HLA-C “blank” alleles express class I gene products. Biochemical analysis of four different HLA-C “blank” polypeptides

Hajek-Rosenmayr, A; Jungl, Lisi; Stammler, Maria; Kirnbauer, M.

doi:10.1007/bf02421170

Cited by 13 publications

(12 citation statements)

References 18 publications

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“…HLA-A, B, C, E, and G HC (15,16); the mAb TP25.99 (IgG1) which recognizes distinct determinants expressed on all ␤ 2 m-associated HLA-A, B, C, and E HC and on all ␤ 2 m-free HLA-A, B, C HC except A2, A10, A29, A31, 32, 33, A68.1, A69, and B73 (4,17); and the mAb L31 (9,12) which recognizes a determinant preferentially expressed on ␤ 2 m-free HLA-B HC were produced and characterized as previously described. The BALB/c mouse mAb 655 (IgG1) and its corresponding Ag, the human V␤-17 TCR-derived peptide GYSVSREKKES (p-V␤17), were used as controls.…”

Section: Cellsmentioning

confidence: 99%

β2-Microglobulin-Free HLA Class I Heavy Chain Epitope Mimicry by Monoclonal Antibody HC-10-Specific Peptide

Perosa

Luccarelli

Prete

et al. 2003

The Journal of Immunology

150

163

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mAb HC-10 loses its reactivity with HLA class I (HLA-I) H chain (HC) following its association with β2-microglobulin (β2m). Furthermore, the HC-10 defined epitope appears to be involved in the pathogenesis of spondyloarthropathies, because HC-10 reduced their incidence in HLA-B27+β2m°/MHC class II knockout mice. This study has characterized the determinant recognized by HC-10. Panning of a phage display peptide library with HC-10 resulted in isolation of the motif PxxWDR, which could be aligned with P57, W60, D61, and R62 of the first domain of the HLA-I HC allospecificities reactive with HC-10. The 55EGPEYWDR(N/E)T64 (p-1) is the shortest motif-bearing peptide that reacts with HC-10 and inhibits its binding to soluble HLA-B7 HC, irrespective of whether N (p-1a) or E (p-1b) is present at position 63. By contrast, HC-10 did not react with six additional peptides, each bearing motif amino acid substitutions present in HC-10-not-reactive HLA-I allospecificities. The p-1-derived Qp-1, synthesized with the additional conserved Q54, which displays the highest in vitro reactivity with HC-10, was the only one to induce in mice IgG resembling HC-10 in their fine specificity. Mapping of the HC-10-defined determinant suggests that the lack of mAb reactivity with β2m-associated HLA-I HC is caused by blocking by the peptide in the groove of β2m-associated HLA-I HC, though a role of HC conformational changes following its association with β2m cannot be excluded. This information contributes to our understanding of the molecular basis of the antigenic profiles of β2m-free and β2m-associated HLA-I HC and may serve to develop active specific immunotherapy of spondyloarthropathies.

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Section: Cellsmentioning

confidence: 99%

β2-Microglobulin-Free HLA Class I Heavy Chain Epitope Mimicry by Monoclonal Antibody HC-10-Specific Peptide

Perosa

Luccarelli

Prete

et al. 2003

The Journal of Immunology

150

163

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“…In most human populations, the products of 10-50% of the HLA-C alleles are not recognized by the human alloantisera used in HLA typing and are therefore defined as serologically "blank" alleles (9). However, biochemical analysis (10) and DNA cloning (11,12) demonstrate that the blank alleles are associated with functional genes and that the failure of human alloantisera to recognize HLA-C blanks is not caused by the absence of a functional HLA-C molecule at the cell surface. Snary et al (13) reported in 1977 that HLA-C molecules are expressed at the cell surface at levels much lower than either HLA-A or -B.…”

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confidence: 99%

Low HLA-C expression at cell surfaces correlates with increased turnover of heavy chain mRNA.

McCutcheon

Gumperz

Smith

et al. 1995

The Journal of Experimental Medicine

160

116

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SummaryIn comparison with HLA-A and -B, the protein products of the HLA-C locus are poorly characterized, in part because of their low level of expression at the cell surface. Here, we examine how protein-protein interactions during assembly and regulation of the mRNA level affect cell surface expression of HLA-C. We find that intrinsic properties of the HLA-C heavy chain proteins do not correlate with low cell surface expression: HLA-C heavy chains associate and dissociate with fl2-microglobulin (fl2m) at rates comparable to those found for HLA-A and -B, and increased competition for fl2m does not alter the surface expression of HLA-C. From studies of chimeric genes spliced from the HLA-B7 and -Cw3 genes, we find that chimeric proteins containing the B7 peptide-binding groove can have low cell surface expression, suggesting that inefficiency in binding peptides is not the cause of low cell surface expression for HLA-C. The surface levels of HLA-A, -B, or -C in cells transfected with cDNA can be similar, implicating noncoding regions of HLA-C heavy chain genes in the regulation of surface expression. We find that HLA-C mRNA is expressed at lower levels than HLA-B mRNA and that this difference results from faster degradation of the HLA-C message. Experiments examining chimeric B7/Cw3 and B7/Cw6 genes suggest that a region determining low expression of HLA-C is to be found between the 3' end of exon 3 and a site in the 3' untranslated region, '~600 bases downstream of the translation stop codon.

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“…Among these, only 8 are identifiable by serology, whereas 18 specificities for HLA-A locus and 28 for HLA-B locus are readily recognized by human alloantisera or monoclonal antibodies (11). Due to their weak immunogenicity and the lack .of specific reagents, >20% of HLA-C alleles are undetected and typed as "blank" in most populations (12)(13)(14); this fact has so far prevented critical evaluation of the role of HLA-Cw in transplantation.…”

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confidence: 99%

HLA-Cw allele analysis by PCR-restriction fragment length polymorphism: study of known and additional alleles.

Tatari¹,

Fortier²,

Bobrynina³

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

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We describe a technique for HLA-Cw genotyping by digestion of PCR-amplified genes with restriction endonucleases. Locus-specific primers selectively amplified HLA-Cw sequences from exon 2 in a single PCR that avoided coamplification of other classical and nonclassical class I genes. Amplified DNAs were digested with selected enzymes. Sixty-three homozygous cell lines from International Histocompatibility Workshop X and 113 unrelated individual cells were genotyped for HLA-Cw and compared with serology. The present protocol can distinguish 23 alleles corresponding to the known HLA-Cw sequences. Genotyping of serologically undetectable alleles (HLA-Cw Blank) and of heterozygous cells was made possible by using this method. Six additional HLA-Cw alleles were identified by unusual restriction patterns and confirmed by sequencing; this observation suggests the presence of another family of allele-sharing clusters in the HLA-B locus. This PCR-restriction endonuclease method provides a simple and convenient approach for HLA-Cw DNA typing, allowing the definition of serologically undetectable alleles, and will contribute to the evaluation of the biological role of the HLA-C locus.

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HLA-C “blank” alleles express class I gene products. Biochemical analysis of four different HLA-C “blank” polypeptides

Cited by 13 publications

References 18 publications

β2-Microglobulin-Free HLA Class I Heavy Chain Epitope Mimicry by Monoclonal Antibody HC-10-Specific Peptide

β2-Microglobulin-Free HLA Class I Heavy Chain Epitope Mimicry by Monoclonal Antibody HC-10-Specific Peptide

Low HLA-C expression at cell surfaces correlates with increased turnover of heavy chain mRNA.

HLA-Cw allele analysis by PCR-restriction fragment length polymorphism: study of known and additional alleles.

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