Induction of long-term heart graft survival in HLA class I transgenic mice by intrathymic injection of HLA class I peptides.
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Amino Acid Sequence↗
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Lymphocyte programmed cell death is mediated via HLA class II DR.
HLA class II molecules are constitutively expressed on human B lymphocytes and are induced on human T lymphocytes after activation, through which signal transduction via these molecules has been extensively described. We have observed cell death of as many as 60% after stimulation of lymphocytes via HLA class II DR molecules, but not via DP or DQ. Propidium iodide fluorescence, DNA fragmentation and morphology of the dead cells were examined. The reported cell death was very rapid, and independent of Fc receptors and of complement. A morphologically distinct sub-population of activated B cells was sensitive to HLA-DR mediated death, while resting B lymphocytes from the same donor did not die as a result of HLA class II mediated stimulation. Death via HLA-DR was distinguishable from necrosis. Cytoskeletal integrity, serine/threonine phosphatase activity and endonucleases were required for the pathway leading to HLA-DR mediated death. The 'ladder' pattern of DNA fragmentation which typically characterizes apoptosis was not observed, despite the observation of cell and nuclear shrinkage normally associated with apoptosis. These data suggest that HLA class II mediated death is a means of rapidly removing either T or B lymphocytes which have already served their role in the immune response, thereby avoiding the inflammatory responses associated with necrosis and concentrating the ligands for new TCR and/or CD4 interactions.
Antibodies, Monoclonal↗
[Polymorphism of HLA class I loci HLA-A, -B, -C, in the Mandenka population from eastern Senegal].
A sample of 162 Mandenkalu from Eastern Senegal has been typed for three HLA class I loci: HLA-A, -B and -C. The Mandenka population presents a very high genetic variability with 15 alleles for locus A, 24 alleles for locus B, and at least 8 alleles for locus C. The calculated heterozygosities for the three loci A, B, and C are respectively 0.884, 0.944 and 0.829. The Mandenkalu allelic frequencies are close to that found in other sub-Saharan populations. They show, however, some peculiarities like the occurrence of the Bw 56 allele and the high frequencies of both B5 and B35.
Alleles↗
Cytomegalovirus infection is associated with absence of alveolar epithelial cell HLA class II antigen expression.
Cytomegalovirus (CMV) pneumonia is associated with the development of secondary immunosuppression with resultant bacterial and fungal superinfections. Because class II HLA expression within the lung may be important in normal pulmonary cell-mediated immunity, the association of CMV infection of alveolar epithelial cells (AEC) with an absence of HLA class II antigens was tested. Using dual-labeling immunohistochemistry to detect CMV, AEC, endothelial cells, macrophages, and HLA class II antigens, lung tissue from patients whom died with CMV pneumonia was examined. Seventy-five percent of infected cells were AEC. In contrast to adjacent noninfected AEC, which expressed HLA-DR antigens, 91% of infected AEC were negative. There was no difference in this expression pattern between patients with or without AIDS. The absence of HLA class II antigens on infected AEC may account, in part, for the secondary immunosuppression associated with CMV pneumonia.
AIDS-Related Opportunistic Infections↗
Cell-surface expression of human histocompatibility leucocyte antigen (HLA) class II-associated invariant chain (CD74) does not always correlate with cell-surface expression of HLA class II molecules.
The human histocompatibility leucocyte antigen (HLA) class II-associated invariant chain comprises at least four polypeptides. One of these is expressed as a membrane-bound subunit and has been designated as CD74. We investigated the expression of CD74 on B- and T-cell types utilizing monoclonal antibodies (mAb) specific for the c-terminus of CD74. All B cells tested expressed CD74 regardless of their HLA phenotypes. High and low CD74 expressors were provisionally assigned based on quantitative variations found in some haplotypes. A mutant cell with selective deletions of class II loci DR and DQ but with retention of DP and additional class II heterodimers synthesize normal amounts of CD74. In contrast, however, a mutant with a total class II deletion had diminished expression of CD74, suggesting that at least one of the class II isotypes is essential for full constitutive expression of CD74. Major histocompatibility complex (MHC) class II negative T-cell lines and CD3+ T cell isolated from peripheral blood did not express CD74. However, allostimulated T cells which express de novo induced class II determinants also did not express CD74. Taken together, these results show that CD74 is expressed on B cells and unexpectedly is not synthesized on de novo-induced class II positive T-cell clones.
