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Biomedical subjects

H A Stephens

Publications and source records attributed to H A Stephens.

At least 19 recordsLinked to original sources
PubMed2005

Does the polymorphism of MHC class II promoters matter?

The promoters of genes of the major histocompatibility complex vary not only because of linkage disequilibrium with their coding sequences but also, we argue, because of natural selection that acts particularly strongly on MHC II gene promoters. Thus, the promoter of H2Eb varies more than that of H2K, to an extent that cannot be accounted for by coding variation, and the same applies to HLA.DRB1 in comparison with H2D. We discuss how transduction by lentivirus vectors followed by adoptive transfer of monoclonal T cells could be used to test the functional activity of variant mouse promoters in vivo, and how homologous recombination in suitable cell lines might provide a short cut to obtaining promoter knock-ins.

Animals↗
PubMed2001

HIV-specific cytotoxic T lymphocytes, HLA-A11, and chemokine-related factors may act synergistically to determine HIV resistance in CCR5 delta32-negative female sex workers in Chiang Rai, northern Thailand.

Understanding how highly HIV-exposed individuals remain HIV uninfected may be useful for HIV vaccine design and development of new HIV prevention strategies. To elucidate mechanisms associated with resistance to HIV infection, immunologic and genetic factors were examined in 14 HIV-exposed but persistently seronegative (HEPS) female sex workers from Chiang Rai, northern Thailand and in ethnically matched, HIV-positive (n = 9) and HIV-negative women (n = 9). The HEPS women were identified in a study of commercial sex workers who had an HIV-1 incidence of 20.3 per 100 person-years. A high frequency of HLA-A11 was observed in HEPS women (86%) compared with northern Thai controls (56%). HIV-specific cytotoxic T lymphocyte (CTL) lytic responses were detected in cryopreserved peripheral blood mononuclear cells (PBMCs), using HLA-A-matched subtype E HIV-1 peptides in four of seven (57%) HEPS women, eight of eight HIV-positive women, and zero of nine HIV-negative unexposed controls (p = 0.019 HEPS women vs. HIV-negative controls). CTL lysis levels were low, but responses were detected to peptides from Nef, Pol, Gag, and Env. Nef responses predominated in HEPS women. Compared with controls, HEPS women tended to have higher frequencies of CCR5 promotor 59402GG and SDF-1 3'UTR 801A genotypes known to influence HIV transmission or course of disease. HEPS women also had higher levels of spontaneous RANTES production by PBMCs than other groups. Each of these factors could potentially contribute to HIV resistance. As most HEPS women had one or more of these factors, they may prevent HIV infection synergistically by blocking HIV cell entry, delaying its dissemination, or killing HIV-infected cells.

Adult↗
PubMed2001

Distribution of natural killer cell immunoglobulin-like receptor sequences in three ethnic groups.

Killer cell immunoglobulin-like receptors (KIRs) are members of a group of molecules that specifically recognize HLA class I ligands and are found on subsets of human lymphopoetic cells. The number of KIR loci can vary between individuals, resulting in a heterogeneous array of possible KIR genes. The range of observed profiles has been explained by the occurrence of two haplotype families termed A and B which can be distinguished on the basis of certain KIR sequences. Here we attempted to determine whether the frequencies of putative KIR loci and the two haplotype groups vary in three ethnically defined, healthy, and unrelated control populations, namely UK Caucasoid (n=136), Palestinian (n=105) and Thai (n=119). We molecularly typed genomic DNA for the presence of 12 putative KIR loci, KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL4, KIR3DL1, KIR3DL2, KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS4, KIR2DS5, and KIR3DS1, using modified PCR sequence-specific primers. The patterns of KIR locus frequencies combined with the similar linkage disequilibrium values suggest that there was a distinction in the distribution of the two broad haplotype groups between the populations studied. The A haplotype was always the most prevalent, but the ratio of A to B varied between populations. The frequency of B haplotype was highest in the Palestinians and lowest in the Thais (Pc<0.0001).

