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。     

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     

华北汉族人群HLA单倍型研究

对北京附近河北省固安县地区的１０３个多子女家庭进行了ＨＬＡ－Ａ、Ｂ、Ｃ、ＤＲ、Ｂｆ、Ｃ２、Ｃ４Ａ、和Ｃ４Ｂ等八个位点的等位基因的分型，分析了八个位点的ＨＬＡ扩展单倍型，揭示出中国华北地区汉族人群ＨＬＡ单倍型的面貌。研究证明ＨＬＡ单倍型各位点间的等位基因呈高度的连锁不平衡，并显示出中国人不同于其他人种的特点。同时讨论了ＨＬＡ单倍型分析的重要意义。     

T细胞表面6种细胞表型的变化与大型癌分期及术式的关系

应用流式细胞仪检测３９例大肠癌患者手术前后Ｔ细胞表面６种细胞表型。发现随着Ｄｕｋｅｓ分期的增高，术前ＣＤ３，ＣＤ４，ＣＤ４／ＣＤ８，ＣＤ１６，ＣＤ６９及ＣＤ＾３＋／ＨＬＡ－ＤＲ＾＋下降，ＣＤ８逐渐增高；Ａ期大肠癌患者机体免疫功能活跃，术前ＣＤ３，ＣＤ４高于对照组，ＣＤ８，ＣＤ４／ＣＤ８，ＣＤ１６，ＣＤ＾＋３／ＨＬＡ－ＤＲ＾＋与对照组相同．     

中国广东汉族群体HLAⅡ类基因多态性的研究

为探讨中国广东汉族群体ＨＬＡⅡ类基因多态性，采用ＰＣＲ／ＳＳＯ方法，随机选择１０２名广东籍汉族人进行了ＨＬＡⅡ类基因的ＤＮＡ分型。测定了包括ＨＬＡ－ＤＲＢ１，ＤＲＢ３，ＤＲＢ５，ＤＱＡ１，ＤＱＢ１和ＤＰＢ１等６个基因座位的等位基因。结果：共检出２３种ＤＲＢ１，３种ＤＲＢ３，４种ＤＲＢ５，８种ＤＱＡ１，１２种ＤＱＢ１和１２种ＤＰＢ１基因。该人群的ＨＬＡⅡ类等位基因多态性的典型性表现在ＨＬＡ－ＤＲＢ＊１２０２的不寻常优势和ＤＲＢ１＊０２单倍型的结构的高度复杂性。还发现了很高频率的一个近年才被正式命名的ＤＰ新型：ＨＬＡ－ＤＰＢ１＊２１０１，并且此型具有极不寻常的ＤＲＢ１＊１２０２－ＤＰＢ１＊２１０１的连锁不平衡。为分子流行病学研究提供了资料。     

抗磷脂抗体阳性SLE患者HLA DRB1、DQA1、DQB1基因单倍型研究

本文采用ＰＣＲ ＲＦＬＰ技术对抗磷脂抗体阳性（ＡＰＡ＋）ＳＬＥ患者ＨＬＡ ＤＲＢ１、ＤＱＡ１ 和ＤＱＢ１ 基因进行分型研究, 同时以上海地区汉族随机人群作对照, 发现这类病人的ＤＲＢ１＊ ０８０３ ＤＱＡ１＊ ０１０３ ＤＱＢ１ ＊０６０１ 单倍型频率显著增高（ Ｐ＜ ０－０１） 相对危险率为４－４５, 说明该疾病与此单倍型存在着很强的关联。     

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。     

HLA—DR,DQ基因多态性与系统性红斑狼疮相关性的研究

应用聚合酶链反应结合顺序特异的寡核苷酸探针杂交（ＰＣＲ／ＳＳＯＰＨ）方法对江苏籍汉族ＳＬＥ患者和健康对照组ＨＬＡ－ＤＲＢ１、ＤＱＡ１：ＤＱＢ１基因作寡核苷酸分型。结果发现患者组中ＤＲＢ１＊１５０１、ＤＱＡ１＊０１０２等位基因频率及ＨＬＡ－ＤＲＢ１＊１５０１、－ＤＱＡ１＊０１０２、－ＤＱＢ１＊０６０２单倍型频率均明显高于正常对照组；相反，ＤＲＢ１＊０４（ＤＲ４）、ＤＱＡ１＊０６０１频率则明显低于正常对照组。所有ＤＱＢ１等位基因频率在两组间无显著差异，而ＤＱＡ１＊０１０２仅存在于ＤＲ２阳性的个体之中，推测汉族ＳＬＥ的易感基因可能靠近ＤＲ位点，且与单倍型ＨＬＡ－ＤＲＢ１＊１５０１、－ＤＱＡ１＊０１０２、－ＤＱＢ１＊０６０２紧密连锁，该单倍型可作为汉族ＳＬＥ易感的遗传标记。相反ＤＲ４，ＤＱＡ１＊０６０１则对ＳＬＥ发病可能有一定的保护性。     

