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PubMed2002

Tobacco reduces membrane HLA class I that is restored by transfection with transporter associated with antigen processing 1 cDNA.

HLA class I molecules are recognized by CTL that eliminate virally infected and malignantly transformed cells presenting foreign peptide-a process termed immunosurveillance. Many tumors have reduced levels of membrane HLA class I. Tumor cells with mutations that reduce HLA class I avoid immunosurveillance and continue to proliferate. As tobacco use can induce tumors, we examined the effect of tobacco extracts on membrane HLA class I. These studies show that culture of cells in media containing tobacco extracts reduces membrane HLA class I, but not other proteins, on primary keratinocytes and other cell types. Culture in tobacco extracts, but not extracts of other substances, reduces TAP1 protein, but does not reduce expression of HLA class I H chain, L chain, or the housekeeping protein beta-actin. The reduction of TAP1 protein occurs within 4 h and is dose-dependent. Culture in tobacco extracts reduces TAP1 protein abundance, but not steady-state mRNA abundance. Tobacco-treated cells show defects in HLA class I biosynthesis similar to those found in TAP1-deficient cell lines. Transfection with TAP1 cDNA restores TAP1 protein abundance, HLA class I biosynthesis, and cell surface expression. Combined, these data show that culture in tobacco extracts reduces TAP1 protein abundance and membrane HLA class I levels. Reduction in membrane HLA class I could permit subsequent malignant transformation of cells to be undetected by the immune system.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

HLA class I defects in malignant lesions: what have we learned?

Depending on the tumor types, HLA class I antigen downregulation or loss has been found in 16% to 50% of malignant lesions in many malignancies with a clinical association with histopathological markers of poor prognosis of the disease and with reduced free interval and survival. These findings may reflect the escape of tumor cells with HLA class I abnormalities from recognition and destruction by HLA class I-restricted, tumor-associated antigen-specific cytotoxic T lymphocytes. This possibility has stimulated investigations on the mechanisms underlying HLA class I antigen abnormalities in malignant cells. Distinct molecular defects underlying an abnormal HLA class I phenotype have been identified and characterized. These defects range from structural alterations of the genes which encode HLA class I antigen subunits to deregulation of antigen processing machinery components responsible for a functional HLA class I antigen expression. These findings, in conjunction with those of clinical recurrence of lesions with HLA class I antigen loss following T cell-based immunotherapy in patients, suggests that immunoselection may play a role in the generation of malignant lesions with HLA class I antigen abnormalities. This possibility has stressed the need to effectively monitor functional HLA class I antigen expression in malignant lesions in the application of T cell-based immunotherapy as well as to develop strategies to circumvent the negative impact of immunoselection.

Gene Expression Regulation, Neoplastic↗
PubMed1995

An HLA class I peptide-binding assay based on competition for binding to class I molecules on intact human B cells. Identification of conserved HIV-1 polymerase peptides binding to HLA-A*0301.

A peptide-binding assay employing the HLA class I molecules on intact human B cells is described. The peptide antigens are stripped from the HLA class I molecules by mild acid treatment, after which the cells are incubated with a FL-labeled reference peptide together with different concentrations of the peptide of interest. The effectiveness by which the latter peptide competes for binding to the HLA class I molecules is assayed by measuring the amount of HLA-bound FL-labeled reference peptide with FACscan analysis. The assay is easy to perform because there is no need to purify HLA class I molecules, or to transfect cells with HLA class I molecules, and no radioactive label is used. Moreover, large panels of HLA-typed human B-cell lines are available as tools for peptide binding to a vast array of HLA molecules. The binding assay was optimized and validated with peptides of known binding capacity to either HLA-A*0201 or HLA-A*0301. The kinetics of peptide binding in this assay were shown to be comparable to that in assays employing soluble HLA class I molecules. Application of the assay in the search for potential HLA-A*0301 restricted CTL epitopes, derived from HIV-1 polymerase, resulted in the identification of five high-affinity binding peptides.