Alleles↗
PubMed2001

MICA and MICB genes: can the enigma of their polymorphism be resolved?

The human MHC class I chain-related genes (MICA and MICB) are located within the HLA class I region of chromosome 6. Their organization, expression and products differ considerably from classical HLA class I genes. MIC proteins are considered to be markers of "stress" in the epithelia, and act as ligands for cells expressing a common activatory natural killer-cell receptor (NKG2D). Molecular models are now available for the MICA protein, both bound and complexed with NKG2D. MICA molecules appear to be highly flexible and polymorphic, although the functional relevance and implications of their polymorphism have yet to be fully discerned.

Alleles↗
PubMed2000

Genes of the class II and class III major histocompatibility complex are associated with typhoid fever in Vietnam.

The influence of genes of the major histocompatibility complex (MHC) class II and class III loci on typhoid fever susceptibility was investigated. Individuals with blood culture-confirmed typhoid fever and control subjects from 2 distinct geographic locations in southern Vietnam were genotyped for HLA-DRB1 and HLA-DQB1 alleles, the gene that encodes tumor necrosis factor (TNF)-alpha (TNFA [-238] and TNFA [-308]), the gene that encodes lymphotoxin-alpha, and alleles of the TNF-alpha microsatellite. HLA-DRB1*0301/6/8, HLA-DQB1*0201-3, and TNFA*2 (-308) were associated with susceptibility to typhoid fever, whereas HLA-DRB1*04, HLA-DQB1*0401/2, and TNFA*1 (-308) were associated with disease resistance. The frequency of all possible haplotypes of the 3 individually associated loci were estimated and were found to be significantly different in typhoid case patients and control subjects (chi2=55.56, 32 df; P=.006). Haplotypes that were either protective (TNFA*1 [-308].DRB1*04) or predisposed individuals to typhoid fever (TNFA*2 [-308].DRB1*0301) were determined. This report identifies a genetic association in humans between typhoid fever and MHC class II and III genes.

Alleles↗
PubMed2000

A comparison of molecular HLA-DR and DQ allele profiles forming DR51-, DR52-, and DR53-related haplotypes in five ethnic Thai populations from mainland southeast Asia.

Using PCR-SSOP typing we have deduced the composition and frequency of HLA-DRB1, -DRB3, -DRB4, -DRB5, -DQA1, and -DQB1 alleles present in DR51-, DR52-, and DR53-related haplotypes, in 519 individuals representative of five ethnic Thai populations recruited in central, northeastern and northern Thailand. In total, we have unequivocally detected at varying frequencies, 17 DR51-related haplotypes, 24 DR52 haplotypes, and 12 DR53 haplotypes in the study groups. We document evidence of north-south gradients of DR51-related haplotypes, whereby the overall frequency of DR51-containing haplotypes is relatively more common in the northern Thai groups. Similarly, within DR53-related haplotypes the frequency of DRB1*0901-containing haplotypes increases in the more northerly groups, and an inverse effect was observed with DRB1*0701-containing haplotypes that were relatively more common in the northeastern and central Thais. We have also compared the class II haplotype profiles of the Thais with the equivalent profiles reported in other non-Thai ethnic groups from mainland and insular SE Asia. One DR51-related haplotype DRB1*1502x, DRB5*0102x, DQA1*0101/4, DQB1*0501, would appear to be characteristic of Thai populations, as it was the most common DR2 haplotype in all five study groups and is also prevalent in other mainland southeast Asians, but is much less evident in the more northern populations of eastern Asia or China.

Alleles↗
PubMed1999

MIC-A allele profiles and HLA class I associations in Behçet's disease.

