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At least 991 records · Page 55Linked to original sources
PubMed1998

Relationship between peptide binding and T cell epitope selection: a study with subtypes of HLA-B27.

The effect of HLA-B27 polymorphism on antigen presentation was analysed by comparing the binding of three Epstein-Barr virus-derived peptide epitopes to HLA-B27 subtypes with their immunogenicity and antigenicity in the context of these subtypes. The effect of altering the major anchor residue Arg2 on binding or on recognition by peptide-specific cytotoxic T lymphocytes (CTL) was also examined. The three peptides bound significantly to all the B*2701-B*2706 subtypes. This did not correlate with the peptides being immunogenic or recognized by specific CTL in the context of only particular subtypes. In addition, of the three viral epitopes tested, those that were immunogenic in B*2702- or B*2705-restricted responses bound to these subtypes less efficiently than one peptide that was immunogenic only in the B*2704 context. Thus, among several potentially immunogenic peptides from the same virus, the antiviral response is not necessarily directed against the one that binds best to the restricting subtype. These results indicate that HLA-B27 polymorphism influences antigen presentation in ways other than simply peptide affinity. Synthetic analogues lacking the canonical Arg2 motif of HLA-B27-bound peptides, even when binding much worse to the restricting subtype, were recognized equally by CTL specific for the parental peptide. This indicates that Arg2 is not required to maintain the structure of the epitope. The implications of these results for pathogenetic models of HLA-B27-associated disease are discussed.

Antigen Presentation↗
PubMed1986

An overview of the restriction fragment length polymorphism of the HLA-D region: its application to individual D-, DR- typing by computerized analyses.

HLA-D/DR alleles as defined by cellular and serological typing can also be identified by biochemical methods. The Southern blot technique provides an additional typing facility which can be applied to DNA obtained from any source of nucleated cells. The polymorphism revealed by Southern blot analyses, the so-called restriction fragment length polymorphism (RFLP), depends upon the restriction enzyme and cDNA probes used. To identify HLA-DR specificities a protocol was developed based on the use of the results of southern blot analyses with several restriction enzymes and cDNA probes within a panel of HLA-D/DR homozygous cells representing the DR1 to DRw8 alleles. First, hybridizations with the 3' untranslated sequence of the DR beta cDNA probe, after digestion of the DNA with PvuII (PvuII-DR beta 3') allows the selective identification of DR1, DR2 and DRw8; DR3, DR5 and DRw6 are found as one group as well as DR4 and DR7 as another. Second, TaqI-DQ alpha hybridization allows the splitting of DRw6-Dw18, DRw6-Dw19 and DRw6-Dw9 from the DR3, DR5 and DRw6 group. The other alleles DR3, DR4, DR5, DRw6-Dw16 and DR7 are revealed by dehybridization and rehybridization of the blot with a DR beta cDNA probe. This protocol was used to test whether in a panel of 30 randomly chosen individuals the HLA-DR typing could be performed. The results were highly concordant to the serotyping. Furthermore by adding the Pst-DR beta and TaqI-DQ alpha RFLPs, most of the MLC defined Dw specificities could also be identified. An overview of the specific fragments described here has been summarized in matrices which can be used as references for DNA-typing in computerized analyses.

Collodion↗
PubMed1997

A generic sequencing based typing approach for the identification of HLA-A diversity.

Sequencing Based Typing (SBT) is a generic approach for the identification of HLA-A polymorphism. This approach includes the high resolution typing of the HLA-A broad reacting groups, HLA-A subtypes and will identify new alleles directly. The SBT approach described here uses a locus specific amplification of DNA from exon 1 to exon 5. The resulting 2,022 bp PCR product serves as a template for the subsequent sequencing reactions. Amplification is followed by direct sequencing of exons 2, 3 and 4 in both orientations with fluorescently labeled primers to define all polymorphic positions leading to a high resolution typing result. In this study the sequence of exons 2 and 3 of a panel of 49 cell lines was determined. In addition, the exon 4 region of 35 cell lines was also sequenced to evaluate the exon 4 polymorphism. The HLA-A type of most of the cells could be identified by sequencing only exons 2 and 3. However, the sequence of exon 4 was required to discriminate A*0201 from A*0209 and A*0207 from A*0215N. In this panel, an identical new "HLA-A*0103" was identified in two Caucasian samples.

