HLA—B51与中国北方汉族中的白塞氏病相关联

对１２０例白塞氏病患者和１００名无关健康人进行了ＨＬ－Ａ－Ａ、－Ｂ、－Ｃ、－ＤＲ和－ＤＱ抗原分型检测，并使用Ｌｙｍｐｈｏ－Ｂ－Ｋｗｉｋ分离出Ｂ－淋巴细胞进行ＨＬＡ－ＤＱ和－ＤＲ分型，用琼脂糖电泳，免疫固定等技术测定了Ｂｆ和Ｃ４同种异型。其中５５．８３％（６７／１２０）患者中检出ＨＬＡ－Ｂ５１，而对照组仅１２％，Ｘ＾２和ＲＲＷ     

中国广东地区汉族补体C4遗传多态性分析

采用国际补体参考实验室方法，分析了广东地区３１９例无血缘关系汉族人Ｃ４多态性。共检出５个Ｃ４Ａ和８个Ｃ４Ｂ同种异型：Ｃ４Ａ５、４、３、２及Ｑ０和Ｃ４Ｂ５、４、２、１、９１、９６、９５及Ｑ０。Ｃ４Ａ以Ａ＊３频率（０．６５３８）最高，Ａ＊４（０．１６３５）、Ａ＊Ｑ０（０．１３９４）及Ａ＊２（０．０４１７）次之。Ｃ４Ｂ以Ｂ＊２（０．４４０７）和Ｂ＊１（０．４１０３）最高，Ｂ＊Ｑ０（０．０９４６）、Ｂ＊４（０．０２４０）及Ｂ＊５（０．０１６０）次之。其余Ｃ４同种异型少见（基因频率均＜０．０１）。杂合Ｃ４ＡＱ０和杂合Ｃ４ＢＱ０表型个体占总体的２３．５１％和１４．１１％，纯合Ｃ４ＡＱ０（Ｃ４ＡＱ０，Ｑ０）和纯合Ｃ４ＢＱ０（Ｃ４ＢＱ０，Ｑ０）均占２．５１％，纯合Ｃ４ＡＱ０、ＢＱ０（Ｃ４ＡＱ０，Ｑ０ＢＱ０，Ｑ０）占０．９４％。此外，发现６例Ｃ４Ｂ重复位点。经Ｈａｒｄｙ－Ｗｅｉｎｂｅｒｇ卡方检验，Ｃ４Ａ和Ｃ４Ｂ基因频率分布达到遗传平衡。     

HLA与IgA缺陷症相关性研究

对２０例ＩｇＡ缺陷症患者进行了ＨＬＡ－Ａ、ＤＲＢ１、ＤＱＡ、ＤＱＢ１位为的抗原分型，同时对１０７例正常进行Ａ、Ｂ分型，其中９１人进行ＤＲ、ＤＱ分型作为对照组。发现ＨＬＡ－ＤＲＢ１＊０８０２（０．２０）ＤＱＡ１＊０４０１（０．２０）、ＤＱＢ１＊０４０２（０．２０）的升高具有显著意义，且这３个位点完全集中在同一条单倍型上。结果表明，选择性ＩｇＡ缺陷症患者确定存在着某些易感基因，在本病的病因和发病机理中     