Recently a new family of non-classical MHC molecules, the MHC class I chain-related protein (MIC), encoded by genes located in the major histocompatability complex have been identified. On the basis of the location of MIC genes and the structure and expression of MIC molecules it has been postulated that MIC may be a susceptibility factor in Behçet's disease (BD). We investigated the association of the 16 described external domain alleles and the transmembrane triplet repeats of MIC-A with BD in a Middle Eastern population. DNA from ninety-five patients and 102 age- and sex-matched controls were analyzed by polymerase chain reaction using allele specific primers. Our results show an increase of MIC-A*009 in the BD patient group 44/95 (46%) compared with controls 24/102 (24%) (chi2=11.3, OR=2.8, P=0.00078). MIC-A*009 was also found to be strongly associated with HLA-B51 in the patients 39/44 (88%) when compared with controls 10/24 (42%) (chi2=4, P=0.04). MIC-A*009 was also found in linkage disequilibrium with HLA-B52, but only in controls. The A6 form of a MIC-A transmembrane triplet repeat was found to be significantly raised in the patients (80/95; 84%;) compared with controls (58/102, 57%) (chi2=17.5, OR=4, P=0.000028). Although the MIC-A associations described are highly significant, the association with HLA-B51 independently remains the most significant factor (chi2=56.8, P<10(-6)). The data suggests that as both MIC-A*009 and A6 are in strong linkage disequilibrium with HLA-B51, they are unlikely to be the susceptibility gene for BD but may be markers for additional risk factors.

Adolescent↗
PubMed1999

Towards a molecular phototyping system for allelic variants of MICA, encoded by polymorphisms in exons 2, 3 and 4 of MHC class I chain-related genes.

In this study we have developed a polymerase chain reaction-sequence-specific primer (PCR-SSP) or phototyping system to analyse the polymorphism of the human MICA gene locus. By scrutinising the reported MICA sequence variations in exons 2, 3 and 4 which encode the extracellular protein domains, we have selected and tested 20 MICA-specific primer mixes that should discriminate between the majority of homozygous and heterozygous combinations of MICA alleles 001-016. We have tested this scheme on DNA prepared from a large number of well-characterised tissue culture cell lines with previously reported MICA nucleotide sequences and found an excellent correlation with the observed PCR-SSP phototypes. We believe that this scheme can also be modified to detect new MICA alleles when they are characterised, as well as be incorporated into standard phototyping protocols to generate allele and haplotype profiles of both classical and non-classical HLA gene loci in test DNA samples.

Alleles↗
PubMed1998

HLA-DR and -DQ associations with melioidosis.

Melioidosis is an important infectious disease of southeast Asia caused by an intracellular bacterium, Burkholderia pseudomallei. Cellular immunity is postulated to play important roles in immunity to melioidosis that may influence the severity and clinical outcome of the disease. The present study was undertaken to investigate possible associations of melioidosis with HLA class II alleles. HLA typing of HLA-DRB1, -DQA1, and -DQB1 was performed using polymerase chain reaction and sequence-specific oligonucleotide hybridization (PCR-SSO). Seventy-nine melioidosis patients and 105 healthy, ethnically and geographically matched controls were studied. Among 24 DRB1 alleles, 7 DQA1 alleles, and 13 DQB1 alleles identified in this population, an association with melioidosis was observed with DRB1*1602 which was increased in melioidosis patients (10.1%) compared to normal controls (4.8%), p = 0.047 (odds ratio (OR) = 2.25). In addition, significant increase of DRB1*1602 allele frequency and decrease of DQA1*03 were also observed in septicemic melioidosis patients, the most severe form of the disease (p = 0.01, OR = 3.10; and p = 0.047, respectively). Furthermore, a trend of association of DRB1*0701, DQA1*0201, and DQB1*0201 with relapse cases of melioidosis was also noted. In contrast, no HLA association was observed in localized melioidosis or melioidosis with diabetes mellitus. These findings provide the suggestive evidence of an immunogenetic basis of certain aspects of melioidosis.