Antigens, Differentiation, B-Lymphocyte↗
Peyronie's disease is associated with an HLA class II antigen, HLA-DQ5, implying an autoimmune etiology.
PURPOSE: Previous studies using serological (protein based) HLA typing methods suggested an association between various HLA antigens and Peyronie's disease. We used a molecular (deoxyribonucleic acid based) HLA typing method to determine whether Peyronie's disease is associated with class II HLA antigens. MATERIALS AND METHODS: Class II HLA typing using the polymerase chain reaction-sequence specific primer method was performed in 31 patients with Peyronie's disease, 19 age matched urological patients with disorders other than Peyronie's disease and 75 major organ donor cadavers representative of the general population. RESULTS: The frequency of HLA-DQ5 was significantly increased in patients with Peyronie's disease (61% HLA-DQ5 positive) compared to age matched disease-free controls (11% HLA-DQ5 positive, corrected p = 0.003) and general population controls (25% HLA-DQ5 positive, corrected p = 0.005). The relative risk for Peyronie's disease associated with HLA-DQ5 was 12.7 and 4.6 compared to age matched and general population controls, respectively. CONCLUSIONS: This study shows a positive association for the HLA class II antigen HLA-DQ5 with Peyronie's disease, suggesting that HLA-DQ5 is a risk factor for Peyronie's disease and implying an autoimmune etiology for this disorder.
Adult↗
Identification of three novel HLA class I alleles: HLA-A*0261, HLA-B*1585 and HLA-B*1587.
Three novel human leucocyte antigen (HLA) class I alleles have been characterized by means of direct DNA sequencing analysis. HLA-A* 0261 showed sequence variation at conserved codon. It differs from HLA-A* 020601 by a single-nucleotide substitution at codon 57 (CCG-->GCG) resulting in an amino acid change from Pro to Ala. The sequences of HLA-B*1585 are similar to those of HLA-B*15010101, but differed five nucleotides on exon 3 resulting in three amino acid changes at residues 94 (Thr-->Ile), 95 (Leu-->Ile) and 103 (Val-->Leu). Likewise, HLA-B*1587 is identical to HLA-B*15010101 except at codons 80-83 (Asn-Leu-Arg-Gly-->Ile-Ala-Leu-Arg) which has been replaced by HLA-Bw4 motif. These alleles seemed to be generated by either a point mutation or a gene conversion-like event from alleles existing in the population with high frequencies.
Adult↗
An In-Depth Review of the Genetics of the Non-Classical HLA Class I Gene HLA-E and Its Effects on Haematopoietic Cell Transplant Outcomes.
HLA-E is a non-classical HLA class I gene with limited reported genetic variability and few published studies into full-gene sequencing or population allele frequencies. Two protein variants, HLA-E*01:01 and HLA-E*01:03, are very common, accounting for 94%-100% of observed alleles in most studies performed to date. Frequently utilised exon-based sequencing strategies have led to the assumption of HLA-E being a near bi-allelic gene; however, recent full-gene sequencing studies have shown a greater degree of genetic variability than initially imagined. We carried out a literature review of HLA-E genotype and ethnicity data, which suggested HLA-E*01:03 is more common in Asian and, in particular, East Asian populations. Furthermore, HLA-E*01:03:02 is more frequently observed than HLA-E*01:03:01 in European and American populations, whereas HLA-E*01:03:01 is found at higher frequencies in Asian populations. It has been proposed that HLA-E may have a role in Haematopoietic Cell Transplantation (HCT) due to its interaction with NK and CD8+ T cells and its non-canonical peptide binding repertoire. Here we also review published literature into the effects of HLA-E genetics on HCT outcomes. Heterogeneity between cohorts muddies the waters; hence, studies report confounding effects of HLA-E genotype and matching on HCT outcomes. The need for further HLA-E sequencing of larger cohorts is evident to gain useful insight into the true genetic variability of HLA-E and its impact on HCT.