北方汉族过敏性紫癜与HLA相关性研究

为了研究过敏性紫癜（ＡＰ）的发病机理中是否有免疫遗传因素参与，采用国际通用的ＮＩＨ标准微量淋巴细胞毒试验方法检测４０例ＡＰ患者的ＨＬＡ－Ⅰ类抗原，并与１００例北方汉族正常人ＨＬＡ－Ⅰ类抗原频率进行比较。利用聚合酶链反应－序列特异性引物技术（ＰＣＲ－ＳＳＰ）对其中３０例ＡＰ患者进行ＨＬＡ－Ⅱ类基因分型，并与１０４例北方汉族正常人的ＨＬＡ－Ⅱ类基因频率进行了比较。发现ＡＰ患者ＨＬＡ－Ａ３０＋３１、Ｂ１３、Ｂ３５、Ｂ４０抗原频率较对照组明显增高（Ａ３０＋３１：Ｐｃ＜０．０１，ＲＲ＝７．９７；Ｂ１３∶ＰＣ＜０．０１，ＲＲ＝６．００，Ｂ３５∶Ｐｃ＜１０－５，ＲＲ＝１０．４０；Ｂ４０∶Ｐｃ＜０．０５，ＲＲ＝３．８５）。ＨＬＡ－ＤＲ１０基因频率在ＡＰ患者较正常对照组明显增高（ＤＲ１０∶Ｐｃ＜１０－５，ＲＲ＝２１．８８），而ＨＬＡ－ＤＱ３、ＤＱ６基因频率较正常对照组明显降低（ＤＱ３∶Ｐｃ＜１０－５，ＲＲ＝０．１３；ＤＱ６∶Ｐｃ＜０．０５，ＲＲ＝０．２３）。提示ＡＰ与ＨＬＡ－Ａ３０＋３１、Ｂ１３、Ｂ３５、Ｂ４０、ＤＲ１０正相关，与ＨＬＡ－ＤＱ３ＤＱ６负相关。     

过敏性哮喘病人备解素因子B的遗传多态性

对６２名已知ＨＬＡ型别的无血缘关系的过敏性哮喘（ＡＡ）患者及４９６名健康人员的ＥＤＴＡ抗凝血浆用琼脂糖高压电泳及免疫固定的方法进行Ｂｆ分型。ＡＡ患者组中，ＢｆＳＳ、ＢｆＳＦ、ＢｆＳＳ０．７、ＢｆＦＦ、ＢｆＦＳ０．７表型分布频率与正常对照组比较均无统计学意义上的差别。提示Ｂ因子本身与ＡＡ发病无直接关联。但把Ｂｆ抗原与ＤＲ、ＤＱ抗原结合起来分析则发现ＡＡ病人中有ＤＲ７、ＤＱ２、ＢｆＳＦ这一表型的频率远远高于正常对照组，ＲＲ值高达２５．７，（ｘ２＝１１．２０，Ｐ＜０．０１）。而ＤＲ７、ＤＱ２、ＢｆＳＦ表型频率则低于正常对照组，ＲＲ值为０．０６（ｘ２＜＝７．２６，Ｐ＜０．０５）这一结果提示编码ＤＲ７、ＤＱ２和ＢｆＳＦ的基因不论以反式或顺式同时存在在染色体上时就大大增强了个体对ＡＡ的易感程度。     

上海地区多发性硬化症与HLAⅡ类基因和抗原处理相？…

探讨上海人群中ＨＬＡⅡ类基因和抗原处理相关基因与多发性硬化症的相关性。方法,用ＰＣＲ－ＲＦＬＰ和ＰＣＲ－ＳＳＯ技术对２１名上海地区无血缘关系的ＭＳ患者和８９名正常人作ＨＬＡⅡ类（ＨＬＡ－ＤＲＢ１,－ＤＱＡ１和－ＤＱＢ１）和抗原处理相关基因（ＴＡＰ１,ＴＡＰ２和ＬＭＰ２）分型。结果患者组ＤＲＢ１＊０４０５、Ｔ 克＊０５０２（Ｐ＝０．００２５）等位基因ＤＲＢ１＊０４０５－ＤＱＡ１＊０３０１－ＤＱＢ１＊     