HLA多态性在广东汉族人群分布的特殊性

目的探讨人类白细胞抗原（ｈｕｍａｎｌｅｕｃｏｃｙｔｅａｎｔｉｇｅｎＨＬＡ）在广东汉族群体中的遗传特征。方法采用免疫磁珠单抗血清学技术进行ＨＬＡ－Ａ、Ｂ分型和聚合酶联反应－序列特异性引物（ｓｅｑｕｅｎｃｅｓｐｅｃｉｆｉｃｐｒｉｍｅｒｓＰＣＲ－ＳＳＰ）进行ＨＬＡ－ＤＲ、ＤＱ分型,调查了４０６名广东汉族健康献血员。结果识别ＨＬＡ－Ａ、Ｂ、ＤＲ和ＤＱ座位１０６个特异性,４１４２条单倍型,发现ＨＬＡ－Ａ３３－Ｂ５８－ＤＲ１７－ＤＱ２和ＨＬＡ－Ａ２－Ｂ４６－ＤＲ９－ＤＱ９在广东汉族中呈现高频率。结论ＨＬＡ－Ａ３３－Ｂ５８－ＤＲ１７－ＤＱ２和ＨＬＡ－Ａ２－Ｂ４６－ＤＲ９－ＤＱ９,这两条单倍型在广东汉族人群中的分布频率与相关文献其他民族和人群相比为显著连锁不平衡单倍型。     

T细胞表面6种细胞表型的变化与大肠癌分期及术式的关系

应用流式细胞仪检测３９例大肠癌患者手术前后Ｔ细胞表面６种细胞表型，发现随着Ｄｕｋｅｓ分期的增高，术前ＣＤ３、ＣＤ４、ＣＤ４／ＣＤ８、ＣＤ１６、ＣＤ６９及ＣＤ３＋／ＨＬＡ－ＤＲ＋逐渐下降，ＣＤ８逐渐增高（Ｐ＜０．０５）；Ａ期大肠癌患者机体免疫功能活跃，术前ＣＤ３、ＣＤ４高于对照组（Ｐ＜０．０５），ＣＤ８、ＣＤ４／ＣＤ８、ＣＤ１６、ＣＤ３＋／ＨＬＡ－ＤＲ＋与对照组相同；根治及姑息性切除术后，ＣＤ８降低，ＣＤ３、ＣＤ４、ＣＤ４／ＣＤ８、ＣＤ１６、ＣＤ６９、ＣＤ３＋／ＨＬＡ－ＤＲ＋升高（Ｐ＜０．０５）；肿瘤未切组术后ＣＤ３、ＣＤ１６、ＣＤ４／ＣＤ８进一步下降（Ｐ＜０．０５）。提示大肠癌患者术前免疫状态与疾病的程度呈负相关，切除肿瘤有益于改善患者细胞免疫功能。     

HLA-associated susceptibility to HIV-1 infection.

We studied HLA antigen distribution of 50 heterosexual partners of HIV+ drug abusers with more than 1 year of sexual exposure to HIV, 36 children born to seropositive mothers and 61 haemophiliac patients exposed to presumably infectious clotting factor concentrates. B52 and B44 antigens were associated with HIV resistance while B51 was associated with HIV susceptibility. Forty-nine HIV+ drug abusers, spouses of heterosexual partners studied and 25 HIV+ mothers of the children were also typed. DR11 phenotype was associated with infectiousness of HIV+ subjects. Our data suggest that the HLA region controls susceptibility to infection with HIV and infectiousness of HIV+ subjects in different risk groups.     

Mismatched human leukocyte antigen alleles protect against heterosexual HIV transmission.

Genetic variation at the human leukocyte antigen (HLA) loci has been shown to be an important risk factor for progression to HIV disease, but its significance in infection is less well understood. We have investigated its role in HIV transmission in a cohort of individuals at risk for heterosexual infection. Analysis of over 80 individuals revealed that that the degree of concordance at HLA A, B, and DR loci differs significantly between transmitting and nontransmitting couples at risk for heterosexual HIV transmission (p <.02), suggesting that allogeneic immune responses may confer a degree of protection against HIV infection. Analysis of the frequencies of specific alleles at the A, B, and DR loci revealed a significantly higher frequency of HLA DR5 among exposed uninfected individuals, relative to population controls.     

