Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The DRB family of human class II major histocompatibility complex (Mhc) loci is unusual in that individuals differ in the number and combination of genes (haplotypes) they carry. Indications are that both the allelic and haplotype polymorphisms of the DRB loci predate speciation. Searching for the evolutionary origins of these polymorphisms, we have sequenced five DRB clones isolated from a cDNA library of a pigtail macaque (Macaca nemestrina) B lymphocyte line. The clones represent five different genes which we designate Mane-DRB*01-Mane-DRB*05. The genes appears to be approximately equidistant from each other, so that allelic relationships between them cannot be established on the basis of the sequence data alone. If positions coding for the peptide-binding region of the class II beta chains are eliminated from sequence comparisons, the Mane-DRB genes appear to be most closely related to the human (HLA) DRB1 genes of the DRw52 group. We interpret this finding to indicate that the ancestral gene of the DRw52 group of human DRB1 alleles separated from the rest of the HLA-DRB1 alleles before the separation of the Old World monkeys (Cercopithecoidea) from the apes (Hominoidea) in the early Oligocene. After this separation, the ancestral DRB1 gene of the DRw52 group duplicated in the Old World monkey lineage to give rise to genes at three loci at least, while in the ape lineage this gene may have remained single and diverged into a number of alleles instead. These findings suggest that some of the polymorphism currently present at the DRB1 locus is greater than 35 Myr old.
Mol Biol Evol 1991 Sep
PMID:Mhc-DRB genes of the pigtail macaque (Macaca nemestrina): implications for the evolution of human DRB genes. 176 59

Glycosphingolipids added to the cell culture medium can be incorporated into the plasma membrane and interfere with the growth of certain cell types. In the past years, previous reports have shown that gangliosides, a class of glycosphingolipids bearing sialic acid can inhibit antigen or mitogen induced T cell proliferative responses in vitro. We report here that the inhibition of PHA induced proliferation by the trisialoganglioside GT1b was not reversed by addition of exogenous IL-1, IL-2, TPA and calcium ionophore. Furthermore, GT1b did not affect IL-2 production by activated T cells. In addition, GT1b ganglioside could also decrease strongly the expression of the T cell antigens CD3, CD2, CD4, CD8 and the alpha/beta T cell receptor antigenic complex whereas it did not affect HLA-class I antigens. By contrast, GT1b modulated only partially membrane expression of activation antigens such as CD25 (Tac) and transferrin receptor and increased the expression of HLA-class II antigens. Moreover CD25 messenger RNA induction was not affected by GT1b treatment of PHA-stimulated T cells. Our results demonstrate that gangliosides, in spite of their anti-proliferative capacity and their modulation effect on T cell antigen membrane expression, do not prevent the progression of T cells into early stages of the activation process.
Mol Immunol 1991 Nov
PMID:Analysis of phenotypic and functional changes during ganglioside-induced inhibition of human T cell proliferation. 183 57

The gene encoding steroid 21-hydroxylase activity, P450c21B, is located in the major histocompatibility complex (MHC) class III region, in close proximity to a highly homologous pseudogene, P450c21A. Recombinations between P450c21B and P450c21A have been shown to result in deficiency of 21-hydroxylase activity, the usual cause of congenital adrenal hyperplasia (CAH). A mutant P450c21 gene from a patient with simple virilizing CAH was identified and shown to be consistent with a recombination between P450c21A and P450c21B. Sequence analysis of the mutant gene showed the recombination site to be located between the first exon and the second intron. The mutant gene encodes a leucine instead of the normal proline at codon 31. This mutation resides on a chromosome bearing the HLA-B44 serotype. A comparison of mutations associated with HLA-B44 and that normally found with the HLA-Bw47 serotype suggests that the HLA-B44 mutations are of more ancient origin. The patient's homologous chromosome has a deletion of P450c21B. Endocrinological testing therefore allows for testing of the mutant gene in genetic isolation. Such testing demonstrated that the patient was capable of producing aldosterone and retaining sodium in response to a low-sodium diet, indicating that the mutant gene encodes an enzyme with partial 21-hydroxylase activity.
J Steroid Biochem Mol Biol 1991 Jun
PMID:Molecular and endocrine characterization of a mutation involving a recombination between the steroid 21-hydroxylase functional gene and pseudogene. 190 48

