HLA-B*2704、05亚型与强直性脊柱炎的临床研究
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摘要
目的：探讨人类白细胞相关抗原HLA-B~*2704、05基因亚型与山东地区强直性脊柱炎(AS)发病及其临床表现、实验室检查及诊断的关系。
方法：采用流式细胞仪法(FCM)对83例AS患者与90例正常对照者的HLA-B~*27抗原进行检测。采用限制性片段多态性聚合酶链反应(PCR-RFLP)方法检测上述两组HLA-B~*2704、05基因亚型频率。类风湿因子(RF)采用乳胶凝集法，C-反应蛋白(CRP)采用免疫比浊法。
结果：FCM法检测HLA-B*27抗原在AS患者中的频率为96.4％，正常对照组为6.6％，两者比较有显著差异(RR=14.30，X~2=132.2，P＜0.05)；PCR-RFLP法检测HLA-B*27基因在AS患者中的频率为95.2％，正常对照组的频率为6.6％，两者比较有显著差异(RR=14.27，X~2=133.4，P＜0.05)；两种方法之间的阳性率无显著性差异(P＞0.05)；男性、女性患者相比HLA-B*27频率无统计学差异(X~2=0.0021，P＞0.05)，但男性患者发病早、病情较重。骶髂关节侵蚀程度、关节变形率和关节外表现(如尿道炎、胃肠炎和葡萄膜炎)在HLA-B*27阳性组高于阴性组，但无统计学差异(统计结果分别为14／79 VS 0／4，P＞0.05；20／79 VS 0／4，P＞0.05；22／79VS 0／4，P＞0.05)。从HLA-B*27阳性的患者和正常人中共检测出两种亚型HLA-B*2704、HLA-B*2705，二者在HLA-B*27阳性的正常人和患者中的分布无差异(分别为X~2=0.373，P＞0.05；X~2=0.0003，P＞0.05)，且两种亚型患者在临床表现和实验室检查无差异。
结论：HLA-B*27与山东地区AS的易感性有关。FCM法和PCR-RFLP法检测HLA-B*27阳性率无显著差异。HLA-B*27基因在男女两性中分布无统计学差异，但男性携带预示发病早，病情较重。骶髂关节侵蚀程度、关节变形率和关节外表
OBJECTIVE: To explore the role of HLA-B*2704、 05 gene subtype in the development of ankylosing spondylitis (AS) and the correlations between HLA-B*27 gene subtype and clinical manifestations, serological characteristics, diagnosis of patients with AS in the Han Nationality of Shandong area population.
METHODS: In 83 AS patients and 90 matched healthy control subjects, HLA-B*27 were detected by using the methods of flow cytometer(FCM). Polymerase chain reaction-restricted frag- ment length polymorphism(PCR-RFLP) were used to get the gene frequencies of HLA-B*2704、05. Rheumatoid factor (RF) was detected by latex agglutination. C-reactive protein (CRP) was determined by immunoturbidimetry.
RESULTS: Compared with controls, an increased gene frequency of HLA-B*27 was found in FCM (RR=14. 30, X~2=132. 2, P < 0. 05) and PCR-RFLP (RR=14.27, X~2=133.4, P < 0.05). Both methods showed no significant differernce (P>0. 05).There was no significant difference between the HLA-B*27~+ and HLA-B*27~- patients with respect to sex (X~2=0. 0021, P>0. 05), sacroiliac joint lesion (14/79 VS 0/4, P> 0.05) and extra-articular manifestations (22/79 VS 0/4, P>0. 05) such as urethritis, enteritis and uveitis. But the disease was more severe in males than that in females. Only two subtypes were detected- HLA-B*2704 and HLA-B*2705. No significant differences were found in the distribution of the different subtypes
方法：采用流式细胞仪法(FCM)对83例AS患者与90例正常对照者的HLA-B~*27抗原进行检测。采用限制性片段多态性聚合酶链反应(PCR-RFLP)方法检测上述两组HLA-B~*2704、05基因亚型频率。类风湿因子(RF)采用乳胶凝集法，C-反应蛋白(CRP)采用免疫比浊法。
结果：FCM法检测HLA-B*27抗原在AS患者中的频率为96.4％，正常对照组为6.6％，两者比较有显著差异(RR=14.30，X~2=132.2，P＜0.05)；PCR-RFLP法检测HLA-B*27基因在AS患者中的频率为95.2％，正常对照组的频率为6.6％，两者比较有显著差异(RR=14.27，X~2=133.4，P＜0.05)；两种方法之间的阳性率无显著性差异(P＞0.05)；男性、女性患者相比HLA-B*27频率无统计学差异(X~2=0.0021，P＞0.05)，但男性患者发病早、病情较重。骶髂关节侵蚀程度、关节变形率和关节外表现(如尿道炎、胃肠炎和葡萄膜炎)在HLA-B*27阳性组高于阴性组，但无统计学差异(统计结果分别为14／79 VS 0／4，P＞0.05；20／79 VS 0／4，P＞0.05；22／79VS 0／4，P＞0.05)。从HLA-B*27阳性的患者和正常人中共检测出两种亚型HLA-B*2704、HLA-B*2705，二者在HLA-B*27阳性的正常人和患者中的分布无差异(分别为X~2=0.373，P＞0.05；X~2=0.0003，P＞0.05)，且两种亚型患者在临床表现和实验室检查无差异。