Major histocompatibility complex genes influence the outcome of HIV infection: Ancestral haplotypes with C4 null alleles explain diverse HLA associations

Several alleles at multiple HLA loci have been found to be associated with infection with human immunodeficiency virus (HIV): HLA A1; B8, B35; Cw7, Cw4; DR1, DR3 and DQ1, are associated with particular disease manifestations and/or disease progression. Furthermore, in a pilot study we have shown an increase in the frequency of C4 null alleles and suggested that all the reported HLA alleles could reflect association with a limited number of ancestral haplotypes (AHs).

On this occasion, we studied 122 Caucasoid patients classified according to Centers for Disease Control (CDC) criteria. The control group consisted of 67 seronegative homosexual or bisexual males at risk of developing HIV infection.

C4 null alleles were unequivocally present in 58% of patients in CDC IV compared with 33% of the seronegative subjects (x² = 5.65, p < 0.05). Furthermore, C4 null alleles could be excluded in only 8% and 16% of CDC III and IV, respectively, but in 30% of the seronegative subjects. An increased frequency of three AHs largely accounted for the increases in C4 null and HLA alleles.

To examine the role of specific AHs we undertook a longitudinal analysis of a subgroup of 26 patients who seroconverted under observation. Seventeen of these patients were followed for 32 to 63 months. All seven patients with the 8.1 AH (A1, CW7, B8, BfS, C4AQ0, C4B1, DR3, DQ2) developed low CD4 lymphocyte counts (<450 × 10⁶/l) compared with only 2 of 10 patients without this haplotype (p < 0.002). All three deaths occurred in patients with the 8.1 AH. The acquired immunodeficiency syndrome developed in three further cases with either 8.1- or B35- bearing (35.x) haplotypes. Sequential CD4/8 ratios showed an early and progressive decline in individuals with 8.1 or 35.x. Since the 8.1 and 35.x AHs contain deletions of the central major histocompatibility complex (MHC) genes, we suggest that the genes affecting HIV infection and progression are within the central MHC region.     

Characterization of an HLA‐C‐restricted CTL response in chronic HIV infection

HIV‐specific CTL play an important role in the host control of HIV infection. HIV‐nef may facilitate escape of HIV‐infected cells from CTL recognition by selectively downregulating the expression of HLA‐A and HLA‐B molecules, while surface expression of HLA‐C is unaffected. The HLA‐C‐restricted CTL responses have previously been largely ignored and poorly characterized. We examined the frequency, function, and phenotype of HLA‐C‐restricted CTL in ten antiretroviral therapy‐naïve Caucasian and African individuals with chronic HIV‐1 infection (for at least 8 years; CD4 cell counts in the range of 50–350) who carried the HLA‐Cw04 allele. HLA‐Cw04‐restricted CTL that recognize a conserved epitope within HIV‐1 envelope (aa 375‐383 SF9) were analyzed using IFN‐γ ELISPOT assays and phenotypic analysis was carried out by flow cytometry. HLA‐C‐restricted CTL play an important role in the HIV‐specific response, and can account for as much as 54% of the total response. HLA‐C‐restricted CTL are functionally and phenotypically identical to HLA‐A‐ and HLA‐B‐restricted CTL. HLA‐C‐restricted CTL in chronic HIV infection are memory cells of an intermediate phenotype, characterized by high CD27 and low CD28 expression and lack of perforin production.     

Major histocompatibility complex (MHC) factors predisposing to and protecting against Graves' eye disease

We investigated the influence of gene mapping within the major histocompatibility complex on the susceptibility to Graves' eye disease. We studied 133 randomly selected patients with Graves' disease, many of whom had eye disease. HLA B8 and DR3 carried the greatest risk for disease but the difference between the two patient groups was not statistically significant. An earlier finding that Hungarian patients with a subset of B8, (B8 + DR7 +) had a greatly enhanced risk for eye disease was confirmed in Newfoundland patients. HLA B8 and DR7 are probably carried on different homologous chromosomes and their interaction enhances eye disease. HLA-DR4 was negatively correlated with eye disease. In particular, a subset of DR4 (B35 + DR4 +) appears to protect against eye disease. We have also derived the haplotypes of 22 probands, half of whom had eye disease. The haplotype data emphasized the high frequency of HLA A1 B8 DR3 C4A*QO and C4B*1 in both patient groups, 15% of the haplotypes in the group with eye disease and 25% in that without eye disease. Forty-one percent of haplotypes in the eye disease group and 32% in the no eye disease group were either C4A*QO or C4B*QO. In one proband with eye disease B8 and DR7 were carried on separate chromosomes. The phenotype DR4, C4A*3 C4B*1 was found in 3/20 haplotypes of patients without eye disease but in 0/20 of patients with eye disease. This finding is in keeping with the increased frequency of the DR4 C4A*3 C4B*1 in the patient group with no eye disease when 94 patients were phenotyped.(ABSTRACT TRUNCATED AT 250 WORDS)     

