukin 1 receptor antagonist anakinra in patients with severe lupus arthritis. Ann Rheum Dis 2005,64:630-633.
[120]Boumpas DT, Furie R, Manzi S, et al.A short course of BG9588 (anti-CD40 ligand antibody) improves serologic activity and decreases hematuria in patients with proliferative lupus glomerulonephritis. Arthritis Rheum 2003,48:719-727.
[121]Davis JC Jr, Totoritis MC, Rosenberg J, Sklenar TA, Wofsy D:Phase I clinical trial of a monoclonal antibody against CD40-ligand (IDEC-131) in patients with systemic lupus erythematosus. J Rheumatol 2001,28:95-101.
[122]Kalunian KC, Davis JC Jr, Merrill JT, Totoritis. MC, Wofsy D:Treatment of systemic lupus erythematosus by inhibition of Tcell costimulation with anti-CD 154:a randomized, doubleblind,placebo-controlled trial. Arthritis Rheum 2002,46:3251-3258.
[123]Mease PJ, Goffe BS, Metz J, VanderStoep A, Finck B, Burge DJ:Etanercept in the treatment of psoriatic arthritis and psoriasis:a randomised trial. Lancet 2000, 356:385-390.
[124]Utset TO, Auger JA, Peace D, et al.Modified anti-CD3 therapy in psoriaticarthritis:a phase Ⅰ/Ⅱ clinical trial. J Rheumatol 2002,29:1907-1913.
[125]Reich K, Nestle FO, Papp K, et al.Infliximab induction and maintenance therapy for moderate-to-severe psoriasis:a phase III,multicentre, double-blind trial. Lancet 2005,66:1367-1374.
[126]Lebwohl M, Christophers E, Langley R, Ortonne JP, Roberts J,Griffiths CE:An international, randomized, double-blind,placebo-controlled phase 3 trial of intramuscular alefacept in patients with chronic plaque psoriasis. Arch Dermatol 2003,139:719-727.
[127]Tyring S, Gottlieb A, Papp K, et al.Etanercept and clinical outcomes, fatigue, and depression in psoriasis:double-blind placebo-controlled randomised phase III trial.Lancet 2006,367:29-35.
[128]Abrams JR, Lebwohl MG, Guzzo CA, et al.CTLA4Ig-mediated blockade of T-cell costimulation inpatients with psoriasis vulgaris. J Clin Invest 1999,103:1243-1252.
[129]Menter A, Kosinski M, Bresnahan BW, Papp KA, Ware JE Jr:Impact of efalizumab on psoriasis-specific patient-reported outcomes. Results from three randomized, placebocontrolled clinical trials of moderate to severe plaque psoriasis. J Drugs Dermatol 2004,3:27-38.
[130]Pariser DM, Gordon KB, Papp KA, et al.Clinical efficacy of efalizumab in patients with chronic plaque psoriasis:results from three randomized placebo-controlled phase Ⅲ trials:part Ⅰ. J Cutan Med Surg 2006.
[131]Mease PJ:Adalimumab:an anti-TNF agent for the treatment of psoriatic arthritis. Expert Opin Biol Ther 2005,5:1491-1504.
[132]Mathieson PW, Cobbold SP, Hale G, et al.Monoclonal-antibody therapy in systemic vasculitis. N Engl J Med 1990,323:250-254.
[133]Lockwood CM, Thiru S, Isaacs JD,et al.Long-term remission of intractable systemic vasculitis with monoclonal antibody therapy. Lancet 1993,341:1620-1622.
[134]Stasi R, Stipa E, Poeta GD, Amadori S, Newland AC, Provan D:Long-term observation of patients with anti-neutrophil cytoplasmic antibody-associated vasculitis treated with rituximab, Rheumatology (Oxford) 2006, in press.94. Nussenblatt RB:Bench to bedside:new approaches to theimmunotherapy of uveitic disease. Int Rev Immunol 2002,21:273-289.
[135]Present DH, Rutgeerts P, Targan S, et al. Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med 1999,340:1398-1405.
[136]Ghosh S, Goldin E, Gordon FH, et al.Natalizumab for active Crohn's disease. N Engl J Med 2003,348:24-32.
[2]和虹,邵宗鸿,刘鸿,等.与异常免疫相关的全血细胞减少症[J].中华血液学杂志,2001,22：79-82.
[3]邵宗鸿.免疫性血细胞减少症的分类及治疗原则.中国实用内科杂志,2006,26(7)：481-482.
[4]付蓉.免疫相关性全血细胞减少症的诊断和治疗.中国实用内科杂志.2006；26(7)：492-495.
[5]Valent P,Horny HP,Bennett JM,et al.Definitions and standards in the diagnosis and treatment of the myelodysplastic syndromes:consensus statements and report from a working conference.Leuk Res,2007,31:727-736.
[6]Wimazal F,Fonatsch C,Thalhammer R,et al.Idiopathic cytopenia of undetermined significance (ICUS) versus low risk MDS:the diagnostic interface.Leuk Res,2007,31:1461-1468.
[7]Hong He,Zonghong Shao, Rong Fu. Hemocytopenia related to immunity detected by modified Coombs test for measuring autoantibody of bone marrow mononuclear cells.BLOOD,2002,100:136b.
[8]Rong Fu, Zonghong Shao, HongLiu. Type, Distribution, and Clinical Significance of Auto-antibody on Bone Marrow Hematopoietic Cells in Patients with Immuno-Related Pancytopenia.BLOOD,2002,100:136b.
[9]Rong Fu, Zonghong Shao, Hong he, et al. The quantities and apoptosis Related protein levels of B lymphocytes in patients with immunorelated pancytopenia. BLOOD,2002,100:171b.
