云南汉族寻常型银屑病患者及与链球菌相关联的HLA-DR基因分型研究
摘要
[目的]研究云南籍汉族寻常型银屑病患者与HLA-DR基因多态性之间的关联性以及与链球菌相关联的云南籍汉族寻常型银屑病患者与HLA-DR基因多态性之间的关联性，研究HLA-DR基因对免疫应答的遗传调控是否可影响链球菌感染后银屑病的发病及临床表现，探讨链球菌感染与银屑病发病的免疫遗传机理及遗传学的分子基础。
[方法]应用序列特异性引物多聚酶链式反应(PCR-SSP)技术，对30例云南汉族咽部未检出致病性链球菌银屑病患者及39例云南汉族健康对照进行HLA-DR基因分型，计算各等位基因RR值，并与36例咽部检出致病性链球菌的云南汉族寻常型银屑病患者HLA-DR基因分型历史资料对比，找出易感基因。
[结果]云南汉族寻常型银屑病患者HLA-DR7基因频率较正常对照组对比增高(28.79％：6.41％，P_c值=0.000＜0.05，RR=9.229)。HLA-DR7基因频率在未检出致病性链球菌组与正常对照组、致病性链球菌感染组间对比，各组间均有显著性差异(20.00％：6.41％：36.11％，P值均＜0.0125，RR均＞3.0)，提示关联强度强。提示
HLA一DR7基因与云南汉族寻常型银屑病相关联，且可能和与链球菌
感染有关银屑病相关联，为与链球菌感染有关银屑病的易感基因。
[结论]在云南汉族人群中，HLA一DR7基因与云南汉族寻常型银
屑病相关联，为云南汉族寻常型银屑病的易感基因，HLA一DR7基因
可能是不同民族、群体银屑病病人共同的易感基因;而且HLA一DR7
基因可能和与链球菌感染有关银屑病相关联，为与链球菌感染有
关银屑病的易感基因，HLA一DR7基因可能对与链球菌感染有关银屑
病的易感有遗传控制作用。
[objective] In order to study the association between HLA-DR alleles polymorphism and susceptibility of psoriatic vulgaris patients in Yunnan Han nationality, at the same time to study the association between HLA-DR alleles polymorphism and susceptibility of psoriatic patients Associated with Streptococcus, find the susceptible gene, study whether or not the HLA-DR alleles modulating the immune response can affect the onset and clinical situation in psoriatic patients after streptococcal infection, explore the immunological and genetic pathogenesis and the molecul basis of genetics in psoriasis with streptococcal infection, [methods] 30 psoriatic vulgaris patients with non-pathogenic streptococcus and 39 normal controls in Yunnan Han nationality were examined for HLA-DR genotyping analysis by polymerase chain reaction with sequence specific primers (PCR-SSP). The historical date of 36 psoriatic patients with
pathogenic streptococcal infection was compared, too. The susceptible gene was found through calculating the RR of alleles.
[results] The HLA-DR7 gene frequence of the whole patients in Yunnan Han nationality was substantially increased (28.79%: 6.41%, Pc=0. 000<0. 05, RR=9. 229). The HLA-DR7 gene frequence was compared among the patients with non-pathogenic streptococcus, normal controls and the patients with pathogenic streptococcal infection respectively. There were significant differences found ( (20.00%: 6.41%: 36.11%, all P <0.0125, all RR >3.0) , the relative risk is high. The HLA-DR7 gene was susceptible gene of psoriatic vulgaris patients in Yunnan Han nationality, and may be susceptible gene of psoriatic vulgaris patients with streptococcal infection especially.
[conclusion] The HLA-DR7 gene is associated with psoriatic vulgaris patients in Yunnan Han nationality and result in the susceptibility to psoriasis, which may be the common susceptible gene of psoriatic patients regardless of nation and group. The HLA-DR7 gene may be susceptible gene of psoriatic vulgaris patients with streptococcal infection especially. The immunogenetic mechanism may participate in the pathogenesis of psoriasis related to streptococcal infection.
