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At least 19 recordsLinked to original sources
PubMed1992

HLA-J, a second inactivated class I HLA gene related to HLA-G and HLA-A. Implications for the evolution of the HLA-A-related genes.

Ragoussis and co-workers (Genomics 4:301) previously described a class I HLA gene (now designated HLA-J) that maps to within 50 kb of HLA-A. The nucleotide sequences of three HLA-J alleles are reported here. Comparison of the nucleotide sequences of HLA-J alleles shows this gene is more related to HLA-G, A, and H than to HLA-B, C, E, and F. All four alleles of HLA-J are pseudogenes because of deleterious mutations that produce translation termination either in exon 2 or exon 4. Apart from these mutations, the predicted proteins have structures similar to those of HLA-A, B, and C molecules. There is, however, little polymorphism at HLA-J and none at functional positions of the Ag-recognition site. The polymorphism is less than found for HLA-H another HLA-A-related pseudogene. HLA-J appears, like HLA-H, to be an inactivated gene that result from duplication of an Ag-presenting locus related to HLA-A. Nucleotide sequence comparisons show that the HLA-A, H, J, and G genes form a well defined group of "HLA-A-related" loci. Evolutionary relationships as assessed by construction of trees suggest the four modern loci: HLA-A, G, H, and J were formed by successive duplications from a common ancestral gene. In this scheme one intermediate locus gave rise to HLA-A and H, the other to HLA-G and J.

Alleles↗
PubMed1992

Peptide binding to HLA-A2 and HLA-B27 isolated from Escherichia coli. Reconstitution of HLA-A2 and HLA-B27 heavy chain/beta 2-microglobulin complexes requires specific peptides.

The specificity of peptide binding by human leukocyte antigen (HLA) class I molecules was investigated in a cell-free direct-binding assay. Peptides were assessed for binding to HLA-A2 and HLA-B27 by measuring the formation of heterotrimeric HLA complexes that consisted of iodinated beta 2-microglobulin, HLA heavy chain fragments isolated from the Escherichia coli cytoplasm, and peptide. In this system, no detectable HLA heavy chain-beta 2-microglobulin complexes were formed unless appropriate peptides were intentionally added to the reconstitution solution. Analysis with monoclonal antibodies demonstrated that these heterotrimeric complexes were correctly folded. Five nonhomologous peptides, known to form complexes with HLA-A2 or HLA-B27 from T-cell functional studies, were tested for their capacity to bind to HLA-A2 and HLA-B27 using the reconstitution assay. Four of the peptides bound to the appropriate class I molecule only. One peptide and some (but not all) substitution analogs of it bound to both HLA-A2 and HLA-B27. The effect of peptide length on binding to HLA-B27 was studied, and it was found that the optimal length was 9 or 10 amino acid residues; however, one peptide that bound to HLA-B27 was 15 amino acids long. All peptides that bound to HLA-B27 in the direct-binding assay also competed with antigenic peptides for binding to HLA-B27 on the surface of intact cells, as determined by a standard cytotoxic T-lymphocyte functional assay. Thus, we conclude that HLA-A2 and HLA-B27 bind distinct but partially overlapping sets of peptides and that, at least in vitro, the assembly of HLA heavy chain-beta 2-microglobulin complexes requires specific peptides.

Amino Acid Sequence↗
PubMed2025

Investigations of HLA-F and HLA-G 3'UTR Polymorphisms in Preeclampsia and Fetal Growth Restriction Indicate a Possible Role of HLA-F-HLA-G Haplotypes and Diplotypes.