I型糖尿病患者的HLA—DR—DQ基因单体型分析

应用ＨＬＡ－ＤＲＢ，ＤＱＢ１序列特异性引物ＰＣＲ扩增方法，鉴定８１例ＩＤＤＭ患者，７个家系和８４例正常对照汉族人群的ＤＲＢ基因多态性及ＩＤＤＭ的ＨＬＡ－ＤＲ－ＤＱ基因单体型。结果表明：（１）ＩＤＤＭ患者ＤＲＢ１＊０３，ＤＲＢ１＊０９等位基因频率明显高于对照组，其频率分别为８．６４％ｖ．ｓ３．０％和２８．４％ｖ．ｓ１６．１（Ｐ〈０．０５）。（２）患者中ＤＲＢ１－ＤＲＢ３／ＤＲＢ１－ＤＲＢ４基因型频率     

IL－4对多发性骨髓瘤患者外周血细胞CD20及HLA－DR表达的影响

本文报道用流式细胞分析技术，检测了２８例多发性骨髓瘤（ＭＭ）患者和２０名健康对照者外周血Ｂ细胞（ＣＤ２０＋）以及Ｂ、Ｔ和单核细胞中ＨＬＡ－ＤＲ＋细胞比率。结果发现，ＭＭ患者ＣＤ２０＋以及Ｂ、Ｔ及单核细胞中ＨＬＡ－ＤＲ＋细胞比率与正常对照组差异非常显著（Ｐ＜０．０１）。加入重组ＩＬ－４，可使８名ＭＭ患者ＣＤ２０＋、ＨＬＡ－ＤＲ＋ＣＤ２０＋、ＨＬＡ－ＤＲ＋单核细胞比率提高非常显著（Ｐ＜０．０１）。而在Ｔ细胞，Ｐ值则＞０．０５。我们认为由于ＩＬ－４分泌减少，一方面使多克隆Ｂ细胞激活及增殖受抑，另一方面使单核细胞ＨＬＡ－ＤＲ抗原表达减少，抗原提呈能力下降可能是ＭＭ发生多克隆免疫球蛋白抑制的重要原因。     

家族性热性惊厥与HLA—D区基因关联性的研究

为探讨家族性热性惊厥与ＨＬＡ－Ｄ区基因的关系，应用限制性片段长度多态性方法，对５０个简单型热性惊厥（ｆｅｂｒｉｌｅｃｏｎｖｕｌｓｉｏｎｓ，ＦＣ）患儿及家系成员进行了人类白细胞抗原（ＨＬＡ）ＤＲ、ＤＱ区等位基因分型，并以１０１例健康人做对照。结果显示，ＨＬＡ－ＤＲ、ＤＱ区各等位基因在ＦＣ患者及有ＦＣ史亲属组中的频率较健康对照组无明显增高；而ＨＬＡ－ＤＲβ９（ＨＬＡＤＲＢ１＊０９０１）及ＤＱβ３ａ（ＤＱＢ１＊０３０２－０３０３，０４０１－０４０２）等位基因的表型频率较健康对照组明显降低。家系中无ＦＣ史亲属组中ＨＬＡ各等位基因的分布与健康对照组无差异。结果提示，ＨＬＡ－ＤＲ、ＤＱ基因区域内未发现与ＦＣ易感性有关的等位基因型。作为健康人群中频率最高的等位基因型。ＨＬＡ－ＤＲβ９和ＤＱβ３ａ等位基因可能具有某种生物学优势，在抵抗ＦＣ发病中起一定作用。     

Ⅰ型糖尿病患者的HLA-DR-DQ基因单体型分析

应用ＨＬＡ－ＤＲＢ，ＤＱＢ１序列特异性引物ＰＣＲ扩增方法，鉴定８１例ＩＤＤＭ患者，７个家系和８４例正常对照汉族人群的ＤＲＢ基因多态性及ＩＤＤＭ的ＨＬＡ－ＤＲ－ＤＱ基因单体型。结果表明：（１）ＩＤＤＭ患者ＤＲＢ１＊０３，ＤＲＢ１＊０９等位基因频率明显高于对照组，其频率分别为８．６４％ｖ．ｓ３．０％和２８．４％ｖ．ｓ１６．１（Ｐ＜０．０５）。（２）患者中ＤＲＢ１－ＤＲＢ３／ＤＲＢ１－ＤＲＢ４基因型频率明显高于对照组，即１９．８％ｖ．ｓ６．７％（Ｐ＜０．０５）。（３）首次证明ＤＲＢ１＊１２等位基因与中国人ＩＤＤＭ正相关。上述结果提示不同种族ＨＬＡ－ＤＲ型别分布的差异，可能是不同种族人群ＩＤＤＭ发病率变化的分子基础。     

