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S H Powis

Publications and source records attributed to S H Powis.

At least 37 records · Page 2Linked to original sources
PubMed1999

Human mesangial cells express inducible macrophage scavenger receptor: an Ap-1 and ets mediated response.

BACKGROUND: Type A scavenger (SR) mediate the uptake of modified low-density lipoproteins by macrophages. The accumulation of lipid via this process is thought to lead to foam cell formation in atherosclerotic plaques. Human mesangial cells (HMC), which can be converted to foam cells in vivo, have not previously been shown to express SR in normal culture. We investigated whether or not there was an inducible form of SR in a human mesangial cell line (HMCL). METHODS: SR activity was analyzed by cellular uptake of fluorescently labeled acetylated low-density lipoprotein using a flow cytometer. SR mRNA expression was examined using RT-PCR followed by Southern blotting. To investigate the molecular mechanism of SR expression, several reporter gene constructs were designed. The first contained a full SR promoter, the second a part of the SR promoter that has both activated protein-1 (AP-1) and ets transcriptional factor binding sites. Other constructs were identical to the second except they contained either AP-1 or ets motif mutations. RESULTS: Phorbol 12-myristate 13-acetate (PMA) increased both the percentage of SR positive cells and SR mean fluorescence intensity. PMA also increased SR mRNA and promoter activity in a time and dose responsive manner. Function analysis showed that both AP-1 and ets motifs were specific response elements to PMA stimulation in HMCL. CONCLUSIONS: The present study suggests that the combination of interaction between AP-1 and ets transcriptional factors may mediate the inducible expression of the SR gene in HMCL, which may contribute to foam cell formation.

Binding Sites↗
PubMed1998

Evaluation of IgA deficiency in Sardinians indicates a susceptibility gene is encoded within the HLA class III region.

IgA deficiency (IgA-D) has been associated with the HLA region, in particular with the North European haplotype HLA-A1, -B8, -DR3, but the exact location of the susceptibility gene(s) is unknown. Some reports suggest that a susceptibility gene is encoded in the class II region, while others implicate the class III region. We exploited differences between the common Sardinian and North European HLA-DR3 haplotypes to help localize the IgA-D susceptibility gene(s). With the knowledge that approximately 13% of HLA-DR3 homozygous individuals of North European origin are IgA-D, we examined 43 HLA-DR3 homozygous Sardinians to find that all had normal serum IgA, IgG and IgM levels. A detailed analysis of their MHC haplotypes indicated a common Sardinian HLA-DR3 haplotype TAP1A, TAP2A, HLA-DQB1*0201, -DQA1*0501, -DRB1*0301, LH1-(Z + 2), D3A-(Z + 2), C4B-0, C4A-L, G11-15, Bf-0-4, C2-a, HSP70-7.5, 9N3-(Z + 10), 82I-(Z - 2), TNFalpha-9, 62-(Z - 20), HLA-B18, -Cw5, -A30 which diverges from the common North European HLA-DR3 haplotype telomeric to the HLA-DR region. In parallel studies of five Sardinians with IgA-D, two of the 10 HLA haplotypes (20%) contained HLA-DR3, a frequency similar to that observed in the background population. One of these was the HLA-DR3- B8 North European haplotype, which occurs rarely in Sardinia. Our data favour the hypothesis that a class III region allele, present on the common North European but not on the Sardinian HLA-DR3 haplotype, confers susceptibility to IgA-D.

Disease Susceptibility↗
PubMed1997

Identification of new HLA class I region genes by sample sequencing.

Although many human major histocompatibility genes have been identified, relatively few have been localized to the class I region. We searched for new class I region genes by sample sequencing, a process in which short stretches of random genomic sequence are generated from cosmids and then compared with sequences deposited in nucleotide databases. Four class I region cosmids were isolated for sample sequencing by screening a chromosome 6 specific cosmid library with probes derived from specific class I region genes or with overlapping class I region yeast artificial chromosomes. Cosmids were sonnicated to produce fragments of 0.5 - 1 kilobases, subcloned, and sequenced using an automated sequencer. Sequences were then compared with nucleotide sequences deposited in the GenBank databases using the BLASTN algorithm. A number of potential new class I region genes were identified, including a cDNA with similarity to the tre oncogene, the trans-activating factor SC1 (TCF19), and a member of the interferon inducible 1 - 8 gene family. These observations suggest that sample sequencing is an efficient method for identifying new class I region genes, which can be applied to other regions of the genome and to other species, and support previous observations that the class I region contains a variety of genes other than those encoding HLA antigens.

Base Sequence↗
PubMed1995

What is the MHC?

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Biological Evolution↗
PubMed1994

Homozygous human TAP peptide transporter mutation in HLA class I deficiency.

Human lymphocyte antigen (HLA) class I proteins of the major histocompatibility complex are largely dependent for expression on small peptides supplied to them by transporter associated with antigen processing (TAP) protein. An inherited human deficiency in the TAP transporter was identified in two siblings suffering from recurrent respiratory bacterial infections. The expression on the cell surface of class I proteins was very low, whereas that of CD1a was normal, and the cytotoxicity of natural killer cells was affected. In addition, CD8+ alpha beta T cells were present in low but significant numbers and were cytotoxic in the most severely affected sibling, who also showed an increase in CD4+CD8+ T cells and gamma delta T cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Insulin-dependent diabetes mellitus and the major histocompatibility complex peptide transporters TAP1 and TAP2: no association in a population with a high disease incidence.