Amino Acid Sequence↗
PubMed1983

Transformation of murine LMTK- cells with purified HLA class I genes. I. Modification of conformation of murine beta 2-microglobulin upon its association with HLA heavy chains.

Murine LMTK- cells were unexpectedly found to cross-react with a murine anti-human beta 2-microglobulin (beta 2-m)monoclonal antibody (m.Ab) after transformation with cosmid clones containing different purified HLA class I genes. The same cross-reactivity was observed with CTP 34 B4 (murine x human) somatic hybrid cells, which express class I molecules constituted of human HLA heavy chains and murine beta 2-m. Inhibition studies of the complement-dependent cytolysis mediated by the cross-reacting m.Ab indicated that isolated murine beta 2-m does not express the cross-reacting determinant, suggesting that its expression by the transformed cells reflects conformational modification of murine beta 2-m upon its association with HLA heavy chains. These results illustrate one of the possible post-translational mechanisms through which the antigenicity of a polypeptide chain can be modified. They might provide a serologic marker of the third domain of HLA class I heavy chains. Finally, because quantitative differences of reactivity with the anti-human beta 2-m m.Ab were observed, depending on the HLA class I genes used for transformation, these results individualize two families of HLA class I heavy chains responsible for different conformational modifications of murine beta 2-m.

Animals↗
PubMed1996

HLA class II signaling mediates cellular activation and programmed cell death.

The class II human leucocyte antigens (HLA class II) are principally peptide presentation molecules. Signal transduction by these molecules has also been shown to transmit activation signals in both B and T lymphocytes by a pathway including protein tyrosine kinase activation, an intracellular calcium flux, and both the activation and transcriptional regulation of protein kinase C (PKC) isoforms. Apoptosis can also result from human leukocyte antigen class II stimulation. Inhibitors of gene transcription were used to inhibit activation and, therefore, to distinguish the signal transduction pathways important for apoptosis. This approach provided evidence that cellular activation and apoptosis undertook separate signaling pathways, and that PKC and intracellular calcium were shared between the two pathways, while tyrosine kinase activity was essential for cell activation. Further studies using cord blood B cells showed that these cells were incapable of generating a calcium flux after HLA class II ligation and were not subject to cell death. The importance of sustained levels of calcium for programmed cell death (PCD) was underlined since the restoration of a calcium flux enabled PCD of cord blood B cells via HLA class II. These results demonstrate that HLA class II stimulation initiates two distinct signal transduction pathways.

Adult↗
PubMed1998

Molecular and immunologic aspects of the nonclassical HLA class I antigen HLA-G: evidence for an important role in the maternal tolerance of the fetal allograft.

PROBLEM: Human leukocyte antigen (HLA)-G is a major histocompatibility complex class I antigen, which is referred to as nonclassical because it displays a tissue-restricted distribution in the placenta, a reduced cytoplasmic domain, a limited polymorphism, and several isoforms. The HLA-G antigen is thought to play an essential role during pregnancy by protecting the semi-allogeneic fetus from recognition and destruction by maternal immune cells. METHOD OF STUDY: Alternative splicing of HLA-G mRNA was analyzed by Southern blot of reverse transcriptase-polymerase chain reaction products from trophoblasts of the first trimester of gestation and term placenta. The regulation of HLA-G gene expression was investigated by electrophoretic mobility shift assays using nuclear extracts from cells expressing different levels of HLA-G gene activity. Using polymerase chain reaction-single strand conformational polymorphism and sequencing, we studied HLA-G gene polymorphism in families from the Centre d'Etude du Polymorphisme Humain in Paris. To understand the function of the HLA-G molecule, cytotoxicity assays were carried out with peripheral blood mononuclear cells or polyclonal natural killer effectors cells from 30 different donors against HLA-G1 and HLA-G2 transfectants. RESULTS: Four main aspects have been elucidated: 1) The primary transcript of the HLA-G gene is alternatively spliced into five main mRNA forms: HLA-G1 (full length), HLA-G2 (minus exon 3), which encodes a membrane-bound isoform associated with beta-2 microglobulin, HLA-G3 (minus exons 3 and 4), HLA-G4 (minus exon 4), and HLA-G5 (plus intron 4), which encodes a soluble form of the HLA-G antigen; 2) specific nuclear factors bind to an important regulatory element located more than 1.2 kb from the HLA-G gene. Three specific complexes are observed in cells that show HLA-G transcriptional activity and an additional factor that could correlate with the repression of HLA-G gene expression that is detected in natural killer cells; 3) we observed an important genomic polymorphism in exon 3 but a very low polymorphism at the protein level; 4) HLA-G1 and HLA-G2 transfectants clearly demonstrated that both HLA-G isoforms are capable of inhibiting natural killer lytic activity. CONCLUSION: These results suggest that HLA-G acts as the public ligand for natural killer inhibitory receptors, thus protecting the fetus against maternal rejection.

