TLR4基因单核苷酸多态与云南汉族人群系统性红斑狼疮相关性研究
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摘要
背景:系统性红斑狼疮是一种以产生自身抗体和免疫复合物为特点的自身免疫性疾病,其病因复杂,是感染、基因及环境各因素间互作的结果。TLR4基因在免疫功能中有重要的作用,一旦被外源或内源性片段,如细菌脂多糖、热休克蛋白等配体所激活,即可通过信号转导激活核转录因子NF-κB,并表达多种细胞因子及趋化因子,是参与天然免疫应答和激活获得性免疫的重要因素。为探究TLR4基因与自身免疫性疾病的联系,我们此次在云南汉族人群中开展系统性红斑狼疮与TLR4基因的相关性研究。
材料与方法:553例系统性红斑狼疮病例及564例健康对照样本均采自昆明医学院第二附属医院。553例病例均符合1997年美国风湿病学会(ACR)对系统性红斑狼疮的修订诊断标准。采用PCR-RFLP和直接测序的方法对纳入研究样本的TLR4基因上3个单核苷酸多态位点(rs10759932,rs41426344,rs11536889)进行多态性检测。检测结果用SPSS11.5、Arelequin3.01、HaploView软件进行计算分析,并用logistic模型进行95%置信区间风险度测算。
结果:1)在病例和正常对照样本中,TLR4中3个位点均检测到多态性。2)单位点分析结果显示rs11536889位点的基因型、等位基因频率在病例和正常对照样本中无显著差异,提示这一位点与系统性红斑狼疮的发生不相关;3)rs41426344的GC杂合突变基因型,rs10759932位点的等位基因C以及CC纯合突变基因型、CT杂合突变基因型均为患病危险因素,提高系统性红斑狼疮患病的风险性(校正后p<0.05)。4)rs41426344位点无论在病例还是正常对照组中的等位基因G、C及基因型频率与HapMap中R24人群(6个高加索人、6个非洲裔美国人、6个亚洲人和6个美国旧金山海湾区的西班牙人)分布频率相近,说明此位点等位基因的分布在不同人群或地域中没有较大的区别;5)rs10759932位点在正常对照组中得到的T的频率比祖先来自于北欧或西欧的美国犹他州居民(CEU)人群低约40%;rs11536889位点等位基因G的分布频率很接近东亚日本人群,而比欧洲高加索人群低11.05%,比非洲约鲁巴人群低23.55%,这在一定程度上提示,这两个位点的等位基因频率分布可能存在一定的地域或人群差异。
结论:在云南汉族人群中,用病例—对照研究方法,对TLR4基因遗传多态与系统性红斑狼疮进行相关性研究,并对云南汉族人群中TLR4基因多态分布频率进行了统计分析,结果显示,TLR4基因上rs41426344和rs10759932位点的遗传多态性与系统性红斑狼疮的发生相关,TLR4基因中rs10759932和rs11536889位点表现出地域、人种的差异。
Background and aims: Systemic lupus erythematosus (SLE) is an autoimmune disorder with the feature of autoantibodies production to a multitude of self-antigens. It can cause tissue and organs injury, and lead to many severe complicating diseases. Toll-like receptors 4(TLR4) plays a key role in innate immune and adaptive immune responses. It is predominantly activated by exogenous and endogenous ligands such as bacterial lipopolysaccharides (LPS), heat shock protein, fragment of hyaluronic acid. Activation of TLR4 can leads to activation of nuclear transcription factor such as NF-κB and expression of various inflammatory cytokines, which are important factors to both innate and adaptive immune. The aim of our study is to investigate the association between TLR4 single nucleotide polymorphisms and SLE in Yunnan Han Population.
Methods: We recruited 553 SLE cases and 564 healthy controls from the Second Affiliated Hospital of Kunming Medical College. All samples are Han Population in Yunnan province and cases’diagnosis fulfilled the criteria of diagnostic guidelines draw up by America College of Rheumatology (ACR). We used polymerase chain reaction (PCR)-restriction fragment length polymerase (RFLP) and direct sequencing techniques to genotyping. The data is analysed by SPSS11.5, Arlequin 3.01, HaploView. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a logistic model.
Results: 1)3 SNPs of TLR4 were all observed polymorphisms. 2)The single-locus analysis of rs11536889 showed it has no relationship with SLE. 3) GC heterozygote of rs41426344 and CT heterozygote, CC homozygote and C allele of rs10759932 may be the risk factors of SLE (adjusted P <0.05). 4) The frequencies of genotype and allele of rs41426344 are very close to the R24 group (6 Caucasian, 6 African American, 6 Asian, 6 Hispanic recruited from San Francisco Bay Area) in HapMap, indicated that might there is no distinct diversity among different population as to the SNP of this site. 5) The frequency of T alellel of rs10759932 in our control group is about 40% less than the CEU population. The G allele frequency of rs11536889 are as the same with Japanese population, while it is 11.05% lower than Caucansian polulation and 23.55% less than Yoruba population. These results showed in a certain extant that these two SNPs distribute variably in different ethnic groups and regions.
Conclusion: This is the first time to analyse the relevance of TLR4 gene polymorphisms to SLE in Chinese Han Population in Yunnan Province. The present results show that TLR4 is a candidate gene related to SLE, and the TLR4 SNPs of rs41426344 and rs10759932 have been detected to be associated with SLE susceptibility. Moreover, the polymorphisms frequencies of TLR4 rs10759932 and rs11536889 are significant different among different ethnic groups.
材料与方法:553例系统性红斑狼疮病例及564例健康对照样本均采自昆明医学院第二附属医院。553例病例均符合1997年美国风湿病学会(ACR)对系统性红斑狼疮的修订诊断标准。采用PCR-RFLP和直接测序的方法对纳入研究样本的TLR4基因上3个单核苷酸多态位点(rs10759932,rs41426344,rs11536889)进行多态性检测。检测结果用SPSS11.5、Arelequin3.01、HaploView软件进行计算分析,并用logistic模型进行95%置信区间风险度测算。
结果:1)在病例和正常对照样本中,TLR4中3个位点均检测到多态性。2)单位点分析结果显示rs11536889位点的基因型、等位基因频率在病例和正常对照样本中无显著差异,提示这一位点与系统性红斑狼疮的发生不相关;3)rs41426344的GC杂合突变基因型,rs10759932位点的等位基因C以及CC纯合突变基因型、CT杂合突变基因型均为患病危险因素,提高系统性红斑狼疮患病的风险性(校正后p<0.05)。4)rs41426344位点无论在病例还是正常对照组中的等位基因G、C及基因型频率与HapMap中R24人群(6个高加索人、6个非洲裔美国人、6个亚洲人和6个美国旧金山海湾区的西班牙人)分布频率相近,说明此位点等位基因的分布在不同人群或地域中没有较大的区别;5)rs10759932位点在正常对照组中得到的T的频率比祖先来自于北欧或西欧的美国犹他州居民(CEU)人群低约40%;rs11536889位点等位基因G的分布频率很接近东亚日本人群,而比欧洲高加索人群低11.05%,比非洲约鲁巴人群低23.55%,这在一定程度上提示,这两个位点的等位基因频率分布可能存在一定的地域或人群差异。
结论:在云南汉族人群中,用病例—对照研究方法,对TLR4基因遗传多态与系统性红斑狼疮进行相关性研究,并对云南汉族人群中TLR4基因多态分布频率进行了统计分析,结果显示,TLR4基因上rs41426344和rs10759932位点的遗传多态性与系统性红斑狼疮的发生相关,TLR4基因中rs10759932和rs11536889位点表现出地域、人种的差异。
Background and aims: Systemic lupus erythematosus (SLE) is an autoimmune disorder with the feature of autoantibodies production to a multitude of self-antigens. It can cause tissue and organs injury, and lead to many severe complicating diseases. Toll-like receptors 4(TLR4) plays a key role in innate immune and adaptive immune responses. It is predominantly activated by exogenous and endogenous ligands such as bacterial lipopolysaccharides (LPS), heat shock protein, fragment of hyaluronic acid. Activation of TLR4 can leads to activation of nuclear transcription factor such as NF-κB and expression of various inflammatory cytokines, which are important factors to both innate and adaptive immune. The aim of our study is to investigate the association between TLR4 single nucleotide polymorphisms and SLE in Yunnan Han Population.
