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Query: UNIPROT:P06889 (Mol)
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The HLA (human major histocompatibility complex, or MHC) region includes three types of class I MHC genes: (1) class Ia loci (HLA-A, -B, and -C), which are highly expressed and polymorphic; (2) class Ib loci, which have much reduced expression and polymorphism; and (3) unexpressed class I pseudogenes. Phylogenetic analysis suggests that both class Ib loci and class I pseudogenes arose by duplication of class Ia loci. 5' regulatory elements conserved in class Ia genes are not conserved in either class Ib or class I pseudogenes, but the former show evidence of purifying selection at nonsynonymous sites in coding regions that is lacking in the latter. In the HLA class I region, there is little correspondence between map distance and phylogenetic distance, suggesting a complex history of tandem gene duplications. Furthermore, separate phylogenetic analysis of different gene regions suggests that several class I genes are evolutionary chaemeras, which presumably have arisen as a result of a process of interlocus recombination. For example, the 5' flanking region of the HLA-92 pseudogene was donated by a gene related to HLA-B and -C; and the HLA-A gene arose when exons 1-3 (and intervening introns) were donated to a gene related to the HLA-70 pseudogene by a gene related to HLA-B and -C.
Mol Biol Evol 1995 Mar
PMID:Origin and evolution of HLA class I pseudogenes. 770 Jan 52

Meiotic recombination does not appear to occur randomly across chromosomes, but rather seems to be restricted to specific regions. A striking example of this phenomenon is illustrated by the HLA class II region. No recombination within the 100 kb encompassing the DRB1-DQA1-DQB1 loci has been reported, whereas the random association of TAP1 with TAP2 alleles suggests the presence of a hotspot for recombination within the 15 kb separating the closest variant sites of these two loci. Recombination rates between loci may provide clues to the functional properties of haplotypes. Absence of recombination may suggest the necessity to keep alleles of certain genes in phase and, alternatively, high recombination rates may suggest selective pressure to diversify haplotypes within the population. To address this issue, recombination rates across the HLA complex were determined using the 59 Centre d'Etude Polymorphisme Humain (CEPH) pedigrees. The allele frequencies of four microsatellite markers which map at sites ranging from the telomeric to centromeric ends of the complex were determined and the markers were used as a rapid means for identification of recombinant chromosomes. Typing these as well as other polymorphic loci within the HLA class I, II and III regions allowed assignment of the segments where recombination occurred. Recombination rates within the class II region (defined here as DRB1 to DPB1) and class III region (defined here as HLA-B to DRB1) regions were 0.74% and 0.94%, respectively, both of which are within an expected range given the standard of 1% recombination rate per megabase of DNA per meiosis.(ABSTRACT TRUNCATED AT 250 WORDS)
Hum Mol Genet 1995 Mar
PMID:Recombination rates across the HLA complex: use of microsatellites as a rapid screen for recombinant chromosomes. 779 97

Motifs for peptides which bind specifically to the human class I major histocompatibility complex molecules HLA-A2 and B7 were determined by sequence analysis of class I-bound peptides selected from a random synthetic library of nonamers. Thirteen individual peptides were sequenced for HLA-A2, twelve individual and nine pooled peptides were sequenced for HLA-B7. Analysis of sequence alignment implicated four peptide positions in potential contact with the class I HLA-A2 molecule and three positions for the HLA-B7 molecule. The results demonstrate that a synthetic peptide library can be used to identify allele-specific motifs for class I molecules, providing information comparable to the results obtained from sequencing endogenous peptides. This method utilizes denatured class I heavy chains, and similar results were obtained using a class I protein purified from mammalian cells or by expression in Escherichia coli. This method has the potential to detect peptides which may not be generated physiologically, but due to their binding properties, may be valuable to predict or engineer immunomodulatory T cell epitopes.
Mol Immunol 1994 Dec
PMID:Peptide sequences binding to MHC class I proteins. 782 69

Identification of CTL epitopes for tumor-specific responses is important for the development of immunotherapies to treat cancer patients. We have developed a strategy to identify potential CTL epitopes based on screening of sequences of target proteins for presence of specific motifs recognized by the most common HLA-A alleles, and identification of high affinity binding peptides using in vitro quantitative assays. A systematic analysis using the sequence of the product of the tumor-associated MAGE-1 gene has been carried out. All possible peptides of nine and ten residues, containing binding motifs for HLA-A1, -A2.1, A-3.2, -A11 and -A24 were synthesized and tested for binding using a quantitative assay. Out of 237 possible peptide/MHC combinations, 47 cases demonstrated good binding affinity (Kd < or = 500 nM). Several peptides were identified as good MHC binders for each one of the five HLA-A alleles studied (five for HLA-A1, 11 for HLA-A2.1, 10 for HLA-A3.2, 16 for HLA-A11 and five for HLA-A24. Furthermore, eight of these peptides were found to bind well to more than one HLA-A allele. These results have important implications for the development of immunotherapeutic vaccines to treat malignant melanoma.
Mol Immunol 1994 Dec
PMID:Identification of potential CTL epitopes of tumor-associated antigen MAGE-1 for five common HLA-A alleles. 782 68