Alternative Splicing↗
PubMed1997

[Binding-peptide motifs of HLA class II molecules susceptible to autoimmune diseases].

Recent advances in knowledge of crystal structures of MHC class II molecules has advanced understanding of the molecular basis for interactions between peptides and HLA class II molecules. Polymorphism of HLA class II molecules influences structures of peptides bound to HLA class II molecules. To elucidate mechanisms for statistical association between particular HLA class II alleles and susceptibility to autoimmune diseases, it is important to identify self peptides presented by disease-susceptible HLA class II molecules and triggering disease-causative autoreactive T cells. In this study, we tried to identify self-peptides triggering autoimmune diseases including rheumatoid arthritis, insulin autoimmune syndrome, insulin dependent diabetes mellitus and infant-onset myasthenia gravis. Susceptibility to all of these diseases in the Japanese population are known to be strongly associated with particular HLA-DR-DQ haplotypes unique to Asians, and clinical features of some of these diseases are different between Caucasians and Asians including Japanese. We investigated differences in binding-peptide motifs between disease susceptible and non-susceptible HLA class II molecules and predicted candidates of autoimmune self-peptides carrying binding-motifs to disease-susceptible HLA class II molecules. Indeed the major epitope for insulin-autoreactive CD4+ T cell was successfully identified by this strategy. We also found heterogeneity in immunogenetic background between Western type and Asian type of multiple sclerosis. Our data indicated that our strategy is useful to identify autoimmune self-peptides, and it is suggested that not only disease-susceptible HLA class II but also self-peptides causing diseases are different between Caucasians and Asians. These differences may well correlate to different clinical manifestations of diseases between the two ethnic groups.

Amino Acid Sequence↗
PubMed1995

Genetic markers on chromosome 19p and prenatal diagnosis of HLA class II-deficient combined immunodeficiency.

HLA class II-deficient combined immunodeficiency (CID) is an inherited disease characterized by a total lack of HLA class II gene expression, due to a regulatory defect affecting these genes. In the family investigated the disease phenotype occurs parallel to an abnormal structural feature of the CD23 antigen. We sequenced parts of the FCER2 gene coding for CD23 and found a restriction fragment length polymorphism (RFLP) that cosegregates with the disease. Analysis of recombinant haplotypes by microsatellites mapping to the chromosomal region 19p13.3 suggests that the disease locus maps between FCER2 and the microsatellite marker D19S424, probably close to D19S216 and D19S177. These data may offer the possibility of a rapid and early prenatal diagnosis of a subgroup of patients with HLA class II-deficient CID.

Amino Acid Sequence↗
PubMed1988

Role of HLA class II and cytokine expression in rheumatoid arthritis.

HLA class II expression is notable in rheumatoid arthritis. We have investigated the mechanism of HLA class II regulation in the joints and found local synthesis, as judged by mRNA levels to be high. The role of antigen presentation in maintaining class II mRNA was explored, and blocking presentation by using monoclonal antibodies to HLA class II inhibited synthesis of mRNA for HLA-DR alpha chain. HLA class II expression is maintained by cytokines and so cytokine production in rheumatoid joints was investigated. It was chosen to use mRNA analysis by slot blotting as a screening assay, and the expression of many cytokines was detected. Levels of these were maintained in culture in the absence of extrinsic stimulation.