结论：HLA-B*27与山东地区AS的易感性有关。FCM法和PCR-RFLP法检测HLA-B*27阳性率无显著差异。HLA-B*27基因在男女两性中分布无统计学差异，但男性携带预示发病早，病情较重。骶髂关节侵蚀程度、关节变形率和关节外表
OBJECTIVE: To explore the role of HLA-B*2704、 05 gene subtype in the development of ankylosing spondylitis (AS) and the correlations between HLA-B*27 gene subtype and clinical manifestations, serological characteristics, diagnosis of patients with AS in the Han Nationality of Shandong area population.
METHODS: In 83 AS patients and 90 matched healthy control subjects, HLA-B*27 were detected by using the methods of flow cytometer(FCM). Polymerase chain reaction-restricted frag- ment length polymorphism(PCR-RFLP) were used to get the gene frequencies of HLA-B*2704、05. Rheumatoid factor (RF) was detected by latex agglutination. C-reactive protein (CRP) was determined by immunoturbidimetry.
RESULTS: Compared with controls, an increased gene frequency of HLA-B*27 was found in FCM (RR=14. 30, X~2=132. 2, P < 0. 05) and PCR-RFLP (RR=14.27, X~2=133.4, P < 0.05). Both methods showed no significant differernce (P>0. 05).There was no significant difference between the HLA-B*27~+ and HLA-B*27~- patients with respect to sex (X~2=0. 0021, P>0. 05), sacroiliac joint lesion (14/79 VS 0/4, P> 0.05) and extra-articular manifestations (22/79 VS 0/4, P>0. 05) such as urethritis, enteritis and uveitis. But the disease was more severe in males than that in females. Only two subtypes were detected- HLA-B*2704 and HLA-B*2705. No significant differences were found in the distribution of the different subtypes
引文
1、Brewerton DA,Hart FD,Caffrey M,et al.Ankylosing spondylitis and HLA-B~* 27.Lancet, 1973,1:904-907.
2、Khan MA.An overview of clinical spectrium and heterogeneity of spondyloarthropathies.Rheu Dis Clin North Am, 1992,18(1): 1-10.
3、Gonzalez-Roces S,Alvarez MV, Conzalez S,et al.HLA-B~*27 polymorphism and wordwide susceptibility to ankylosing spondylitis.Tissue Antigen, 1997,49(2): 116-23.
4、Van der Linden SM,Valkenburg HA,Cats A.Evaluation of diagnostic criteria for ankylosingspondylitis.A proposal for modification of the New York criteria.Arthritis Rheum, 1984,27(4):361-8.
5、Tsuchiya N,Shiota M,Modyama S,et al. Mica Allele Typing of HLA-B~*27 Positive Japanese Patients with Seronegative Spondylarthropathies and Healthy Individuals: Differential Linkage Disequilibrium with HLA-B~*27 Subtypes. Arthritis Rheum, 1998,41 (1):68-73.
6、蒋黎华，范丽安，杨钰琴，等．强直性脊柱炎与HLA-B*27等位基因研究[J]．中国免疫学杂志，1997，13(6)：345-348．
7、I.-H. Chen et al, K. L. Yang, A. Lee,et al. Low frequency of HLA-B~*2706 in Taiwanese patients with ankylosing spondylitis. Blackwell Science Ltd,European Journal of Immunogenetics,2002,29:435-438.