The purpose of the study was to estimate the relative frequency of the known HLA-B27 subtypes among HLA-B27 positive Chukot natives. Using oligotyping of the polymerase chain reaction amplified second and third exons of the HLA-B27 gene in 86 DNA samples from HLA-27 positive individuals were success-fully typed. All had HLA-B*2705, including nine patients with ankylosing spondylitis and Reiter's syndrome, except for one Eskimo who had HLA-B*2702. None had HLA-B*2704, a frequent subtype in Orientals. Considering the HLA-B27 subtypes, the Chukot population groups are genetically more closely related to Caucasians than to Orientals.
Mol Gen Mikrobiol Virusol
PMID:[DNA typing of allelic variants of HLA-B27: HLA-B*2705 is the predominant allele of the aboriginal population of the Chukot peninsula (Eskimos and Chukchi)]. 789 30

The adenovirus early region 3 glycoprotein E3-19k binds to and inhibits expression of class I major histocompatibility complex (MHC)-encoded molecules, which may help infected cells evade immune recognition. The role of specific regions of the class I MHC molecule in the interaction with E3-19k was evaluated using a series of HLA-A2.1-, HLA-A2 variant-, and HLA-B7-expressing cell lines. The monoclonal antibody (mAb) W6/32, which recognizes a monomorphic epitope on class I MHC molecules, readily co-immunoprecipitated E3-19k with HLA-A2.1 and 14 different HLA-A2 variant molecules that differ from HLA-A2.1 by single amino acid substitutions. Thus, no single residue tested in the regions of the class I MHC molecule that bind peptide or the T-cell receptor controls the binding to E3-19k. Additional immunoprecipitations performed with mAbs directed against well-defined epitopes on the surface of HLA-A2.1 revealed a dichotomy in the ability of the mAbs to co-immunoprecipitate HLA-A2.1 and E3-19k. The mAbs LGIII-220 (directed against the C-terminal end of the alpha 1-helix), CR11-351 (directed against the N-terminal end of the alpha 2-helix), and PA2.1 (directed against the middle of the alpha 2-helix and an underlying beta-loop) readily co-precipitated HLA-A2.1 and E3-19k. In contrast, mAbs MA2.1 (directed against the N-terminal end of the alpha 1-helix and the C-terminal end of the alpha 2-helix) and HO-2 (directed against the N-terminal end of the alpha 1-helix) did not co-precipitate E3-19k with HLA-A2.1. Similarly, mAb MB40.2 (directed against residues 169-182 of HLA-B7) also did not co-precipitate E3-19k with HLA-B7. These studies lead to the conclusion that the N-terminal end of the alpha 1-helix and the C-terminal end of the alpha 2-helix play an important role in dictating the ability of the E3-19k protein to bind to the class I MHC molecule.
Mol Immunol 1994 Nov
PMID:Identification of class I MHC regions which bind to the adenovirus E3-19k protein. 796 88

The cytokine interleukin-8 (IL-8) is an important mediator of neutrophil, lymphocyte, and basophil chemotaxis and activation. Earlier we demonstrated that beta interferon (IFN-beta) can inhibit tumor necrosis factor (TNF)-induced IL-8 gene expression at the transcriptional level, apparently by a novel mechanism. To define the cis-acting elements and trans-acting factors involved in this inhibition, DNA constructs containing portions of the 5'-flanking region of the IL-8 gene were linked to the chloramphenicol acetyltransferase (CAT) reporter gene and transfected into human diploid FS-4 fibroblasts. The region spanning positions -98 to +44 was sufficient to confer both inducibility by TNF and inhibition by simultaneous treatment with IFN-beta. Inhibition of TNF- or IL-1-induced CAT activity by IFN-beta or IFN-alpha was also observed when a DNA fragment containing only the NF-IL-6 and NF-kappa B sites (positions -94 to -70) was placed upstream of the homologous or a heterologous minimal promoter. A construct containing three copies of the NF-kappa B element in front of the CAT gene also was inducible by TNF, and this stimulatory effect too was inhibited by IFN-beta, indicating that the NF-kappa B element is sufficient to confer inhibition by IFN-beta. This inhibitory effect was specific for the NF-kappa B site of the IL-8 gene since it was less marked with constructs containing three copies of the NF-kappa B site from the HLA-B7 gene. Gel shift assays with a probe containing the NF-kappa B and NF-IL-6 binding sites of the IL-8 gene (positions -101 to -63) showed that IFN-beta treatment did not block the activation of NF-kappa B proteins or their ability to bind to the NF-kappa B site. However, nuclear extracts from cells treated with TNF in the presence of IFN-beta gave rise to an additional band that appears to contain protein components from the NF-kappa B and NF-IL-6 families. NF-kappa B site-mediated suppression of IL-8 gene expression by IFN-beta represents a hitherto unknown mechanism and target of IFN action.
Mol Cell Biol 1994 Aug
PMID:Transcriptional inhibition of the interleukin-8 gene by interferon is mediated by the NF-kappa B site. 803 8