Alleles↗
PubMed1983

Monoclonal antibodies to HLA recognize monomorphic and polymorphic epitopes on BoLA.

Fourteen monoclonal antibodies recognizing monomorphic and polymorphic epitopes on class I and class II antigens of the human MHC have been assayed on lymphocytes of a panel of 20-150 BoLA typed bovine animals from 12 different breeds. Some monomorphic antibodies cross-reacted and others did not. Two polymorphic monoclonal antibodies in man recognize a polymorphism in cows that follows allospecificities (BoLA-w3, w9) already described. Immunoprecipitation experiments with monomorphic anti-B2m and anti-HLA-DR monoclonal antibodies have shown that these cross-reactions concern BoLA antigens. They also revealed that Ia-like antigens in cattle present the same two chain features characterized in other species.

Animals↗
PubMed1990

Polymorphism of the HLA-DP beta region detected by Southern blot hybridization.

A panel of homozygous cell lines, previously typed by primed lymphocyte test for their DPw specificity, have been studied by restriction fragment length polymorphism analysis, using a DP beta-specific probe. Highly stringent hybridization and washing conditions were used to prevent cross-hybridization with DR- and DQ-specific fragments. Three out of six enzymes employed allowed us to distinguish clustered or single DPw specificities, and by MspI digestion it was possible to detect different patterns within a single specificity such as DPw4. Some of the cell lines have been further studied with synthetic oligonucleotides derived from the polymorphic regions of the second exon of DP beta 1 gene, and, in general, a correlation with the primed lymphocyte test--defined specificities and restriction fragment length polymorphism was found. These data suggest a more extended complexity of the DP region, in addition to that defined as the DPw1-DPw6 segregant series.

Base Sequence↗
PubMed1984

Serologically detectable polymorphism of the HLA-DC alpha-subunit.

Two 8th Workshop alloantisera, 8W1062 and 8W614, which were classified respectively as anti-DR5 and anti-DR3, were found to react with an Ia preparation from LG38 cells (DR5,5) that was depleted of DR and BR molecules and enriched in DC molecules by pretreatment with a monoclonal antibody and an antiserum against alpha-subunits of DR and BR molecules. The reaction of both alloantisera was inhibited by DR3-positive, DR5-positive, and DRW13-positive individuals. This pattern does not correspond to any of the hitherto reported supertypic specificities. Both antisera were shown to bind to the alpha-subunit isolated from the DC-enriched preparation but not to the beta-subunit. The specificity has been named DC alpha 3. Family studies show the segregation according to the HLA haplotype patterns. This demonstrates by formal genetics criteria the HLA linkage of the locus controlling the DC alpha-subunit.

Binding, Competitive↗
PubMed1994

Rapid DNA crossmatch analysis of HLA class II genotypic polymorphisms by temperature gradient gel electrophoresis in unrelated bone marrow donor selection.

The present paper demonstrates the usefulness of the temperature gradient gel electrophoresis (TGGE) as a precise method for the rapid identification of HLA-DR full matched donors by molecular crossmatch analysis. The resulting TGGE fingerprints are highly diverse for different HLA-DR genotypes and identical for samples with identical HLA-DR type, as shown for a panel of 25 randomly selected PCR-SSO pretyped DNA samples. In addition, TGGE analysis of a panel of homozygous typing cell lines (HTCs) established, that even subtle differences in the DR4 subtypes are detectable by TGGE crossmatch analysis. Furthermore, TGGE crossmatch analysis of unrelated donor/patient pairs demonstrated, that only HLA-DR identical patient/donor combinations showed identical TGGE patterns. Thus crossmatch analysis by TGGE presents a novel basis for a rapid and safe unrelated bone marrow donor selection strategy. Only HLA class I identical donors which also show HLA-DR identity in the TGGE crossmatch test are selected for the final confirmation of the HLA class II genes by a suitable DNA subtyping method.