Methods: We recruited 553 SLE cases and 564 healthy controls from the Second Affiliated Hospital of Kunming Medical College. All samples are Han Population in Yunnan province and cases’diagnosis fulfilled the criteria of diagnostic guidelines draw up by America College of Rheumatology (ACR). We used polymerase chain reaction (PCR)-restriction fragment length polymerase (RFLP) and direct sequencing techniques to genotyping. The data is analysed by SPSS11.5, Arlequin 3.01, HaploView. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a logistic model.
Results: 1)3 SNPs of TLR4 were all observed polymorphisms. 2)The single-locus analysis of rs11536889 showed it has no relationship with SLE. 3) GC heterozygote of rs41426344 and CT heterozygote, CC homozygote and C allele of rs10759932 may be the risk factors of SLE (adjusted P <0.05). 4) The frequencies of genotype and allele of rs41426344 are very close to the R24 group (6 Caucasian, 6 African American, 6 Asian, 6 Hispanic recruited from San Francisco Bay Area) in HapMap, indicated that might there is no distinct diversity among different population as to the SNP of this site. 5) The frequency of T alellel of rs10759932 in our control group is about 40% less than the CEU population. The G allele frequency of rs11536889 are as the same with Japanese population, while it is 11.05% lower than Caucansian polulation and 23.55% less than Yoruba population. These results showed in a certain extant that these two SNPs distribute variably in different ethnic groups and regions.
Conclusion: This is the first time to analyse the relevance of TLR4 gene polymorphisms to SLE in Chinese Han Population in Yunnan Province. The present results show that TLR4 is a candidate gene related to SLE, and the TLR4 SNPs of rs41426344 and rs10759932 have been detected to be associated with SLE susceptibility. Moreover, the polymorphisms frequencies of TLR4 rs10759932 and rs11536889 are significant different among different ethnic groups.
引文
[1] J. Font, and R. Cervera, 1982 revised criteria for classification of systemic lupus erythematosus--ten years later. Lupus 2 (1993) 339-41; discussion 343.
[2]于孟学, (Ed.),现代风湿性疾病诊疗手册,中国协和医科大学出版社, 2000.
[3] J.N. Siegel, Development of an FDA guidance document for clinical trials in SLE. Lupus 8 (1999) 581-5.
[4]上海市免疫学研究所临床免疫研究室,系统性红斑狼疮流行病学调查-上海市纺织系统职工患病率初探.医学研究杂志08 (1985).
[5] T.M. Ermakova, L.A. Isaeva, and V.P. Gurbanov, [Systemic lupus erythematosus in adolescent monozygotic twins]. Vopr Revm 13 (1973) 32-7.
[6] T. Kuroda, T. Harada, Y. Wada, A. Oyanagi, Y. Ohfuchi, S. Murakami, S. Hirose, H. Hasegawa, M. Nakano, and F. Gejyo, Systemic lupus erythematosus in identical twins: a case report. Mod Rheumatol 15 (2005) 69-72.
[7] B. Rhodes, J. Meek, J.C. Whittaker, and T.J. Vyse, Quantification of the genetic component of basal C-reactive protein expression in SLE nuclear families. Ann Hum Genet 72 (2008) 611-20.
[8] K.J. Buckman, S.K. Moore, A.J. Ebbin, M.B. Cox, and E.L. Dubois, Familial systemic lupus erythematosus. Arch Intern Med 138 (1978) 1674-6.
[9] M.D. Mayes, Epidemiologic studies of environmental agents and systemic autoimmune diseases. Environ Health Perspect 107 Suppl 5 (1999) 743-8.
[10]叶.胡以松,系统性红斑狼疮发病的环境因素及其与几种趋化因子基因的交互作用.中华流行病学杂志Chinese Journal of Epidemilogy 11 (2004).
[11] A.D. Askanase, and J.P. Buyon, Reproductive health in SLE. Best Pract Res Clin Rheumatol 16 (2002) 265-80.
[12]叶冬青,陆伟,,系统性红斑狼疮HLA-DM基因与环境危险因素研究.中国卫生统计21 (2004).
[13] G. Mor, A. Munoz, R. Redlinger, Jr., I. Silva, J. Song, C. Lim, and F. Kohen, The role of the Fas/Fas ligand system in estrogen-induced thymic alteration. Am J Reprod Immunol 46 (2001) 298-307.
[14] B.S. Handwerger, V. Rus, L. da Silva, and C.S. Via, The role of cytokines in the immunopathogenesis of lupus. Springer Semin Immunopathol 16 (1994) 153-80.
[15] E.K. Marinova, D.B. Nikolova, D.N. Popova, G.B. Gallacher, and N.D. Ivanovska, Suppression of experimental autoimmune tubulointerstitial nephritis in BALB/c mice by berberine. Immunopharmacology 48 (2000) 9-16.
[16]樊.陈宏,雌激素及其受体在红斑狼疮发病中的作用.国际皮肤性病学杂志Int J Dermatol Venereol, November 32 (2006).
[17] Y.Y. Dhaher, B. Greenstein, E. de Fougerolles Nunn, M. Khamashta, and G.R. Hughes, Strain differences in binding properties of estrogen receptors in immature and adult BALB/c and MRL/MP-lpr/lpr mice, a model of systemic lupus erythematosus. Int J Immunopharmacol 22 (2000) 247-54.
[18] J.J. Stewart, Theory and treatment of the X-inactivation chimera in female-prevalent autoimmune disease. Arch Immunol Ther Exp (Warsz) 47 (1999) 355-9.
[19] T.H. Brix, G.P. Knudsen, M. Kristiansen, K.O. Kyvik, K.H. Orstavik, and L. Hegedus, High frequencyof skewed X-chromosome inactivation in females with autoimmune thyroid disease: a possible explanation for the female predisposition to thyroid autoimmunity. J Clin Endocrinol Metab 90 (2005) 5949-53.
[20] S.V. Kozyrev, A.K. Abelson, J. Wojcik, A. Zaghlool, M.V. Linga Reddy, E. Sanchez, I. Gunnarsson, E. Svenungsson, G. Sturfelt, A. Jonsen, L. Truedsson, B.A. Pons-Estel, T. Witte, S. D'Alfonso, N. Barizzone, M.G. Danieli, C. Gutierrez, A. Suarez, P. Junker, H. Laustrup, M.F. Gonzalez-Escribano, J. Martin, H. Abderrahim, and M.E. Alarcon-Riquelme, Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus. Nat Genet 40 (2008) 211-6.
[21] J.E. Salmon, S. Millard, L.A. Schachter, F.C. Arnett, E.M. Ginzler, M.F. Gourley, R. Ramsey-Goldman, M.G. Peterson, and R.P. Kimberly, Fc gamma RIIA alleles are heritable risk factors for lupus nephritis in African Americans. J Clin Invest 97 (1996) 1348-54.