[方法]应用序列特异性引物多聚酶链式反应(PCR-SSP)技术，对30例云南汉族咽部未检出致病性链球菌银屑病患者及39例云南汉族健康对照进行HLA-DR基因分型，计算各等位基因RR值，并与36例咽部检出致病性链球菌的云南汉族寻常型银屑病患者HLA-DR基因分型历史资料对比，找出易感基因。
[结果]云南汉族寻常型银屑病患者HLA-DR7基因频率较正常对照组对比增高(28.79％：6.41％，P_c值=0.000＜0.05，RR=9.229)。HLA-DR7基因频率在未检出致病性链球菌组与正常对照组、致病性链球菌感染组间对比，各组间均有显著性差异(20.00％：6.41％：36.11％，P值均＜0.0125，RR均＞3.0)，提示关联强度强。提示
HLA一DR7基因与云南汉族寻常型银屑病相关联，且可能和与链球菌
感染有关银屑病相关联，为与链球菌感染有关银屑病的易感基因。
[结论]在云南汉族人群中，HLA一DR7基因与云南汉族寻常型银
屑病相关联，为云南汉族寻常型银屑病的易感基因，HLA一DR7基因
可能是不同民族、群体银屑病病人共同的易感基因;而且HLA一DR7
基因可能和与链球菌感染有关银屑病相关联，为与链球菌感染有
关银屑病的易感基因，HLA一DR7基因可能对与链球菌感染有关银屑
病的易感有遗传控制作用。
[objective] In order to study the association between HLA-DR alleles polymorphism and susceptibility of psoriatic vulgaris patients in Yunnan Han nationality, at the same time to study the association between HLA-DR alleles polymorphism and susceptibility of psoriatic patients Associated with Streptococcus, find the susceptible gene, study whether or not the HLA-DR alleles modulating the immune response can affect the onset and clinical situation in psoriatic patients after streptococcal infection, explore the immunological and genetic pathogenesis and the molecul basis of genetics in psoriasis with streptococcal infection, [methods] 30 psoriatic vulgaris patients with non-pathogenic streptococcus and 39 normal controls in Yunnan Han nationality were examined for HLA-DR genotyping analysis by polymerase chain reaction with sequence specific primers (PCR-SSP). The historical date of 36 psoriatic patients with
pathogenic streptococcal infection was compared, too. The susceptible gene was found through calculating the RR of alleles.
[results] The HLA-DR7 gene frequence of the whole patients in Yunnan Han nationality was substantially increased (28.79%: 6.41%, Pc=0. 000<0. 05, RR=9. 229). The HLA-DR7 gene frequence was compared among the patients with non-pathogenic streptococcus, normal controls and the patients with pathogenic streptococcal infection respectively. There were significant differences found ( (20.00%: 6.41%: 36.11%, all P <0.0125, all RR >3.0) , the relative risk is high. The HLA-DR7 gene was susceptible gene of psoriatic vulgaris patients in Yunnan Han nationality, and may be susceptible gene of psoriatic vulgaris patients with streptococcal infection especially.
[conclusion] The HLA-DR7 gene is associated with psoriatic vulgaris patients in Yunnan Han nationality and result in the susceptibility to psoriasis, which may be the common susceptible gene of psoriatic patients regardless of nation and group. The HLA-DR7 gene may be susceptible gene of psoriatic vulgaris patients with streptococcal infection especially. The immunogenetic mechanism may participate in the pathogenesis of psoriasis related to streptococcal infection.
引文
[1] 赵辩．临床皮肤病学．第三版，南京：江苏科技技术出版社，2001．905-907
[2] 叶冬青．皮肤病流行病学．北京：人民卫生出版社，2001．369-370
[3] 邵长庚．我国银屑病的流行和防治现况．中华皮肤科杂志，1996，29(2)：75-76
[4] 郑德先．现代实验血液学研究方法与技术．北京：北京医科大学中国协和医科大学联合出版社，1999．353-358
[5] 赵桐茂．HLA分型原理和应用．上海：上海科学技术出版社，1984．145-240
[6] 叶应妩，王毓三．临床检验操作规程．第二版．南京：东南大学出版社，1997．479-486
[7] Beck S, Trowsdale J.. The human major histocompatability complex: lessons from the DNA sequence. Annu Rev Genomics Hum Genet, 2000,1:117-137
[8] 魏华．HLA分型进展．国外医学免疫学分册，2003，26(1)：23-27
[9] Schwartz DWM, Felser B, Myr MR. The genetics of HLA. Foliabiol, 1995, 41: 123-139