Alleles↗
PubMed1994

Limited polymorphism of the HLA-DQA2 promoter and identification of a variant octamer.

Previous studies have suggested that the HLA-DQA2 gene may be associated with IDDM. The apparently limited allelism at this locus prompted us to investigate whether this association might be with the level of gene expression rather than with specific alleles. The proximal promoter region of HLA-DQA2 was sequenced in three homozygous DR4;DQ8 subjects with IDDM, six homozygous DR3;DQ2 subjects (three healthy controls and three with IDDM), and selected DR4 and DR6 cell lines. This 388-bp region encompassed the known control W/Z/H/S, X, and Y boxes and included a previously unremarked variant octamer sequence 40 bp upstream of the transcription start site. Only one polymorphic site was present among these 15 sequences, found in one DR3;DQ2 subject and a DR6;DQ6 cell line. This indicates that any disease association with HLA-DQA2, at least among DR3;DQ2 individuals, cannot be accounted for solely by polymorphism of the proximal promoter region.

Amino Acid Sequence↗
PubMed2000

Allele-specific HLA-DR typing by mass spectrometry: an alternative to hybridization-based typing methods.

The primer oligomer base extension (PROBE) reaction, combined with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, is used to characterize HLA-DR2 polymorphism. Alleles are distinguished rapidly and accurately by measuring the mass of primer extension products at every known variable region of HLA-DR2 alleles. Since differentiation of alleles by PROBE relies on measuring differences in extension product mass rather than differences in hybridization properties, mistyped alleles resulting from nonspecific hybridization are absent. The method shows considerable potential for high-throughput screening of HLA-DR polymorphism in a chip-based format, including rapid tissue typing of unrelated volunteer donors.

Alleles↗
PubMed1989

Alternative splicing of HLA-DQB transcripts and secretion of HLA-DQ beta-chain proteins: allelic polymorphism in splicing and polyadenylylation sites.

HLA class II antigens are highly polymorphic cell-surface proteins involved in initiation and regulation of the immune response. Allelic sequence variation primarily affects the structure of the first external domains of alpha and beta component chains. Here we provide evidence for other types of allelic polymorphism for the genes encoding these chains. Sequences of two cDNA clones corresponding to HLA-DQB mRNAs from an HLA-homozygous cell line exhibit both alternative splicing and read-through of polyadenylylation. Furthermore, alternative splicing that deletes the transmembrane exon is associated with only a subset of HLA-DQB alleles, while the polyadenylylation-site read-through is found in a larger subset. This suggest that polymorphic cis-acting elements within the HLA-DQB gene control both processing steps. Proteins, presumably encoded by alternatively spliced mRNAs lacking transmembrane exons, are immunoprecipitated with a monomorphic monoclonal antibody directed against HLA-DQ. These proteins are found in supernatants of cultured cell lines for which secretion is predicted, but not in those of cell lines that do not contain alternatively spliced mRNAs.

Alleles↗
PubMed1998

Heterogeneity of rheumatoid arthritis: from phenotypes to genotypes.