Alleles↗
PubMed1998

Serological and molecular analysis of HLA class I and II alleles in Thai patients with psoriasis vulgaris.

The HLA class I and class II alleles in 67 patients with type I psoriasis vulgaris, 23 patients with type II psoriasis vulgaris and 140 healthy individuals were analyzed. The frequencies of HLA-A2, -B46, -B57 and DQB1*0303 were significantly increased in type I psoriasis compared to the controls (Pc<0.05). Molecular analysis of HLA-A2 alleles showed an increase in HLA-A*0207 and a decrease in HLA-A*0203 in type I psoriasis. HLA-DQB1*0301 was significantly decreased in type I psoriasis compared to the normal controls (Pc<0.05). No association of any alleles with type II psoriasis was observed. This data demonstrated two susceptible haplotypes: HLA-A1-B57-DRB1*0701-DQA1*0201-DQB1*0303 (AH57.1) and HLA-A2-B46-DRB1*0901-DQA1*0301-DQB1*0303 (AH46.1) for type I psoriasis in the Thai population. Besides, the haplotype AH46.1 was also associated with type II psoriasis.

Adult↗
PubMed1998

Predominance of HLA-restricted cytotoxic T-lymphocyte responses to serotype-cross-reactive epitopes on nonstructural proteins following natural secondary dengue virus infection.

We examined the memory cytotoxic T-lymphocytic (CTL) responses of peripheral blood mononuclear cells (PBMC) obtained from patients in Thailand 12 months after natural symptomatic secondary dengue virus infection. In all four patients analyzed, CTLs were detected in bulk culture PBMC against nonstructural dengue virus proteins. Numerous CD4+ and CD8+ CTL lines were generated from the bulk cultures of two patients, KPP94-037 and KPP94-024, which were specific for NS1.2a (NS1 and NS2a collectively) and NS3 proteins, respectively. All CTL lines derived from both patients were cross-reactive with other serotypes of dengue virus. The CD8+ NS1.2a-specific lines from patient KPP94-037 were HLA B57 restricted, and the CD8+ NS3-specific lines from patient KPP94-024 were HLA B7 restricted. The CD4+ CTL lines from patient KPP94-037 were HLA DR7 restricted. A majority of the CD8+ CTLs isolated from patient KPP94-024 were found to recognize amino acids 221 to 232 on NS3. These results demonstrate that in Thai patients after symptomatic secondary natural dengue infections, CTLs are mainly directed against nonstructural proteins and are broadly cross-reactive.

CD4-Positive T-Lymphocytes↗
PubMed1997

HLA-A, -B, -DRB1, -DQA1, and -DQB1 polymorphism in Thais.

In this study we examined HLA-A, -B, -DRB1, -DQA1, and -DQB1, gene allele, and haplotype frequencies in two ethnic Thai populations. We compared these frequencies to the known HLA class I and II allele profiles of non-Thai mainland and insular Southeast (SE) Asians. HLA-A locus gene and allele frequencies, are comparatively homogeneous in both Thai and non-Thai SE Asians. In contrast, HLA-B; -DRB1, -DQA1, and -DQB1 gene and allele frequencies, show more ethnic and geographic variation in SE Asians. Conserved haplotypes, or combinations of linked HLA class I and II alleles were detected in Thais, but at relatively low frequencies. It would appear that ethnic Thais, reflect an admixture of peoples from both the northern mainland and southern island groups of SE Asia.

China↗
PubMed1997

HLA class II allele frequencies in northern Thais (Kamphaeng Phet).

The polymorphism of HLA class II genes (HLA-DRB1, -DQA1, -DQB1 and -DPB1) was investigated in 97 normal Northern Thais (NT) from Kamphaeng Phet province using PCR-SSO typing. Allele frequencies (AF) have been determined. DRB1*1202 (17.5%), DRB1*1502 (16.5%), DQA1*0101 (25.8%), DQA1*0102 (21.7%), DQB1*0502 (22.7%), DPB1*0501 (23.2%) and DPB1*1301 (22.7%) showed the highest frequencies in each locus. These results were more similar to those observed in Present-day Thais (PDT) and Central Thais (CT) than Northern Thais from Chiang Mai (CM) and Dai Lue (DL). However, the data presented in this population study should be useful in many fields, such as anthropology, organ transplantation, disease susceptibility and evolutionary genetics.