Humans↗
Molecular studies of a rare DR2/LD-5a/DQw3 HLA class II haplotype. Multiple genetic mechanisms in the generation of polymorphic HLA class II genes.
A cDNA library was constructed from a homozygous B lymphoblastoid cell line (REM) obtained from an individual of a long isolated American Indian tribe, the Warao. The REM cell line expresses serologically defined determinants, DR2 and DQw3, and the T lymphocyte-defined (Dw/LD) specificity, LD-5a. T cells can recognize differences between FJO (a DR2/DQw1 cell line that expresses the Dw specificity MN2) and REM for both DR and DQ molecules. cNDA clones encoding the polymorphic DR beta 1-, DR beta 2-, DQ beta-, and DQ alpha-chains were sequenced and compared with other DR and DQ gene sequences. The DR beta 1-sequence of REM is identical to the DR beta 1-sequence of FJO; the DR beta 2-sequence is also identical to that of FJO except for one amino acid difference at position 67 in the polymorphic first domain (Leu in REM, Phe in FJO) due to a single point mutation. The DQ beta-sequence is identical to that of DR4/DQw3 haplotype; the DQ alpha is different from the DQ alpha of DR4/DQw3 haplotype and identical to the DQ alpha of both the DR3/DQw2 haplotype of a Raji cell line and the DR5/DQw3 haplotype in deduced amino acid sequence. Taken together, these findings suggest that: 1) a single amino acid difference (position 67) in the third hypervariable region of the first domain of the DR beta 2-chain in the DR2 haplotype is apparently sufficient for stimulating T cell responses; 2) the DQw3 serologic specificity may be defined mainly by the DQ beta-rather than DQ alpha-chain; and 3) multiple genetic events have probably occurred to generate the rarely found REM (DR2/LD-5a/DQw3) haplotype.
Amino Acid Sequence↗
Identification of three novel HLA class I alleles: HLA-B*3928, HLA-B*400104 and HLA-B*4437.
Three new human leukocyte antigen (HLA) class I alleles have been identified in the Tissue Typing Laboratory in Sydney, Australia. Sequence analysis of exon 2 and exon 3 of the HLA-B gene revealed the novel polymorphism. A silent substitution of C to T at nucleotide position 369 has been identified for the HLA-B*400104 allele when compared to the closest matched allele, HLA-B*400101. The HLA-B*3928 allele was identified with a nucleotide substitution of G to C at position 362 when compared to the closest matched allele, HLA-B*390101, resulting in an amino acid substitution of Arginine to Threonine. A nucleotide substitution of C to G at position 572 resulting in the amino acid change Serine to Tryptophan was identified in the new allele HLA-B*4437, when compared to the closest matched allele HLA-B*440301. Both amino acid substitutions implicate a different specificity and affinity of antigen binding for the alleles HLA-B*3928 and HLA-B*4437.
Alleles↗
Dissection of HLA class II haplotypes in HLA-DR4 homozygous individuals.