[10]Fu R, Shao ZH, Liu H,et al.Role of B lymphocyte and its subpopulations in pathogenesis of immunorelated pancytopenia.Chin Med Sci J,2007,22(3):199-202.
[11]Xing LM, Shao ZH, Fu R, et al.Subtypes of B lymphocytes in patients with autoimmune hemocytopenia. Chin Med Sci J,2007,22(2):128-131.
[12]陈瑾,付蓉,李丽娟等.骨髓单个核细胞Coomb's试验阳性的血细胞减少患者骨髓液补体水平变化及其意义.中华血液学杂志,2009,30(7)：544-547.
[13]王一浩,付蓉,邵宗鸿等.骨髓单个核细胞Coombs实验+血细胞减少患者骨髓巨噬细胞数量及功能的研究.中华血液学杂志,200930(8)：538-542.
[14]Fu R, Wang Y H, Shao Z H et al. Study on the Ratio and Function of nacrophages in the Patients with BMMNC Test(+) Hematocytopenia[J]. Blood(ASH Annual Meeting Abstracts),2008; 112:4656.
[15]Fu R, Wang Y H, Shan Z H et al. Study on the mechanism of'ei'formationin the bone nlal'l'ow snxXIm of the patients with BMMNC—Coombs test(+) Hematoeytepenia[J]. Blood(ASH Annual Meeting Al,8tmcts),2008; 112:4753.
[16]Leeuwen EF,van JT,Engelfriet CP,et al.Specificity of autoantibodies in autoimmune thrombocytopenia.Blood,1982 59:23-26.
[17]William C,Paul H,Haering P,Beat S.Conformational modulation of purified Glycoprotein (GP) Ⅱb-Ⅲa allows proteolytic generation of active fragments from either active or inactive GP Ⅱb-IIIa. J Biol Chem,1992267:18844-51.
[18]Joel S,Bennett F,Gaston V,Douglas B.Identification of the fibrinogen receptor on human platelets by photoaffinity labeling J Biol Chem,1982;257;8049-54.
[19]Szatkowski NS,Kunicki TJ,Aster RH.Identification of glycoprotein Ib as a target for autoantibody in idiopathic(autoimmune) thrombocytopenic purpuraBlood,1986 67:310-315.
[20]Pedersen SK,Sloane AJ,Prasad SS,et al.An immunoproteomic approach for identification of clinical biomarkers for monitoring disease.Mol Cell Proteomics,2005, 4:1052-1060.
[21]Khole V, Wakle M.A testis specific auto-antigen TSA70 belongs to Odf2/Cenexin family. Soc Reprod Fertil Suppl,2007,63:159-171.
[22]Bohring C,Krause E,Habermannn B,et al.Isolation and identification of sperm membrane antigens recognized by antisperm antibodies,and their possible role in immunological infertility disease.Mol Hum Reprod,2001,7:113-118.
[23]Nahm DH, Lee KH, Shin JY, Ye YM, Kang Y, Park HS.Identification of alpha-enolase as an autoantigen associated with severe asthma.J Allergy Clin Immunol,2006,118(2):376-381.
[24]Lupi I, Broman KW, Tzou SC, Gutenberg A, Martino E, Caturegli P.Novel autoantigens in autoimmune hypophysitis. Clin Endocrinol (Oxf),2008,10
[25]Nakamura M,Tsutsumi K,Ooka S,et al.Identification of b-tubulin isoform V as an autoantigen in allergic rhinitis by a proteomic approach.Microbiol Immunol.2004 48(5):427-34.
[26]Chen M, Zhao MH, Zhang YK, Wang HY.Antineutrophil cytoplasmic autoantibodies in patients with systemic lupus erythematosus recognize a novel 69 kDa target antigen of neutrophil granules.Nephrology (Carlton),2005,10(5):491-495.
[27]Leddy JP,Wikinson SL,et al.Erythrocyto membrance proteins reactive with IgG anti-red blood cell autoantibodies:II.antibodies coprecipitating band 3 and glycophorin A.Blood,1994,84(2):650-6.
[28]Barker RN, Casswell KM, Reid ME, Sokol RJ, Elson CJ.Identification of autoantigens in autoimmune haemolytic anaemia by a non-radioisotope immunoprecipit-ation method. Br J Haematol,1992,82(1):126-132.
[29]Uchida K,Akita Y,Matsuo K,Identification of autoantigens in sjogren's syndrome by SEREX. Immunology,2005,116:53-63.
[30]Robert J,Oliver W,Autoantibody microarrays for biomarker discovery.Expert Rev.Proteomics,2007,4:261-272.
[31]Oliver W,Robert J Joshua R,et al.Identifying autoantigens as theranostic targets:antigen arrays and immunoproteomics approaches.Molecular Therapeutics 2008,10(2):107-15.
[32]和虹,邵宗鸿,曹增等.骨髓单个核细胞抗人球蛋白分型试验[J].中华血液学杂志,2000,21：550-551.
[33]和虹,邵宗鸿.改良直接抗人球蛋白试验的进展.中华检验医学杂志.2001,24(5)：313-315.
[34]邵宗鸿,付蓉.免疫相关性血细胞减少症—一种新认知的疾病(上).中国医刊,2005,40：5-8.
[35]邵宗鸿,付蓉.免疫相关性血细胞减少症—一种新认知的疾病(下).中国医刊,2005,41：6-9.
[36]邵宗鸿,付蓉,王化泉。免疫相关性血细胞减少症发病机制研究.中国免疫学杂志,2009,25(7)：587-590.
[37]付蓉,邵宗鸿,和虹等.免疫相关性会血细胞减少患者骨髓B淋巴细胞数量及凋亡相关蛋白水平[J].中华血液学杂志,2002；23(5)：236-240.