[22] J.B. Harley, M.E. Alarcon-Riquelme, L.A. Criswell, C.O. Jacob, R.P. Kimberly, K.L. Moser, B.P. Tsao, T.J. Vyse, C.D. Langefeld, S.K. Nath, J.M. Guthridge, B.L. Cobb, D.B. Mirel, M.C. Marion, A.H. Williams, J. Divers, W. Wang, S.G. Frank, B. Namjou, S.B. Gabriel, A.T. Lee, P.K. Gregersen, T.W. Behrens, K.E. Taylor, M. Fernando, R. Zidovetzki, P.M. Gaffney, J.C. Edberg, J.D. Rioux, J.O. Ojwang, J.A. James, J.T. Merrill, G.S. Gilkeson, M.F. Seldin, H. Yin, E.C. Baechler, Q.Z. Li, E.K. Wakeland, G.R. Bruner, K.M. Kaufman, and J.A. Kelly, Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat Genet 40 (2008) 204-10.
[23] M. Michel, J.C. Piette, E. Roullet, F. Duron, C. Frances, L. Nahum, N. Pelletier, I. Crassard, S. Nunez, C. Michel, J. Bach, and E. Tournier-Lasserve, The R131 low-affinity allele of the Fc gamma RIIA receptor is associated with systemic lupus erythematosus but not with other autoimmune diseases in French Caucasians. Am J Med 108 (2000) 580-3.
[24] R. Zuniga, G.S. Markowitz, T. Arkachaisri, E.A. Imperatore, V.D. D'Agati, and J.E. Salmon, Identification of IgG subclasses and C-reactive protein in lupus nephritis: the relationship between the composition of immune deposits and FCgamma receptor type IIA alleles. Arthritis Rheum 48 (2003) 460-70.
[25]孙.沈南, FCGR2A基因多态性与系统性红斑狼疮相关性研究.中华风湿病学杂志Chin J Rheumatol 8 (2004).
[26] F.B. Karassa, T.A. Trikalinos, and J.P. Ioannidis, Role of the Fcgamma receptor IIa polymorphism in susceptibility to systemic lupus erythematosus and lupus nephritis: a meta-analysis. Arthritis Rheum 46 (2002) 1563-71.
[27] C.B. Foster, S. Zhu, H.C. Erichsen, T. Lehrnbecher, E.S. Hart, E. Choi, S. Stein, M.W. Smith, S.M. Steinberg, P. Imbach, T. Kuhne, and S.J. Chanock, Polymorphisms in inflammatory cytokines and Fcgamma receptors in childhood chronic immune thrombocytopenic purpura: a pilot study. Br J Haematol 113 (2001) 596-9.
[28] S.N. Yap, M.E. Phipps, M. Manivasagar, S.Y. Tan, and J.J. Bosco, Human Fc gamma receptor IIA (FcgammaRIIA) genotyping and association with systemic lupus erythematosus (SLE) in Chinese and Malays in Malaysia. Lupus 8 (1999) 305-10.
[29] Z.T. Chu, N. Tsuchiya, C. Kyogoku, J. Ohashi, Y.P. Qian, S.B. Xu, C.Z. Mao, J.Y. Chu, and K. Tokunaga, Association of Fcgamma receptor IIb polymorphism with susceptibility to systemic lupus erythematosus in Chinese: a common susceptibility gene in the Asian populations. Tissue Antigens 63 (2004) 21-7.
[30] L.J. Smyth, N. Snowden, D. Carthy, C. Papasteriades, A. Hajeer, and W.E. Ollier, Fc gamma RIIapolymorphism in systemic lupus erythematosus. Ann Rheum Dis 56 (1997) 744-6.
[31] M. Botto, E. Theodoridis, E.M. Thompson, H.L. Beynon, D. Briggs, D.A. Isenberg, M.J. Walport, and K.A. Davies, Fc gamma RIIa polymorphism in systemic lupus erythematosus (SLE): no association with disease. Clin Exp Immunol 104 (1996) 264-8.
[32] H. Mao, T.S. Ferguson, S.M. Cibulsky, M. Holmqvist, C. Ding, H. Fei, and I.B. Levitan, MONaKA, a novel modulator of the plasma membrane Na,K-ATPase. J Neurosci 25 (2005) 7934-43.
[33]张鑫,韩建文,, PXK基因多态性与汉族人系统性红斑狼疮易感性关联分析.
[34] G.J. Freeman, A.J. Long, Y. Iwai, K. Bourque, T. Chernova, H. Nishimura, L.J. Fitz, N. Malenkovich, T. Okazaki, M.C. Byrne, H.F. Horton, L. Fouser, L. Carter, V. Ling, M.R. Bowman, B.M. Carreno, M. Collins, C.R. Wood, and T. Honjo, Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 192 (2000) 1027-34.
[35]薛.夏敏,系统性红斑狼疮患儿PD-1分子的表达.临床儿科杂志Journal of Clinical Pediatrics 26 (2008).
[36] H. Nishimura, T. Honjo, and N. Minato, Facilitation of beta selection and modification of positive selection in the thymus of PD-1-deficient mice. J Exp Med 191 (2000) 891-8.
[37] R. Pullmann, Jr., J. Lukac, M. Skerenova, J. Rovensky, J. Hybenova, V. Melus, S. Celec, R. Pullmann, and R. Hyrdel, Association between systemic lupus erythematosus and insertion/deletion polymorphism of the angiotensin converting enzyme (ACE) gene. Clin Exp Rheumatol 17 (1999) 593-6.
[38] B. Rigat, C. Hubert, F. Alhenc-Gelas, F. Cambien, P. Corvol, and F. Soubrier, An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 86 (1990) 1343-6.
[39] S.K. Nath, S. Han, X. Kim-Howard, J.A. Kelly, P. Viswanathan, G.S. Gilkeson, W. Chen, C. Zhu, R.P. McEver, R.P. Kimberly, M.E. Alarcon-Riquelme, T.J. Vyse, Q.Z. Li, E.K. Wakeland, J.T. Merrill, J.A. James, K.M. Kaufman, J.M. Guthridge, and J.B. Harley, A nonsynonymous functional variant in integrin-alpha(M) (encoded by ITGAM) is associated with systemic lupus erythematosus. Nat Genet 40 (2008) 152-4.
[40] S. Han, X. Kim-Howard, H. Deshmukh, Y. Kamatani, P. Viswanathan, J.M. Guthridge, K. Thomas, K.M. Kaufman, J. Ojwang, A. Rojas-Villarraga, V. Baca, L. Orozco, B. Rhodes, C.B. Choi, P.K. Gregersen, J.T. Merrill, J.A. James, P.M. Gaffney, K.L. Moser, C.O. Jacob, R.P. Kimberly, J.B. Harley, S.C. Bae, J.M. Anaya, M.E. Alarcon-Riquelme, K. Matsuda, T.J. Vyse, and S.K. Nath, Evaluation of imputation-based association in and around the integrin-alpha-M (ITGAM) gene and replication of robust association between a non-synonymous functional variant within ITGAM and systemic lupus erythematosus (SLE). Hum Mol Genet 18 (2009) 1171-80.
[41] W. Yang, M. Zhao, N. Hirankarn, C.S. Lau, C.C. Mok, T.M. Chan, R.W. Wong, K.W. Lee, M.Y. Mok, S.N. Wong, Y. Avihingsanon, I.O. Lin, T.L. Lee, M.H. Ho, P.P. Lee, W.H. Wong, P.C. Sham, and Y.L. Lau, ITGAM is associated with disease susceptibility and renal nephritis of systemic lupus erythematosus in Hong Kong Chinese and Thai. Hum Mol Genet 18 (2009) 2063-70.
