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PubMed2003

Cellular and molecular basis of natural killer and natural killer-like activity.

The capability of killing various tumors or cells infected by certain viruses is a property shared by natural killer (NK) cells and by a subset of cytolytic T lymphocytes (CTLs) termed NK-CTL. Recent analysis of the molecular basis in these phenomena, however, revealed rather different molecular mechanisms. Thus, while NK cell cytotoxicity is regulated by a complex balance between activating signals (delivered by non HLA-class I-specific triggering receptors) and inhibitory signals (delivered by HLA-class I-specific receptors) the effector function of NK-CTL reflects the TCR-mediated recognition of the poorly polymorphic HLA-E.

Animals↗
PubMed2003

Human leukocyte antigen-C in short- and long-term liver graft acceptance.

In liver transplantation, rejection is still an important problem, and the role of human leukocyte antigens (HLA) has not been clearly established. At present, the possible involvement of HLA-C antigen in liver transplantation is still unexplored. The aim of this work was to analyze the influence of HLA-C polymorphism on the outcome of liver transplantation. For this purpose, genotyping of 100 orthotopic liver transplant recipient-donor pairs for HLA-C was performed with polymerase chain reaction-sequence-specific primers (PCR-SSPs). Liver recipients were stratified according to the occurrence of acute rejection. Patients without acute rejection were found to have a lower frequency of the HLA-Cw*06 allele compared with those with acute rejection or the control group. Moreover, when the role of HLA-C dimorphism was analyzed, natural killer (NK)1-alloantigens were found to be predominant in recipients without acute rejection. When the match of HLA-C single alleles and NK-alloantigens between donor and recipient was analyzed, it appeared that the frequency of acute rejection gradually decreased with decrease of the number of allele mismatches. Graft survival was increased when the number of mismatches in both HLA-C or NK-alloantigens was lower. In conclusion, the HLA-C locus may play a role in liver graft alloreactivity or allotolerance and, therefore, may be useful to avoid acute rejection and to achieve graft acceptance, resulting in a better final outcome in liver transplantation.

Acute Disease↗
PubMed1998

The complete genomic sequence of 424,015 bp at the centromeric end of the HLA class I region: gene content and polymorphism.

We report here the genomic sequence of the centromeric portion of HLA class I, extending 424,015 bp from tumor necrosis factor alpha to a newly identified gene approximately 20 kb telomeric of Otf-3. As a source of DNA, we used cosmids centromeric of HLA-B that had been mapped previously with conventional restriction digestion and fingerprinting and previously characterized yeast artificial chromosomes subcloned into cosmids and mapped with multiple complete digest methodologies. The data presented provide a description of the gene content of centromeric HLA class I including new data on intron, promoter and flanking sequences of previously described genes, and a description of putative new genes that remain to be characterized beyond the structural information uncovered. A complete accounting of the repeat structure including abundant di-, tri-, and tetranucleotide microsatellite loci yielded access to precisely localized mapping tools for the major histocompatibility complex. Comparative analysis of a highly polymorphic region between HLA-B and -C was carried out by sequencing over 40 kb of overlapping sequence from two haplotypes. The levels of variation observed were much higher than those seen in other regions of the genome and indeed were higher than those observed between allelic HLA class I loci.

Centromere↗
PubMed2000

Genome-wide analysis of single-nucleotide polymorphisms in human expressed sequences.

Single-nucleotide polymorphisms (SNPs) have been explored as a high-resolution marker set for accelerating the mapping of disease genes. Here we report 48,196 candidate SNPs detected by statistical analysis of human expressed sequence tags (ESTs), associated primarily with coding regions of genes. We used Bayesian inference to weigh evidence for true polymorphism versus sequencing error, misalignment or ambiguity, misclustering or chimaeric EST sequences, assessing data such as raw chromatogram height, sharpness, overlap and spacing, sequencing error rates, context-sensitivity and cDNA library origin. Three separate validations-comparison with 54 genes screened for SNPs independently, verification of HLA-A polymorphisms and restriction fragment length polymorphism (RFLP) testing-verified 70%, 89% and 71% of our predicted SNPs, respectively. Our method detects tenfold more true HLA-A SNPs than previous analyses of the EST data. We found SNPs in a large fraction of known disease genes, including some disease-causing mutations (for example, the HbS sickle-cell mutation). Our comprehensive analysis of human coding region polymorphism provides a public resource for mapping of disease genes (available at http://www.bioinformatics.ucla.edu/snp).