Strong Association of Idiopathic Membranous Nephropathy (IMN) with HLA-DR 3 and MT-2 without Involvement of HLA-B 18 and no Association to BfF1

The present study investigated the distribution of HLA-antigens and Bf alleles in a group of 21 patients suffering from biopsy proven Idiopathic Membranous Nephropathy (IMN). A statistically significant increase of HLA-DR3 (76.2%) was detected in the patient group as well as an increase of MT-2 (86%), which is a new supertypic specificity defined within the 8th International Histocompatibility Workshop 1980. No association between BfF1 and IMN can be deduced from this study. Only the common Bf alleles (BfFF, BfFS, BfSS) were found in the patient group presented here. Also the previously reported association between HLA-B18 and IMN was not corroborated by this study. Not a single IMN-patient typed positive for HLA-B 18. Thus the presence of two different HLA-DR-Bf-B linkage groups (HLA-DR3/BfF1/HLA-B18 and HLA-DR3/Bf; all alleles/HLA-B8) may point to at least two different immunological mechanisms underlying IMN.     

HLA-linked genetic markers in Chinese and other Oriental populations

The polymorphic variants of the HLA-linked genetic markers Bf, C2, C4 and GLO—I were studied in three mongoloid populations. Analysis of linkage disequilibrium between these markers and HLA-A, B, C and DR antigens was carried out on test results from 140 unrelated Chinese individuals. The phenotypes BfS and GLO-2 were found at significantly higher frequencies than in Caucasians. BfS was associated with B12 in Japanese but not in Chinese. A single individual with the rare Bf variant SI was found. No C2 deficient individuals were observed. The C2C (common) allele occurred at a gene frequency of 0.949 and the more basic allele C2B at 0.039. The acidic variant, C2A, was observed at a frequency of 0.011 and appeared to be associated with BfF. Eighty-nine per cent of the Chinese were phenotypically C4FS. In contrast to Bf and C2, each of which is coded for by codominant alleles at a single genetic locus, C4 is coded for by two genes, C4F (Rodgers) and C4S (Chido). The C4F locus allele, C4F1 (extra fast), was strongly associated with HLA-B17, as has been found in other populations, but a new association of the C4S locus deficiency allele, C4s° (Ch-), with B17 was also observed. All HLA-B17;C4s° haplotypes were BfS positive. As has been previously found in Caucasian populations, individuals of the C4F phenotype (i.e. genotypically Fs°Fs°) were all found to be Chido negative. The frequencies of the various HLA-linked genetic markers, however, as much as the frequencies and associations of the HLA antigens themselves, distinguish these populations from other ethnic groups.     

Three-Point Association of HLA-A,B,Bf Haplotypes Deduced in 200 Parents of 100 Families

The association of HLA-A and -B antigens with Bf alleles was investigated in 200 parents from 100 unrelated families. There were significant associations between HLA-A3 and Bf-F, B7 and Bf-S, B8 and Bf-S, B12 and Bf-F, and BW35 and Bf-F. Three-point HLA-A,B,Bf haplotype frequencies, linkage disequilibrium parameters, and chi-square values were determined both from the genotype and from the pheno-type data. Although the HLA-B,Bf associations involve antigens that are also present in the highly associated A,B and B,D haplotypes of the Caucasian population, there was—with the possible exception of HLA-A3,B7,Bf-S–no significant three-point association for HLA-A,B,Bf.     