8、Yang et al. Polymorphism of HLA-B~*27 in Taiwanese Chinese.Tissue Antigens 2004,63: 476-479.
9、Sesma Laura, Montserrat Veronica, Lamas Jose Rarnon, et al.The peptide repertoires of HLA-B~*27 subtypes differentially associated to spondyloarthropathy(B~*2704 and B~*2706) differ by specific changes at three anchor positions[J]. J Biol Chem,2002,277(19): 16744-16749. Kanga U, Mehra NK, Lopez-Larrea C, Lardy NM, Kumar A,Feltkamp
10、TE.Seronegative spondyloarthropathies and HLAB27 subtypes: a study of Asian Indians. Clin Rheumatol 1996,15 (Suppl 1): 13-8.
11、Garcia-Femandez S, Gonzalez S, Blanco M, et al. New insights regarding HLA-B~*27 diversity in the Asian population[J]. Tissue Antigens, 2001,58 (4):259-262.
12、Garcia F, Marina A, Lopez de Castro JA. Lack of carboxylterminal tyrosine distinguishes the B~*2706-bound peptide repertoire from those of B~*2704 and other HLA-B~*27 subtypes associated to ankylosing spondylitis. Tissue Antigens 1997; 49:215-21.
13、Agathi Varnavidou-Nicolaidou, Katerina Karpasitou,Dora Georgiou, Galatia Stylianou,et al.HLA-B~*27 in the Greek Cypriot Population:Distribution of Subtypes in Patients With Ankylosing Spondylitis and Other HLA-B~*27-related Diseases. The Possible Protective Role of B~*2707.Human Immunology 2004,65:1451-1454.
14、F. S. Oguz et al. HLA B-27 subtypes in turkish patients with spondyloarthropathy and healthy controls. Disease Markers, 2004,20: 309-312.
15、Ana Cipriani, Sergio Rivera, Manzttr Hassanhi, et al. HLA-B~*27 Subtypes Determination in Patients With Ankylosing Spondylitis From Zulia, Venezuela, Human Immunology,2003,64: 745-749.
16、Shankarkumar et al. HLA-B~*27 diversity in Western Indians. Tissue Antigens 2002,60: 98-101.
17、Lopez-Larrea, C., K. Sujirachato, N. K. Mehra, P. Chiewsilp, D. Isarangkura, U. Kanga, O. Dominguez, E. Coto, M. Pena, and F. Setien.1995.HLA-B~*27 subtypes in Asian patients with ankylosing spondylitis: evidence for new associations.Tissue Antigens,1995,45:169-176.
18、Nasution AR, Mardjuadi A, Kunmartini S, et al. HLA-B~*27 subtypes positively and negatively associated with spondyloarthropathy. J Rheumatol, 1997,24:1111-1114.
19、Ren, EC, Koh WH,Sim D,et al. Possible protective role of HLA-B~*2706 for ankylosing spondylitis. Tissue Antigens,1997,49:67-69.
20、D'Amato M,Fiorillo MT,Carcassi C, et al. Relevance of residue 116 of HLA-B~*27 in determining susceptibility to ankylosing spondylitis. Eur J Immunol. 1995, 25:3199-3201.
21、Marchionni, L., V. Modena, R. Roggero, et al.I. The polymorphism of HLA-B~*27 and the seronegative spondyloarthropathies in the Italian population [abstract]. In 13th European Histocompatibility Conference, Crete,1999.European Federation for Immunogenetics, p.36.
22、Brown, M.A. et al. Ankylosing spondylitis in West Africans-evidence for a non-HLA-B~*27 protective effect. Ann. Rheum. Dis. 1997,56: 68-70.
23、林剑浩，吕厚山，冯传汉等．强直性脊柱炎与HLA-B~*27亚型．中华外科杂志，1996，34(6)：333-335．
24、韩军艳，熊平，严鹏，邵诗颖等．采用PCR-SSP方法检测强直性脊柱炎患者HLA-B*27亚型．第三军医大学学报，2003，25(15)：1394-1395．
25、林琳，吴凤歧，张新根，等．少儿强直性脊柱炎与幼儿类风湿性关节炎HLA-B*27亚型的鉴别诊断[J]．中华微生物学和免疫学杂志，2003，23：215-218．
26、黄烽，杨春花．强直性脊柱炎临床及免疫发病机制的研究进展[J]．中国免疫学杂志，2001；17(6)：281-285．
27、Hammer RE,Maika SD,Richardson JA,et al.Spontaneous inflammafory disease in transgenic rats expressing HLA-B~*27 and human beta 2m: an animal model of HLA-B~*27 associated human disorders.Cell, 1990;63(5): 1099-1112.