HLA-F and HLA-G may be involved in the pathogeneses of preeclampsia and fetal growth restriction (FGR). However, the functions of HLA-F and HLA-G in placental dysfunction remain unclear. The aim was to investigate differences in the prevalence of specific HLA-F and HLA-G gene allelic polymorphisms, genotypes, haplotypes, and diplotypes between controls and cases with preeclampsia or FGR. In total, blood samples from 365 pregnant females (controls, n = 192; preeclampsia, n = 164; FGR, n = 19) in their second and third trimester, and corresponding cordial blood samples (reflecting newborns, n = 160) were obtained after delivery. Genomic DNA was sequenced with a focus on the specific gene polymorphisms in the HLA-F gene locus, especially the single nucleotide polymorphisms (SNPs) rs1362126 (G/A), rs2523405 (T/G) and rs2523393 (A/G), as well as the rs371194629 (14-bp ins/del) in the 3'UTR of HLA-G. Haplotype and diplotype distributions were obtained using PHASE v2.1, and linkage disequilibrium analyses were performed. SNPs in the HLA-F gene locus and the 3'UTR of HLA-G were not associated with the risk of preeclampsia or FGR. The SNPs did not correlate with fetal-placental weight ratio, deviation of birth weight at gestational age, and placental weight. However, a trend towards an absence of certain HLA-F-HLA-G extended diplotypes in preeclampsia was observed. The current study does not support associations of the investigated HLA-F SNPs with preeclampsia or FGR. However, further studies are needed to evaluate the possible role of certain fetal HLA-F-HLA-G extended haplotypes and diplotypes in preeclampsia.

Humans↗
PubMed2025

Extensive Analysis of Genetic Diversity in HLA-DMA, HLA-DMB, HLA-DOA and HLA-DOB: Characterisation of 236 Novel Alleles.

HLA-DMA, -DMB, -DOA and -DOB are non-classical HLA Class II genes that play a crucial role in the selection of highly stable HLA Class II/peptide complexes on antigen-presenting cells. Although the genes were initially thought to have a limited diversity with less than 13 alleles per gene documented in the IPD-IMGT/HLA Database in 2022, recent studies suggest a potential impact of certain alleles on the outcome of hematopoietic cell transplantation. To gain a deeper understanding of allelic diversity, we sequenced HLA-DMA, -DMB, -DOA and -DOB of 1880 potential stem cell donors from Germany, Poland, Great Britain and Chile, achieving full-gene resolution. Remarkably, we identified 3968 previously undescribed sequences, including 28 distinct novel proteins. The observed allele frequencies were consistent across all studied populations with one dominating protein for each gene: HLA-DMA*01:01 (> 77%), HLA-DMB*01:01 (> 63%), HLA-DOA*01:01 (> 97%) and HLA-DOB*01:01 (> 77%). Notably, a much higher diversity was observed in full-genomic resolution. Finally, we submitted 51 distinct novel sequences for HLA-DMA, 58 for HLA-DMB, 80 for HLA-DOA and 47 for HLA-DOB to the IPD-IMGT/HLA Database. This comprehensive reference database update will not only simplify future genotyping of HLA-DMA, -DMB, -DOA and -DOB but will hopefully also enhance our understanding of the complex process of peptide selection and loading to the HLA Class II proteins.

Humans↗
PubMed1989

Sequence and gene transfer analyses of HLA-CwBL18 (HLA-C blank) and HLA-Cw5 genes. Implications for the control of expression and immunogenicity of HLA-C antigens.

Our previous studies suggested that a serologically undetectable HLA-C blank allele (HLA-CwBL18) is either a variant Cw5 allele or a novel HLA-C Ag. To examine these possibilities, the CwBL18 and Cw5 genes from the TCC (HLA-A1, -A2, -B52, -B18, -Cw-, -Cw-) and QBL (HLA-A26, -B18, -Cw5) EBV-transformed B lymphoblastoid cell lines (LCL) were cloned, sequenced, and transferred into HLA-A, -B, -C null LCL mutant .221 cells. The CwBL18 Ag was detected on the cell surface of CwBL18 transferents by flow cytometry with the anti-class I mAb W6/32 but not by complement-mediated cytotoxicity with currently available HLA-C specific antisera. Sequence analysis of the Cw-BL18 gene indicated that the CwBL18 Ag is "C"-like because it contains all C-locus-specific residues and amino acid replacements commonly found in HLA-C alleles. However, the amino acid sequence of the CwBL18 Ag is unusual; CwBL18 lacks unique allele-specific residues when compared with the sequences of other HLA-C alleles. Moreover, apart from the C-locus-specific differences, the sequence of CwBL18 is identical to the HLA class I consensus sequence. This striking homology of CwBL18 to other HLA class I alleles suggests that CwBL18 may be a weak Ag. Taken together, these data demonstrate that CwBL18 is not a variant Cw5 Ag but is a newly described HLA-C Ag. In contrast to CwBL18, the Cw5 Ag is serologically detectable on the cell surface of Cw5 transferents with HLA-specific allo-antisera. Rather unexpectedly, Cw5 was usually expressed at a lower level than CwBL18 on the surface of .221 transferents as evaluated by W6/32 mAb binding analyses. The sequence of Cw5 revealed several unique amino acid replacements. Two of these substitutions, at residue 35 of the alpha 1 domain and residue 275 of the transmembrane domain, may be responsible for the reduced cell surface expression of Cw5. Additional unique replacements at residues 138 and 177 of the alpha 2 domain suggest that these amino acids may be important in the formation of an epitope recognized by a Cw5-specific antibody.