[42] K. Taga, H. Mostowski, and G. Tosato, Human interleukin-10 can directly inhibit T-cell growth. Blood 81 (1993) 2964-71.
[43]李.姚煦系统性红斑狼疮患者外周血单个核细胞白细胞介素10受体水平的研究.中华风湿病学杂志Chin J Rheumatol 9 (2005) 42-7.
[44]王.孙志达, ,南京医科大学学报, 2006, 26(9) : 7412 744 .系统性红斑狼疮患者血清中I L-10抑制抗原递呈细胞表面HLA2 DR和CD80的表达.南京医科大学学报26 (2006).
[45]王.姚婷MCSF、I L-10对单核细胞I L-12、I L-18产生及HLADR和CD80表达的影响.细胞与分子免疫学杂志20 (2004) 672-69
[46] L. Llorente, W. Zou, Y. Levy, Y. Richaud-Patin, J. Wijdenes, J. Alcocer-Varela, B. Morel-Fourrier, J.C. Brouet, D. Alarcon-Segovia, P. Galanaud, and D. Emilie, Role of interleukin 10 in the B lymphocyte hyperactivity and autoantibody production of human systemic lupus erythematosus. J Exp Med 181 (1995) 839-44.
[47] H. Ishida, T. Muchamuel, S. Sakaguchi, S. Andrade, S. Menon, and M. Howard, Continuous administration of anti-interleukin 10 antibodies delays onset of autoimmunity in NZB/W F1 mice. J Exp Med 179 (1994) 305-10.
[48]叶. .刘玲系统性红斑狼疮患者外周血单核细胞HLA-DR的表达和I L- 10水平的变化.中华风湿病学杂志Chin J RheumatolChinese Journal of Rheumatology 3 (2005).
[49] R.Y. Lin, M.E. Astiz, J.C. Saxon, D.C. Saha, and E.C. Rackow, Relationships between plasma cytokine concentrations and leukocyte functional antigen expression in patients with sepsis. Crit Care Med 22 (1994) 1595-602.
[50] E.R. Unanue, and P.M. Allen, The basis for the immunoregulatory role of macrophages and other accessory cells. Science 236 (1987) 551-7.
[51] A. Poltorak, X. He, I. Smirnova, M.Y. Liu, C. Van Huffel, X. Du, D. Birdwell, E. Alejos, M. Silva, C. Galanos, M. Freudenberg, P. Ricciardi-Castagnoli, B. Layton, and B. Beutler, Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282 (1998) 2085-8.
[52] B. Lemaitre, E. Nicolas, L. Michaut, J.M. Reichhart, and J.A. Hoffmann, The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86 (1996) 973-83.
[53] M.J. Williams, A. Rodriguez, D.A. Kimbrell, and E.D. Eldon, The 18-wheeler mutation reveals complex antibacterial gene regulation in Drosophila host defense. EMBO J 16 (1997) 6120-30.
[54] K.V. Anderson, Toll signaling pathways in the innate immune response. Curr Opin Immunol 12 (2000) 13-9.
[55] R. Medzhitov, P. Preston-Hurlburt, and C.A. Janeway, Jr., A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388 (1997) 394-7.
[56] S.T. Qureshi, L. Lariviere, G. Leveque, S. Clermont, K.J. Moore, P. Gros, and D. Malo, Endotoxin-tolerant mice have mutations in Toll-like receptor 4 (Tlr4). J Exp Med 189 (1999) 615-25.
[57] L. Kruglyak, Prospects for whole-genome linkage disequilibrium mapping of common disease genes. Nat Genet 22 (1999) 139-44.
[58] M. Cargill, D. Altshuler, J. Ireland, P. Sklar, K. Ardlie, N. Patil, N. Shaw, C.R. Lane, E.P. Lim, N. Kalyanaraman, J. Nemesh, L. Ziaugra, L. Friedland, A. Rolfe, J. Warrington, R. Lipshutz, G.Q. Daley, and E.S. Lander, Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nat Genet 22 (1999) 231-8.
[59] W.M. Howell, M. Jobs, U. Gyllensten, and A.J. Brookes, Dynamic allele-specific hybridization. A new method for scoring single nucleotide polymorphisms. Nat Biotechnol 17 (1999) 87-8.
[60] F.A. Eggerding, A one-step coupled amplification and oligonucleotide ligation procedure for multiplex genetic typing. PCR Methods Appl 4 (1995) 337-45.
[61] V. Lyamichev, A.L. Mast, J.G. Hall, J.R. Prudent, M.W. Kaiser, T. Takova, R.W. Kwiatkowski, T.J.Sander, M. de Arruda, D.A. Arco, B.P. Neri, and M.A. Brow, Polymorphism identification and quantitative detection of genomic DNA by invasive cleavage of oligonucleotide probes. Nat Biotechnol 17 (1999) 292-6.
[62] The International HapMap Project. Nature 426 (2003) 789-96.
[63] I. Cheng, S.J. Plummer, G. Casey, and J.S. Witte, Toll-like receptor 4 genetic variation and advanced prostate cancer risk. Cancer Epidemiol Biomarkers Prev 16 (2007) 352-5.
[64]张学军,刘树琴,红斑狼疮与自身免疫疾病,人民卫生出版社.
[65] N.C. Arbour, E. Lorenz, B.C. Schutte, J. Zabner, J.N. Kline, M. Jones, K. Frees, J.L. Watt, and D.A. Schwartz, TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet 25 (2000) 187-91.
[66] E. Lorenz, J.P. Mira, K.L. Frees, and D.A. Schwartz, Relevance of mutations in the TLR4 receptor in patients with gram-negative septic shock. Arch Intern Med 162 (2002) 1028-32.
[67] J.Q. Hang, S. Rajendran, Y. Yang, Y. Li, P.W. In, H. Overton, K.E. Parkes, N. Cammack, J.A. Martin, and K. Klumpp, Activity of the isolated HIV RNase H domain and specific inhibition by N-hydroxyimides. Biochem Biophys Res Commun 317 (2004) 321-9.
[68] X.H. Liang, W. Cheung, C.K. Heng, and D.Y. Wang, Absence of the toll-like receptor 4 gene polymorphisms Asp299Gly and Thr399Ile in Singaporean Chinese. Ther Clin Risk Manag 1 (2005) 243-6.
[69] B. Zheng, Q. Li, C. Wei, J. Qin, T. Shou, R. Zhou, J. Shao, Y. Yang, and C. Xiao, Lack of association of TLR4 gene Asp299Gly and Thr399Ile polymorphisms with rheumatoid arthritis in Chinese Han population of Yunnan Province. Rheumatol Int (2010).
[70] Z.X. Duan, P.F. Zhu, H. Dong, W. Gu, C. Yang, Q. Liu, Z.G. Wang, and J.X. Jiang, Functional significance of the TLR4/11367 polymorphism identified in Chinese Han population. Shock 28 (2007) 160-4.
[71] Q.S. Guo, B. Xia, Y. Jiang, S.A. Morre, L. Cheng, J. Li, J.B. Crusius, and A.S. Pena, Polymorphisms of CD14 gene and TLR4 gene are not associated with ulcerative colitis in Chinese patients. Postgrad Med J 81 (2005) 526-9.
[72] P.L. Cheng, H.L. Eng, M.H. Chou, H.L. You, and T.M. Lin, Genetic polymorphisms of viral infection-associated Toll-like receptors in Chinese population. Transl Res 150 (2007) 311-8.