In order to identify better markers for HLA-DR4-associated autoimmune disorders, we have studied the complexity of the HLA class II region in DR4-positive cells at the DNA level and compared the DNA polymorphism with that defined by serology, mixed lymphocyte culture (MLC) reactivity, and protein chemistry. At the DNA level, HLA-DR4 can be characterized by a homogeneous pattern of bands hybridizing to HLA class II cDNA probes. Besides, subtypes can be defined within DR4 using HLA-DR beta, -DQ alpha, and -DQ beta cDNA probes in Southern blot analysis. Three subtypes are found using the DR beta cDNA probe. One of these subtypes correlates with the cellularly defined Dw15 specificity, another with the serologically defined LB4 and LB14 specificities. None of the restriction fragment length polymorphism (RFLP) patterns coincide with the MLC-defined DR4 subtypes Dw4, Dw10, Dw13, and Dw14 separately. Variation of two fragments hybridizing to the DQ alpha cDNA probe obtained after either Pvu II or Taq I digestion yields three subtypes. Pvu II- and Eco RI-digested DR4 DNA give rise to three DQ beta detectable subtypes. Correlation between these subtypes, isoelectric point variation of DQ molecules, and the DQ-related allelic system TA10/2B3 are demonstrated. Some of the patterns obtained with DQ alpha and DQ beta cDNA probes display heterozygosity in the DQ region, as demonstrated by family segregation. No correlation was observed between DQ and the cellularly defined Dw determinants. A new polymorphism has been obtained with the DQ alpha probe, probably due to DX polymorphism. DR beta RFLP divides the LB14 supertypic specificity into two new subtypes. A combination of the four different techniques applied to a panel of 16 DR4 homozygous cell lines reveals at least nine different haplotypes in DR4. These newly defined haplotypes may be of help in further studies concerning the relationship of micropolymorphism with several diseases.
Cell Line↗
Binding of 8-mer to 11-mer peptides carrying the anchor residues to slow assembling HLA class I molecules (HLA-B*5101).
The binding of 303 8-mer to 11-mer peptides carrying the anchor residues at P2 and the C-terminus to HLA-B*5101 molecules was examined by a stabilization assay in which peptides were incubated with RMA-S-B*5101 cells at 26 degrees C for 3 h. Analysis of the binding of these peptides to HLA-B*5101 molecules showed that Pro and Ala at P2, and Ile, Val, and Leu at the C-terminus functioned as anchor residues, while Gly at P2 and Met at the C-terminus were weak anchors. Pro was a stronger anchor residue than Ala at P2, while Ile was the strongest anchor at the C-terminus. Among 8-mer to 11-mer peptides, the 9-mer peptides showed the strongest binding to HLA-B*5101 molecules. This is in contrast to our recent findings that 10-mer and 11-mer peptides bind to HLA-B*3501 molecules as effectively as 9-mer peptides. Since both HLA class I molecules have the same B-pocket and the binding peptides carry the same anchor residues, it is assumed that the structure of the F-pocket may restrict the length of binding peptides. The ability of HLA-B*5101 binding peptides to stabilize the HLA-B*5101 molecules was markedly lower than that of HLA-B*3501 binding peptides to stabilize the HLA-B*3501 molecules. It is known that HLA-B*5101 is a slow assembling molecule, while HLA-B*3501 assembles rapidly. The results imply that the slow assembling of HLA-B*5101 molecules results from the low affinity of peptides to HLA-B*5101 molecules.
Cell Line↗
HLA Class I protein expression in the human placenta.