Amino Acid Sequence↗
PubMed1990

Specificity and frequency of primary anti-HLA cytotoxic T lymphocytes in normal and HLA-B27.2-, HLA-B27.5-, and HLA-Cw3-transgenic mice. A transgenic model for MHC xenoantigen recognition.

Previous studies have shown that the lymphocytes of naive mice produce a strong primary CTL responses in vitro to human MHC class I Ag presented by HLA-transgenic mouse (TGM) cells. A limiting dilution (LD) assay was used to analyze this xenoreactive CTL repertoire in mice. Frequencies of HLA class I-specific CTL precursors (CTLp) were estimated in naive normal and HLA-B27.2-, -B27.5- and HLA-Cw3-double TGM (i.e., mice expressing HLA and human beta 2-microglobulin (hu beta 2m]. The xenoreactive CTLp frequencies were compared to frequencies of CTLp to H-2 alloantigens estimated in naive normal mice. The results showed that the frequencies of HLA class I-specific CTLp are comparable with those of alloreactive CTLp. This overlap in CTLp frequencies suggests that HLA class I xenoantigens are recognized by primary mouse CTL as allelic variants of H-2K and H-2D. This was confirmed in split well analysis by the observation that the xenoreactive response was not restricted by self-MHC of the responding mouse. Thus, primary HLA class I-specific mouse CTL clones recognized their target Ag regardless of whether they were expressed on H-2-mismatched mouse cells or on human cells. The frequencies of HLA class I-specific CTLp in HLA-TGM were comparable to those in normal mice. We propose that MHC allo- and xenoreactive CTL responses are not caused by the activation of CTLp specific for self-MHC plus peptide but to the activation of CTLp recognizing MHC allo- and xenoantigens directly or as peptides presented by their native MHC molecules.

Animals↗
PubMed1985

Comparison of HLA class I gene sequences. Derivation of locus-specific oligonucleotide probes specific for HLA-A, HLA-B, and HLA-C genes.

The major histocompatibility complex in man contains at least 20 class I genes. Included within this family are three closely linked loci with 11-47 codominant alleles that encode the classical transplantation antigens HLA-A, -B, and -C. The study of individual HLA-A, -B, and -C genes is complicated both by the high degree of sequence homology among all members of the class I gene family and by the high degree of polymorphism exhibited by HLA-A, -B, and -C genes. Identification of potential locus-specific regions suitable for use as unique probes has been limited by the small number of nucleotide sequences available for comparison. In the present study, the nucleotide sequences of two cDNA clones, designated HLA-4 and HLA-10, that encode previously unsequenced alleles of HLA-C and HLA-A genes, respectively, are compared with those of other class I genes. From these intergenic and interallelic comparisons, it was deduced that the nucleotide sequence encoding amino acids 291-299 of the transmembrane region showed sufficient divergence between loci and similarity between alleles, to be suitable for the generation of locus-specific probes. Synthetic oligonucleotides were generated and shown to be highly locus-specific in hybridization. These probes were used successfully for the quantitation of the relative amounts of mRNA transcribed in human liver from HLA-A, -B, and -C genes; they should greatly simplify future studies of restriction fragment length polymorphisms of HLA-A, -B, and -C alleles as genetic markers of disease susceptibility.