Although many studies have established an association between insulin-dependent diabetes mellitus (IDDM) and the class II region of the human major histocompatibility complex (MHC), it has been difficult to assign susceptibility to a single locus. Recently, two antigen-processing genes, TAP1 and TAP2, have been identified within the region. Previous studies have reached conflicting conclusions as to the role of these genes in IDDM; it is uncertain whether an increased frequency of the allele TAP2A and a concomitant decrease in TAP2B are independent disease associations or secondary to linkage disequilibrium (LD) between TAP2A and HLA-DR3. To further investigate this question, we have characterized TAP1 and TAP2 alleles in 129 IDDM patients from Sardinia, a population with limited genetic heterogeneity and a high disease incidence. When compared to 90 random controls, the only significant difference was a decrease in the minor allele TAP2C in patients. However, when HLA-DR and -DQ matched controls were compared, this difference disappeared. Further analysis suggested that TAP2C was in LD with HLA-DRB1*1401 and subtypes of HLA-DRB1*11, alleles which were not observed in the IDDM population. LD was also observed between other TAP and HLA-DR alleles, in particular between TAP2A and HLA-DR3 in both patients and controls. Our data supports the conclusion that there is no primary association between TAP2 alleles and IDDM, and that previously reported associations may be due to LD with other class II loci.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Analysis of the MHC class II encoded components of the HLA class I antigen processing pathway in ankylosing spondylitis.

OBJECTIVES: The evaluation of the role of polymorphism within the class II encoded antigen processing genes, LMP2 and TAP, in susceptibility to ankylosing spondylitis (AS). METHODS: Eighty five patients with ankylosing spondylitis, 35 B27 positive healthy controls, and 55 unrelated healthy controls were studied. TAP1 and TAP2 alleles were assigned by ARMS PCR, and LMP2 alleles were assigned by restriction enzyme digestion of a PCR product. RESULTS: The TAP1C allele was increased in the AS group (6%) compared with random controls (1%), p = 0.03 and TAP2E was increased in AS (3.5%) compared with random controls (0%), p = 0.05. However, the frequencies of these alleles were also increased in B27 matched controls. There were no differences in LMP2 allele or genotype frequencies between AS and either of the control groups. Partitioning of patients according to presence or absence of uveitis did not reveal any significant associations. CONCLUSIONS: Increases of the minor TAP alleles, 1C and 2E, in AS reflect linkage disequilibrium between these alleles and HLA-B27. Polymorphism of the class I antigen processing pathway does not contribute significantly to AS susceptibility nor to the development of anterior uveitis associated with AS.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

An antigen processing polymorphism revealed by HLA-B8-restricted cytotoxic T lymphocytes which does not correlate with TAP gene polymorphism.

In previous studies of antigen presentation through HLA-B27, we identified a healthy person whose lymphoblastoid cells do not present three B27-restricted viral epitopes to specific cytotoxic T lymphocytes (CTL), despite adequate cell surface expression of HLA-B2702 of normal sequence. Similar findings were observed in all members of his family sharing the HLA-A3-B2702 haplotype. The original donor, NW, carries HLA-B8 on his other class I haplotype, which his daughter, HW, has inherited. We now report a failure to present an HLA-B8-restricted epitope from influenza nucleoprotein following viral infection of NW cells, although exogenous added peptide is still presented normally. However, cells from HW, which do not carry the A3-B2702 haplotype, present the expected epitope after viral infection. Another B8-restricted epitope, from human immunodeficiency virus-gag, is presented equally well by both cell lines when infected with gag-vaccinia. This antigen processing phenotype does not correlate with any of the known human TAP-1 and TAP-2 polymorphisms.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

TAP1 and TAP2 polymorphism in coeliac disease.

Coeliac disease is strongly associated with HLA-DQ2, but it is possible that additional major histocompatibility complex genes also confer disease susceptibility. Encoded close to HLA-DQ are two genes, TAP1 and TAP2, whose products are believed to transport antigenic peptides from the cytoplasm into the endoplasmic reticulum. Comparison of 81 coeliac disease patients with caucasoid controls revealed an increased frequency of the alleles TAP1A and TAP2A in the patient population. However, no significant difference was found when patients were compared with HLA-DR and -DQ matched controls, indicating linkage disequilibrium between TAP1A, TAP2A, and HLA-DQ2. The TAP gene products do not have a major influence on susceptibility or resistance to coeliac disease in a Northern European Caucasoid population.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Alleles and haplotypes of the MHC-encoded ABC transporters TAP1 and TAP2.

TAP1 and TAP2 are two major histocompatibility complex (MHC) genes, located between HLA-DP and -DQ, whose products form a transporter molecule involved in endogenous antigen processing. Polymorphic residues have been described in both genes and, in this study, we have identified another polymorphic site within the adenosine triphosphate (ATP)-binding domain of TAP2. We have used the amplification refractory mutation system (ARMS) polymerase chain reaction (PCR) to characterize TAP1 and TAP2 alleles and haplotypes in a reference panel of 115 homozygous typing cell lines. Of four possible TAP1 alleles, we observed three, and of eight possible TAP2 alleles, we observed five. Among 88 (homozygous typing cells) (HTCs) homozygous at HLA-DR, -DQ and -DP, 80 were also homozygous at TAP1 and TAP2. Of 27 HTCs homozygous at HLA-DR and -DQ, but heterozygous at -DP, 14 were homozygous at TAP1 or TAP2 and 13 heterozygous, consistent with recombination taking place either side of the TAP loci. Of the fifteen possible combinations of TAP1 and TAP2 alleles, we observed eleven, each at a frequency similar to that predicted by individual allele frequencies. In this ethnically heterogenous panel there is no indication that particular combinations of TAP1 and TAP2 have been maintained together.

ATP Binding Cassette Transporter, Subfamily B, Mem↗