Antibody Formation↗
PubMed2005

Coordinated downregulation of the antigen presentation machinery and HLA class I/beta2-microglobulin complex is responsible for HLA-ABC loss in bladder cancer.

Downregulation of MHC class I expression is a widespread phenomenon used by tumor cells to escape antitumor T-cell-mediated immune responses. These alterations may play a role in the clinical course of the disease. The aim of our study was to investigate the molecular mechanism underlying the absence of HLA-class I molecule expression in bladder cancer cells. Microdissected tumor tissues were characterized by real-time quantitative PCR for the expression of HLA-ABC, beta2-microglobulin and the members of the antigen processing machinery (APM) of HLA class I molecules (LMP2, LMP7, TAP1, TAP2 and tapasin). Our results showed that irreversible HLA loss by mutations in the beta2-microglobulin gene was not the cause of low HLA class I expression in bladder cancers. In contrast, we observed a coordinated transcription downregulation of HLA-ABC and beta2-microglobulin and APM genes in microdissected tumor tissue derived from bladder carcinomas. This mechanism may represent a major factor for the downregulation of HLA class I expression and in the subsequent direct recognition of cancer cells by cytolytic T lymphocytes. Because this regulatory mechanism is frequently reversible by IFN-gamma treatment, we conclude that HLA class I expression should be a major consideration for immunotherapeutic purposes in patients with bladder cancer.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

HLA class I typing by PCR: HLA-B27 and an African B27 subtype.

We describe a rapid method of HLA class I typing using the polymerase chain reaction and oligonucleotide hybridisation that eliminates the requirements for viable lymphocytes and allows subtypes to be defined. We have used this to demonstrate that the predominant subtype of HLA-B27 in the Gambia, West Africa, is HLA-B*2703, which is very rare or absent in other racial groups. This subtype differs from the common Caucasian HLA-B27 subtypes in its recognition by cytotoxic T cells. We propose that HLA*B-2703, unlike other HLA-B27 subtypes, may not be associated with ankylosing spondylitis, thus accounting in part for the rarity of this condition in black populations.

Adult↗
PubMed1992

Structural and functional analysis of monomorphic determinants recognized by monoclonal antibodies reacting with the HLA class I alpha 3 domain.

To identify mAb reacting with the HLA class I alpha 3 domain, 14 mAb recognizing monomorphic determinants expressed on HLA-A, B, and C Ag or restricted to HLA-B Ag were screened in indirect immunofluorescence with mouse L cells expressing HLA-B7/H-2Kb chimeric Ag. mAb CR1S63, CR10-215, CR11-115, and W6/32 were found to react with the HLA class I alpha 3 domain in addition to the alpha 2 domain. mAb Q1/28 and TP25.99 were found to react only with the HLA class I alpha 3 domain. The determinants recognized by the six mAb were mapped on the HLA class I alpha 3 domain by indirect immunofluorescence staining of L cells expressing H-2Kb Ag containing different segments of the HLA-B7 alpha 3 domain chimerized with the H-2Kb alpha 3 domain. mAb TP25.99 reacts with chimeric Ag containing the HLA-B7 184 to 199 stretch, mAb CR10-215 and CR11-115 react with chimeric Ag containing the HLA-B7 184 to 246 stretch, mAb CR1S63 and Q1/28 react with chimeric Ag containing the HLA-B7 184 to 256 stretch, and mAb W6/32 reacts with chimeric Ag containing the whole HLA-B7 alpha 3 domain. Functional analysis using human CD8 alpha-bearing mouse H-2Kb-specific T cell hybridoma cells (HTB-Leu2) showed that only mAb TP25.99 inhibited IL-2 production by HTB-Leu2 cells stimulated with L cells expressing KbKbB7 Ag. This inhibition may occur because of the spatial proximity of the determinant defined by mAb TP25.99 to the CD8 alpha binding loop and/or because of change(s) in the conformation of the CD8 alpha binding loop induced by the binding of mAb TP25.99 to the HLA class I molecule. Furthermore, mAb TP25.99 inhibited the cytotoxicity of CD8-dependent and CD8-independent CTL clones. These results indicate that mAb TP25.99 has unique specificity and functional characteristics. Therefore it represents a valuable probe to characterize the role of the HLA class I alpha 3 domain in immunologic phenomena.