[73] Y.C. Lin, Y.M. Chang, J.M. Yu, J.H. Yen, J.G. Chang, and C.J. Hu, Toll-like receptor 4 gene C119A but not Asp299Gly polymorphism is associated with ischemic stroke among ethnic Chinese in Taiwan. Atherosclerosis 180 (2005) 305-9.
[74] Y.S. Kim, Y.J. Hwang, S.Y. Kim, S.M. Yang, K.Y. Lee, and B. Park Ie, Rarity of TLR4 Asp299Gly and Thr399Ile polymorphisms in the Korean population. Yonsei Med J 49 (2008) 58-62.
[75] F.P. Mockenhaupt, J.P. Cramer, L. Hamann, M.S. Stegemann, J. Eckert, N.R. Oh, R.N. Otchwemah, E. Dietz, S. Ehrhardt, N.W. Schroder, U. Bienzle, and R.R. Schumann, Toll-like receptor (TLR) polymorphisms in African children: Common TLR-4 variants predispose to severe malaria. Proc Natl Acad Sci U S A 103 (2006) 177-82.
[76] A. Carvalho, A. Marques, P. Maciel, and F. Rodrigues, Study of disease-relevant polymorphisms in the TLR4 and TLR9 genes: a novel method applied to the analysis of the Portuguese population. Mol Cell Probes 21 (2007) 316-20.
[77] W. Koch, P. Hoppmann, A. Pfeufer, A. Schomig, and A. Kastrati, Toll-like receptor 4 gene polymorphisms and myocardial infarction: no association in a Caucasian population. Eur Heart J 27 (2006) 2524-9.
[78] J. Hang, W. Zhou, H. Zhang, B. Sun, H. Dai, L. Su, and D.C. Christiani, TLR4 Asp299Gly and Thr399Ile polymorphisms are very rare in the Chinese population. J Endotoxin Res 10 (2004) 238-40.
[79] A.A. Awomoyi, P. Rallabhandi, T.I. Pollin, E. Lorenz, M.B. Sztein, M.S. Boukhvalova, V.G. Hemming, J.C. Blanco, and S.N. Vogel, Association of TLR4 polymorphisms with symptomatic respiratory syncytial virus infection in high-risk infants and young children. J Immunol 179 (2007) 3171-7.
[80] E.S. Kang, and J. Lee, Genotypic analysis of Asp299Gly and Thr399Ile polymorphism of Toll-like receptor 4 in systemic autoimmune diseases of Korean population. Rheumatol Int 27 (2007) 887-9.
[81] R.P. Jansen, mRNA localization: message on the move. Nat Rev Mol Cell Biol 2 (2001) 247-56.
[82] D. Curtis, R. Lehmann, and P.D. Zamore, Translational regulation in development. Cell 81 (1995) 171-8.
[83] N. Sonenberg, mRNA translation: influence of the 5' and 3' untranslated regions. Curr Opin Genet Dev 4 (1994) 310-5.
[84] P. Macdonald, Diversity in translational regulation. Curr Opin Cell Biol 13 (2001) 326-31.
[85] A. Bashirullah, R.L. Cooperstock, and H.D. Lipshitz, RNA localization in development. Annu Rev Biochem 67 (1998) 335-94.
[86] D. St Johnston, The intracellular localization of messenger RNAs. Cell 81 (1995) 161-70.
[87] G. Pesole, S. Liuni, G. Grillo, F. Licciulli, F. Mignone, C. Gissi, and C. Saccone, UTRdb and UTRsite: specialized databases of sequences and functional elements of 5' and 3' untranslated regions of eukaryotic mRNAs. Update 2002. Nucleic Acids Res 30 (2002) 335-40.
[88] C.J. Decker, and R. Parker, Mechanisms of mRNA degradation in eukaryotes. Trends Biochem Sci 19 (1994) 336-40.
[89] C.A. Beelman, and R. Parker, Degradation of mRNA in eukaryotes. Cell 81 (1995) 179-83.
[90] S. Banus, R.W. Bottema, C.L. Siezen, R.J. Vandebriel, J. Reimerink, M. Mommers, G.H. Koppelman, B. Hoebee, C. Thijs, D.S. Postma, T.G. Kimman, and F.F. Stelma, Toll-like receptor 4 polymorphism associated with the response to whole-cell pertussis vaccination in children from the KOALA study. Clin Vaccine Immunol 14 (2007) 1377-80.
[91] Y.H. Hwang, H. Ro, I. Choi, H. Kim, K.H. Oh, J.I. Hwang, M.H. Park, S. Kim, J. Yang, and C. Ahn, Impact of polymorphisms of TLR4/CD14 and TLR3 on acute rejection in kidney transplantation. Transplantation 88 (2009) 699-705.
[92] L. Excoffier, and M. Slatkin, Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. Mol Biol Evol 12 (1995) 921-7.
[93] G.C. Johnson, L. Esposito, B.J. Barratt, A.N. Smith, J. Heward, G. Di Genova, H. Ueda, H.J. Cordell, I.A. Eaves, F. Dudbridge, R.C. Twells, F. Payne, W. Hughes, S. Nutland, H. Stevens, P. Carr, E. Tuomilehto-Wolf, J. Tuomilehto, S.C. Gough, D.G. Clayton, and J.A. Todd, Haplotype tagging for the identification of common disease genes. Nat Genet 29 (2001) 233-7.
[2]于孟学, (Ed.),现代风湿性疾病诊疗手册,中国协和医科大学出版社, 2000.
[3] J.N. Siegel, Development of an FDA guidance document for clinical trials in SLE. Lupus 8 (1999) 581-5.
[4]上海市免疫学研究所临床免疫研究室,系统性红斑狼疮流行病学调查-上海市纺织系统职工患病率初探.医学研究杂志08 (1985).
[5] T.M. Ermakova, L.A. Isaeva, and V.P. Gurbanov, [Systemic lupus erythematosus in adolescent monozygotic twins]. Vopr Revm 13 (1973) 32-7.
[6] T. Kuroda, T. Harada, Y. Wada, A. Oyanagi, Y. Ohfuchi, S. Murakami, S. Hirose, H. Hasegawa, M. Nakano, and F. Gejyo, Systemic lupus erythematosus in identical twins: a case report. Mod Rheumatol 15 (2005) 69-72.
[7] B. Rhodes, J. Meek, J.C. Whittaker, and T.J. Vyse, Quantification of the genetic component of basal C-reactive protein expression in SLE nuclear families. Ann Hum Genet 72 (2008) 611-20.
[8] K.J. Buckman, S.K. Moore, A.J. Ebbin, M.B. Cox, and E.L. Dubois, Familial systemic lupus erythematosus. Arch Intern Med 138 (1978) 1674-6.
[9] M.D. Mayes, Epidemiologic studies of environmental agents and systemic autoimmune diseases. Environ Health Perspect 107 Suppl 5 (1999) 743-8.
[10]叶.胡以松,系统性红斑狼疮发病的环境因素及其与几种趋化因子基因的交互作用.中华流行病学杂志Chinese Journal of Epidemilogy 11 (2004).
[11] A.D. Askanase, and J.P. Buyon, Reproductive health in SLE. Best Pract Res Clin Rheumatol 16 (2002) 265-80.
[12]叶冬青,陆伟,,系统性红斑狼疮HLA-DM基因与环境危险因素研究.中国卫生统计21 (2004).
[13] G. Mor, A. Munoz, R. Redlinger, Jr., I. Silva, J. Song, C. Lim, and F. Kohen, The role of the Fas/Fas ligand system in estrogen-induced thymic alteration. Am J Reprod Immunol 46 (2001) 298-307.
[14] B.S. Handwerger, V. Rus, L. da Silva, and C.S. Via, The role of cytokines in the immunopathogenesis of lupus. Springer Semin Immunopathol 16 (1994) 153-80.
