HLA-DRB基因多态性与异位性皮炎易感性的相关性研究
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摘要
异位性皮炎(Atopic Dermatitise, AD)是一种慢性炎症性皮肤病，常伴有家族史，血清IgE水平升高，多同时伴有哮喘和变应性鼻炎。发病机制尚未明确。目前公认AD是多基因病，遗传和环境共同作用导致发病。国外学者对AD易感基因的研究越来越多，如13q12，3q21，1q21等，然而各国学者研究结论并不十分一致，这可能与AD的诊断原则不同、外显率不同和研究策略不同等因素有关。不同种族、地区基因分布频率不同，因此，有必要对天津地区AD患者的易感基因进行研究。
人类白细胞抗原(Human Leucocyte Antigen, HLA)在免疫应答中起关键作用，尤其是HLA-Ⅱ类基因区，可通过免疫应答基因和免疫抑制基因调节人的免疫应答，参与免疫应答的遗传控制。因此研究AD与HLA-Ⅱ类基因的关系可进一步明确AD发病机制。
本研究主要检测HLA-DRB等位基因，DR_3基因的单链构象多态性分析，以及抗户尘螨特异性IgE(抗d_1sIgE)、抗粉尘螨特异性IgE(抗d_2sIgE)、抗屋尘异性IgE(抗h_1 sIgE)、抗多价食物特异性IgE(包括鸡蛋白、牛奶、鱼、花生、小麦、黄豆，抗fx5E sIgE)、抗多价霉菌特异性IgE(包括点青霉、分枝孢菌、烟曲霉、白色念珠菌、交链孢菌、蠕孢菌，抗mx_2 sIgE)比较，初步探讨HLA-DRB基因对免疫调节的作用。
第一部分：选用序列特异性引物聚合酶链反应(Polymerase Chain Reaction, PCR)方法，对AD患者进行HLA-DRB等位基因分型，结果在外源性AD(Extrinic type of "pure" AD, EAD)组和合并有哮喘和变应性鼻炎组DR_3基因频率高于对照组(P＜0.05)，而DR_6基因频率低于对照组(P＜0.05)。内源性AD(Instrinic type of
硕士研究生学位论文
，讲e，’AD，IAD)组各等位基因与对照组比较均无统计意义。EAD组HLA~D凡的
相对危险度(Rel如ve凡sk，RR)是5 27，HLA~D风的双是0.10，合并有哮喘和变
应性鼻炎组HLA~DR3的RR值是3.59，HLA臼D风的既是0，该结果提示携带有
HLA.D凡的个体较易患EAD，携带有HLA一D风的个体较不易患病。HLA口D风是外
源性异位性皮炎的易感基因，HLA.D风是外源性异位性皮炎和同时伴有哮喘和变应
性鼻炎的异位性皮炎患者的抗陛基因。
第二部分:用PCR-单链构象多态性技术(Single~S饥川d CO刊自nn曲。
Pof帅o印hism，SsCP)对HLA一D凡阳性的16例AD患者和5例健康对照者的D凡
扩增产物进行分析，结果只有1例AD患者的ssCP带型与正常对照不同(卜0.05)，
提示携带有H工A .DR3的个体较易患AD，但该个体的I丑A一R3基因与正常人比较可
能无碱基差别，并非因为HLA~DR3基因突变导致AD的发病。
第三部分:用放射变应源吸附实验(R月dloalle堪05份beni Test，RAST)检测
HLA~D凡阳性患者血清抗hls域、抗dl slgE、抗也slgE、抗mXZsl四、抗丘SE slgE，
结果16例标本中，1例抗h，sl萝阳性，3例抗dlslgE阳性，12例抗也51萝阳性，1
例抗叮以2 slgE阳性，4例抗丘SE slgE阳性，HLA.D凡与抗姚slgE比较有统计意义
(P<0.05)。提示粉尘蜗进入机体后、，经抗原呈递细胞(内正gen阮望城运9 Cell，APC)
加工处理后，‘育舒哆特异地和HLAOR3分子结合，形成复合物，然后被飞细胞识别，
刺激分泌白介素并和白介素13，诱导产生特异性IgE，从而调节机体对粉尘蜗的免疫
应答，导致异位性皮炎的发生。
Atopic Dermatitise (AD) is a chronic inflammatory skin disease, and is often accompanied by families history. Serum IgE level is high and asthma and allergic rhinitis often exit. Pathogenesis is not well known. It is agreed that AD is a polygenic disease, heritage and environment leading to its development Foreign learner pay more and more attention to the susceptible gene(ig.l3q12,3q21,1q21) of AD. Howerer,they didn't reach an agreement. This might relate to the difference of AD diagnostic criterion,penetrance,,study strategy,ect. The distributive frequency varies in different areas and ethnics. So it is necessary to study the susceptible gene of AD in tianjin area.