[38]付蓉,邵宗鸿,刘鸿等.免疫相关全血细胞减少患者骨髓造血祖细胞增殖功能及Th细胞功能观察[J].中华血液学杂志,2004；25(4)：213—216
[39]郑文洁,唐福林,赵岩等.系统性血管炎中抗内皮细胞抗体的检测及其靶抗原研究,中华医学杂志,2005,85(46)：3272-76.
[40]Jia X,Li QChen Z,et al. Expression and identification of type 1 diabetes associated autoantigen IA-2,Chin Med J,2003,116(4):524-8.
[41]Oliver W,Robert J,Joshua R,et al.Identifying autoantigens as theranostic targets:antigen arrays and immunoproteomics approaches.Molecular Therapeutics 2008,10(2):107-115.
[42]Catherine L,Patrick M.Biology of erythropoietin.Haematologica,1998;83:724-732.
[43]Marc A.Kerenyi,Florian Grebien,Helmuth Gehart,et al.Stat5 regulates cellular iron uptake of erythroid cells via IRP-2 and TfR-l.Blood,2008 112:3878-88.
[44]Madhu P.Menon,Jing Fang,Don M.Wojchowski.Core erythropoietin receptor signals for late erythroblast development.Blood,2006 107:2662-72.
[45]Florian Grebien,Marc A,Kerenyi,et al.Stat5 activation enables etythropoiesis in the absence of EpoR and Jak2.Blood,2008 111:4511-22.
[46]Berg CP,Stein GM,Keppeler H,Gregor M,Wesselborg S,Lauber K.Apoptosis-associated antigens recognized by autoantibodies in patients with the autoimmune liver disease primary biliary cirrhosis. Apoptosis,2007,30.
[47]McMillan R.Autoantibodies and autoantigens in chronic immune thrombo-Cytopenic purpura.J Semin Hemotol,2000;37:239-48.
[48]Huang Y, Cai J, Ji L, Li Y.Classifying G-protein Coupled receptors with baggingclassification tree. Computational Biology and Chemistry,2004 28,275-280.
[49]Ji, T.H., Grossmann, M. and Ji,1. (1998) G protein-coupled receptors. I. Diversit-y of receptor-ligand interactions. J Biol C hem 273:17299-17302.
[50]Gether, U. and Kobilka, B.K. (1998) G protein-coupled receptors.11. Mechanism of agonist activation. J Biol Chem 273:1 7979-1 7982.
[51]Milligan G.Constitutive activity and inverse agonises of G protein-coupled receptors:a current perspective.Mol Pharmacol,2003,64(6):1271-1276.
[52]Levin MC,Marullo S,Muntaner O,et al.The myocardium-protective Gly-49 variant of the beta 1-adrenergic receptor exhibits constitutive activity and increased desensitization and down-regulation.J Biol Chem,2002,277(34):30429-30435.
[53]Costa T,Hertz A.Antagonists with negative intrinsic activity at delta opiod receptors coupled to GTP-binding proteins.Proc Natl Acad Sci USA,1989,86(19): 7321-7325.
[54]Zdebska E,Wozniewicz B,Adamowicz A,et al.Short report:erythrocyte membranes from a patient with congenital dyserythropoietic anemia type I (CDA I) show identical,although less pronounced,glycoconjugate abnoralities to those from patients with CDAⅡ (HEMPAS).Br J Haematol,2000,110(4):998-1001.
[55]Kameh H,Landolt C,Charuk J H,et al.Structural and functional consequences of an N-glycosylation mutation (HEMPAS) affecting human eruthrocyte membrane glycoproteins.Biochem Cell Biol,1998,76(9):823-835.
[56]Liu DN, He ZY, Li JS. Relationship between Helicobacter pylori infection, virulence of Hp and myocardial infarction.Zhongguo Weixunhuan Zazhi 2004; 8: 26-29.
[57]Feng-hua Guo,Xiao-mei Yan,Chun-xiang Fan,et al.Cross-reactivity of anti-H pylori antibodies with membrane antigens of human erythrocytes.World J Gastroenterol 2007;13(27):3742-3746.
[58]S anchez L, Calvo M, Brock JH:Biological role of lactoferrin. Arch Dis Child 67:657,1992.
[59]Headon DR:Human Lactoferrin:Production at large scale, characterization and applications. Lactoferrin Structure, Function and Applications, Wiley Publ,2000, p415.
[60]Crouch SP, Slater KJ, Fletcher J:Regulation of cytokine release from mononuclear cells by the iron-binding protein lactoferrin.Blood 80:235,1992.
[61]Machnicki M, Zimecki M, Zagulski T:Lactoferrin regulates the release of tumour necrosis factor alpha and interleukin 6 in vivo.Int J Exp Pathol 74:433,1993.
[62]Mazurier J, Legrand D, Hu WL, Montreuil J, Spik G:Expression of human lactotransferrin receptors in hytohemagglutininstimulated human peripheral blood lymphocytes. Isolation of the receptors by antiligand-affinity chromatography. Eur J Biochem 179:481,1989.
[63]Iyer S, Lonnerdal B:Lactoferrin, lactoferrin receptors and iron metabolism. Eur J Clin Nutr 47:232,1993.
[64]张之南,沈悌主编.血液病诊断及疗效标准.第三版,北京：科学技术出版社,2007.
[I]Kurien BT,Scofield RH.Autoimmunity and oxidatively modified autoantigens. Autoimmune Rev,2008,7:567-573.
[2]Scofield RH,Kurien BT,Ganick S, et al.Modification of lupus-associated 60-kDa Ro protern with the lipid oxidation product 4-hydroxy-2-nonenal increases antigenicity and facilitates epitope spreading.Free Radic Biol Med,2005,38:719-728.