Cytotoxic T lymphocytes (CTL) specific for autologous human melanoma have been successfully generated in vitro from tumor bearing lymph nodes without any stimulation by the autologous tumor. Tumor-involved lymph node cells (LNC) were cultured in serum free medium (AIM-V) containing 1,000 U/ml of recombinant interleukin-2. The best expansion and specific cytotoxicity of CTL were achieved in 4 to 6 weeks of culture. The predominant populations in cultured LNC-derived CTL were CD2+, CD3+, CD4-, CD8+, CD56-, and HLA-DR+ T cells. These data suggested that tumor-involved LNC may provide an alternative source for the generation of tumor-specific CTL in adoptive immunotherapy.
Mol Biother 1991 Jun
PMID:Generation of human autologous melanoma-specific cytotoxic T cells from tumor-involved lymph nodes. 191 Jun 25

The expression of HLA antigens by a tumor may determine its progression and metastatic potential by influencing the immune response to that tumor. The upregulation of HLA antigen expression on some cell types by interferons (IFNs) may contribute to their antitumor activity. Malignant mesothelioma (MM) is a tumor that has a poor prognosis and is unaffected by conventional therapy, although immunotherapy has not been adequately assessed. In this study, we have examined the constitutive and IFN-inducible expression of class I and class II HLA antigens on MM cell lines using indirect immunofluorescence and Northern blotting. All MM cell lines constitutively expressed class I, but not class II, surface antigen, and all three class I loci (HLA-A, HLA-B, and HLA-C) were expressed. The MM cell lines were heterogeneous in their response to the IFNs. Treatment with IFN-alpha marginally increased class I surface expression, but not class II. Class I mRNA was, however, clearly increased in all cell lines after IFN-alpha treatment, suggesting that class I surface antigen was already maximally expressed. IFN-gamma increased class I mRNA expression in all but one cell line and induced DR expression on three of the cell lines. DQ-beta, but not DQ-alpha, mRNA was inducible in the same three cell lines, but DQ surface antigen was never demonstrable.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1991 Sep
PMID:HLA antigen expression and malignant mesothelioma. 191 Aug 7

A point mutation within exon 7 producing an amino acid coding change and a recognition site for the endonuclease Ncol has been reported in the HLA-Bw47-linked CYP21A pseudogene and some mutant CYP21B (steroid 21-hydroxylase) genes of patients with congenital adrenal hyperplasia (CAH). Whether this mutation is deleterious was not demonstrated. We analyzed DNA from various subjects for the presence of the exon 7 Ncol site: group 1, 10 normal subjects; group 2, 11 patients with salt-losing CAH; and group 3, 18 members of an Amish pedigree in which 10 expressed HLA-Bw47 not linked to CAH. Southern blots of Ncol-digested genomic DNA which were hybridized with CYP21 cDNA showed that four subjects of group 1 had a heterozygous Ncol pattern. In group 2, seven patients had the Ncol site; two of them were homozygous for the site and had deletions of both CYP21B genes. The other five were heterozygous for the Ncol site, which was linked to a CYP21B deletion and a HLA-Bw47 haplotype. In group 3, no one exhibited the exon 7 Ncol site. To map the Ncol sites to CYP21A or CYP21B in the normal subjects, DNA from the four Ncol heterozygous subjects was double digested with Ncol and Mbol and hybridized with CYP21 cDNA. Ncol-Mbol fragments unique to CYP21A were identified in all four, but the smaller CYP21B-specific fragments were not detected. Their genomic DNA in the region of exon 7 (bases +1167 to +2058) was then amplified, cloned, and sequenced.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Endocrinol 1990 Sep
PMID:Exon 7 Ncol restriction site within CYP21B (steroid 21-hydroxylase) is a normal polymorphism. 197 47

Type I (insulin-dependent) diabetes in humans is characterized by a T cell mediated destruction of insulin-secreting pancreatic beta cells. This autoimmune response is very similar to that seen in the non-obese diabetic (NOD) mouse strain. Originally bred from the ICR cataract-prone strain, NOD mice spontaneously develop T cell mediated insulitis and type I diabetes by the age of 6 months. Backcross studies with the NOD mouse strain indicate segregation of at least three recessive genes. One of these, Iddm-1, has been shown to be tightly linked to the mouse MHC, H-2 on chromosome 17. Comparative studies with diabetic patients has also shown linkage to human HLA with protective and predisposing haplotypes being present within the population. In this study we have attempted to identify restriction fragment length polymorphisms (RFLPs) between the genomes of the NOD mouse strain and the diabetes-resistant strain C57BL/10. Such polymorphic loci will be used to screen DNAs from backcross animals that are diagnosed diabetic in an attempt to identify probes linked to the non-H2 disease susceptibility genes.
Mol Cell Probes 1990 Dec
PMID:Detection of DNA polymorphisms between two inbred mouse strains--limitations of restriction fragment length polymorphisms (RFLPs). 198 36