Amino Acid Sequence↗
PubMed1999

Polymorphism and evolution of HLA class I and II genes and molecules.

Genes in the HLA complex, the human major histocompatibility complex (MHC), encode polymorphic HLA class I and II molecules that help T lymphocytes recognise and respond to foreign antigens. Certain HLA class I allotypes also regulate the response of natural killer cells. HLA class I and II molecules with little or no polymorphism contribute a variety of functions to the immune response, as do class I molecules coded by genes outside of the HLA region. Knowledge of the organisation of HLA class I and II genes, of the nucleotide sequences of their alleles, and the three-dimensional structures of their protein products, has facilitated analysis of the evolution and polymorphism of HLA class I and II genes and molecules. In turn, these analyses have provided insight into the mechanisms and selective forces driving change in the HLA complex.

Genes, MHC Class I↗
PubMed1992

Enhanced expression of HLA class I by inhibited replication of hepatitis B virus.

HLA class I display on hepatitis B virus (HBV)-infected hepatocytes is important for limiting HBV infection. However, the effect of HBV replication on HLA class I expression on host cells has not been determined. Since acyclovir is known to inhibit HBV replication of the novel cell line HB611, which was transfected with HBV genome using human hepatoblastoma cells as the recipient and continuously replicates HBV DNA, we analyzed HLA class I expression on acyclovir-treated HB611 by quantitative flow cytometry. The results demonstrated that acyclovir treatment clearly increases the level of HLA class I on HB611, and suggested that HBV replication inhibits expression of HLA class I on infected hepatocytes. This effect of HBV replication on the host cell may be a means by which HBV evades immune surveillance to maintain chronic infection.

Acyclovir↗
PubMed1998

HLA class I and II alleles and susceptibility to generalized pustular psoriasis: significant associations with HLA-Cw1 and HLA-DQB1*0303.

HLA alleles in generalized pustular psoriasis (GPP) were investigated to clarify the etiology and/or pathogenesis of this disease. Not only serological typing of HLA class I and II antigens but also genotyping of HLA class II alleles were carried out in twenty-six unrelated Japanese patients with GPP. These patients were classified according to their history of psoriasis vulgaris (PV). Serological typing revealed a significantly high incidence of HLA-Cw1 (Pc = 0.04) in the patients as compared with Japanese healthy controls. The frequency of HLA-B46 was particularly high in the patients with GPP and a previous history of PV. Genotyping of HLA class II alleles showed a highly significant increase in HLA-DQB1*0303 (Pc = 0.01) in the patients vs. the healthy controls. In particular, HLA-DQB1*0303 was significantly more frequent in the patients with no prior history of PV than in those with a history of PV. Analysis on linkage disequilibrium showed remarkably different patterns for HLA class II haplotypes between the patients and the healthy controls. Based on the comparative analysis among the amino acid sequences of the beta 1-domain of the HLA-DQB1*03 alleles, proline at residue 55 was suggested to be important as a common amino acid for determination of the susceptibility to GPP. These results revealed not only an association between the etiology and/or pathogenesis of GPP and HLA, but also different mechanisms of the immune response between the patients with GPP and PV.

Amino Acid Sequence↗
PubMed2004

Soluble HLA class I and HLA-DR plasma levels in patients with anterior uveitis.