Alleles↗
PubMed1988

Hybrid genes between HLA-A2 and HLA-A3 constructed by in vivo recombination allow mapping of HLA-A2 and HLA-A3 polymorphic antigenic determinants.

HLA-A2 and -A3 genes have been modified in their third exon (second domain) by using in vivo recombination. In this method Escherichia coli are transfected with a plasmid which contains two highly homologous sequences (e.g., the third exons of HLA-A2 and -A3) and has been linearized by cleavage between these two sequences. Circularization takes place in the bacteria by homologous recombination leading to hybrid A2-A3 sequences. The analysis by DNA sequencing of a number of such recombinants shows that they indeed occur by homologous recombination (no insertions or deletions) and that the probability of crossing over decreases as the distance from the free end of DNA in the homologous region increases. No double recombinants were observed. These hybrid exons were reinserted into either HLA-A2 or HLA-A3 genes, thus generating a panel of functional hybrid genes containing one or several HLA-A2 specific substitutions in an HLA-A3 background or vice versa. These genes were expressed by transfection into murine P815-high transfection efficiency recipient cells. Serologic analysis leads to the conclusion that expression of polymorphic antigenic determinants specific for HLA-A2 (detected with M58, A2A28M1, and CR11.351 mAb) is linked to the presence of threonine residue (amino acid (AA) 142) and/or histidine residue (AA 145) and valine residue (AA 152). The expression of specific HLA-A3 polymorphic determinants (recognized by GAP-A3 mAb) is correlated with the existence of a asparagine residue (AA 127) and a aspartic residue (AA 161). But aspartic residue 161 contributes with glutamic acid residue 152 in the formation of the A3 epitope recognized by the anti-A3 mAb X1.23.2.

Antibodies, Monoclonal↗
PubMed1989

Molecular mapping of a new public HLA class I epitope shared by all HLA-B and HLA-C antigens and defined by a monoclonal antibody.

It has previously been shown that a mouse monoclonal antibody, designated 4E, reacts with an epitope common to all HLA-B and -C antigens and those of the HLA-Aw19 cross-reactive group, namely, HLA-A29, -A30, -A31, -A32, -Aw33, and -Aw74. In order to pinpoint the amino acid residues which comprise the public specificity recognized by 4E, and HLA-A29 cDNA clone was isolated and its predicted amino acid sequence compared with those of other cloned HLA class I genes. The isolated HLA-A29 cDNA corresponded to the rarer of the two A29 variant alleles, A29.1. Two amino acid residues of HLA-A29.1, gln-144 and arg-151, were found in all 24 HLA-B and HLA-C alleles examined but were present in only one of 15 HLA-A alleles for which sequence data are available. Importantly, this exceptional allele was HLA-A32, another member of the HLA-Aw19 cross-reactive group. Gln-144 and arg-151 should be capable of jointly contributing to the binding site for 4E, as they are situated in successive alpha-helical subregions and are predicted to be juxtaposed in the three-dimensional HLA molecule. Four other residues in the first or second external domains of HLA-A29.1 (thr-9, leu-62, gln-63, and his-102) were unique among the HLA-A alleles, but none of these was found in corresponding positions of HLA-B of -C alleles and thus failed to correlate with presence or absence of the 4E determinant. These observations are consistent with the notion that gln-144 and arg-151 define a determinant common to HLA-B, HLA-C, and the HLA-Aw19 cross-reactive group and the binding site of the monoclonal antibody 4E.

Amino Acid Sequence↗
PubMed1986

HLA-Dw specificity assignments are independent of HLA-DQ, HLA-DR, and other class II specificities and define a biologically important segregant series which strongly activates a functionally distinct T cell subset.