Alleles↗
PubMed1995

The presence of the HLA class II allele DPB1*0501 in ethnic Thais correlates with an enhanced vaccine-induced antibody response to a malaria sporozoite antigen.

In this study, we examined the correlation between the frequency of allelic variants of the class II human leukocyte antigen (HLA) DR, DQ and DP gene loci and the quantitative humoral immune response observed in 71 Thai volunteers, subsequent to vaccination with a conjugated subunit vaccine. This vaccine was designed to induce antibodies directed against the immunodominant repeat region of the Plasmodium falciparum circumsporozoite (CS) protein. The presence of the DPB1*0501, a relatively common allele in Asian populations, was found to be associated with high vaccine-induced CS repeat-specific antibody responses in the volunteers. Given the increasing focus on the use of subunit vaccines in the control of infectious diseases, consideration of the influence of class II allele frequencies in ethnically diverse recipient populations may be important.

Adult↗
PubMed1994

HLA-DPB1 polymorphism in the Thais of Southeast Asia.

In this study we examined DPB1 allele frequencies in five ethnic Thai populations resident in different regions of Thailand and neighboring countries. In contrast to other Asian and Pacific populations such as the Japanese, Chinese, Korean, and Papua New Guineans, where DPB1*0501 has consistently been shown to be the most frequent allele, NE Thais and Thai-Khmers demonstrate a prevalence of DPB1*1301. Comparison of DPB1 allele frequencies in the Thais of SE Asia, with known frequencies in the Chinese and Japanese populations of E Asia, would appear to confirm previous calculations of genetic divergence between these Oriental populations.

Alleles↗
PubMed1992

Identification of genetic susceptibility loci for insulin-dependent diabetes in Sudan.

In this study we report, for the first time, the molecular analysis of HLA-DR and DQ gene frequencies in a large cohort of well-characterized type 1 (insulin-dependent) diabetes mellitus (IDDM) patients (n = 72), and ethnically matched controls (n = 59) collected in sub-Saharan Africa. High molecular mass DNA was prepared and analysed in Southern blots and by oligonucleotide typing. We have shown a strong positive association between IDDM and the Asp 57- DQB1 allele *0201 (DQw2). A rare DR4, DQw2 haplotype was also identified at high frequency in the IDDM cohort. We can now confirm that the association between Asp 57- DQB1 alleles and IDDM, previously reported in ethnically diverse cohorts collected in Western Europe, North America, and South Asia, is also present in an IDDM cohort collected in Africa.

Adolescent↗
PubMed1992

HLA-DP polymorphism in Sudanese controls and patients with insulin-dependent diabetes mellitus.

Human leukocyte antigen (HLA) genes are candidates for susceptibility to insulin-dependent diabetes mellitus (IDDM). The association of IDDM with particular DR and DQ alleles has been reported in all populations studied, but its association with HLA-DP alleles has been controversial. To address this question we analyzed 19 DPB1 and 2 DPA1 alleles and their associations in well-characterized Sudanese (an admixture of Arab and Black) IDDM patients (n = 71) and ethnically matched controls (n = 86) using polymerase chain reaction-sequence specific oligonucleotide (PCR-SSO) typing. There were no significant differences between the patient and control groups in the DPB1 frequencies. DPB1*0201, *0401 and DPA1*01 were the most frequent alleles in both IDDM patients and control subjects. Significant positive and negative associations between DPB1 and DPA1 alleles were detected in both groups. A novel DPB1 allele included in DPB1*1701 was identified.

Alleles↗