The maternal tolerance to the semiallogeneic fetus is still a central theme in reproductive immunology. During placentation, fetally-derived, genetically dissimilar tissue and cells come into close contact with maternal tissue and cells, thus forming the so-called feto-maternal interface. The most extensive contact between fetally-derived and maternal blood cells is formed by the villous trophoblastic barrier, where the syncytiotrophoblast surface permanently floats in maternal blood. Further contact is made by some extravillous cytotrophoblast cells, either located at villous tips, in so-called cell islands, or the endovascular trophoblast population within the uteroplacental spiral arteries. The third contact zone is the so-called junctional zone within the decidua where the invading extravillous trophoblast cells encounter all maternal tissue leukocytes, which are mainly NK cells, macrophages and T cells; this junctional zone extends at the edge of the placenta to the amnio-chorionic membranes where the chorionic laeve trophoblast has intimate contact with decidua tissue. It is worth mentioning that evidence has shown that even in healthy pregnancies fetal and maternal lymphoid cells are able to transgress the trophoblastic barrier, which, anatomically, seems completely impermeable. Because of this intimate contact of foreign cells to the foreign immune system it is important to define the antigenic status of the placental cells, in particular with respect to antigens of the Major Histocompatibility complex. The role of the highly polymorphic classical class I molecules HLA -A, -B, -C, which are expressed on almost all somatic cells, is the induction of a specific immune response by presenting peptide antigens to T cells. In contrast, the non-classical HLA class I molecules HLA-G and HLA-E are thought to be involved in the induction of immune tolerance by acting as ligands for inhibitory receptors present on NK cells and macrophages. The non-classical HLA-E is also expressed ubiquitously, but HLA-G expression is characterized by a unique tissue expression mainly in the human placenta. A further feature of HLA-G is that its mRNA has undergone alternative splicing, resulting in at least 6 different isoforms, encoding different proteins: 4 membrane-bound and 2 soluble forms, which could simultaneously maintain different functions depending on their molecular structure. In our immunohistochemical study we investigated the expression of classical and non-classical HLA class I proteins in human placenta using various mAbs, which were kindly provided by the groups of A. Ziegler, D. Geraghty, O. Genbacev, MT. McMaster, A. King, YW. Loke and Ph. Le Bouteiller. For HLA-A,-B detection we used the antibody LA45; for detection of HLA-C,-B mAbs Tü149 and HC10. HLA-C expression alone was detected with mAb L31. HLA-G expression was studied using antibodies 4H84, G233, 87G, 16G1 and BFL.1. For HLA-E staining we used antibodies DT9 and V16. The classical HLA class I proteins are expressed in all non-trophoblastic cells including the fetal and maternal cells. Comparison of HLA-A and HLA-B staining intensities within the villous stroma indicates that during first trimester of pregnancy the fetal HLA-B proteins are expressed before HLA-A appears. Among the trophoblast populations, the syncytiotrophoblast does not show any HLA class I staining, but the extravillous cells express high amounts of HLA-G together with HLA-C. King and co-workers have shown recently, using methods other than immunohistochemistry, that first trimester extravillous trophoblast cells are also likely to express HLA-E. By contrast we did not detect HLA-E in any trophoblasts with antibodies DT9 and V16. There is still an ongoing and also controversial discussion about which kinds of cells in the placenta, other than extravillous trophoblast, express which kind of the HLA-G isoforms. Depending on the antibodies and the different immunohistochemical techniques used, different results have been described: Antibody 16G1 specific for soluble HLA-G labels syncytiotrophoblast, antibody BFL.1 endothelial cells of chorionic fetal blood vessels and antibody 87G Hofbauer cells. All these HLA-G labelings, apart from extravillous trophoblasts, are in complete contrast to the reaction pattern (merely extravillous trophoblast) given by antibody 4H84, which recognizes all HLA-G isoforms -including the soluble ones- through an epitope located on the a 1-domain of HLA-G. Future studies employing isoform-specific antibodies, which are not yet available for all of the possible isoforms, will elucidate the function and expression pattern of HLA-G in the human placenta.
Antibody Specificity↗
Pretransplant rejection risk assessment through enzyme-linked immunosorbent assay analysis of anti-HLA class I antibodies.