[3]Barzilai O,Ram M,Shoenfeld Y.Viral infection can induce the production of autoantibodies.Curr Opin Rheumatol,2007,19:636-643.
[4]Leeuwen EF,van JT,Engelfriet CP,et al.Specificity of autoantibodies in autoimmune thrombocytopenia.Blood,1982 59:23-26.
[5]Szatkowski NS,Kunicki TJ,Aster RH.Identification of glycoprotein Ib as a target for autoantibody in idiopathic(autoimmune) thrombocytopenic purpuraBlood,1986 67:310-315.
[6]William C,Paul H,Haering P,Beat S.Conformational modulation of purified Glycoprotein (GP) Ⅱb-Ⅲa allows proteolytic generation of active fragments from either active or inactive GP Ⅱb-Ⅲa. J Biol Chem,1992267:18844-51.
[7]Joel S,Bennett F,Gaston V,Douglas B.Identification of the fibrinogen receptor on human platelets by photoaffinity labeling.J Biol Chem,1982;257;8049-54.
[8]Inogradova O,Velyvis A,Velyviene A,et al.A structural mechanism of integrin alpha(IIb)beta(3)'inside-out'activation as regulated by its cytoplasmic face.Cell,2002, 110:587.
[9]Kyra C,Debbie L,David P.Identification of Shc as the primary protein bingding to the tyrosine-phosphorylated β3 subunit of αⅡbβ3 during outside-in integrin platelet signaling.J Bio Chemistry,2000,275:36423-36429.
[10]Collet JP,Montalescot G,Lesty C,et al.A structural and dynamic investigation of the facilitating effect of glycoprotein Ⅱb/Ⅲa inhibitors in dissolving platelet rich clots.Circ Res,2002,90:428-434.
[11]Rocha-Singh KI,Trokey J.Combined glycoprotein Ⅱb/Ⅲa receptor inhibition and loe-dose fibrinolysis for peripheral arterial thrombosis.Catheter Cardiovasc Interv,2002,55:457-460.
[12]Pedersen SK,Sloane AJ,Prasad SS,et al.An immunoproteomic approach for identification of clinical biomarkers for monitoring disease.Mol Cell Proteomics,2005, 4:1052-1060.
[13]Frampton QMoriya S,Pearson JD,et al.Identification of candidate endothelial cell autoantigens in systemic lupus erythematosus using a molecular cloning strategy:a role for ribosomal P protein P0 as an endothelial cell autoantigen.Rheuatlolgy,2000,39:1114-1120.
[14]Guilpain P,Servettaz A,Tamby MC,et al.a combined SDS-PAGE and proteomics approach to identify target autoantigens in healthy individuals and patients with autoimmune diseases.Ann N Y Acad Sci,2007,1109:538-549.
[15]Berg CP,Stein GM,Keppeler H,et al.Apoptosis-associated antigens recognized by autoantibodies in patients with the autoimmune liver disease primary biliaty cirrhosis.Apoptosis,2008,13:63-75.
[16]Lunardi C,Bason C,Dolcino M,et al.Antiflagellin antibodies recognize the autoantigens Toll-like Receptor 5 and Pals 1-associated tight junction protein and induce monocytes activation and increased intestinal permeability in Crohn's disease.J Intern Med,2009,265:250-265.
[17]Jadali Z,Sanati MH.The autoimmune diseases manifested by production of autoantibodies:the autoantigens identified by random peptide library.Asthma Immunol,2008,7:115-131.
[18]裴斐,赵明辉,汪莺昱等.狼疮肾炎中新发现的抗肾小球系膜细胞抗体靶抗原的鉴定.中华医学杂志,2004,84：194-198.
[19]郑文洁,唐福林,赵岩等.系统性血管炎中抗内皮细胞抗体的检测及其靶抗原研究.中华医学杂志,2005,85：3272-3276.
[20]Gajbhiye R,Suryawanshi A,Khan S, et al.Multipe endometrial antigens are targeted in autoimmune endometriosis.Reprod Biomed Online,2008,16:817-824.
[21]Nakamura M,Tsutsumi K,Ooka S,et al.Identification of β-tubulin isoform V as an autoantigen in allergic rhinitis by a proteomic approach.Microbiol Immunol,2004, 48:427-434.
[22]Berg CP,Stein GM,Keppeler H,et al,Apoptosis-associated antigens recognized by autoantibodies in patients with the autoimmune liver disease primary biliaty cirrhosis.Apoptosis,2008,13:63-75.
[23]Lupi I,Broman KW,Tzou SC,et al.Novel autoantigens in autoimmune hypophysitis.Clin Endocrinol (Oxf),2008,69:269-278.
[24]Chen M,Zhao MH,Zhang Y,et al.Antineutrophil cytoplasmic autoantibodies in patients with systemic lupus erythematosus recognize a novel 69kDa target antigen of neutrophil gtanules.Nephrology(Carlton) 2005,10:491-495.
[25]Nahm DH,Lee KH,Shin JY,et al.Identification of alpha-enolase as an autoantigen associated with severe asthma.J Allergy Clin Immunol,2006,118:376-381.
[26]Bohring C,Krause E,Habermannn B,et al.Isolation and identification of sperm membrane antigens recognized by antisperm antibodies,and their possible role in immunological infertility disease.Mol Hum Reprod,2001,7:113-118.
[27]Jia X,Li G,Chen Z,et al. Expression and identification of type 1 diabetes associated autoantigen IA-2.Chin Med J,2003,116:524-528.