Human Leucocyte Antigen(HLA) plays a key role in immunoreactivity, especially HLA-II gene region, which regulate immunoreactivity by immunoreactive gene and immunoinhibit gene and attend the heritacy control of immunoreactivity. Thus we can know further the pathogenesis of AD by studying the relation between AD and HLA-II gene.
In our study, HLA-DRB allele is tested,single-strand conformation polymorphism (SSCP) of DR3 is analysized and anti-h1 sIgE,anti-d1 sIgE,anti-d2 sIgE,anti-mx2 sIgE,anti-fx5E slgE is compared,to investigate the function of HLA-DRB in immunity regulation.
First part:Polymerase Chain Reaction(PCR) is used to classify the HLA-DRB allel. The DR3 frequency of extrinic type of "pure" AD (BAD) group and complicated group is higher than cntrol(P<0.05),DR6 lower than control(P<0.05). There is no significance between instrinic type of "pure" AD (IAD) and control. In EAD,the relative rate(RR) of HLA-DR3,HLA-DR6 is 5.27, 0.10 respectively. In AD companing asthma and allergic rhinitis ,it is
3.59, 0.00 respectively. It is indicated that people with HLA-DR3 are reliable to EAD,while people with HLA-DRg are not. HLA-DR3 is the susceptible gene of BAD, while HLA-DRj is the resistant gene of BAD and AD companing asthma and allergic rhinitis.
Second part: DR3 multiphified products of 16 AD patients and 5 healthy controls with HLA-DR3 positive are tested by PCR-SSCP. There is only one patient whose SSCP band type is different from that of controls(PX).05). It is shown that indiduals carrying HLA-DR3 are reliable to AD, But there is no base difference between these people and the heality. It is not HLA-DR3 gene mutation that lead to the development of AD.
Third part: Radioallergosorbent Test (RAST) is used to test the serum anti-h1 slgE ,anti-d, sIgE,anti-d2 sIgE,anti-mx2 sIgE,anti-fx5E sIgE in HLA-DR3 positive patients.Among 16 specimens,one anti-h, sIgE,three anti-d, slgE, twelve anti-d2 sIgE, one anti-mx2 sIgE,four anti-fx5E sIgE positive ,respetively. The comparsion between DR3 and anti-d2 sIgE has significance(P<0.05). It is indicated that entering the bodg,mite can be processed by antigen presenting cell(APC), then combine with HLA-DR3 specifically and form complex which can be identified by Th2 cell,stimulating the secretion of IL-4JL-13 and inducing the development of specific IgE. In this way, the immunoreactivity of body to mite is regulated and AD is induced.