HLA antigens and complotypes in insulin-dependent diabetes mellitus

One hundred and thirty-six Finnish patients with insulin-dependent (type I) diabetes mellitus were investigated for the HLA-A, B, D and DR antigens as well as the Bf and C4 allotypes. The statistically significant increase in the frequencies of HLA-A9, B8, B15, Dw3, Dw4, DR3, DR4, C4A0 and C4B3 was observed when compared with the healthy controls. About 79% of the patients had HLA-DR4, and 53% had HLA-DR3 antigens. A rare C4 allele C4B3 was found in 21% of the patients, whereas only in 2% among the controls (relative risk 16.35). The etiological fraction (EF) values indicated that HLA D/DR alleles were the best markers for IDDM, the observed EF for HLA-DR4 in diabetes was as high as 0.70. Examination of HLA, Bf and C4 phenotypes suggested that at least two supratypes "B15 BfS C4A3B3 D(R)4" and "B8 BfS C4A0B1 D(R)3" were markers for the susceptibility to type I diabetes, one third of our patients had either of these supratypes. The protective role of DR2 and Dw2 antigens was also confirmed: no HLA-Dw2 positive patients and only one with HLA-DR2 was found.     

DNA polymorphism of major histocompatibility complex class II and class III genes in systemic lupus erythematosus

We investigated the Taq I digested DNA restriction fragment length polymorphism (RFLP) of the Major Histocompatibility Complex (MHC) class II genes: HLA-DRB, -DQA, and the class III genes: C4 and 21-hydroxylase(CYP21) in 56 caucasoid patients with systemic lupus erythematosus (SLE) and 62 control subjects in order to define the molecular variation of these genes and their association with SLE. The results showed that the gene frequencies of both HLA-DR2 and -DR3 were significantly increased in the SLE population compared to normal subjects (DR2: 21.4% vs 10.7% chi 2 = 4.5. DR3: 29.6% vs 13.3%; chi 2 = 8.3). A high frequency of C4A and CYP21A gene deletions was also found in SLE patients (SLE 52%, normals 24%). All of 22 SLE patients, and 12 of 15 normal subjects who had C4A and CYP21A gene deletions had a 10.0kb Taq 1 DRB RFLP attributable to the presence of HLA-DR3. Family studies showed linkage of C4A/CYP21A deletions with HLA-B8 and -DR3, and confirmed the previously demonstrated association of the HLA-B8, DR3, C4A*Q0, C4*B1, Bf*S, C2*C haplotype with SLE. Deletions affecting the C4A and CYP21A genes were the commonest cause of C4A null alleles in SLE. No strong association between C4 null phenotype or C4 gene deletion, as determined by RFLP, was observed in patients who possessed DR2.     

HLA-A,B,C and DR antigens, GLO I and Bf marker profiles in 75 Cape Coloured patients with systemic lupus erythematosus (SLE)

HLA-A,B,C and DR antigens were tested in 75 Cape Coloured systemic lupus erythematosus (SLE) patients, and the GLO I and Bf markers in 51. The patients with HLA-DR2 had a relative risk significantly greater than one (p=0.0005). Twenty-two (29%) patients had only one detectable DR antigen. Of these, 11 (50%) were found to have DR2 only. The HLA-DR7 antigen was associated with severe disease (p less than 0.02). Bf and GLO I markers were not associated with SLE.     

Evaluation of sequence-specific priming and real-time polymerase chain reaction assays for detecting HLA-B*51 alleles confirmed by sequence-based typing

The human leukocyte antigen (HLA)-B*51 genotype is one of the well-known genetic factors associated with the development of Behcet's disease. We evaluated three sequence-specific priming (SSP) assays and one real-time PCR assay for detecting HLA-B*51 alleles using 93 whole blood samples, which were genotyped by high-resolution sequence-based typing (SBT). All HLA-B*51 alleles determined by SBT were detected by the four evaluated assays, and the results for all HLA-B alleles other than HLA-B*51 were negative on all assays. Thus, all HLA-B51 tests showed 100% sensitivity and 100% specificity for detecting HLA-B*51 alleles. The three SSP assays and the real-time PCR test for HLA-B*51 genotyping are simple, but reliable for detecting HLA-B*51 alleles in clinical laboratories.     