[28]Oliver W,Robert J,Joshua R,et al.Identifying autoantigens as theranostic targets:antigen arrays and immunoproteomics approaches.Molecular Therapeutics, 2008,10:107-115.
[29]Uchida K,Akita Y,Matsuo K,Identification of autoantigens in sjogren's syndrome by SEREX. Immunology,2005,116:53-63.
[30]Robert J,Oliver W,Autoantibody microarrays for biomarker discovery.Expert Rev.Proteomics,2007,4:261-272.
[31]Zhang ZJ, Lee CSY, Lider O, et al. Suppression of adjuvant arthritis in lewis rats by oral administration of type Ⅱ collegen. J Immunol,1990,145:2489-2493.
[32]Nussenblatt RB, Caspi RR, Mahdi R, et al. Inhibition. of S-antigen induced experimental autoimmune uveoretinitis by oral induction of tolerance with S-antigen. J Immunol,1990,144:1689-1695.
[33]Wang ZY, He B, Qiao J, et al. Suppression of experimental autoimmune myasthenia gravis and experimental allergic encephalomyelitis by oral administration of acetycholine receptor and myelin basic protein:double tolerance. J Neuroimmunol, 1995,63:79-86.
[34]Zhang ZJ, Davidson L, Eisenbarth G, et al. Suppression of diabetes in the NOD mouse by oral administration of porcine insulin. Proc Natl Acad Sci USA,1991, 88:10252-10256.
[35]Higgins PJ, Weiner HL. Suppression of experimental autoimmune encephalomyelitis by oral administration of myelin basic protein and its fragments. J Immunol,1988,140:440-445.
[36]Meyer Al, Benson JM, Gienapp LE, et al. Suppression of murine chronic relapsing experimental autoimmune encephalomyelitis by the oral administration of myelin basic protein. J Immunol,1996,157:4230-4238.
[37]Miller A, Lider O, Al-Sabbagh A, et al. Suppression of experimental autoimmune encephalomyelitis by oral administration of myelin basic protein. V. hierarchy of suppressionby myelin basic protein from different species. J neuroimmunol,1992,39:243-250.
[38]Whitacre CC, Gienapp IE, Meyer A, et al. Treatment of autoimmune diseases by oral tolerance to autoantigens. Clin Immunol Immunopathol,&nbs p;1996,80:31-37.
[39]Shi FD, Bai XF, Li HL, et al. Nasal tolerance in experimental autoimmune myasthenia gravis (EAMG):induction of protective tolerance in primed animals. clin Exp Immunol,1998,111:506-512.
[40]Whitacre CC, Gienapp IE, Orosz CG, et al. Oral tolerance in experimental autoimmune encephalomyelitis. J Immunol,1991,147:2155-2163.
[41]Johnson JG, Jenkins MK. The role of anergy in peripheral T cell unresponsiveness.Life Sci.1994,55:1767-1780.
[42]Evavold BD, Sloan-Lancaster J, Allen PM. Tickling the TCR:Selective T-cellfunctions stimulated by altered peptide ligands.Immunol. Todayl993,14: 602-609.
[43]Miller A, Lider O, Weiner HL. Antigen-driven bystander suppression after oral administration of antigens. J Exp Med,1991,174:791-798.
[44]Tisch R, Yang X-D, Singer SM, et al. Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice. Nature 1993,366: 72-75.
[45]Kaufman DL, Clare-Salzler M, Tian J, et al.Spontaneous loss of T-cell toleranceto glutamic acid decarboxylase in murine insulin-dependent diabetes. Nature 1993,366:69-72.
[46]Weiner HL, Zhang ZJ, Khoury SJ, et al. Antigen-driven peripheral immune tolerance. Ann NY Acad Sci,1991,636:227-232.
[47]Ma CG, Zhang GX, Xiao BG, et al. Suppression of experimental autoimmune myasthenia gravis by nasal administration of acaetylcholine receptor. J neuroimmunol, 1995,58:51-60.
[48]Ma CG, Zhang GX, Xiao BG, et al. Cellular mRNA expression of IFN-γ IL-4 and TGF-β in rat nasally tolerized against experimental autoimmune myasthenia gravis. Clin Exp Immunol,1996,104:509-517.
[49]Weiner HL, Mackin GA, Matsui M, et al. Double-blind pilot trial of tolerization with myelin antigens in multiple sclerosis. Science.1993,259:1321-1324.
[50]Weiner HL, Friedman A, Miller A, et al. Oral tolerance:Immunologic mechanisms and treatment of murine and human organ-specific autoimmune diseases by oral administration of autoantigens. Ann Rev Immunol,1994,12:809-837.
[51]Weiner HL. Oral tolerance:immune mechanisms and treatment of autoimmune diseases. Immunology Today,1997,18:335-343.
[52]Trentham DE, Dynesium-Trentham A, Orav EJ, et al. Effects of oral administratiion of type II collagen on rheumatoid arthritis. Science, 1993,261:1727-1730.
[53]Chatenoud L.Immune therapies of autoimmune diseases:are we approaching a real cure?Curr Opin Immunol.2006 10; 18(6):710-717.
[54]Snowden JA,Passweg J,Moore JJ,et al.Autologous hemopoietic stem cell transplantation in severe rheumatoid arthritis:a report from th EBMT and ABMTR.J Rheumatlo 2004,31:482-488.
[55]Fassas A,Passweg JR,Anagnostopoulos A,et al.Hematopoietic stem cell transplantation for ultiple sclerosis.A retrospective multicenter study.J Neurol 2002.249:1088-1097.
[56]Brennan FM,Chantry D,Jackson A,et al.Inhibitory effect of TNG Alpha antibodies on synovial cell interleukin-1 production in rheumatoid arthritis.Lancet 1989,2:244-247.