[15] E.K. Marinova, D.B. Nikolova, D.N. Popova, G.B. Gallacher, and N.D. Ivanovska, Suppression of experimental autoimmune tubulointerstitial nephritis in BALB/c mice by berberine. Immunopharmacology 48 (2000) 9-16.
[16]樊.陈宏,雌激素及其受体在红斑狼疮发病中的作用.国际皮肤性病学杂志Int J Dermatol Venereol, November 32 (2006).
[17] Y.Y. Dhaher, B. Greenstein, E. de Fougerolles Nunn, M. Khamashta, and G.R. Hughes, Strain differences in binding properties of estrogen receptors in immature and adult BALB/c and MRL/MP-lpr/lpr mice, a model of systemic lupus erythematosus. Int J Immunopharmacol 22 (2000) 247-54.
[18] J.J. Stewart, Theory and treatment of the X-inactivation chimera in female-prevalent autoimmune disease. Arch Immunol Ther Exp (Warsz) 47 (1999) 355-9.
[19] T.H. Brix, G.P. Knudsen, M. Kristiansen, K.O. Kyvik, K.H. Orstavik, and L. Hegedus, High frequencyof skewed X-chromosome inactivation in females with autoimmune thyroid disease: a possible explanation for the female predisposition to thyroid autoimmunity. J Clin Endocrinol Metab 90 (2005) 5949-53.
[20] S.V. Kozyrev, A.K. Abelson, J. Wojcik, A. Zaghlool, M.V. Linga Reddy, E. Sanchez, I. Gunnarsson, E. Svenungsson, G. Sturfelt, A. Jonsen, L. Truedsson, B.A. Pons-Estel, T. Witte, S. D'Alfonso, N. Barizzone, M.G. Danieli, C. Gutierrez, A. Suarez, P. Junker, H. Laustrup, M.F. Gonzalez-Escribano, J. Martin, H. Abderrahim, and M.E. Alarcon-Riquelme, Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus. Nat Genet 40 (2008) 211-6.
[21] J.E. Salmon, S. Millard, L.A. Schachter, F.C. Arnett, E.M. Ginzler, M.F. Gourley, R. Ramsey-Goldman, M.G. Peterson, and R.P. Kimberly, Fc gamma RIIA alleles are heritable risk factors for lupus nephritis in African Americans. J Clin Invest 97 (1996) 1348-54.
[22] J.B. Harley, M.E. Alarcon-Riquelme, L.A. Criswell, C.O. Jacob, R.P. Kimberly, K.L. Moser, B.P. Tsao, T.J. Vyse, C.D. Langefeld, S.K. Nath, J.M. Guthridge, B.L. Cobb, D.B. Mirel, M.C. Marion, A.H. Williams, J. Divers, W. Wang, S.G. Frank, B. Namjou, S.B. Gabriel, A.T. Lee, P.K. Gregersen, T.W. Behrens, K.E. Taylor, M. Fernando, R. Zidovetzki, P.M. Gaffney, J.C. Edberg, J.D. Rioux, J.O. Ojwang, J.A. James, J.T. Merrill, G.S. Gilkeson, M.F. Seldin, H. Yin, E.C. Baechler, Q.Z. Li, E.K. Wakeland, G.R. Bruner, K.M. Kaufman, and J.A. Kelly, Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat Genet 40 (2008) 204-10.
[23] M. Michel, J.C. Piette, E. Roullet, F. Duron, C. Frances, L. Nahum, N. Pelletier, I. Crassard, S. Nunez, C. Michel, J. Bach, and E. Tournier-Lasserve, The R131 low-affinity allele of the Fc gamma RIIA receptor is associated with systemic lupus erythematosus but not with other autoimmune diseases in French Caucasians. Am J Med 108 (2000) 580-3.
[24] R. Zuniga, G.S. Markowitz, T. Arkachaisri, E.A. Imperatore, V.D. D'Agati, and J.E. Salmon, Identification of IgG subclasses and C-reactive protein in lupus nephritis: the relationship between the composition of immune deposits and FCgamma receptor type IIA alleles. Arthritis Rheum 48 (2003) 460-70.
[25]孙.沈南, FCGR2A基因多态性与系统性红斑狼疮相关性研究.中华风湿病学杂志Chin J Rheumatol 8 (2004).
[26] F.B. Karassa, T.A. Trikalinos, and J.P. Ioannidis, Role of the Fcgamma receptor IIa polymorphism in susceptibility to systemic lupus erythematosus and lupus nephritis: a meta-analysis. Arthritis Rheum 46 (2002) 1563-71.
[27] C.B. Foster, S. Zhu, H.C. Erichsen, T. Lehrnbecher, E.S. Hart, E. Choi, S. Stein, M.W. Smith, S.M. Steinberg, P. Imbach, T. Kuhne, and S.J. Chanock, Polymorphisms in inflammatory cytokines and Fcgamma receptors in childhood chronic immune thrombocytopenic purpura: a pilot study. Br J Haematol 113 (2001) 596-9.
[28] S.N. Yap, M.E. Phipps, M. Manivasagar, S.Y. Tan, and J.J. Bosco, Human Fc gamma receptor IIA (FcgammaRIIA) genotyping and association with systemic lupus erythematosus (SLE) in Chinese and Malays in Malaysia. Lupus 8 (1999) 305-10.
[29] Z.T. Chu, N. Tsuchiya, C. Kyogoku, J. Ohashi, Y.P. Qian, S.B. Xu, C.Z. Mao, J.Y. Chu, and K. Tokunaga, Association of Fcgamma receptor IIb polymorphism with susceptibility to systemic lupus erythematosus in Chinese: a common susceptibility gene in the Asian populations. Tissue Antigens 63 (2004) 21-7.
[30] L.J. Smyth, N. Snowden, D. Carthy, C. Papasteriades, A. Hajeer, and W.E. Ollier, Fc gamma RIIapolymorphism in systemic lupus erythematosus. Ann Rheum Dis 56 (1997) 744-6.
[31] M. Botto, E. Theodoridis, E.M. Thompson, H.L. Beynon, D. Briggs, D.A. Isenberg, M.J. Walport, and K.A. Davies, Fc gamma RIIa polymorphism in systemic lupus erythematosus (SLE): no association with disease. Clin Exp Immunol 104 (1996) 264-8.
[32] H. Mao, T.S. Ferguson, S.M. Cibulsky, M. Holmqvist, C. Ding, H. Fei, and I.B. Levitan, MONaKA, a novel modulator of the plasma membrane Na,K-ATPase. J Neurosci 25 (2005) 7934-43.
[33]张鑫,韩建文,, PXK基因多态性与汉族人系统性红斑狼疮易感性关联分析.
[34] G.J. Freeman, A.J. Long, Y. Iwai, K. Bourque, T. Chernova, H. Nishimura, L.J. Fitz, N. Malenkovich, T. Okazaki, M.C. Byrne, H.F. Horton, L. Fouser, L. Carter, V. Ling, M.R. Bowman, B.M. Carreno, M. Collins, C.R. Wood, and T. Honjo, Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 192 (2000) 1027-34.
[35]薛.夏敏,系统性红斑狼疮患儿PD-1分子的表达.临床儿科杂志Journal of Clinical Pediatrics 26 (2008).
[36] H. Nishimura, T. Honjo, and N. Minato, Facilitation of beta selection and modification of positive selection in the thymus of PD-1-deficient mice. J Exp Med 191 (2000) 891-8.