[10] 苏枭．HLA-Ⅱ类基因与人类疾病相关性研究进展．国外医学免疫学分册，2000，24(4)：233-238
[11] O. Olerup, H. Zetterquist. HLA-DR typing by PCR amplification with sequence-specific primers(PCR-SSP) in 2 hours: An alternative to serological DR typing in clinical practice including donor-recipient matching in cadaveric transplantations. Tissue Antigen, 1992, 39: 225-235
[12] 巴德年．当代免疫学技术与应用．北京：北京医科大学中国协和医科大学联合出版社，1998，509-510
[13] 邓建强．HLA和疾病的相关性．西安医科大学学报，1998，19(4)：650-652
[14] Balendran N, Clough RL, Arguello JR, et al. Characterization of the major susceptibility region for psoriasis at chromosome 6p21.3. J Invest Dermatol, 1999,1139(3):322-328
[15] Jonathan N.W.N. Baker. Genetic aspects of psoriasis. Clin Exp Dermatol, 2001,26:321-325
[16] 张学军等．寻常型银屑病遗传模式分析．中华医学遗传学杂志，2002，19(2)：108-114
[17] Prinz JC. Psoriasis vulgaris- a sterile antibacterial skin reaction mediated by cross-reative T cells? An immunological view of the pathophysiology of psoriasis. Clin Exp Dermatol,2001, 26, 326-323
[18] Schmitt EM, Boehncke WH, Stander M, et al. Oligonucleotide typing reveals association of type Ⅰ psoriasis with the HLA-DRB1~*07001,-DQA1~*0201, -DQB1~*0303 extended haplotype. J Invest Dermatol, 1996,100(6):749-752
[19] Jee SH, Tsai TF, Tsai WL, et al. HLA-DRB1*0701 and DRB1*1401 are associated with genetic susceptibility to psoriasis vulgaris in a Taiwanese population. Br J Dermatol, 1998,139(6):978-983
[20] Kim, TG Lee, HJ Youn, et al. The association of psoriasis with human leukocyte antigens in Koreanpopulation and the influence of age of onset and sex. J Invest Dermatol, 2000, 114(2): 309-313
[21] Saeki H, Kuwata S, Nakagawa H, et al. Analysis of HLA class Ⅱ and TAP alleles in Japanese patients with psoriasis vulgaris. Hum Immunol, 1998,59(8):503-11
[22] 刘述文，李恒进，陈香美，等．银屑病患者HLA-DR基因分型的研究．中华皮肤科杂志，1995，28(4)：80-82
[23] 张庆端，冯辉，崔宁，等．中国北方寻常型银屑病与HLA-DRBI基因关联的研究．中华医学遗传学杂志。1999，16(3)：194-195
[24] Nickoloff BJ. The immunologic and genetic basis of psoriasis. Arch Dermatol, 1999,135(9):1104-1110
[25] Travers, J.B., Hamid, Q.A., Norris. D.A.,et al. Epidermal HLA-DR and the enhancement of cutaneous reactivity to superantigenic toxins in psoriasis. J. Clin. Invest, 1999,104:1181-1189
[26] Baker BS, Bokth S, Powles A, et al. Group A streptococcal antigen-specific T lymphocytes in guttate psoriatic lesions. Br J Dermatol, 1993,128(5):493-9
[27] ABul H, Mahmoud F Al ,Saleh Q, et al. Profiles of activated T lymphocytes in peripheral blood of Kuwaiti psoriasis vulgaris patients. The Journal of dermatology, 2002, 29(4): 202-208
[28] Ferenczi K, Burack L, Pope M, et al. CD69, HLA-DR and the IL-2R identify persistently activated T cells in psoriasis vulgaris lesional skin: blood and skin comparisons by flow cytometry. J Autoimmun, 2000,14(1):63-78
[29] 罗海波，方平楚．A群链球菌的研究进展．国外医学·微生物学分册，1999，22(6)：17-20
[30] Guilherme L, Oshiro SE, Fae KC, et al. T-cell reactivity against
streptococcal antigens in the periphery mirrors reactivity of heart-infiltrating T lymphocytes in rheumatic heart disease patients. Infect Immun, 2001,69(9):5345-5351
[31] Prinz JC, Vollmer S, Boehncke WH, et al. Selection of conserved TCR VDJ rearrangements in chronic psoriasis plaques indicates a common antigen in psoriasis vulgaris. Eur 3 Immunol, 1999,29(10):3360-3368