[57]Feldmann M.Development of anti-TNF Therapy for rheumatoid arthritis.Nat Rev Imunol 20002,2:364-371.
[58]Williams RO,feldmann M,Maini RN.Anti-tumor necrosis factor ameliorates joint disease in murine collagen-induced arthritis.Proc Natl Acad Sci USA 1992,89:9784-9788.
[59]Elliott MJ,Maini RN,Feldmann M,et al. Treatment of rheumatoid arthritis with chinmeric monoclonal antibodies to tumor necrosis factor alpha.Arhtritis Rheum 1993,36:1681-1690.
[60]Elliott MJ, Maini RN,Feldmann M,et al.Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis.Lancet 1994,344:1105-1110.
[61]Maini RN,St Clari EW,Breedveld F,et al.Infliximab (chimeric anti-tumor necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate:a randomized phase III trial.ATTRACT Study Group.Lancet 1999,354:1932-1939.
[62]Lipsky PE,van der Heijde D,St clair EW,et al.Infliximab and methotrexate in the treatment of rheumatoid arthritis.anti-tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study group.Rheumatoid Arthritis with therapy study group.N Engl J Med 2000,343:1594-1602.
[63]Boye J, Elter T, Engert A:An overview of the current clinical use of the anti-CD20 monoclonal antibody rituximab. Ann Oncol 2003,14:520-535.
[64]Riley JK, Sliwkowski MX:CD20:a gene in search of a function. Semin Oncol 2000, Suppl 12:17-24.
[65]Lonberg N, Huszar D:Human antibodies from transgenic mice.Int Rev Immunol 1995,13:65-93.
[66]Tedder TF, Isaacs CM:Isolation of cDNAs encoding the CD 19 antigen of human and mouse B lymphocytes. A new member of the immunoglobulin superfamily. J Immunol 1989,143:712-717.
[67]Loffler A, Kufer P, Lutterbuse R, et al.A recombinant bispecific single-chain antibody, CD19 x CD3, induces rapid and high lymphoma-directed cytotoxicity by unstimulated T lymphocytes. Blood 2000,95:2098-2103.
[68]Loffler A, Gruen M, Wuchter C, Schriever F, et al.Efficient elimination of chronic lymphocytic leukaemia B cells by autologous T cells with a bispecific anti-CD 19/anti-CD3 single-chain antibody construct. Leukemia 2003,17:900-909.
[69]Satterthwaite AB, Witte ON:The role of Bruton's tyrosine kinase in B-cell development and function:a genetic perspective.Immunol Rev 2000,175:120-127.
[70]Gold MR:To make antibodies or not:signaling by the B-cell antigen receptor. Trends Pharmacol Sci 2002,23:316-324.
[71]Niiro H, Clark EA:Regulation of B-cell fate by antigen-receptor signals. Nat Rev Immunol 2002,2:945-956.
[72]Tsukada S, Saffran DC, Rawlings DJ, Parolini O, Allen RC, KlisakI, Sparkes RS, Kubagawa H, Mohandas T, Quan S, Belmont W,Cooper MD, Conley ME, Witte ON: Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia.Cell 1993,72:279-290.
[73]Sato S, Ono N, Steeber DA, Pisetsky DS, Tedder TF:CD19 regulates B lymphocyte signaling thresholds critical for the development of B-1 lineage cells and autoimmunity. J Immunol 1996,157:4371-4378.
[74]Sato S, Hasegawa M, Fujimoto M, Tedder TF, Takehara K:Quantitative genetic variation in CD19 expression correlates with autoimmunity. J Immunol 2000, 165:6635-6643.
[75]Mackay F, Browning JL:BAFF:a fundamental survival factor for B cells. Nat Rev Immunol 2002,2:465-475.
[76]Mackay F, Mackay CR:The role of BAFF in B-cell maturation,T-cell activation and autoimmunity. Trend Immunol 2002,23:113-115.
[77]Mackay F, Woodcock SA, Lawton P, et al.Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations.J Exp Med 1999, 190:1697-1710.
[78]Khare SD, Sarosi I, Xia XZ, et al.Severe B cell hyperplasia and autoimmune disease in TALL-1 transgenic mice. Proc Natl Acad Sci USA 2000,97:3370-3375.
[79]Do RK, Hatada E, Lee H, Tourigny MR, Hilbert D, Chen-Kiang S:Attenuation of apoptosis underlies B lymphocyte stimulator enhancement of humoral immune response. J Exp Med 2000,192:953-964.
[80]Chaillous L, Lefevre H, Thivolet C, et al.Oral insulin administration and residual beta-cell function inrecent-onset type 1 diabetes:a multicentre randomized controlled trial. Diabete Insuline Orale group.Lancet 2000,356:545-549.
[81]Ergun-Longmire B, Marker J, Zeidler A, et al.Oral insulin therapy to prevent progression of immune-mediated(type 1) diabetes. Ann N Y Acad Sci 2004, 1029:260-277.
[82]Chatenoud L:CD3-specific antibody-induced active tolerance:from bench to bedside. Nat Rev Immunol 2003,3:123-132.
[83]Chatenoud L, Baudrihaye MF, Chkoff N, Kreis H, Goldstein G,Bach JF: Restriction of the human in vivo immune response against the mouse monoclonal antibody OKT3.J Immunol 1986,137:830-838.
[84]Abramowicz D, Schandene L, Goldman M, et al.Release of tumor necrosis factor, interleukin-2,and gamma-interferon in serum after injection of OKT3 monoclonal antibody in kidney transplant recipients.Transplantation 1989, 47:606-608.