A staged pattern of cathepsin B cleavage of MHC class II alpha, beta-bound invariant (Ii) chain and release of fragments was defined. Charge-loss mutations in the Ii chain were created in three clusters of cathepsin B putative cleavage sites R78K80K83K86, K137K143, and R151K154. Products of HLA-DR1 alpha, beta and wild type (WT) or mutant Ii genes, co-transfected into COS1 cells, were cleaved by cathepsin B and immunoprecipitated by antibodies either to MHC class II chains or to different Ii epitopes. In WT Ii, cathepsin B digestion generated two forms of p21 Ii fragments: a p21 recognized by anti-C-terminus antibodies and a p21 recognized by an antibody to a determinant near the N-terminus. C-terminal p21 was released from MHC class II alpha, beta chains upon its formation while N-terminal p21 remained associated with MHC class II alpha, beta chains. Mutations at K137K143 inhibited the generation of N-terminal p21 by cathepsin B. Mutation at R78K80K83K86 led to an accumulation of MHC class II-bound N-terminal p21 without the appearance of MHC class II-bound p14, p10, and p6 fragments after cathepsin B digestion. These results indicate that cathepsin B cleaves wild type Ii first about K137K143 to produce a MHC class II-associated N-terminal p21, which is then cleaved about R78K80K83K86 to generate p14, p10 and finally p6 which still associates with MHC class II alpha, beta chains. This pattern of staged cleavage and release of Ii might be related to a concerted mechanism regulating the binding of antigenic peptides to MHC class II molecules.
Mol Immunol 1994 Jul
PMID:Cathepsin B cleavage and release of invariant chain from MHC class II molecules follow a staged pattern. 803 34

Quantitative assays to measure the binding of defined synthetic antigenic peptides and purified MHC class I molecules are described for several common human HLA-A alleles (A1, A2.1, A3, A11 and A24). Under appropriate conditions, the binding of radiolabeled peptides to purified MHC class I molecules is very effective, highly specific, and appears to be dependent on the specific sequence motif of the peptide as defined by critical anchor residue positions. Establishment and optimization of the assay reveals that a relatively high fraction of the MHC class I molecules isolated from EBV transformed B cell line sources is capable of binding exogenously added peptide. Scatchard analysis for all alleles yields 5-10% occupancy values. There is a stringent peptide size requirement that is reflected by the direct influence of peptide length on the binding affinity. The peptide-MHC class I interactions demonstrate remarkable similarity to peptide-MHC class II interactions, both in overall affinity and kinetic behavior. The immunological relevance of the peptide-MHC class I binding assay is also demonstrated by measuring the affinity of a panel of previously described HLA restricted peptides for their HLA restriction element. In 91% (10/11) of the cases, the peptides bound with affinities of 50 nM or less, and in the remaining 9% (1/11) of the cases, in the 50 to 500 nM range. Thus, these data provide the first quantitative estimate of what level of HLA-A binding affinity is associated with a diverse panel of immunodominant CTL epitopes in man.
Mol Immunol 1994 Aug
PMID:Peptide binding to the most frequent HLA-A class I alleles measured by quantitative molecular binding assays. 804 72

Sequence comparisons of 14 distinct MHC class I cDNA clones isolated from species representing the three major taxonomic lineages of Felidae (domestic cat lineage, ocelot lineage, and pantherine lineage) revealed that feline MHC class I alleles have highly mosaic structures with short polymorphic sequence motifs that are rearranged between alleles of individual MHC loci, between MHC class I genes within cat species, and between homologous MHC loci in different species. The pattern of sequence variation in felids supports the role of the following factors in production and maintenance of MHC variation: (1) gradual spontaneous mutation; (2) selective pressure to conserve certain residues but also to vary in hypervariable regions, notably residues that functionally participate in antigen recognition and presentation; and (3) recombination-mediated gene exchange between alleles and between related genes. The overall amount of genetic variation observed among MHC class I genes in the Felidae family is no greater than the amount of variation within any outbred cat species (i.e., domestic cat, ocelot). The occurrence of equivalent levels of polymorphism plus the simultaneous persistence of the same sequence motifs in divergent feline species suggest that most MHC class I nucleotide site polymorphism predated species divergences. Ancient polymorphisms have been transmitted through the speciation events and modern feline MHC class I alleles were derived by recombinational exchange of polymorphic sequence motifs. Moreover, some of these sequence motifs were found in other mammalian MHC class I genes, such as classical human HLA-B5, nonclassical human HLA-E class I genes, and bovine class I genes. These results raise the prospect of an ancient origin for some motifs, although the possibility of convergence in parallel mammalian radiations cannot be excluded.
J Mol Evol 1994 Jul
PMID:Exchanges of short polymorphic DNA segments predating speciation in feline major histocompatibility complex class I genes. 806 70


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