人类白细胞抗原(Human Leucocyte Antigen, HLA)在免疫应答中起关键作用，尤其是HLA-Ⅱ类基因区，可通过免疫应答基因和免疫抑制基因调节人的免疫应答，参与免疫应答的遗传控制。因此研究AD与HLA-Ⅱ类基因的关系可进一步明确AD发病机制。
本研究主要检测HLA-DRB等位基因，DR_3基因的单链构象多态性分析，以及抗户尘螨特异性IgE(抗d_1sIgE)、抗粉尘螨特异性IgE(抗d_2sIgE)、抗屋尘异性IgE(抗h_1 sIgE)、抗多价食物特异性IgE(包括鸡蛋白、牛奶、鱼、花生、小麦、黄豆，抗fx5E sIgE)、抗多价霉菌特异性IgE(包括点青霉、分枝孢菌、烟曲霉、白色念珠菌、交链孢菌、蠕孢菌，抗mx_2 sIgE)比较，初步探讨HLA-DRB基因对免疫调节的作用。
第一部分：选用序列特异性引物聚合酶链反应(Polymerase Chain Reaction, PCR)方法，对AD患者进行HLA-DRB等位基因分型，结果在外源性AD(Extrinic type of "pure" AD, EAD)组和合并有哮喘和变应性鼻炎组DR_3基因频率高于对照组(P＜0.05)，而DR_6基因频率低于对照组(P＜0.05)。内源性AD(Instrinic type of
硕士研究生学位论文
，讲e，’AD，IAD)组各等位基因与对照组比较均无统计意义。EAD组HLA~D凡的
相对危险度(Rel如ve凡sk，RR)是5 27，HLA~D风的双是0.10，合并有哮喘和变
应性鼻炎组HLA~DR3的RR值是3.59，HLA臼D风的既是0，该结果提示携带有
HLA.D凡的个体较易患EAD，携带有HLA一D风的个体较不易患病。HLA口D风是外
源性异位性皮炎的易感基因，HLA.D风是外源性异位性皮炎和同时伴有哮喘和变应
性鼻炎的异位性皮炎患者的抗陛基因。
第二部分:用PCR-单链构象多态性技术(Single~S饥川d CO刊自nn曲。
Pof帅o印hism，SsCP)对HLA一D凡阳性的16例AD患者和5例健康对照者的D凡
扩增产物进行分析，结果只有1例AD患者的ssCP带型与正常对照不同(卜0.05)，
提示携带有H工A .DR3的个体较易患AD，但该个体的I丑A一R3基因与正常人比较可
能无碱基差别，并非因为HLA~DR3基因突变导致AD的发病。
第三部分:用放射变应源吸附实验(R月dloalle堪05份beni Test，RAST)检测
HLA~D凡阳性患者血清抗hls域、抗dl slgE、抗也slgE、抗mXZsl四、抗丘SE slgE，
结果16例标本中，1例抗h，sl萝阳性，3例抗dlslgE阳性，12例抗也51萝阳性，1
例抗叮以2 slgE阳性，4例抗丘SE slgE阳性，HLA.D凡与抗姚slgE比较有统计意义
(P<0.05)。提示粉尘蜗进入机体后、，经抗原呈递细胞(内正gen阮望城运9 Cell，APC)
加工处理后，‘育舒哆特异地和HLAOR3分子结合，形成复合物，然后被飞细胞识别，
刺激分泌白介素并和白介素13，诱导产生特异性IgE，从而调节机体对粉尘蜗的免疫
应答，导致异位性皮炎的发生。
Atopic Dermatitise (AD) is a chronic inflammatory skin disease, and is often accompanied by families history. Serum IgE level is high and asthma and allergic rhinitis often exit. Pathogenesis is not well known. It is agreed that AD is a polygenic disease, heritage and environment leading to its development Foreign learner pay more and more attention to the susceptible gene(ig.l3q12,3q21,1q21) of AD. Howerer,they didn't reach an agreement. This might relate to the difference of AD diagnostic criterion,penetrance,,study strategy,ect. The distributive frequency varies in different areas and ethnics. So it is necessary to study the susceptible gene of AD in tianjin area.
Human Leucocyte Antigen(HLA) plays a key role in immunoreactivity, especially HLA-II gene region, which regulate immunoreactivity by immunoreactive gene and immunoinhibit gene and attend the heritacy control of immunoreactivity. Thus we can know further the pathogenesis of AD by studying the relation between AD and HLA-II gene.
In our study, HLA-DRB allele is tested,single-strand conformation polymorphism (SSCP) of DR3 is analysized and anti-h1 sIgE,anti-d1 sIgE,anti-d2 sIgE,anti-mx2 sIgE,anti-fx5E slgE is compared,to investigate the function of HLA-DRB in immunity regulation.