Several lines of evidence indicate that HLA-Dw, as defined by HTC typing, is not the result of the combined stimulatory effect of HLA-DR and DQ. Therefore, responder cells do not have to share HLA-DQ antigens with the stimulator HTCs to give a typing response. The common HLA-DR-DQ associations observed in HTCs correspond to different patterns of linkage disequilibrium in different populations. HLA-DQ and HLA-Dw are functionally heterogeneous. Although HLA-DQ molecules may play a role in primary stimulation, this role is distinct from that of Dw determinants which have strong lymphocyte activating properties. The role of the HLA-DQ determinants on the other hand, is one of modulating the total T cell response by controlling the proliferation of suppressor and cytotoxic cells. The primary MLC response is the result of the proliferative effect of HLA-Dw, DR, DP, and other associated determinants, in conjunction with a modulatory effect of DQ molecules. However, HLA-Dw (as detected by HTC typing) are DR associated determinants which are immunodominant in primary MLR. The genes of the HLA-DR subregion have been named DR by the WHO nomenclature committee. This subregion encodes the HLA-DR specificities and the DRw52 and DRw53 determinants. Unfortunately this nomenclature does not take into account the need to define the genetic basis of the HLA-Dw determinants--whether they are encoded by separate genes within the HLA-DR subregion or whether they are encoded by as yet unspecified genes in the HLA class II region in linkage disequilibrium with HLA-DR DRw52/53. There are at least three and possibly four beta chain genes in the HLA-DR subregion, all in strong linkage disequilibrium with each other. Some of these are expressed in most haplotypes while others are not; some behave as pseudogenes in some haplotypes and in others, all the genes are expressed. All the genes of the class II region have not been fully characterized. HLA-Dw determinants may be specified by one or more of these genes. When more information becomes available, the genetic and molecular basis of the HLA-Dw series as well as the functional heterogeneity and antigenic strength of the various class II determinants will be better understood.

Epitopes↗
PubMed1986

Highly polymorphic products of both HLA-DR and HLA-DQ genes contribute to the polymorphism of the HLA-DRw13 haplotype.

We studied the polymorphisms of HLA-DR and HLA-DQ products from HLA-DRw13 haplotypes by analyzing the restriction of influenza A-specific cloned T cells from an HLA-DRw13,DQw1,Dw19 homozygous individual. The results show that some functional epitopes, which can be borne by either HLA-DR or HLA-DQ molecules, are strictly correlated with the HLA-Dw19 subtype of HLA-DRw13. This clearly indicates that both HLA-DR and HLA-DQ products contribute to the HLA-Dw19 subdivision of HLA-DRw13. At least two different restricting epitopes are borne by DR products: one is correlated with the HLA-DRw13 serologically defined specificity, which includes Dw19 and Dw18 haplotypes; the other is correlated with the only HLA-Dw19 subtype of HLA-DRw13. Restricting epitopes borne by DQ molecules have been found on Dw19 cells only. DQ-restricted clones were unable to react with DQw1 APC of any other haplotypes tested, including DR1, DR2-long, DR2-short, and DRw14, demonstrating a high degree of functional polymorphism among the serologically defined DQw1 specificities.

Antigen-Presenting Cells↗
PubMed1989

HLA gene amplification and hybridization analysis of polymorphism. HLA matching for bone marrow transplantation of a patient with HLA-deficient severe combined immunodeficiency syndrome.

The treatment of choice for certain immunodeficiency syndromes and hematological disorders is bone marrow transplantation (BMT). The success of BMT is influenced by the degree of HLA compatibility between recipient and donor. However, aberrant expression of HLA sometimes makes it difficult, if not impossible, to determine the patient's HLA type by standard serological and cellular techniques. We describe here the application of new molecular biological techniques to perform high resolution HLA typing independent of HLA expression. A patient with HLA-deficient severe combined deficiency was HLA typed using in vitro amplification of the HLA genes and sequence-specific oligonucleotide probe hybridization (SSOPH). Two major advances provided by this technology are:detection of HLA polymorphism at the level of single amino acid differences; and elimination of a requirement for HLA expression. Although the patient's lymphocytes lacked class II HLA proteins, polymorphism associated with DR7,w53;DQw2;DRw11a (a split of DR5), w52b (a split of DRw52);DQw7 were identified. The patient's class I expression was partially defective, and typing was accomplished by a combination of serological (HLA-A and -C) and SSOPH analysis (HLA-B). Complete patient haplotypes were predicted after typing of family members [A2;B35(w6); Cw4; DRw11a(w52b);DQw7 and A2;B13(w4); Cw6;DR7(w53); DQw2]. Potential unrelated donors were typed and a donor was selected for BMT.