[37] R. Pullmann, Jr., J. Lukac, M. Skerenova, J. Rovensky, J. Hybenova, V. Melus, S. Celec, R. Pullmann, and R. Hyrdel, Association between systemic lupus erythematosus and insertion/deletion polymorphism of the angiotensin converting enzyme (ACE) gene. Clin Exp Rheumatol 17 (1999) 593-6.
[38] B. Rigat, C. Hubert, F. Alhenc-Gelas, F. Cambien, P. Corvol, and F. Soubrier, An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 86 (1990) 1343-6.
[39] S.K. Nath, S. Han, X. Kim-Howard, J.A. Kelly, P. Viswanathan, G.S. Gilkeson, W. Chen, C. Zhu, R.P. McEver, R.P. Kimberly, M.E. Alarcon-Riquelme, T.J. Vyse, Q.Z. Li, E.K. Wakeland, J.T. Merrill, J.A. James, K.M. Kaufman, J.M. Guthridge, and J.B. Harley, A nonsynonymous functional variant in integrin-alpha(M) (encoded by ITGAM) is associated with systemic lupus erythematosus. Nat Genet 40 (2008) 152-4.
[40] S. Han, X. Kim-Howard, H. Deshmukh, Y. Kamatani, P. Viswanathan, J.M. Guthridge, K. Thomas, K.M. Kaufman, J. Ojwang, A. Rojas-Villarraga, V. Baca, L. Orozco, B. Rhodes, C.B. Choi, P.K. Gregersen, J.T. Merrill, J.A. James, P.M. Gaffney, K.L. Moser, C.O. Jacob, R.P. Kimberly, J.B. Harley, S.C. Bae, J.M. Anaya, M.E. Alarcon-Riquelme, K. Matsuda, T.J. Vyse, and S.K. Nath, Evaluation of imputation-based association in and around the integrin-alpha-M (ITGAM) gene and replication of robust association between a non-synonymous functional variant within ITGAM and systemic lupus erythematosus (SLE). Hum Mol Genet 18 (2009) 1171-80.
[41] W. Yang, M. Zhao, N. Hirankarn, C.S. Lau, C.C. Mok, T.M. Chan, R.W. Wong, K.W. Lee, M.Y. Mok, S.N. Wong, Y. Avihingsanon, I.O. Lin, T.L. Lee, M.H. Ho, P.P. Lee, W.H. Wong, P.C. Sham, and Y.L. Lau, ITGAM is associated with disease susceptibility and renal nephritis of systemic lupus erythematosus in Hong Kong Chinese and Thai. Hum Mol Genet 18 (2009) 2063-70.
[42] K. Taga, H. Mostowski, and G. Tosato, Human interleukin-10 can directly inhibit T-cell growth. Blood 81 (1993) 2964-71.
[43]李.姚煦系统性红斑狼疮患者外周血单个核细胞白细胞介素10受体水平的研究.中华风湿病学杂志Chin J Rheumatol 9 (2005) 42-7.
[44]王.孙志达, ,南京医科大学学报, 2006, 26(9) : 7412 744 .系统性红斑狼疮患者血清中I L-10抑制抗原递呈细胞表面HLA2 DR和CD80的表达.南京医科大学学报26 (2006).
[45]王.姚婷MCSF、I L-10对单核细胞I L-12、I L-18产生及HLADR和CD80表达的影响.细胞与分子免疫学杂志20 (2004) 672-69
[46] L. Llorente, W. Zou, Y. Levy, Y. Richaud-Patin, J. Wijdenes, J. Alcocer-Varela, B. Morel-Fourrier, J.C. Brouet, D. Alarcon-Segovia, P. Galanaud, and D. Emilie, Role of interleukin 10 in the B lymphocyte hyperactivity and autoantibody production of human systemic lupus erythematosus. J Exp Med 181 (1995) 839-44.
[47] H. Ishida, T. Muchamuel, S. Sakaguchi, S. Andrade, S. Menon, and M. Howard, Continuous administration of anti-interleukin 10 antibodies delays onset of autoimmunity in NZB/W F1 mice. J Exp Med 179 (1994) 305-10.
[48]叶. .刘玲系统性红斑狼疮患者外周血单核细胞HLA-DR的表达和I L- 10水平的变化.中华风湿病学杂志Chin J RheumatolChinese Journal of Rheumatology 3 (2005).
[49] R.Y. Lin, M.E. Astiz, J.C. Saxon, D.C. Saha, and E.C. Rackow, Relationships between plasma cytokine concentrations and leukocyte functional antigen expression in patients with sepsis. Crit Care Med 22 (1994) 1595-602.
[50] E.R. Unanue, and P.M. Allen, The basis for the immunoregulatory role of macrophages and other accessory cells. Science 236 (1987) 551-7.
[51] A. Poltorak, X. He, I. Smirnova, M.Y. Liu, C. Van Huffel, X. Du, D. Birdwell, E. Alejos, M. Silva, C. Galanos, M. Freudenberg, P. Ricciardi-Castagnoli, B. Layton, and B. Beutler, Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282 (1998) 2085-8.
[52] B. Lemaitre, E. Nicolas, L. Michaut, J.M. Reichhart, and J.A. Hoffmann, The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86 (1996) 973-83.
[53] M.J. Williams, A. Rodriguez, D.A. Kimbrell, and E.D. Eldon, The 18-wheeler mutation reveals complex antibacterial gene regulation in Drosophila host defense. EMBO J 16 (1997) 6120-30.
[54] K.V. Anderson, Toll signaling pathways in the innate immune response. Curr Opin Immunol 12 (2000) 13-9.
[55] R. Medzhitov, P. Preston-Hurlburt, and C.A. Janeway, Jr., A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388 (1997) 394-7.
[56] S.T. Qureshi, L. Lariviere, G. Leveque, S. Clermont, K.J. Moore, P. Gros, and D. Malo, Endotoxin-tolerant mice have mutations in Toll-like receptor 4 (Tlr4). J Exp Med 189 (1999) 615-25.
[57] L. Kruglyak, Prospects for whole-genome linkage disequilibrium mapping of common disease genes. Nat Genet 22 (1999) 139-44.
[58] M. Cargill, D. Altshuler, J. Ireland, P. Sklar, K. Ardlie, N. Patil, N. Shaw, C.R. Lane, E.P. Lim, N. Kalyanaraman, J. Nemesh, L. Ziaugra, L. Friedland, A. Rolfe, J. Warrington, R. Lipshutz, G.Q. Daley, and E.S. Lander, Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nat Genet 22 (1999) 231-8.
[59] W.M. Howell, M. Jobs, U. Gyllensten, and A.J. Brookes, Dynamic allele-specific hybridization. A new method for scoring single nucleotide polymorphisms. Nat Biotechnol 17 (1999) 87-8.
[60] F.A. Eggerding, A one-step coupled amplification and oligonucleotide ligation procedure for multiplex genetic typing. PCR Methods Appl 4 (1995) 337-45.
[61] V. Lyamichev, A.L. Mast, J.G. Hall, J.R. Prudent, M.W. Kaiser, T. Takova, R.W. Kwiatkowski, T.J.Sander, M. de Arruda, D.A. Arco, B.P. Neri, and M.A. Brow, Polymorphism identification and quantitative detection of genomic DNA by invasive cleavage of oligonucleotide probes. Nat Biotechnol 17 (1999) 292-6.
[62] The International HapMap Project. Nature 426 (2003) 789-96.
[63] I. Cheng, S.J. Plummer, G. Casey, and J.S. Witte, Toll-like receptor 4 genetic variation and advanced prostate cancer risk. Cancer Epidemiol Biomarkers Prev 16 (2007) 352-5.
[64]张学军,刘树琴,红斑狼疮与自身免疫疾病,人民卫生出版社.