First part:Polymerase Chain Reaction(PCR) is used to classify the HLA-DRB allel. The DR3 frequency of extrinic type of "pure" AD (BAD) group and complicated group is higher than cntrol(P<0.05),DR6 lower than control(P<0.05). There is no significance between instrinic type of "pure" AD (IAD) and control. In EAD,the relative rate(RR) of HLA-DR3,HLA-DR6 is 5.27, 0.10 respectively. In AD companing asthma and allergic rhinitis ,it is
3.59, 0.00 respectively. It is indicated that people with HLA-DR3 are reliable to EAD,while people with HLA-DRg are not. HLA-DR3 is the susceptible gene of BAD, while HLA-DRj is the resistant gene of BAD and AD companing asthma and allergic rhinitis.
Second part: DR3 multiphified products of 16 AD patients and 5 healthy controls with HLA-DR3 positive are tested by PCR-SSCP. There is only one patient whose SSCP band type is different from that of controls(PX).05). It is shown that indiduals carrying HLA-DR3 are reliable to AD, But there is no base difference between these people and the heality. It is not HLA-DR3 gene mutation that lead to the development of AD.
Third part: Radioallergosorbent Test (RAST) is used to test the serum anti-h1 slgE ,anti-d, sIgE,anti-d2 sIgE,anti-mx2 sIgE,anti-fx5E sIgE in HLA-DR3 positive patients.Among 16 specimens,one anti-h, sIgE,three anti-d, slgE, twelve anti-d2 sIgE, one anti-mx2 sIgE,four anti-fx5E sIgE positive ,respetively. The comparsion between DR3 and anti-d2 sIgE has significance(P<0.05). It is indicated that entering the bodg,mite can be processed by antigen presenting cell(APC), then combine with HLA-DR3 specifically and form complex which can be identified by Th2 cell,stimulating the secretion of IL-4JL-13 and inducing the development of specific IgE. In this way, the immunoreactivity of body to mite is regulated and AD is induced.
引文
1. Schultz LF Atopic dermatitis: a genetic-epidemiologic study in a population-based twin sample. J Am Acad Dermatol. 1993,28(5 Pt 1):719-23
2. Bradley M,Kockum I,Soderhall C Characterization by phenotype of families with atopic dermatitis. Acta Derm Venereol. 2000;80(2): 106-10.
3．顾恒，陈祥生，陈崑 特应性皮炎诊断标准的评价 中华皮肤科杂志，2000，33(4)：222～226．
4．金伯泉 细胞和分子免疫学 世界图书出版公司，1998，248～9
5. Campbell RD, Trosdale J. Map of the human MHC. Immunolopy Today 1993,14:349-52
6. Bodmer JG, Marsch SGE, Albert ED Nomenclature for factors of the HLA system, 1991. Hum Immunol 1992;34:4-18
7. Tak WM,john JL,simard DK Handbook of Immune Response Genes Dlenum Press. New York 1998,16-24
8．林学颜，张玲 现代细胞与分子免疫学科学出版社，1999，101～2
9. Albert ED,Bodmer WF, Bontrop RE Nomenclature for factors of the HLA system,2002. Tissue Antigen 2002,60:407-64
10. Brown JH, Jardetzky Three dimensional structure of the human class Ⅱ histocompatibility antigen HLA-DR1. Nature 1993;364:33-9
11．龚非力 基础免疫学 湖北科学技术出版社 1998，355
12. Svejgaard A,Platz P, Ryder LP HLA and disease 1982-a survey, Immunol Rev 1983;70:191-218
13． Coleman RC Genetic studies of atopy and atopic dermatitis. British Journal of Dermatology. 1997; 136:1-5
14． Hidehisa MD,Shoji MD HLA and atopic dermatitis with high serum IgE levels. J Allergy Clin Immunol 1994:94:575-83
15． Hidehisa MD,Shoji MD Analysis of disease-associated amino acid epitopes on HLA class II molecules in atopic dermatitis. J Allergy Clin Immunol 1995:96:1061-8
16． Svejgaard E, Jakobsen B,Svejgaard A studies of HLA-ABC and DR antigens in pure atopic dermatitis and atopic dermatitis combined with allergic respiratory disease. Acta Derm Venered. 1985,114(8) : 72-6