28、Breban M, Fernandez-sueiro JL,Richardson JA,etal.T cells, but not thymic exposure to HLA-B~*27,are reguired for the inflammatory disease of HLA-B~*27 transgenic raits.J Immunol, 1996; 156(2):794-803.
29、Khare SD, Luthra HS, David CS,et al.Spontaneous inflammatory arthritis in HLA-B~*27 transgenic mice lacking beta 2-microglobulin: a model of human spondyloarthropathies. Exp Med 1995, 182:1153-1158.
30、Crew MD,Effros RB,Walford RL,etal.Transgenic mice expressing a truncated Peromyscus Leucopus TNF-alpha gene manifest an arthritis resem-bling ankylosing spondylitis. J Intereron Cytoking Res. 1998,18(4):219-25.
31、邓洁，冯兴华．强直性脊柱炎的中西医研究思路．北京中医药大学学院 2000；23(增刊)：94．
32、丁海明，吕厚山，陈占昆，等．转HLA-B~*2704基因小鼠模型的建立．中华风湿病学杂志，2000；4(1)：11-14．
33、Taurog JD.Arthritis in HLA-B~*27 transgenic animals. TheAmeri-can.J Medical Sciences,1988;316:250-256.
34、Carcia F,Marina A,Lopez de Castro JA.Tissue Antigen, 1997,49(3pt 1):215-221.
35、Benjamin, R. and Parham, P. Guilt by association: HLA-B~*27 and ankylosing spondylitis. Immunol Today,1990,11: 137-142.
36、顾明敏等．全基因组扫描寻找强直性脊柱炎的易感基因位点．遗传学报，2004，31(3)：217～220．
37、Brown M A,Pile K D,Kennedy L G,Campbell D,Andrew L,March R, Shatfort J L,Weeks D E,Calin A,Wordsworth P.A Genome-wide screen for susceptibility loci in ankylosing spondylitis.Arthritis Rheum, 1998,41 (4):588～595.
38、Laval S H,Timms A,Edwards S,Bradbury L,Brophy S,Milieie A,Rubin L,Siminovitch K A,Weeks D E,Calin A, Wordsworth B P, Brown M A.Whole-genome screening in ankylosing spondylitis:evidence of non-MHC genetic-susceptibility loci.Am J Hum Genet,2001,68(4):918～926.
39、Martinez-Borra et al.HLA-B~*27 Alone Rather than B27-Related Class Ⅰ Haplotypes Contributes to Ankylosing Spondylitis Susceptibility。Human Immunology,2000,61:131-139.
40、M. D. De Juan et al. HLA-A~*2402 and a Microsatellite (D6S248) Are Secondary Independent Susceptibility Markers to Ankylosing Spondylitis in Basque Patients.Human Immunology,2004,65:175-180.
41、Sieper J, Kingsley G, et al. Recent advances in the pathogenesis of reactive arthritis. Immunol Today, 1996, 17:160-163.
42、Parham P et al. Presentation of HLA class Ⅰ-derived peptides:potential involvement in allorecognition and HLA-B~*27-associated arthritis. Immunol Rev,1996, 154:137-54.
43、Westman P, Partanen J, Leirisalo-Repo M, Koskimies S,et al. Different DRB1~*04 alleles predominate in the Finnish random population and in HLA-B~*27-positive subpopulations.Tissue Antigens,1994,44:329-331.
44、Tuokko J, Reijonen H, Ilonen J, et al. Increase of HLA-DRB1~*0408 and-DQB1~*0301 in HLA-B~*27 positive reactive arthritis. Ann Rheum Dis,1997,56:37-42.
45、Khare SD, Bull MJ, Hansen J, et al.Spontaneous disease in HLA-B~*27 transgenic mice in independent of MHC class Ⅱ molecules: a direct role for B~*27 heavy chains and not B~*27 derived peptides. J Immunol,1998,160:101-106.