Rheumatoid arthritis (RA) is now recognized as a multigene disorder with a number of genetic polymorphisms contributing to disease pathogenesis. Here, we propose that the diagnostic category of RA includes multiple subtypes of disease and that the different phenotypes of RA correlate to different genotypes. Support for this concept has come from a reappraisal of the clinical heterogeneity of RA and the observation that HLA-DRB1 polymorphisms are useful in describing genetic heterogeneity of RA phenotypes. A series of HLA-DRB1 genes has been identified as RA associated, and in recent years emphasis has been put on the sequence similarities of these alleles. An alternative view focuses on the amino acid variations found in RA-associated HLA-DRB1 alleles with different alleles being enriched in distinct subtypes of RA. Rheumatoid factor-positive destructive joint disease is predominantly associated with the HLA-DRB1*0401 allele, while HLA-DRB1*0404 and B1*0101 predispose for milder and often seronegative disease. Expression of disease-associated alleles on both haplotypes carries a high risk for extra-articular manifestations. In particular, patients homozygous for HLA-DRB1*0401 frequently develop rheumatoid vasculities on follow-up. Besides HLA gene polymorphisms, abnormalities in the generation and function of CD4 T cells and in inflammatory pathways established in synovial lesions can be used to dissect patient subsets with different variants of RA. Emergence of CD28-deficient CD4 T cells identifies RA patients with extra-articular manifestations. These cells undergo clonal expansion in vivo, produce high amounts of IFN-gamma, and exhibit autoreactivity. Concordance of monozygotic twins for the expression of CD4+ CD28- T cells suggests a role for genetic factors in the generation of these unusual T cells. Evidence for heterogeneity of the synovial component of RA comes from studies describing three distinct patterns of lymphoid organization in the synovium. Based upon the topography of tissue-infiltrating mononuclear cells, diffuse, follicular, and granulomatous variants of rheumatoid synovitis can be distinguished. Each pattern of lymphoid organization correlates with a unique profile of tissue cytokines, demonstrating that several pathways of immune deviation modulate disease expression in RA. A dissection of RA variants would have major implications on how the disease is studied, treated, and managed. Identifying combinations of RA risk genes that correlate with disease variants could, therefore, become an important diagnostic tool.

Alleles↗
PubMed1995

HLA, Gm, and Km polymorphisms and immunity to infectious diseases in South Amerinds.

Isolated South Amerinds, a population at very high risk from infectious disease, mount good immune responses to pneumococcal polysaccharides, viral antigens and other immunogens. No unusual immunoglobulin allotype or HLA antigen, which might explain the high risk from infectious disease, was found among them. Responses are examined in relation to the immunogenetic markers that are most prevalent. Amerinds with Gm 1,2,17,21 responded less well than persons without this haplotype to 10 of 12 pneumococcal polysaccharides, and those who were homozygous at the HLA class I loci responded less well to viral antigens. However, these differences are not strong and there are few such findings relative to the number of possibilities examined. The most distinctive immunogenetic characteristic of these populations is their low level of polymorphism at all tested loci. Their susceptibility to infectious agents can be attributed to this genetic uniformity and a consequent ability of pathogens to adapt to the population.

Adult↗
PubMed2000

Molecular analysis of HLA-DRB1, -DQA1 and -DQB1 polymorphism in Turkey.

We report the evaluation of MHC class II polymorphism in the population of Turkey. HLA-DRB1, -DQA1 and -DQB1 have been investigated by polymerase chain reaction and sequence-specific oligonucleotide probe hybridisations (PCR/SSO) and sequence-specific priming (SSP) in 250 randomly selected healthy individuals. We also report the allelic distribution of these genes. The most frequent alleles detected were DRB1*1101 (0.104), *0301 (0.092), *0701 (0.090), DQA1*0501 (0.334), *0102 (0.164) and *03 (0.148) and DQB1*0301 (0.256), *02 (0.164), *0302 (0.128). The frequent 'putative' three-locus haplotypes carry the most frequent alleles at these loci. The most frequently detected class II "haplotypes" are DRB1*1101 DQA1*0501 DQB1*0301 (0.100), DRB1*0301 DQA1*0501 DQB1*02 (0.092) and DRB1*0701 DQA1*0201 DQB1*02 (0.072). The distribution of alleles and 'putative' haplotypes has shown common features with other Mediterranean populations. The results extend the HLA map to another Mediterranean country and provide a database for further HLA-disease association studies and transplantation applications.

Alleles↗