Base Sequence↗
PubMed1983

HLA-DS molecules and their relation to supertypic specificities.

We have analyzed the structures of HLA-DS molecules from DR1, 2, 3, 4, 5, and 7 cell lines by two-dimensional gel electrophoresis and examined the relationship of HLA-DS molecules to those expressing the supertypic specificities MT1, MB3, and MT3. These studies have allowed us to conclude that the HLA-DS locus is as polymorphic as HLA-DR and that the MT1 and MB3 supertypic specificities reside on DS molecules. Furthermore, MT1 molecules from DR1, DR2, and DRw6 cell lines are structurally different as are MB3 molecules from DR4 and DR5 cell lines. In addition, studies using two MT3 specific reagents, a monoclonal antibody, 109d6, and an alloantiserum, Hon, suggest that MT3 is a cross-reactive determinant present on products of two different loci: a DS4 molecule and a DR7-like molecule.

Antibodies, Monoclonal↗
PubMed1993

HLA class I sequence-based typing.

HLA oligogenotyping has been used successfully to characterize most phenotypically undetectable variants of class II genes. Limitations inherent to the class I system have, however, complicated the application of this and other molecular approaches to HLA class I typing. We have previously shown that HLA class II polymorphism can be analyzed by a SBT approach. Here we present a class I-SBT strategy that provides complete sequence information for the two most polymorphic exons of the HLA-A, -B, and -C alleles. HLA class I SBT is based on direct sequencing of PCR-amplified HLA-A, -B, and -C cDNAs and requires a total of six cDNA -PCR-sequencing reactions (two per locus) and 13 different oligonucleotides. Each combination of oligonucleotides per reaction results in locus-specific sequence ladders and allows identification of both alleles in heterozygotes. Application of HLA-A, HLA-B, and HLA-C SBT to 26 homozygous and 32 serologically heterozygous samples has resulted in the identification of 24 novel class I nucleotide sequences encoding 17 new major histocompatibility complex class I products. An unexpected high degree of heterogeneity was found at the HLA-C locus with 14 novel sequences. Although there was a good correlation between the serologic phenotypes and SBT results, HLA-C SBT of most HLA-C serologically homozygous samples (heterozygous for HLA-A and/or -B) revealed heterozygozity (six of eight). SBT, the first molecular typing approach that has been generalized to both class I and class II genes, may be of special interest in applications demanding high sensitivity and specificity, such as in paternity testing or in the evaluation of the effects of sequence allelism in the outcome of unrelated bone marrow transplantation.

Alleles↗
PubMed1986

Antibody dependent cellular cytotoxicity mediated by HLA-class II specific monoclonal antibodies.

The ability of mouse monoclonal antibodies (MoAbs) directed against HLA-class II molecules to mediate in Antibody Dependent Cellular Cytotoxicity (ADCC) was investigated. The results indicate that both MoAbs to monomorphic and polymorphic HLA-DR and DQ determinants are able to mediate ADCC in an antigen specific manner. However, not all antibodies mediate ADCC to a similar extent. Furthermore, antibodies were identified that appeared to mediate ADCC in an HLA-DR haplotype dependent fashion. These results indicate that the inhibition of HLA-class II specific proliferative responses by anti-class II MoAbs may be influenced by ADCC directed against class II positive stimulator cells.

Animals↗
PubMed1996

Presentation of HLA class I-derived peptides: potential involvement in allorecognition and HLA-B27-associated arthritis.

Some 25 years ago, when purified HLA class I allotypes were first being analyzed, of major concern was that the papain used for solubilization might produce a mess of proteolytic fragments that would prove impossible to separate and sequence. Those fears proved unfounded (Parham et al. 1975), and the homogeneity of the preparations was sufficient to allow crystallization and determination of the three-dimensional structure (Bjorkman et al. 1987). Ironically the least ordered region of the electron density map provoked the most interest because it gave a first view of the diverse peptides bound by an MHC molecule. With this image a second chapter of HLA class I biochemistry began, its charge to determine the structures of bound peptides and their influence on the immune system. The extraordinary polymorphism of HLA class I heavy chains now seems quite manageable compared to the vast complexity of the peptides, and our present ignorance as to which ones are important for health and disease. The comparative weakness of most HLA class I associations with disease has made HLA-B27 an especially favored target for investigation, and more is known of the structure and peptide-presenting function of HLA-B27 than for any other HLA-B allotype (López de Castro 1994). Much of this information relates to the native HLA-B27 molecule and has been collected in the belief that disease is a direct consequence of its antigen-presenting function. If one subscribes to the relevance of the transgenic rodent models, this position has almost become untenable. For rats and mice 'non-functional' forms of HLA-B27 are the agents of disease, raising the possibility that B27-associated arthritis is induced by HLA class II presentation of a B27-derived peptide, a variant of the mechanism advanced for the classical HLA class II-associated diseases: type 1 diabetes, multiple sclerosis and rheumatoid arthritis (Gregersen et al. 1987, Roudier et al. 1989, Cucca & Todd 1996, Hall & Bowness 1996). Such speculation invites the obvious question as to whether other diseases associated with HLA class I and chronic inflammation, HLA-C and psoriasis for example (Tiilikainen et al. 1980, Yanagisawa et al. 1995), result from class II presentation of class I peptides.