[32] Menssen A, Trommler P, Vollmer S, et al. Evidence for antigen-specfic cellular immune response in skin lesions of patients with psoriasis vulgaris. J Immunol, 1995, 155(8): 4078-4083
[33] Krain LS, Newcomer VD, Terasaki PI. HL-A antigen in psoriasis. N Engl J Med ,1973,288:1245
[34] Bertrams J, Lattke C, Kuwert E. Correlation of antistreptolysin-O-titer to HLA13 in psoriasis. N Engl J Med, 1974, 291(12) :631
[35] Mallon E, Bunce M, Savoie H, et al. HLA-C and guttate psoriasis. Br J Dermatol, 2000, 143(6) :1177-1182
[36] Weisenseel P, Laumbacher B, Besgen P, et al. Streptococcal infection distinguishes different types of psoriasis. J Med Genet, 2002 ,39(10):767-768
[37] Muto-M, Date Y, Ichimiya M, et al. Significance of antibodies to streptococcal Mprotein in psoriatic arthritis and their association with HLA-A~*0207. Tissue Antigens, 1996,48(6):645-650
[38] Yarwood JM, Leung DY, Schlievert PM, et al. Evidence for the involvement of bacterial superantigens in psoriasis, atopic
dermatitis, and Kawasaki syndrome. FEMS Microbiol Lett, 2000,192(1):1-7
[39] Elder, JT Nair, RP Henseler,, et al. The genetics of psoriasis 2001: the odyssey continues. Arch Dermatol. 2001,137(11):1447-1454
[40] Vejbaesya S, Eiermann TH, Suthipinititharm P, et al. Serological and molecular analysis of HLA class Ⅰ and Ⅱ alleles in Thai patients with psoriasis vulgaris. Tissue Antigens, 1998, 52(4): 389-392
[2] 叶冬青．皮肤病流行病学．北京：人民卫生出版社，2001．369-370
[3] 邵长庚．我国银屑病的流行和防治现况．中华皮肤科杂志，1996，29(2)：75-76
[4] 郑德先．现代实验血液学研究方法与技术．北京：北京医科大学中国协和医科大学联合出版社，1999．353-358
[5] 赵桐茂．HLA分型原理和应用．上海：上海科学技术出版社，1984．145-240
[6] 叶应妩，王毓三．临床检验操作规程．第二版．南京：东南大学出版社，1997．479-486
[7] Beck S, Trowsdale J.. The human major histocompatability complex: lessons from the DNA sequence. Annu Rev Genomics Hum Genet, 2000,1:117-137
[8] 魏华．HLA分型进展．国外医学免疫学分册，2003，26(1)：23-27
[9] Schwartz DWM, Felser B, Myr MR. The genetics of HLA. Foliabiol, 1995, 41: 123-139
[10] 苏枭．HLA-Ⅱ类基因与人类疾病相关性研究进展．国外医学免疫学分册，2000，24(4)：233-238
[11] O. Olerup, H. Zetterquist. HLA-DR typing by PCR amplification with sequence-specific primers(PCR-SSP) in 2 hours: An alternative to serological DR typing in clinical practice including donor-recipient matching in cadaveric transplantations. Tissue Antigen, 1992, 39: 225-235
[12] 巴德年．当代免疫学技术与应用．北京：北京医科大学中国协和医科大学联合出版社，1998，509-510
[13] 邓建强．HLA和疾病的相关性．西安医科大学学报，1998，19(4)：650-652
[14] Balendran N, Clough RL, Arguello JR, et al. Characterization of the major susceptibility region for psoriasis at chromosome 6p21.3. J Invest Dermatol, 1999,1139(3):322-328
[15] Jonathan N.W.N. Baker. Genetic aspects of psoriasis. Clin Exp Dermatol, 2001,26:321-325
[16] 张学军等．寻常型银屑病遗传模式分析．中华医学遗传学杂志，2002，19(2)：108-114
[17] Prinz JC. Psoriasis vulgaris- a sterile antibacterial skin reaction mediated by cross-reative T cells? An immunological view of the pathophysiology of psoriasis. Clin Exp Dermatol,2001, 26, 326-323
[18] Schmitt EM, Boehncke WH, Stander M, et al. Oligonucleotide typing reveals association of type Ⅰ psoriasis with the HLA-DRB1~*07001,-DQA1~*0201, -DQB1~*0303 extended haplotype. J Invest Dermatol, 1996,100(6):749-752
[19] Jee SH, Tsai TF, Tsai WL, et al. HLA-DRB1*0701 and DRB1*1401 are associated with genetic susceptibility to psoriasis vulgaris in a Taiwanese population. Br J Dermatol, 1998,139(6):978-983