HLA antigen and haplotype frequencies in Greeks

A random panel of 189 healthy Greek subjects was HLA typed for A, B and DR antigens. The alleles of these loci were found to be in Hardy-Weinberg equilibrium. Compared with other European Caucasoid populations, the frequencies of A9, B5, B18, B35, DR2 and DR5 were raised and that of B8 lowered. Significant linkage disequilibrium was found between a number of A/B, B/DR and A/DR antigen combinations. Some of the antigen associations usually seen in Caucasoid populations were also present in this sample (A1-B8-DR3, B14-DR1, B15-DR4) although others were missing (A3-B7-DR2, B35-DR1, B44-DR4). In addition, some antigen combinations have not been previously described. The most frequent two locus haplotypes in the Greek population are B8-DR3 and B18-DR5.     

HLA‐A, ‐B, ‐DR allele group frequencies in 7007 kidney transplant list patients in 27 UK centres

This observational study aims to determine the HLA specificity frequencies of patients on the UK renal transplant list, which can be used as a resource for those laboratories that support the UK renal transplant programme. Whilst the HLA specificity frequencies may differ from that of the general population, it is the individuals on the transplant list who are in need of a new kidney, which has to be provided from the general population. Any differences in protein allele frequencies between this patient population and the general population are likely to be minimal because of the very large number of patients included. The HLA‐A, ‐B and ‐DR allele group frequencies from 7007 patients on the UK kidney transplant list (August, 2009) were analysed. HLA types had been submitted to NHSBT to register patients on the UK deceased donor kidney waiting list. The data were submitted from 27 different registering centres throughout the UK. Within this data set, 25 different HLA‐A, 50 HLA‐B and 18 HLA‐DR allele groups were present. The most common allele groups at each locus were ‐A2 (phenotype frequency 42.6%), ‐B44 (phenotype frequency 23.3%) and –DR4 (phenotype frequency 29.8%). The least common allele groups at each locus were ‐A19, ‐ A43, ‐B16, ‐B21, ‐B22, ‐B83 and ‐DR5. Reports of HLA frequency (protein allotype) data from populations as large as this are not readily available adding value to this observational study.     

HLA antigens and susceptibility to myasthenia gravis

HLA-A, -B, -C and -DR antigen frequencies determined in a group of 73 myasthenia gravis (MG) patients were compared with those of a control group of 205 subjects. The strongest positive association with MG was found antigens B8 and DR3 (relative risks 9.56 and 8.84 respectively). Analysis of our data indicates that both antigens, independently from their linkage disequilibrium, are involved in susceptibility to MG. No relationship between HLA antigens on thymic pathology was observed in our material. In male MG patients the association with DR3 was weaker than in female patients. The difference in DR3 frequency between male and female patients was statistically significant; no significant difference was found for antigen B8. It appears that DR3 contributes to development of MG only in females. In male patients aged more than 30 years at the onset of disease, MG was not associated with B8 or DR3. In contrast, in female patients aged more than 30 years at the onset of disease there was a strong association of B8 and DR3 with the disease.     

HLA disease association and protection in HIV infection among African Americans and Caucasians

In a previous investigation, we demonstrated an increased progression of overt AIDS in the African American population compared to the Caucasian population as reflected by the significantly lower absolute number of CD4+ lymphocytes detected in the African American population in an earlier study. The present study elucidates some of the possible genetic factors which may contribute to disease association or protection against HIV infection. The HLA phenotypes expressed as A, B, C, DR and DQw antigens were revealed by the Amos-modified typing procedure. NIH scoring was utilized to designate positive cells taking up trypan blue. A test of proportion equivalent to the chi 2 approximation was used to compare the disease population (n = 62; 38 African Americans, 24 Caucasians) to race-matched normal heterosexual local controls (323 African Americans, 412 Caucasians). Significant p values were corrected for the number of HLA antigens tested. HLA markers associated with possible protection from infection for African Americans were Cw4 and DRw6, whereas Caucasians expressed none. Disease association markers present in the African American population were A31, B35, Cw6, Cw7, DR5, DR6, DRw11, DRw12, DQw6 and DQw7, whereas in the Caucasian population A28, Aw66, Aw48, Bw65, Bw70, Cw7, DRw10, DRw12, DQw6 and DQw7 were demonstrated. The highest phenotypic frequency for a disease association marker in the study was for HLA-DR5 (62.9%) in the HIV-infected African American population without Kaposi's sarcoma compared to a frequency of 28.9% for the regional control group (p = 0.0012). We conclude that genetic factors do have a role in HIV infection since only 50-60% of those exposed to the AIDS virus will become infected.