17． 钱起丰，徐静娟 异位性皮炎患者中HLA单倍型A30-B13-DR7的分布 临床皮肤 科杂志 1995(2) ：89
18． Li PK,Poon AS,Hawkins BR Restriction fragment Length polymorphism of HLA-DQ and-DR allogenotypes in normal southern Chinese. Tissue Antigen 1993 ,NOV;42(5) :502-8
19． Imanishi T, Akaza T, Kimura A Allele and haplotype frequencies for HLA and complement loci in various ethnic groups. Ibid, 1998,101 (9) : 1065
20． Wuthrich,Brunello MD Clinical aspects epidemiology, and prognosis of AD. American College of Allergy, Asthma,&Immunology. 1999,83(5) :464-70
21． 谭建明，谢桐，徐琴君 人类白细胞抗原-DR标准血清学分型与基因分型的比较 研究Nail Med J China 1997，77(1) ：28-30
22． Hershey GK, Friedrich Mf,Esswein LA The association of atopy with a gain-of-function mutation in the alpha subunit of the interleukin-4 receptor. N Ergl J Med. 1997,337(24) : 1720-5
23． 林万明，杨瑞馥，黄尚志 PCR技术操作和应用指南 人们军医出版社 1993，161
24． Benacerraf B, Mcdevitt O Histocompatibility-linked immune response genes. Science 1972,175:273
25． MalcolmB,Deborah MB HLA-DR2,[HLA-B7,SC31,DR2] ,and[HLA-B8,SC01,DR3] Haplotypes Distinguish Subjects with Asthms from those with Rhinits only in ragweed pollen allergy. The Journal of Immunology 1992,148(52) :411-6
26． Howell WM, Holgate ST HLA genetics and allergic disease. Thorax 1995;50:815-8
27． Blumenthal MN,Caraballo L HLA-linked susceptibility to house dust mite-induced asthma. Dis Markers 1989,7(4) :201-8
28． Perichon B,Krishnamoorthy R Asthma and HLA system. Alleg-Immunol 1991,23:301-30
29． Caraballo LR, Hernandez M HLA haplotype segregation in families with allergic asthma. Tissue Antigen 1990;35:182-6
30． Scalabrin DM3avbek S Use of specific IgE in assessing the relevance of fungal and dust mite allergens to atopic dermatitis:a comparison with asthmatic and nonasthmatic control subjects. J Allergy Clin Immunol 1999;104:1273-9
31． Sauda T, Yasue T Effectiveness of house mite allergen avoidance through clean room theragy in Patients with AD. J Allergy Clin Immunol 1992;89:653-7
32． Tan BB, Wealel D Double blind controlled trial of effect of house dust mite allergen avoidance on atopic dermatitis. Lancet 1996;347:15-8
33． Schafer T, Heinrich J Association between severity of atopic eczema and degree of sensitization to aeroallergens in schoolchildren. J Allergy Clin Immunol 1999; 104:1280-4
34． Shoji MD, Masami Bs Polymorphisms of transporter associated with antigen processing genes in actopic dermatitis. J Allergy Clin Immunol 1994:94:565-74
35． Ismail A,Bousaffara R,Kaziz J Polymorphism in transporter antigen peptides gene (TAP1) associated with atopy in Tunisians. J Allergy. Clin Immunol 1997,99(2) :216-23
36． Shoji MD, Masami Bs HLA-DM gene polymorphisms in actopic dermatitis. J Allergy Clin Immunol 1996;98:5192-200
37． Coleman R,Trembath RQHarper JI Genetic studies of atopy and atopic dermatitis. Br J Dermatol 1997,136(1) :1-5
38． Folster-Holst R,Moises HW,Yang L Linkage between atopy and the IgE high-affinity receptor gene at 11q13 in atopic dermatitis families. Hum Genrt 1998,102(2) :236-9
39． Oiso N,Fukai KJshii M interleukin 4 receptor alpha chain polymorphism Gln551 Arg is associated with adult atopic dermatitis in Japan. Br J Dermatol,2000,142(5) : 1003-6
40． Liu X,Nickel R,Beyer K An EL-13 coding region variant is associated with a high total serum IgE level and atopic dermatitis in the German multicenter atopy study (MAS-90) . Allergy Clin Immunol. 2000,106(1Pt1) 167:70
2. Bradley M,Kockum I,Soderhall C Characterization by phenotype of families with atopic dermatitis. Acta Derm Venereol. 2000;80(2): 106-10.