[20] Kim, TG Lee, HJ Youn, et al. The association of psoriasis with human leukocyte antigens in Koreanpopulation and the influence of age of onset and sex. J Invest Dermatol, 2000, 114(2): 309-313
[21] Saeki H, Kuwata S, Nakagawa H, et al. Analysis of HLA class Ⅱ and TAP alleles in Japanese patients with psoriasis vulgaris. Hum Immunol, 1998,59(8):503-11
[22] 刘述文，李恒进，陈香美，等．银屑病患者HLA-DR基因分型的研究．中华皮肤科杂志，1995，28(4)：80-82
[23] 张庆端，冯辉，崔宁，等．中国北方寻常型银屑病与HLA-DRBI基因关联的研究．中华医学遗传学杂志。1999，16(3)：194-195
[24] Nickoloff BJ. The immunologic and genetic basis of psoriasis. Arch Dermatol, 1999,135(9):1104-1110
[25] Travers, J.B., Hamid, Q.A., Norris. D.A.,et al. Epidermal HLA-DR and the enhancement of cutaneous reactivity to superantigenic toxins in psoriasis. J. Clin. Invest, 1999,104:1181-1189
[26] Baker BS, Bokth S, Powles A, et al. Group A streptococcal antigen-specific T lymphocytes in guttate psoriatic lesions. Br J Dermatol, 1993,128(5):493-9
[27] ABul H, Mahmoud F Al ,Saleh Q, et al. Profiles of activated T lymphocytes in peripheral blood of Kuwaiti psoriasis vulgaris patients. The Journal of dermatology, 2002, 29(4): 202-208
[28] Ferenczi K, Burack L, Pope M, et al. CD69, HLA-DR and the IL-2R identify persistently activated T cells in psoriasis vulgaris lesional skin: blood and skin comparisons by flow cytometry. J Autoimmun, 2000,14(1):63-78
[29] 罗海波，方平楚．A群链球菌的研究进展．国外医学·微生物学分册，1999，22(6)：17-20
[30] Guilherme L, Oshiro SE, Fae KC, et al. T-cell reactivity against
streptococcal antigens in the periphery mirrors reactivity of heart-infiltrating T lymphocytes in rheumatic heart disease patients. Infect Immun, 2001,69(9):5345-5351
[31] Prinz JC, Vollmer S, Boehncke WH, et al. Selection of conserved TCR VDJ rearrangements in chronic psoriasis plaques indicates a common antigen in psoriasis vulgaris. Eur 3 Immunol, 1999,29(10):3360-3368
[32] Menssen A, Trommler P, Vollmer S, et al. Evidence for antigen-specfic cellular immune response in skin lesions of patients with psoriasis vulgaris. J Immunol, 1995, 155(8): 4078-4083
[33] Krain LS, Newcomer VD, Terasaki PI. HL-A antigen in psoriasis. N Engl J Med ,1973,288:1245
[34] Bertrams J, Lattke C, Kuwert E. Correlation of antistreptolysin-O-titer to HLA13 in psoriasis. N Engl J Med, 1974, 291(12) :631
[35] Mallon E, Bunce M, Savoie H, et al. HLA-C and guttate psoriasis. Br J Dermatol, 2000, 143(6) :1177-1182
[36] Weisenseel P, Laumbacher B, Besgen P, et al. Streptococcal infection distinguishes different types of psoriasis. J Med Genet, 2002 ,39(10):767-768
[37] Muto-M, Date Y, Ichimiya M, et al. Significance of antibodies to streptococcal Mprotein in psoriatic arthritis and their association with HLA-A~*0207. Tissue Antigens, 1996,48(6):645-650
[38] Yarwood JM, Leung DY, Schlievert PM, et al. Evidence for the involvement of bacterial superantigens in psoriasis, atopic
dermatitis, and Kawasaki syndrome. FEMS Microbiol Lett, 2000,192(1):1-7
[39] Elder, JT Nair, RP Henseler,, et al. The genetics of psoriasis 2001: the odyssey continues. Arch Dermatol. 2001,137(11):1447-1454
[40] Vejbaesya S, Eiermann TH, Suthipinititharm P, et al. Serological and molecular analysis of HLA class Ⅰ and Ⅱ alleles in Thai patients with psoriasis vulgaris. Tissue Antigens, 1998, 52(4): 389-392