Alleles↗
PubMed1989

Cytotoxic T cell responses in HLA-A2.1 transgenic mice. Recognition of HLA alloantigens and utilization of HLA-A2.1 as a restriction element.

Previous studies have indicated that the frequency of murine CTL precursors (CTLp) for human class I molecules is one to two orders of magnitude lower than that for murine class I alloantigens, and that this is due to species-specific structural differences between these molecules. Transgenic mice expressing the human class I MHC Ag HLA-A2.1 were used to examine changes in the frequency of class I HLA-specific precursors after T cell differentiation in an HLA-A2.1 positive environment. The HLA-A2.1 gene product was expressed at levels comparable to those of the endogenous H-2Db molecule in thymus, bone marrow, and spleen. By limiting dilution analysis, it was observed that the frequencies of CTLp in transgenic mice responding to the human alloantigens HLA-B7 or HLA-A2.2 were comparable to or lower than those in normal C57BL/6 mice, regardless of whether the Ag was presented on human or murine cells. Thus, expression of a human class I molecule in these animals did not result in an expansion of the number of CTLp specific for other human class I Ag. In addition, the frequency of HLA-A2.1-restricted, influenza specific CTLp was substantially lower than the frequency of H-2b restricted CTLp, indicating a poor utilization of HLA-A2.1 as a restricting element. Finally, the frequencies of CTLp for HLA-A2.1 expressed on syngeneic murine tumor cells were decreased significantly. Thus, expression of HLA-A2.1 in these animals appeared to induced tolerance to this Ag. Interestingly, however, these mice were not tolerant to the HLA-A2.1 molecule expressed on human cells. This indicates that the HLA-A2.1 associated epitopes expressed on murine and human cells differ and suggests that, under these circumstances, HLA-A2.1 acts as a restricting element for human nominal Ag. These results are discussed in the context of current models of T cell repertoire development.

Animals↗
PubMed1989

Allelic variation in HLA-B and HLA-C sequences and the evolution of the HLA-B alleles.

Several new HLA-B (B8, B51, Bw62)- and HLA-C (Cw6, Cw7)-specific genes were isolated either as genomic cosmid or cDNA clones to study the diversity of HLA antigens. The allele specificities were identified by sequence analysis in comparison with published HLA-B and -C sequences, by transfection experiments, and Southern and northern blot analysis using oligonucleotide probes. Comparison of the classical HLA-A, -B, and -C sequences reveals that allele-specific substitutions seem to be rare events. HLA-B51 codes only for one allele-specific residue: arginine at position 81 located on the alpha 1 helix, pointing toward the antigen binding site. HLA-B8 contains an acidic substitution in amino acid position 9 on the first central beta sheet which might affect antigen binding capacity, perhaps in combination with the rare replacement at position 67 (F) on the alpha 1 helix. HLA-B8 shows greatest homology to HLA-Bw42, -Bw41, -B7, and -Bw60 antigens, all of which lack the conserved restriction sites Pst I at position 180 and Sac I at position 131. Both sites associated with amino acid replacements seem to be genetic markers of an evolutionary split of the HLA-B alleles, which is also observed in the leader sequences. HLA-Cw7 shows 98% sequence identity to the JY328 gene. In general, the HLA-C alleles display lower levels of variability in the highly polymorphic regions of the alpha 1 and alpha 2 domains, and have more distinct patterns of locus-specific residues in the transmembrane and cytoplasmic domains. Thus we propose a more recent origin for the HLA-C locus.

Amino Acid Sequence↗
PubMed1987

Unusual expression of HLA molecules at the surface of murine cells transfected with HLA-B7 or HLA-A11 genes.