Anterior uveitis (AU) is an autoimmune disease frequently associated with HLA-B27 antigen. Because of the immune regulatory properties of soluble human leukocyte antigen (sHLA) molecules, we quantified sHLA class I (sHLA-I) and sHLA-DR plasma levels in HLA-typed AU patients (n = 60). Randomly selected healthy individuals (n = 128) and HLA-B27 antigen-positive individuals (n = 24) with HLA phenotype frequencies similar to the HLA-B27 antigen-positive AU patients served as control panels. As expected, HLA-B27 phenotype was significantly increased in AU patients (n = 60), compared to healthy controls. Mean sHLA-I levels in AU patients were slightly higher than in randomly selected healthy controls. Regarding AU subgroups, elevated sHLA-I levels were only found in HLA-B27 antigen-negative patients. Compared to controls, sHLA-DR levels were significantly increased in AU patients and the subgroups of HLA-B27 antigen-negative and -positive patients but not Fuchs' heterochromic cyclitis (FHC). AU patients negative for HLA-B27 antigen with a chronic course had higher sHLA-DR levels than those with an acute course. The presence of associated systemic diseases in AU patients was related to elevated sHLA-DR levels. Secretion of sHLA-DR in blood differs among the various forms of AU. Systemic immune activation was present in AU but not in FHC.

HLA-DR Antigens↗
PubMed2004

Responses of peptide-specific T cells to stimulation with polystyrene beads carrying HLA class I molecules loaded with single peptides.

Cell-sized microbeads carrying single peptide-loaded HLA class I molecules were prepared for HLA-A2 and HLA-B7 by a simple procedure which transfers single peptide-loaded HLA class I molecules from cultured cells to polystyrene beads using anti-peptide antibodies directed to an intracellular segment of HLA-A alpha chains. The surface density of peptide-loaded HLA class I molecules on beads was comparable to that on the peptide-loaded cells. HLA-A2 beads loaded with an HCV peptide HCV1073 were tested for stimulation activity on an HCV1073-specific CD8+ T cell clone NS3-1. A substantial level of gamma-IFN production was induced. The stimulation was peptide-specific. The efficiency was dependent on the bead concentration and the surface HLA class I density on beads and enhanced significantly by co-coupling of anti-CD28 to peptide-loaded beads. The peptide-loading efficiency on HLA class I molecules and the transfer efficiency of HLA class I molecules to polystyrene beads were reasonably high for HLA-A2 and HLA-B7. Thus, polystyrene beads carrying these single peptide-loaded HLA class I molecules are potentially useful in further analysis of the co-stimulatory or inhibitory factors involved in CD8+ T cell responses and eventually in detection of cytotoxic T cells in PBLs.

Amino Acid Sequence↗
PubMed1999

Distinct regulation of HLA class II and class I cell surface expression in the THP-1 macrophage cell line after bacterial phagocytosis.

Expression of HLA and CD1b molecules was investigated in the THP-1 macrophage cell line within 2 weeks following phagocytosis of mycobacteria or Escherichia coli. During the first 2-3 days, cell surface expression of HLA class II and CD1b was drastically down-modulated, whereas HLA class I expression was up-modulated. In the following days both HLA class II and CD1b expression first returned to normal, then increased and finally returned to normal with kinetics similar to that observed for the steadily increased HLA class I. The initial down-modulation of HLA class II and CD1b cell surface antigens was absolutely dependent on phagocytosis of bacteria. Further studies indicated that initial HLA class II cell surface down-modulation (1) was not due to reduced transcription or biosynthesis of mature HLA class II heterodimers, (2) was only partially, if at all, rescued by treatment with IFN-gamma, although both mRNA and corresponding intracellular proteins increased up to sixfold with respect to untreated cells, and (3) resulted in failure of THP-1 cells to process and present mycobacterial antigens to HLA-DR-restricted antigen-specific T cell lines. The existence of a transient block of transport of mature HLA class II heterodimers to the cell surface in the first days after phagocytosis of bacteria may have negative and positive consequences: it decreases APC function early but it may increase it later by favoring optimal loading of bacterial antigens in cellular compartments at high concentration of antigen-presenting molecules.

Antigen Presentation↗