46、Robert A.Colbert,et al. Hla-B~*27 misfolding:a solution to the spondyloarthropathy conundrum.Molecular medicine tory.2000,6:224-230.
47、Manni Luthra-Guptasarma, Balvinder, et al.HLA-B~*27 lacking associated b2-microglobulin rearranges to auto-display or cross-display residues 169-181: a novel molecular mechanism for spondyloarthropathies. FEBS Letters,2004,575: 1-8.
48、Barbara Uchanska-Ziegler, Andress Ziegler, et al. Ankylosing spondylitis:a b2-deposition disease?.TRENDS in Immunology,2003,24 (2):73-76.
49、Neumuller J, Fischer M. Eberl R.,et al.Fallure of the serological determination of HLA-B~*27 due to antigen masking in patients with ankylosing spondylitis.Rheumatol Int 1993; 13:163-7.
50、Albrecht J. Muller HA, et al. HLA-B~*27 typing by use of low Cytofluorometry. Clin Chem 1987;33:1619-23.
51、Minden K,Kiessling U,Listing J,et al.Prognosis of patients with juvenile chronic arthritis and juvenile spondyloarthropathy.J Rheumatol,2000,27:2256-2263.
52、Prieur AM,Chedeville G.Prognosis factors in juvenile idiopathic arthritis.Curr Rhermatol,2001,3:371-378.
53、赖建铭，吴凤歧，郭玉红等．幼年强直性脊柱炎临床特点HLA-B~*27亚型的相关性研究．中华风湿病学杂志，2004，8(10)：617-619．
2、Khan MA.An overview of clinical spectrium and heterogeneity of spondyloarthropathies.Rheu Dis Clin North Am, 1992,18(1): 1-10.
3、Gonzalez-Roces S,Alvarez MV, Conzalez S,et al.HLA-B~*27 polymorphism and wordwide susceptibility to ankylosing spondylitis.Tissue Antigen, 1997,49(2): 116-23.
4、Van der Linden SM,Valkenburg HA,Cats A.Evaluation of diagnostic criteria for ankylosingspondylitis.A proposal for modification of the New York criteria.Arthritis Rheum, 1984,27(4):361-8.
5、Tsuchiya N,Shiota M,Modyama S,et al. Mica Allele Typing of HLA-B~*27 Positive Japanese Patients with Seronegative Spondylarthropathies and Healthy Individuals: Differential Linkage Disequilibrium with HLA-B~*27 Subtypes. Arthritis Rheum, 1998,41 (1):68-73.
6、蒋黎华，范丽安，杨钰琴，等．强直性脊柱炎与HLA-B*27等位基因研究[J]．中国免疫学杂志，1997，13(6)：345-348．
7、I.-H. Chen et al, K. L. Yang, A. Lee,et al. Low frequency of HLA-B~*2706 in Taiwanese patients with ankylosing spondylitis. Blackwell Science Ltd,European Journal of Immunogenetics,2002,29:435-438.
8、Yang et al. Polymorphism of HLA-B~*27 in Taiwanese Chinese.Tissue Antigens 2004,63: 476-479.
9、Sesma Laura, Montserrat Veronica, Lamas Jose Rarnon, et al.The peptide repertoires of HLA-B~*27 subtypes differentially associated to spondyloarthropathy(B~*2704 and B~*2706) differ by specific changes at three anchor positions[J]. J Biol Chem,2002,277(19): 16744-16749. Kanga U, Mehra NK, Lopez-Larrea C, Lardy NM, Kumar A,Feltkamp
10、TE.Seronegative spondyloarthropathies and HLAB27 subtypes: a study of Asian Indians. Clin Rheumatol 1996,15 (Suppl 1): 13-8.
11、Garcia-Femandez S, Gonzalez S, Blanco M, et al. New insights regarding HLA-B~*27 diversity in the Asian population[J]. Tissue Antigens, 2001,58 (4):259-262.
12、Garcia F, Marina A, Lopez de Castro JA. Lack of carboxylterminal tyrosine distinguishes the B~*2706-bound peptide repertoire from those of B~*2704 and other HLA-B~*27 subtypes associated to ankylosing spondylitis. Tissue Antigens 1997; 49:215-21.