The HLA-B7 and HLA-A11 molecules expressed on murine transfectants have been analysed by one- and two-dimensional polyacrylamide gel electrophoresis (PAGE). Two different murine cells, L and P815-HTR have been compared, because it has been previously established that P815 transfectants were much more sensitive to human cytolytic cells than L transfectants. Three kinds of HLA molecules were present on these cells: (1) normal HLA molecules with 2D-PAGE profiles identical to those of the molecules isolated from human cells; (2) HLA molecules of usual size but with more various charges than HLA molecules detected on human cells. This heterogeneity was constantly found with cells expressing HLA-B7 or -A11 antigens, both in L and in P815 transfectants, including several clones. These forms were detected by anti-HLA monoclonal antibodies and by antipeptide (from HLA-B7) antibodies; (3) other unusual products corresponding to shorter heavy chains: molecules of various mol. wts and charges were detected in HLA-B7 but not in HLA-A11 transfectants. They were observed using antipeptide sera but were not seen with anti-HLA monoclonal antibodies. These products were possibly related to the DNA used for transfection and it cannot be excluded that such abnormalities only detectable by antipeptide sera would exist in other transfectants. The functional discrepancies between P815 and L transfectants cannot be clearly explained by these biochemical results.

Animals↗
PubMed1982

Structure of crossreactive human histocompatibility antigens HLA-A28 and HLA-A2: possible implications for the generation of HLA polymorphism.

The primary structure of two highly crossreactive human histocompatibility antigens, HLA-A28 and HLA-A2, has been determined to 96% and 90%, respectively, of the papain-solubilized molecules. Their sequences have been compared with the sequence of HLA-B7 and with each other in order to outline the sites of diversity. The overall homology between HLA-B7 and these HLA-A antigens is 86%. A large majority of the differences are located between residues 43 and 195. Within this area, substitutions cluster in at least three segments--residues 65-80, 105-116, and 177-194. HLA-A28 and HLA-A2 show 96% homology. Most of the differences fall within segments 65-74 and 107-116. These results strongly support the suggestion that residues in these segments are integral parts of the alloantigenic determinants of HLA-A28 and HLA-A2. It is further proposed that these three clusters may constitute major, albeit not exclusive, sites of antigenic diversity in human histocompatibility antigens. The nature of the differences among HLA-B7, HLA-A28, and HLA-A2 in the first variable segment suggests that gene conversion might play some role in the generation of HLA polymorphism.

Amino Acid Sequence↗
PubMed1992

Effect of the substitutions in the alpha helix and the beta sheet of HLA class I molecule on allorecognition of T cells specific for HLA-B51 and HLA-Bw53.

HLA-B51 and HLA-Bw53 differ by eight amino acids on the alpha 2 domain. Of these eight amino acid substitutions, two are in the alpha helix and six are in the beta sheet. The effect of these substitutions on allorecognition of HLA-B51-specific cytotoxic T lymphocyte (CTL) clones and HLA-Bw53-specific CTL clones was investigated using chimeric antigen (Ag) between HLA-B51 and HLA-Bw53. Of 12 HLA-B51-specific CTL clones, recognition of one clone was abolished by the substitutions on the beta sheet alone, that of two clones by the substitutions on the alpha helix alone, and that of nine clones not only by the substitutions on the alpha helix but also by those on the beta sheets. On the other hand, of 17 HLA-Bw53-specific CTL clones, recognition of 10 clones was affected by the substitutions on the alpha helix alone and that of 7 clones not only by the substitutions on the alpha helix but also by those on the beta sheet. The present study demonstrated that the substitutions (residues 152 and 171) on the alpha helix critically affect recognition of HLA-B51-specific CTL clones and HLA-Bw53-specific CTL clones and that the substitutions on the beta sheet affect also recognition of the majority of HLA-B51-specific CTL clones and 40% of HLA-Bw53-specific CTL clones. These results indicate that the substitutions at the floor of the peptide binding groove affect recognition of allogeneic CTL.

Amino Acid Sequence↗