[85]Alegre ML, Peterson LJ, Xu D, et al.A non-activating "humanized" anti-CD3 monoclonal antibody retains immunosuppressive properties in vivo. Transplantation 1994,57:1537-1543.
[86]Bolt S, Routledge E, Lloyd I, et al.The generation of a humanized, nonmitogenic CD3 monoclonal antibody which retains in vitro immunosuppressive properties. Eur J Immunol 1993,23:403-411.
[87]Chatenoud L:CD3-specific antibodies restore self-tolerance:mechanisms and clinical applications. Curr Opin Immunol 2005,17:632-637.
[88]Plain KM, Chen J, Merten S, He XY, Hall BM:Induction of specific tolerance to allografts in rats by therapy with non-mitogenic,non-depleting anti-CD3 monoclonal antibody:association with TH2 cytokines not anergy. Transplantation 1999,67:605-613.
[89]Belghith M, Bluestone JA, Barriot S, Megret J, Bach JF,Chatenoud L: TGF-beta-dependent mechanisms mediate restoration of self-tolerance induced by antibodies to CD3 in overt autoimmune diabetes. Nat Med 2003,9:1202-1208.
[90]Chatenoud L, Primo J, Bach JF:CD3 antibody-induced dominant self tolerance in overtly diabetic NOD mice.J Immunol 1997,158:2947-2954.
[91]Kohm AP, Williams JS, Bickford AL, et al.Treatment with non mitogenic anti-CD3 monoclonal antibody induces CD4+ T cell unresponsiveness and functional reversal of established experimental autoimmune encephalomyelitis. J Immunol 2005,174:4525-4534.
[92]Herold KC, Hagopian W, Auger JA, et al.Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med 2002,346:1692-1698.
[93]Herold KC, Gitelman SE, Masharani U, et al.A single course of anti-CD3 monoclonal antibody hOKT3g1 (Ala-Ala) results in improvement in C-peptide responses and clinical parameters for at least 2 years after onset of type 1 diabetes. Diabetes 2005,54:1763-1769.
[94]Keymeulen B, Vandemeulebroucke E, Ziegler AG, et al.Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med 2005, 352:2598-2608.
[95]Chatenoud L, Salomon B, Bluestone JA:Suppressor T cells —they're back and critical for regulation of autoimmunity!Immunol Rev 2001,182:149-163.
[96]Ochi H, Abraham M, Ishikawa H, et al.Oral CD3-specific antibody suppresses autoimmune encephalomyelitis by inducing CD4+CD25SLAP+ T cells. Nat Med 2006,12:627-635.
[97]Moreau T, Thorpe J, Miller D, et al.Preliminary evidence from magnetic resonance imaging for reduction in disease activity after lymphocyte depletion in multiple sclerosis Lancet 1994,344:298-301.
[98]Coles AJ, Wing MG, Smith S, et al.Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis. Lancet 1999,354:1691-1695.
[99]Miller DH, Khan OA, Sheremata WA, et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2003,348:15-23.
[100]Polman CH, O'Connor PW, Havrdova E, et al.A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006,354:899-910.
[101]Furst DE, Weisman M, Paulus HE, et al.Intravenous human recombinant tumor necrosis factor receptor p55-Fc IgGl fusion protein, Ro 45-2081 (lenercept):results of a dose-finding study in rheumatoid arthritis.J Rheumatol 2003,30:2123-2126.
[102]Moreland LW, Baumgartner SW, Schiff MH, et al.Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. N Engl J Med 1997,337:141-147.
[103]Klareskog L, Gaubitz M, Rodriguez-Valverde V, Malaise M,Dougados M, Wajdula J:A long-term, open-label trial of the safety and efficacy of etanercept (ENBREL(R)) in patients with rheumatoid arthritis not treated with other DMARDs (3-yearinterim report). Ann Rheum Dis 2006.
[104]den Broeder A, van de Putte L, Rau R, Set al.A single dose, placebo controlled study of the fully human anti-tumor necrosis factor-alpha antibody adalimumab (D2E7) in patients with rheumatoid arthritis.J Rheumatol 2002,29:2288-2298.
[105]Schiff MH, Burmester GR, Kent JD, Pangan AL, Kupper H,Fitzpatrick SB, Donovan C:Safety analyses of adalimumab (HUMIRA) in global clinical trials and US postmarketing surveillance of patients with rheumatoid arthritis. Ann Rheum Dis 2006,65:889-894.
[106]Isaacs JD, Watts RA, Hazleman BL, et al.Humanised monoclonal antibody therapy for rheumatoid arthritis. Lancet 1992,340:748-752.
[107]Kremer JM, Westhovens R, Leon M, et al.Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig.N Engl J Med 2003,349:1907-1915.
[108]Genovese MC, Becker JC, Schiff M, et al.Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med 2005,353:1114-1123.
[109]Moreland LW, Alten R, Van den Bosch F, et al.Costimulatory blockade in patients with rheumatoid arthritis:a pilot, dose-finding, double-blind, placebo-controlled clinical trial evaluating CTLA-4Ig and LEA29Y eighty-five days afterthe first infusion. Arthritis Rheum 2002,46:1470-1479.
[110]Fleischmann RM, Schechtman J, Bennett R, et al.Anakinra, a recombinant human interleukin-1 receptorantagonist (r-metHuIL-1ra), in patients with rheumatoid arthritis:a large, international, multicenter,placebo-controlled trial. Arthritis Rheum 2003,48:927-934.
[111]Fleischmann RM, Tesser J, Schiff M, et al.Safety of extended treatment with anakinra in patients with rheumatoid arthritis. Ann Rheum Dis 2006,65:1006-1012.
[112]Edwards JC, Szczepanski L, Szechinski J, et al.Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 2004, 350:2572-2581.