Soluble HLA enzyme-linked immunosorbent assays (ELISAs) for the detection of anti-HLA class I immunoglobulin G (IgG), IgG1, IgG2, IgG3, IgG4, IgM, and IgA antibodies were developed and used to analyze retrospectively the correlation between pretransplant allosensitization and posttransplant rejection episodes in renal allograft recipients. Enzyme-linked immunosorbent assay plates were coated with 46 different soluble HLA preparations representing 40 different HLA class I antigens. After incubation with a serum specimen, bound antibodies were detected with a peroxidase-conjugated antibody. Serum specimens from 85 patients were analyzed. All patients tested positive by microlymphocytotoxicity (ie, >5% panel-reactive antibody [PRA]). Approximately half (56%) of the patients had experienced one or more rejection episodes within 12 months posttransplantation. Fifty-five patients tested positive by ELISA (total IgG %PRA >10%). A strong correlation between first-year rejection and ELISA-detected anti-HLA class I IgG1 was observed (P = 0.0004). The predictive value for IgG1 and first-year rejection was 77.5%, demonstrating that ELISA results identify patients at high risk of rejecting the transplanted kidney. Anti-HLA class I total IgG detected by ELISA also correlated with first-year rejection episodes (P = 0.04). The presence of anti-HLA class I IgG2, IgG3, IgG4, or IgM was not predictive of first-year rejection episodes. Anticlass I IgA antibodies were only found in combination with anti-class I IgG1 antibodies.
Antibody Specificity↗
HLA class II transgenic mice: the chance to unravel the basis of HLA class II associations with disease.
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Animals↗
Invariant chain trimers are sequestered in the rough endoplasmic reticulum in the absence of association with HLA class II antigens.
HLA class II antigens are heterodimeric cell surface glycoproteins that interact with antigenic peptides to form complexes recognizable by CD4-positive T cells. During their biosynthesis, class II antigens are retained in a post-Golgi compartment in association with the invariant chain, which dissociates before class II cell surface expression. To address whether the invariant chain mediates this post-Golgi retention, its transport and assembly were examined in cells that do not express HLA class II antigens. Pulse-chase analysis and endoglycosidase digestions showed that very little invariant chain proceeded as far as the trans-Golgi in class II-negative cell lines. Immunofluorescence studies suggested that in these cells the invariant chain is sequestered in the RER. Gel filtration and cross-linking data showed that RER-localized invariant chain is present as trimers or aggregated trimers. Multimerization is mediated by lumenal interactions; a proteolytic fragment of the invariant chain corresponding to the lumenal domain remained trimeric as determined by cross-linking analysis. Similar transport and structural characteristics were observed for a pool of excess invariant chain in class II-positive cells, suggesting that an excess of invariant chain in the ER may be important for class II antigen function. These results have important implications for the transport of cellular proteins in general and for the role of the invariant chain in class II antigen biosynthesis.
B-Lymphocytes↗
Impact of peptides on the recognition of HLA class I molecules by human HLA antibodies.
MHC class I molecules expressed on cell surfaces are composed of H chain, beta2-microglobulin and any of a vast array of peptides. The role of peptide in the recognition of HLA class I by serum HLA Abs is unknown. In this study, the solid-phase assay of a series (n = 11) of HLA-A2-reactive, pregnancy-induced, human mAbs on a panel (n = 12) of recombinant monomeric HLA-A2 molecules, each containing a single peptide, revealed peptide selectivity of the mAbs. The flow cytometry membrane staining intensities on the HLA-A2-transduced cell line K562, caused by these mAbs, correlated with the number of monomer species detected by the mAbs. Flow cytometry staining on HLA-A2-bearing cell lines of a variety of lineages was indicative of tissue selectivity of these HLA-A2 mAbs. This tissue selectivity suggests that the deleterious effect on allografts is confined to alloantibodies recognizing only HLA class I loaded with peptides that are derived from tissue-specific and household proteins. Since Abs that are only reactive with HLA loaded with irrelevant peptides are expected to be harmless toward allografts, the practice of HLA Ab determination on lymphocyte-derived HLA deserves reconsideration.
Antibodies, Monoclonal↗
The studies of HLA class II (HLA-DR) system by PCR-SSO typing and the relationship with serological method.
By using two methods together, namely, the conventional serological typing and the new method which is oligonucleotide typing, in order to study the HLA system, it was concluded that the new method was better. Some subtypes were detectable from the new method, whereas, the serological typing yielded negative results such as DRB1 subtype "0103". This method, therefore, provided more information in order to study the HLA system. However, the new method was twice as expensive as the conventional serological method.
Adult↗