3．顾恒，陈祥生，陈崑 特应性皮炎诊断标准的评价 中华皮肤科杂志，2000，33(4)：222～226．
4．金伯泉 细胞和分子免疫学 世界图书出版公司，1998，248～9
5. Campbell RD, Trosdale J. Map of the human MHC. Immunolopy Today 1993,14:349-52
6. Bodmer JG, Marsch SGE, Albert ED Nomenclature for factors of the HLA system, 1991. Hum Immunol 1992;34:4-18
7. Tak WM,john JL,simard DK Handbook of Immune Response Genes Dlenum Press. New York 1998,16-24
8．林学颜，张玲 现代细胞与分子免疫学科学出版社，1999，101～2
9. Albert ED,Bodmer WF, Bontrop RE Nomenclature for factors of the HLA system,2002. Tissue Antigen 2002,60:407-64
10. Brown JH, Jardetzky Three dimensional structure of the human class Ⅱ histocompatibility antigen HLA-DR1. Nature 1993;364:33-9
11．龚非力 基础免疫学 湖北科学技术出版社 1998，355
12. Svejgaard A,Platz P, Ryder LP HLA and disease 1982-a survey, Immunol Rev 1983;70:191-218
13． Coleman RC Genetic studies of atopy and atopic dermatitis. British Journal of Dermatology. 1997; 136:1-5
14． Hidehisa MD,Shoji MD HLA and atopic dermatitis with high serum IgE levels. J Allergy Clin Immunol 1994:94:575-83
15． Hidehisa MD,Shoji MD Analysis of disease-associated amino acid epitopes on HLA class II molecules in atopic dermatitis. J Allergy Clin Immunol 1995:96:1061-8
16． Svejgaard E, Jakobsen B,Svejgaard A studies of HLA-ABC and DR antigens in pure atopic dermatitis and atopic dermatitis combined with allergic respiratory disease. Acta Derm Venered. 1985,114(8) : 72-6
17． 钱起丰，徐静娟 异位性皮炎患者中HLA单倍型A30-B13-DR7的分布 临床皮肤 科杂志 1995(2) ：89
18． Li PK,Poon AS,Hawkins BR Restriction fragment Length polymorphism of HLA-DQ and-DR allogenotypes in normal southern Chinese. Tissue Antigen 1993 ,NOV;42(5) :502-8
19． Imanishi T, Akaza T, Kimura A Allele and haplotype frequencies for HLA and complement loci in various ethnic groups. Ibid, 1998,101 (9) : 1065
20． Wuthrich,Brunello MD Clinical aspects epidemiology, and prognosis of AD. American College of Allergy, Asthma,&Immunology. 1999,83(5) :464-70
21． 谭建明，谢桐，徐琴君 人类白细胞抗原-DR标准血清学分型与基因分型的比较 研究Nail Med J China 1997，77(1) ：28-30
22． Hershey GK, Friedrich Mf,Esswein LA The association of atopy with a gain-of-function mutation in the alpha subunit of the interleukin-4 receptor. N Ergl J Med. 1997,337(24) : 1720-5
23． 林万明，杨瑞馥，黄尚志 PCR技术操作和应用指南 人们军医出版社 1993，161
24． Benacerraf B, Mcdevitt O Histocompatibility-linked immune response genes. Science 1972,175:273
25． MalcolmB,Deborah MB HLA-DR2,[HLA-B7,SC31,DR2] ,and[HLA-B8,SC01,DR3] Haplotypes Distinguish Subjects with Asthms from those with Rhinits only in ragweed pollen allergy. The Journal of Immunology 1992,148(52) :411-6
26． Howell WM, Holgate ST HLA genetics and allergic disease. Thorax 1995;50:815-8
27． Blumenthal MN,Caraballo L HLA-linked susceptibility to house dust mite-induced asthma. Dis Markers 1989,7(4) :201-8
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