[113]Emery P, Fleischmann R, Filipowicz-Sosnowska A, et al.The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment:results of a phase ⅡB randomized, double-blind,placebo-controlled, dose-ranging trial. Arthritis Rheum 2006,54:1390-1400.
[114]Sigidin YA, Loukina GV, Skurkovich B, Skurkovich S:Randomized, double-blind trial of anti-interferon-gamma antibodies in rheumatoid arthritis. Scand J Rheumatol 2001,30:203-207.
[115]Lovell DJ, Giannini EH, Reiff A, Cawkwell GD, et al.Etanercept in children with polyarticular juvenile rheumatoid arthritis. Pediatric Rheumatology Collaborative Study Group.N Engl J Med 2000,342:763-769.
[116]Verbsky JW, White AJ:Effective use of the recombinant interleukin 1 receptor antagonist anakinra in therapy resistant systemic onset juvenile rheumatoid arthritis.J Rheumatol 2004,31:2071-2075.
[117]Leandro MJ, Cambridge G, Edwards JC, Ehrenstein MR,Isenberg DA:B-cell depletion in the treatment of patients with systemic lupus erythematosus:a longitudinal analysis of 24 patients. Rheumatology (Oxford) 2005,44:1542-1545.
[118]Looney RJ, Anolik J, Sanz I:B lymphocytes in systemic lupuserythematosus: lessons from therapy targeting B cells.Lupus 2004,13:381-390.
[119]Ostendorf B, Iking-Konert C, Kurz K, Jung G, Sander O,Schneider M: Preliminary results of safety and efficacy of the interleukin 1 receptor antagonist anakinra in patients with severe lupus arthritis. Ann Rheum Dis 2005,64:630-633.
[120]Boumpas DT, Furie R, Manzi S, et al.A short course of BG9588 (anti-CD40 ligand antibody) improves serologic activity and decreases hematuria in patients with proliferative lupus glomerulonephritis. Arthritis Rheum 2003,48:719-727.
[121]Davis JC Jr, Totoritis MC, Rosenberg J, Sklenar TA, Wofsy D:Phase I clinical trial of a monoclonal antibody against CD40-ligand (IDEC-131) in patients with systemic lupus erythematosus. J Rheumatol 2001,28:95-101.
[122]Kalunian KC, Davis JC Jr, Merrill JT, Totoritis. MC, Wofsy D:Treatment of systemic lupus erythematosus by inhibition of Tcell costimulation with anti-CD 154:a randomized, doubleblind,placebo-controlled trial. Arthritis Rheum 2002,46:3251-3258.
[123]Mease PJ, Goffe BS, Metz J, VanderStoep A, Finck B, Burge DJ:Etanercept in the treatment of psoriatic arthritis and psoriasis:a randomised trial. Lancet 2000, 356:385-390.
[124]Utset TO, Auger JA, Peace D, et al.Modified anti-CD3 therapy in psoriaticarthritis:a phase Ⅰ/Ⅱ clinical trial. J Rheumatol 2002,29:1907-1913.
[125]Reich K, Nestle FO, Papp K, et al.Infliximab induction and maintenance therapy for moderate-to-severe psoriasis:a phase III,multicentre, double-blind trial. Lancet 2005,66:1367-1374.
[126]Lebwohl M, Christophers E, Langley R, Ortonne JP, Roberts J,Griffiths CE:An international, randomized, double-blind,placebo-controlled phase 3 trial of intramuscular alefacept in patients with chronic plaque psoriasis. Arch Dermatol 2003,139:719-727.
[127]Tyring S, Gottlieb A, Papp K, et al.Etanercept and clinical outcomes, fatigue, and depression in psoriasis:double-blind placebo-controlled randomised phase III trial.Lancet 2006,367:29-35.
[128]Abrams JR, Lebwohl MG, Guzzo CA, et al.CTLA4Ig-mediated blockade of T-cell costimulation inpatients with psoriasis vulgaris. J Clin Invest 1999,103:1243-1252.
[129]Menter A, Kosinski M, Bresnahan BW, Papp KA, Ware JE Jr:Impact of efalizumab on psoriasis-specific patient-reported outcomes. Results from three randomized, placebocontrolled clinical trials of moderate to severe plaque psoriasis. J Drugs Dermatol 2004,3:27-38.
[130]Pariser DM, Gordon KB, Papp KA, et al.Clinical efficacy of efalizumab in patients with chronic plaque psoriasis:results from three randomized placebo-controlled phase Ⅲ trials:part Ⅰ. J Cutan Med Surg 2006.
[131]Mease PJ:Adalimumab:an anti-TNF agent for the treatment of psoriatic arthritis. Expert Opin Biol Ther 2005,5:1491-1504.
[132]Mathieson PW, Cobbold SP, Hale G, et al.Monoclonal-antibody therapy in systemic vasculitis. N Engl J Med 1990,323:250-254.
[133]Lockwood CM, Thiru S, Isaacs JD,et al.Long-term remission of intractable systemic vasculitis with monoclonal antibody therapy. Lancet 1993,341:1620-1622.
[134]Stasi R, Stipa E, Poeta GD, Amadori S, Newland AC, Provan D:Long-term observation of patients with anti-neutrophil cytoplasmic antibody-associated vasculitis treated with rituximab, Rheumatology (Oxford) 2006, in press.94. Nussenblatt RB:Bench to bedside:new approaches to theimmunotherapy of uveitic disease. Int Rev Immunol 2002,21:273-289.
[135]Present DH, Rutgeerts P, Targan S, et al. Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med 1999,340:1398-1405.
[136]Ghosh S, Goldin E, Gordon FH, et al.Natalizumab for active Crohn's disease. N Engl J Med 2003,348:24-32.