[65] N.C. Arbour, E. Lorenz, B.C. Schutte, J. Zabner, J.N. Kline, M. Jones, K. Frees, J.L. Watt, and D.A. Schwartz, TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet 25 (2000) 187-91.
[66] E. Lorenz, J.P. Mira, K.L. Frees, and D.A. Schwartz, Relevance of mutations in the TLR4 receptor in patients with gram-negative septic shock. Arch Intern Med 162 (2002) 1028-32.
[67] J.Q. Hang, S. Rajendran, Y. Yang, Y. Li, P.W. In, H. Overton, K.E. Parkes, N. Cammack, J.A. Martin, and K. Klumpp, Activity of the isolated HIV RNase H domain and specific inhibition by N-hydroxyimides. Biochem Biophys Res Commun 317 (2004) 321-9.
[68] X.H. Liang, W. Cheung, C.K. Heng, and D.Y. Wang, Absence of the toll-like receptor 4 gene polymorphisms Asp299Gly and Thr399Ile in Singaporean Chinese. Ther Clin Risk Manag 1 (2005) 243-6.
[69] B. Zheng, Q. Li, C. Wei, J. Qin, T. Shou, R. Zhou, J. Shao, Y. Yang, and C. Xiao, Lack of association of TLR4 gene Asp299Gly and Thr399Ile polymorphisms with rheumatoid arthritis in Chinese Han population of Yunnan Province. Rheumatol Int (2010).
[70] Z.X. Duan, P.F. Zhu, H. Dong, W. Gu, C. Yang, Q. Liu, Z.G. Wang, and J.X. Jiang, Functional significance of the TLR4/11367 polymorphism identified in Chinese Han population. Shock 28 (2007) 160-4.
[71] Q.S. Guo, B. Xia, Y. Jiang, S.A. Morre, L. Cheng, J. Li, J.B. Crusius, and A.S. Pena, Polymorphisms of CD14 gene and TLR4 gene are not associated with ulcerative colitis in Chinese patients. Postgrad Med J 81 (2005) 526-9.
[72] P.L. Cheng, H.L. Eng, M.H. Chou, H.L. You, and T.M. Lin, Genetic polymorphisms of viral infection-associated Toll-like receptors in Chinese population. Transl Res 150 (2007) 311-8.
[73] Y.C. Lin, Y.M. Chang, J.M. Yu, J.H. Yen, J.G. Chang, and C.J. Hu, Toll-like receptor 4 gene C119A but not Asp299Gly polymorphism is associated with ischemic stroke among ethnic Chinese in Taiwan. Atherosclerosis 180 (2005) 305-9.
[74] Y.S. Kim, Y.J. Hwang, S.Y. Kim, S.M. Yang, K.Y. Lee, and B. Park Ie, Rarity of TLR4 Asp299Gly and Thr399Ile polymorphisms in the Korean population. Yonsei Med J 49 (2008) 58-62.
[75] F.P. Mockenhaupt, J.P. Cramer, L. Hamann, M.S. Stegemann, J. Eckert, N.R. Oh, R.N. Otchwemah, E. Dietz, S. Ehrhardt, N.W. Schroder, U. Bienzle, and R.R. Schumann, Toll-like receptor (TLR) polymorphisms in African children: Common TLR-4 variants predispose to severe malaria. Proc Natl Acad Sci U S A 103 (2006) 177-82.
[76] A. Carvalho, A. Marques, P. Maciel, and F. Rodrigues, Study of disease-relevant polymorphisms in the TLR4 and TLR9 genes: a novel method applied to the analysis of the Portuguese population. Mol Cell Probes 21 (2007) 316-20.
[77] W. Koch, P. Hoppmann, A. Pfeufer, A. Schomig, and A. Kastrati, Toll-like receptor 4 gene polymorphisms and myocardial infarction: no association in a Caucasian population. Eur Heart J 27 (2006) 2524-9.
[78] J. Hang, W. Zhou, H. Zhang, B. Sun, H. Dai, L. Su, and D.C. Christiani, TLR4 Asp299Gly and Thr399Ile polymorphisms are very rare in the Chinese population. J Endotoxin Res 10 (2004) 238-40.
[79] A.A. Awomoyi, P. Rallabhandi, T.I. Pollin, E. Lorenz, M.B. Sztein, M.S. Boukhvalova, V.G. Hemming, J.C. Blanco, and S.N. Vogel, Association of TLR4 polymorphisms with symptomatic respiratory syncytial virus infection in high-risk infants and young children. J Immunol 179 (2007) 3171-7.
[80] E.S. Kang, and J. Lee, Genotypic analysis of Asp299Gly and Thr399Ile polymorphism of Toll-like receptor 4 in systemic autoimmune diseases of Korean population. Rheumatol Int 27 (2007) 887-9.
[81] R.P. Jansen, mRNA localization: message on the move. Nat Rev Mol Cell Biol 2 (2001) 247-56.
[82] D. Curtis, R. Lehmann, and P.D. Zamore, Translational regulation in development. Cell 81 (1995) 171-8.
[83] N. Sonenberg, mRNA translation: influence of the 5' and 3' untranslated regions. Curr Opin Genet Dev 4 (1994) 310-5.
[84] P. Macdonald, Diversity in translational regulation. Curr Opin Cell Biol 13 (2001) 326-31.
[85] A. Bashirullah, R.L. Cooperstock, and H.D. Lipshitz, RNA localization in development. Annu Rev Biochem 67 (1998) 335-94.
[86] D. St Johnston, The intracellular localization of messenger RNAs. Cell 81 (1995) 161-70.
[87] G. Pesole, S. Liuni, G. Grillo, F. Licciulli, F. Mignone, C. Gissi, and C. Saccone, UTRdb and UTRsite: specialized databases of sequences and functional elements of 5' and 3' untranslated regions of eukaryotic mRNAs. Update 2002. Nucleic Acids Res 30 (2002) 335-40.
[88] C.J. Decker, and R. Parker, Mechanisms of mRNA degradation in eukaryotes. Trends Biochem Sci 19 (1994) 336-40.
[89] C.A. Beelman, and R. Parker, Degradation of mRNA in eukaryotes. Cell 81 (1995) 179-83.
[90] S. Banus, R.W. Bottema, C.L. Siezen, R.J. Vandebriel, J. Reimerink, M. Mommers, G.H. Koppelman, B. Hoebee, C. Thijs, D.S. Postma, T.G. Kimman, and F.F. Stelma, Toll-like receptor 4 polymorphism associated with the response to whole-cell pertussis vaccination in children from the KOALA study. Clin Vaccine Immunol 14 (2007) 1377-80.
[91] Y.H. Hwang, H. Ro, I. Choi, H. Kim, K.H. Oh, J.I. Hwang, M.H. Park, S. Kim, J. Yang, and C. Ahn, Impact of polymorphisms of TLR4/CD14 and TLR3 on acute rejection in kidney transplantation. Transplantation 88 (2009) 699-705.
[92] L. Excoffier, and M. Slatkin, Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. Mol Biol Evol 12 (1995) 921-7.
[93] G.C. Johnson, L. Esposito, B.J. Barratt, A.N. Smith, J. Heward, G. Di Genova, H. Ueda, H.J. Cordell, I.A. Eaves, F. Dudbridge, R.C. Twells, F. Payne, W. Hughes, S. Nutland, H. Stevens, P. Carr, E. Tuomilehto-Wolf, J. Tuomilehto, S.C. Gough, D.G. Clayton, and J.A. Todd, Haplotype tagging for the identification of common disease genes. Nat Genet 29 (2001) 233-7.