Animals↗
PubMed1991

Study of HLA class I, class II and complement genes (C2, C4A, C4B and BF) in Japanese psoriatics and analysis of a newly-found high-risk haplotype by pulsed field gel electrophoresis.

Genetic polymorphisms of HLA antigens and HLA-linked serum complement components (C2, C4A, C4B and BF) were investigated in 79 Japanese patients suffering from psoriasis. HLA typing revealed increased frequencies of HLA-A1, A2, B39, Bw46, Cw6, Cw7 and Cw11. Among complement components, positive associations were obtained with C4A4 and C4B2 and a negative association with BFF. The major histocompatibility complex haplotype (supratype), HLA-A2-Cw11-Bw46-C2C-BFS-C4A4-C4B2-DRw8 is purported to be a new high-risk haplotype in Japanese patients with psoriasis. Analysis of patients with this supratype via pulsed field gel electrophoresis showed the existence of specific, extensive DNA deletions near HLA-DR genes, but no disease-specific patterns could be observed by means of this technique. The newly-found high-risk haplotype indicates racial and ethnic differences among psoriatic patients.

Alleles↗
PubMed2001

Resolution of cis-trans ambiguities between HLA-DRB1 alleles using single-strand conformation polymorphisms and sequencing.

DNA-based typing of HLA alleles occasionally results in the inability to assign a specific allele because of ambiguity in associating two or more polymorphisms to the same or to alternate homologs (cis/trans ambiguity). Since most individuals are heterozygous at a given HLA locus, the highest level of confidence in definition is obtained when the alleles are tested in isolation. By using single-strand conformation polymorphisms (SSCP) to separate heterozygous HLA-DRB1 alleles, followed by sequencing of separated conformers, we have achieved resolution of previously ambiguous assignments without the need for additional probes or primers.

Alleles↗
PubMed2000

TNFA promoter polymorphism and susceptibility to brucellosis.

The aim of this study was to investigate the possible influence of the tumor necrosis factor alpha (TNFA) gene promoter polymorphisms and HLA class II genes on the susceptibility to or development of human brucellosis. TNFA genotypes (at positions -308 and -238) were determined in 59 patients with brucellosis and 160 healthy controls by polymerase chain reaction-restriction fragment length polymorphism. There were no significant differences between the patients and the controls for the TNFA-238 genotypes. However, when the overall TNFA-308 genotype distribution of the brucella patients was compared with that of the control subjects, a significant skewing was observed (P = 0.02). The TNFA-308.1/2 genotype was present at significantly higher frequency in the total patient as a whole compared with control subjects (30% versus 15%; P = 0.01, odds ratio (OR) 2.49, 95% confidence interval (CI) 1.16-5.33). No statistically significant differences in the distribution of HLA-DRB1 or DQB1 alleles were observed between brucella patients and control subjects. Stratification to correct for interdependence of TNFA-308.2 and HLA-DR3 alleles confirmed that, in spite of their strong linkage disequilibrium, the association of TNFA-308.2 with brucellosis was independent of HLA-DR3.

Adolescent↗
PubMed2003

Differential expression of HLA class II genes associated with disease susceptibility and progression in rheumatoid arthritis.