The three-dimensional structure of the human histocompatibility antigen HLA-A2 was determined at 3.5 A resolution by a combination of isomorphous replacement and iterative real-space averaging of two crystal forms. The monoclinic crystal form has now been refined by least-squares methods to an R-factor of 0.169 for data from 6 to 2.6 A resolution. A superposition of the structurally similar domains found in the heterodimer, alpha 1 onto alpha 2 and alpha 3 onto beta 2m, as well as the latter pair onto the ancestrally related immunoglobulin constant domain, reveals that differences are mainly in the turn regions. Structural features of the alpha 1 and alpha 2 domains, such as conserved salt-bridges that contribute to stability, specific loops that form contacts with other domains, and the antigen-binding groove formed from two adjacent helical regions on top of an eight-stranded beta-sheet, are analyzed. The interfaces between the domains, especially those between beta 2m and the HLA heavy chain presumably involved in beta 2m exchange and heterodimer assembly, are described in detail. A detailed examination of the binding groove confirms that the solvent-accessible amino acid side-chains that are most polymorphic in mouse and human alleles fill up the central and widest portion of the binding groove, while conserved side-chains are clustered at the narrower ends of the groove. Six pockets or sub-sites in the antigen-binding groove, of diverse shape and composition, appear suited for binding side-chains from antigenic peptides. Three pockets contain predominantly non-polar atoms; but others, especially those at the extreme ends of the groove, have clusters of polar atoms in close proximity to the "extra" electron density in the binding site. A possible role for beta 2m in stabilizing permissible peptide complexes during folding and assembly is presented.
J Mol Biol 1991 May 20
PMID:Refined structure of the human histocompatibility antigen HLA-A2 at 2.6 A resolution. 203 58

In order to determine how T cell-presented peptides associate with the antigen binding sites (desetopes) of class I major histocompatibility complex (MHC) molecules and how they might be scavenged from an endogenous processing pathway for transfer to those molecules, we characterized the binding of two synthetic peptides restricted by HLA-B37 or HLA-A2 to class I MHC molecules and to cellular proteins of histotyped cell lines, by gel filtration and photo-affinity labeling techniques. In gel filtration binding studies, each peptide associated with immunopurified class I MHC molecules from cells with its restricting, histotype, but little was bound to class I MHC molecules from cells without the restricting histotype and none was bound to bovine serum albumin. After crosslinkage of a radioiodinated photoreactive derivative of influenza virus nucleoprotein peptide NP(336-355Y) and immunoprecipitations with antibodies to class I MHC molecules, that peptide was found to bind to immunopurified class I MHC molecules from HLA-B37+ but not HLA-B37- cells. Binding of the [125I]NP peptide increased from 6 to 12 hr of incubation and was competed by unlabeled, NP peptide but not by HLA-A2-restricted, influenza virus matrix MA(57-73). The principal microsomal membrane proteins binding [125I]NP were about 65, 45 and 33 kD.
Mol Immunol
PMID:Binding of radioiodinated influenza virus peptides to class I MHC molecules and to other cellular proteins as analyzed by gel filtration and photoaffinity labeling. 206 16

Two new allelic exon-2 HLA-DRB sequences have been identified by using universal and also specific DRB primers. They may correspond to a previously unidentified DRB gene (DRB sigma) and define a new supratypic group ("DRw54") which includes DR1, DR"Br", DR2 and DRw10 bearing HLA haplotypes. This is probably the last HLA-DRB gene to be described in the standard DR haplotypes on the bases of the number of TaqI RFLPs obtained. Sequence comparison with their respective DP and DQ sequences shows that DRB sigma is unequivocally placed within the DRB family and also a constructed "neighbouring homology tree" indicates that DRB sigma gene is probably the eldest in the DRB family, thus the first to diverge from the ancestral DRB gene. An hypothetically deduced DRB sigma beta 1 protein domain was found to be quite different from the corresponding DRB1, DRB3, DRB4 and DRB5 products, since residues 40-55 would bear a longer alpha-helical conformation and would also exist a loss of both the extended conformation at residues 50-54 and the alpha-helix at residues 64-71. Thus, the putative DRB sigma protein would be remarkably different to other DRB ones. Also, a DRB sigma partial transcript (exon-2) has been obtained by PCR of cDNA by using specific DRB sigma oligonucleotides, but a specific Northern blot hybridization has not been achieved.
Mol Immunol
PMID:Exon-2 nucleotide sequences, polymorphism and haplotype distribution of a new HLA-DRB gene: HLA-DRB sigma. 206 26


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