Allelic distribution of HLA-B*5 in HLA-B5-positive Israeli patients with Behçet''s disease

In order to investigate the sub-typing of the B5 antigen in Israeli (Jewish and Arabic) patients with Beh?et's disease (BD) allele-specific genotyping of B51 and B52 alleles was performed in Israeli BD patients and healthy controls. Among the HLA-B51-positive BD patients, B*5101 was found to be the predominant allele, identified in 62% of all BD patients and 78% of Jewish BD patients. HLA-B*5101 was also the predominant allele in HLA-B51-positive healthy controls. HLA-B*5108 and B*5104 alleles were identified in 23% and 15% of B51-positive BD patients, respectively. The HLA-B*5201 allele was identified in all HLA-B52-positive patients and controls. Our study suggests that both HLA-B*5101 and HLA-B*5201 are the dominant alleles of HLA-B5 in Israeli BD patients.     

Extended HLA haplotypes in families with insulin-dependent diabetes mellitus in Northern Finland

Haplotypes including HLA, Bf and C4 loci were analyzed in a material comprising 55 families with diabetic children. One hundred and ten haplotypes found in IDDM patients were compared with 101 haplotypes present only in healthy family members. Two complotypes, BfSC4A3B3 and SC4A0B1 . were significantly more common (P <0.05) in the diabetic haplotypes, and these were in most cases found in haplotypic combinations with HLA-B15,Dw4,DR4 and HLA-B8.Dw3,DR3 genes, respectively. The B8/DR3 haplotype was better conserved, as 72% included the BfSC4A0B1 complotype as compared with only 35% of the B15/DR4 haplotypes with "high risk" C4A3B3 complement alleles (p <0.05). DR3 was found in 26% of the diabetic haplotypes and DR4 in 43%. DR4 associated with the Dw4 in 69% of cases and with D w14 in 26% of the diabetic haplotypes. Our results confirm that the two phenotypes found earlier to be associated with IDDM in Northern Finland, e.g. "B15, BfS, C4A3B3, Dw4, DR4" and "B8, BfS, C4A0B1, Dw3, DR3" are inherited as haplotypes.     

A weak association of HLA-B*2702 with Behçet's disease

This study aimed to analyse the association of HLA-B alleles other than -B51 with Beh?et's disease (BD). We also investigated the frequency of HLA-B alleles sharing the same natural killer cell immunoglobulin-like receptor (KIR) binding sequence with HLA-B51. Broad-genotyping of HLA-B locus by PCR-SSOP in 174 Turkish BD patients and 191 healthy controls confirmed the strong association of B*51 with BD (60.9% in BD patients, 24.6% in healthy controls, OR = 4.78). No other HLA-B allele was identified showing an association with BD after adjusting for multiple testing or by using relative predispositional effects (RPE) analysis after the deletion of B*51. HLA-B alleles reacting with the sequence specific oligonucleotide probe 23, which corresponds to the KIR binding site of B*51, were found to be positive in 127 BD patients (73%) and 90 controls (47%) (OR = 3.03, 95% CI 2-4.7). The repeated RPE analysis after separating HLA-B alleles carrying B51-KIR binding sequence as distinct alleles within a broad-type allele group revealed B*2702 allele as the only allele showing an association with BD after the deletion of B*51. Selective increase of B*2702, the only B*27 allele carrying the same KIR binding sequence with B*51, warrants investigation of the possibility of interaction of HLA molecules with KIRs on NK or other T cells in the pathogenesis of BD.