OBJECTIVE: Rheumatoid arthritis (RA)-associated HLA class II genes are assumed to promote susceptibility to and/or progression of the disease. Among the various modes of action proposed so far is the effect of the differential expression of HLA class II genes in different types of antigen-presenting cells on the Th1/Th2 balance. The aim of this study was to investigate the differential expression of genes encoded within the RA-associated HLA-DR4 superhaplotype and within the neutral DR7 and DR9 superhaplotypes. METHODS: The promoters encoded within these 3 haplotypes were first analyzed for sequence polymorphisms. To test for functional consequences, we assumed that the binding of nuclear factors to the promoter elements was correlated with the transcription activity, and we used surface plasmon resonance technology. To that end, oligonucleotides representing the polymorphic regulatory sequences and nuclear extracts from a monocyte cell line and a B cell line were used. RESULTS: While the promoters of the highly polymorphic HLA-DRB1*04, *07, and *09 alleles showed comparable binding of nuclear factors, differential binding was observed for the 2 promoters that drive the relatively nonpolymorphic DRB4 alleles in linkage disequilibrium with DRB1. Interestingly, analysis of RA patients positive for DR4, DR7, and DR9 revealed the segregation of radiographic progression with the stronger of the 2 DRB4 promoters, independent of the DRB1 allele. Moreover, DRB1*04 alleles in RA patients showed a reduced association with the DRB4 splice variant, completely preventing DRB4 expression. CONCLUSION: Our findings represent the first evidence of a correlation between the differential expression of HLA class II genes and both the susceptibility and the progression of RA.

Adult↗
PubMed1996

HLA-C typing of eleven Papua New Guineans: identification of an HLA-Cw4/Cw2 hybrid allele.

HLA-C polymorphism of 11 individuals from Papua New Guinea was studied by serology and DNA typing (SSP ARMS-PCR). To resolve certain discrepancies HLA-C alleles were cloned and sequenced. Five alleles were identified by sequencing, four of which; Cw*0304, Cw*0401, Cw*12022 and Cw*1502 have been identified previously in other populations. The fifth allele, which was found in four individuals is a novel HLA-C allele. The new allele, called HLA-Cw*0403 is most similar to HLA-Cw*0401, differing by 10 nucleotides, 9 of which are located in the region from nucleotide 98 to 218. This region of Cw*0403 is identical to both HLA-Cw*0201 and Cw*02022. The 9 nucleotide differences between Cw*0401 and Cw*0403 result in 6 amino acid differences in the alpha 1 domain. These amino acids in Cw*0403 may contribute to the serological typing of some, but not all Cw*0403 expressing cells. The Final difference between Cw*0401 and Cw*0403 is a coding substitution at nucleotide 979 in exon 5. The guanine found in Cw*0403 is identical to all HLA-C alleles except HLA-Cw*0401, which has an adenine. The Cw*0403 allele was most likely formed by a gene conversion event between Cw*02 and Cw*04, involving a minimum of 121 to a maximum of 215 nucleotides.

Alleles↗
PubMed1995

Susceptibility and resistance alleles of human leukocyte antigen (HLA) DQA1 and HLA DQB1 are shared in endocrine autoimmune disease.

Because particular human leukocyte antigen (HLA) DQ alleles are the major predisposing factors for type 1 diabetes mellitus (IDDM), we investigated whether they are shared by other endocrine autoimmune diseases. We, therefore, analyzed the HLA DQ genotypes of 171 patients with IDDM, 271 with Graves' disease (GD), 65 with Hashimoto's thyroiditis, 51 with postpartum thyroiditis, 53 with Addison's disease (AD), and 271 healthy controls. HLA DQA1 and DQB1 alleles were defined by polymerase chain reaction and sequence-specific oligonucleotide hybridization as well as by single strand conformational polymorphism analysis. HLA DQA1*0501 was significantly more frequent in IDDM (60%), GD (65%), and AD (70%) than in controls (43%); DQA1*0301 was significantly more frequent only in IDDM (67% vs. 30% controls). The heterozygous state DQA1*0301/*0501 was found in 9% of controls and 35% of IDDM (relative risk, 5.6). An arginine at position 52 on either DQA1 allele was significantly more frequent in patients with IDDM (94%), GD (80%), and AD (89%) compared with controls (66%). HLA DQB1*0201 and DQB1*0302 were more frequent in IDDM patients (*0201, 62% vs. 36% in controls, *0302, 59% vs. 19% controls), whereas DQB1*0602 was less frequent in IDDM (4%) and GD (18% vs. 31% of controls). In conclusion, endocrine autoimmunity has a common immunogenetic background; susceptibility is conferred by DQA1*0501 as well as an arginine at position 52 of DQA1 alleles, and protection against IDDM and GD is conferred by DQB1*0602.

Addison Disease↗