13、Agathi Varnavidou-Nicolaidou, Katerina Karpasitou,Dora Georgiou, Galatia Stylianou,et al.HLA-B~*27 in the Greek Cypriot Population:Distribution of Subtypes in Patients With Ankylosing Spondylitis and Other HLA-B~*27-related Diseases. The Possible Protective Role of B~*2707.Human Immunology 2004,65:1451-1454.
14、F. S. Oguz et al. HLA B-27 subtypes in turkish patients with spondyloarthropathy and healthy controls. Disease Markers, 2004,20: 309-312.
15、Ana Cipriani, Sergio Rivera, Manzttr Hassanhi, et al. HLA-B~*27 Subtypes Determination in Patients With Ankylosing Spondylitis From Zulia, Venezuela, Human Immunology,2003,64: 745-749.
16、Shankarkumar et al. HLA-B~*27 diversity in Western Indians. Tissue Antigens 2002,60: 98-101.
17、Lopez-Larrea, C., K. Sujirachato, N. K. Mehra, P. Chiewsilp, D. Isarangkura, U. Kanga, O. Dominguez, E. Coto, M. Pena, and F. Setien.1995.HLA-B~*27 subtypes in Asian patients with ankylosing spondylitis: evidence for new associations.Tissue Antigens,1995,45:169-176.
18、Nasution AR, Mardjuadi A, Kunmartini S, et al. HLA-B~*27 subtypes positively and negatively associated with spondyloarthropathy. J Rheumatol, 1997,24:1111-1114.
19、Ren, EC, Koh WH,Sim D,et al. Possible protective role of HLA-B~*2706 for ankylosing spondylitis. Tissue Antigens,1997,49:67-69.
20、D'Amato M,Fiorillo MT,Carcassi C, et al. Relevance of residue 116 of HLA-B~*27 in determining susceptibility to ankylosing spondylitis. Eur J Immunol. 1995, 25:3199-3201.
21、Marchionni, L., V. Modena, R. Roggero, et al.I. The polymorphism of HLA-B~*27 and the seronegative spondyloarthropathies in the Italian population [abstract]. In 13th European Histocompatibility Conference, Crete,1999.European Federation for Immunogenetics, p.36.
22、Brown, M.A. et al. Ankylosing spondylitis in West Africans-evidence for a non-HLA-B~*27 protective effect. Ann. Rheum. Dis. 1997,56: 68-70.
23、林剑浩，吕厚山，冯传汉等．强直性脊柱炎与HLA-B~*27亚型．中华外科杂志，1996，34(6)：333-335．
24、韩军艳，熊平，严鹏，邵诗颖等．采用PCR-SSP方法检测强直性脊柱炎患者HLA-B*27亚型．第三军医大学学报，2003，25(15)：1394-1395．
25、林琳，吴凤歧，张新根，等．少儿强直性脊柱炎与幼儿类风湿性关节炎HLA-B*27亚型的鉴别诊断[J]．中华微生物学和免疫学杂志，2003，23：215-218．
26、黄烽，杨春花．强直性脊柱炎临床及免疫发病机制的研究进展[J]．中国免疫学杂志，2001；17(6)：281-285．
27、Hammer RE,Maika SD,Richardson JA,et al.Spontaneous inflammafory disease in transgenic rats expressing HLA-B~*27 and human beta 2m: an animal model of HLA-B~*27 associated human disorders.Cell, 1990;63(5): 1099-1112.
28、Breban M, Fernandez-sueiro JL,Richardson JA,etal.T cells, but not thymic exposure to HLA-B~*27,are reguired for the inflammatory disease of HLA-B~*27 transgenic raits.J Immunol, 1996; 156(2):794-803.
29、Khare SD, Luthra HS, David CS,et al.Spontaneous inflammatory arthritis in HLA-B~*27 transgenic mice lacking beta 2-microglobulin: a model of human spondyloarthropathies. Exp Med 1995, 182:1153-1158.
30、Crew MD,Effros RB,Walford RL,etal.Transgenic mice expressing a truncated Peromyscus Leucopus TNF-alpha gene manifest an arthritis resem-bling ankylosing spondylitis. J Intereron Cytoking Res. 1998,18(4):219-25.
31、邓洁，冯兴华．强直性脊柱炎的中西医研究思路．北京中医药大学学院 2000；23(增刊)：94．
32、丁海明，吕厚山，陈占昆，等．转HLA-B~*2704基因小鼠模型的建立．中华风湿病学杂志，2000；4(1)：11-14．
33、Taurog JD.Arthritis in HLA-B~*27 transgenic animals. TheAmeri-can.J Medical Sciences,1988;316:250-256.
34、Carcia F,Marina A,Lopez de Castro JA.Tissue Antigen, 1997,49(3pt 1):215-221.
35、Benjamin, R. and Parham, P. Guilt by association: HLA-B~*27 and ankylosing spondylitis. Immunol Today,1990,11: 137-142.
36、顾明敏等．全基因组扫描寻找强直性脊柱炎的易感基因位点．遗传学报，2004，31(3)：217～220．
37、Brown M A,Pile K D,Kennedy L G,Campbell D,Andrew L,March R, Shatfort J L,Weeks D E,Calin A,Wordsworth P.A Genome-wide screen for susceptibility loci in ankylosing spondylitis.Arthritis Rheum, 1998,41 (4):588～595.
38、Laval S H,Timms A,Edwards S,Bradbury L,Brophy S,Milieie A,Rubin L,Siminovitch K A,Weeks D E,Calin A, Wordsworth B P, Brown M A.Whole-genome screening in ankylosing spondylitis:evidence of non-MHC genetic-susceptibility loci.Am J Hum Genet,2001,68(4):918～926.
39、Martinez-Borra et al.HLA-B~*27 Alone Rather than B27-Related Class Ⅰ Haplotypes Contributes to Ankylosing Spondylitis Susceptibility。Human Immunology,2000,61:131-139.
40、M. D. De Juan et al. HLA-A~*2402 and a Microsatellite (D6S248) Are Secondary Independent Susceptibility Markers to Ankylosing Spondylitis in Basque Patients.Human Immunology,2004,65:175-180.
41、Sieper J, Kingsley G, et al. Recent advances in the pathogenesis of reactive arthritis. Immunol Today, 1996, 17:160-163.
42、Parham P et al. Presentation of HLA class Ⅰ-derived peptides:potential involvement in allorecognition and HLA-B~*27-associated arthritis. Immunol Rev,1996, 154:137-54.
43、Westman P, Partanen J, Leirisalo-Repo M, Koskimies S,et al. Different DRB1~*04 alleles predominate in the Finnish random population and in HLA-B~*27-positive subpopulations.Tissue Antigens,1994,44:329-331.
44、Tuokko J, Reijonen H, Ilonen J, et al. Increase of HLA-DRB1~*0408 and-DQB1~*0301 in HLA-B~*27 positive reactive arthritis. Ann Rheum Dis,1997,56:37-42.
45、Khare SD, Bull MJ, Hansen J, et al.Spontaneous disease in HLA-B~*27 transgenic mice in independent of MHC class Ⅱ molecules: a direct role for B~*27 heavy chains and not B~*27 derived peptides. J Immunol,1998,160:101-106.
46、Robert A.Colbert,et al. Hla-B~*27 misfolding:a solution to the spondyloarthropathy conundrum.Molecular medicine tory.2000,6:224-230.
47、Manni Luthra-Guptasarma, Balvinder, et al.HLA-B~*27 lacking associated b2-microglobulin rearranges to auto-display or cross-display residues 169-181: a novel molecular mechanism for spondyloarthropathies. FEBS Letters,2004,575: 1-8.
48、Barbara Uchanska-Ziegler, Andress Ziegler, et al. Ankylosing spondylitis:a b2-deposition disease?.TRENDS in Immunology,2003,24 (2):73-76.
49、Neumuller J, Fischer M. Eberl R.,et al.Fallure of the serological determination of HLA-B~*27 due to antigen masking in patients with ankylosing spondylitis.Rheumatol Int 1993; 13:163-7.
50、Albrecht J. Muller HA, et al. HLA-B~*27 typing by use of low Cytofluorometry. Clin Chem 1987;33:1619-23.
51、Minden K,Kiessling U,Listing J,et al.Prognosis of patients with juvenile chronic arthritis and juvenile spondyloarthropathy.J Rheumatol,2000,27:2256-2263.
52、Prieur AM,Chedeville G.Prognosis factors in juvenile idiopathic arthritis.Curr Rhermatol,2001,3:371-378.
53、赖建铭，吴凤歧，郭玉红等．幼年强直性脊柱炎临床特点HLA-B~*27亚型的相关性研究．中华风湿病学杂志，2004，8(10)：617-619．