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PubMed2005

Induction of obliterative airway disease by anti-HLA class I antibodies.

Anti-HLA class I Abs are associated with the development of bronchiolitis obliterans syndrome (BOS) after lung transplantation. BOS is characterized histologically by fibrosis and airway epithelial cell apoptosis. We have previously shown that anti-HLA class I Abs induce proliferation, growth factor production and apoptosis in airway epithelial cells in vitro. Thus, this study was designed to determine whether anti-HLA class I Abs alone could induce obliterative airway disease (OAD) in heterotopic murine tracheal allografts. Toward this, HLA-A*0201-transgenic tracheal allografts were transplanted into Rag1-deficient mice treated with the W6/32 anti-HLA class I mAb. Allografts were harvested at days +30, +45, +60 and +90. Allografts displayed epithelial metaplasia by day +45, epithelial destruction and mild cellular infiltration by day +60 and complete lumen obliteration and moderate cellular infiltration by day +90. Anti-HLA class I Abs induced the production of several growth factors and growth factor receptors and apoptosis of parenchymal cells in the allograft. In addition, anti-HLA class I Abs induced macrophages and granulocytes infiltration. The results from this study demonstrate that anti-HLA class I Abs play an important role in the pathogenesis of OAD by inducing growth factor production, apoptosis and chemotaxis of inflammatory cells.

Animals↗
PubMed2002

Soluble HLA class I induces NK cell apoptosis upon the engagement of killer-activating HLA class I receptors through FasL-Fas interaction.

The engagement of the activating isoforms of C-type lectin inhibitory receptor (CLIR) or killer Ig-like receptor (KIR) by their natural ligands, represented by soluble HLA-I (sHLA-I) molecules, induced programmed cell death of natural killer (NK) cells. Indeed, NK cell apoptosis elicited by either putative HLA-E and HLA-F (sHLA-I non-A, -B, -C, and -G) or sHLA-I-Cw4 or -Cw3 from untransfected or -Cw4 or -Cw3 alleles transfected HLA-A(-), B(-), C(-), G(-), E(+), F(+) 721.221 lymphoblastoid cell line, respectively, was blocked by covering the corresponding activating receptor with either anti-CLIR- or anti-KIR-specific monoclonal antibodies (mAbs). After sHLA-I-activating receptor interaction, NK cells produced and released Fas ligand (FasL), which in turn led to NK cell apoptosis by interacting with Fas at the NK cell surface. Blocking anti-Fas mAb, or anti-FasL mAb, inhibited sHLA-I-mediated apoptosis via activating receptor in NK cell clones. This apoptosis was inhibited by NK cell treatment with cyclosporin A, whereas this drug had no effect on activating receptor-mediated activation of cytolysis. Conversely, concanamycin A, an inhibitor of vacuolar type H(+)-adenosine triphosphatase (H(+)-ATPase) of granules, inhibited activating receptor-induced NK cell cytolysis, suggesting that activating receptor-mediated apoptosis and cytolysis can use different intracellular pathways. Furthermore, a large amount of interferon-gamma (IFN-gamma) was detectable in culture supernatant of activating receptor(+) NK cells incubated with the appropriate sHLA-I ligand. Again, cyclosporin A, but not concanamycin A, strongly reduced activating receptor-mediated IFN-gamma production. This suggests that activating receptor-induced apoptosis of NK cells could play a role in eliminating potentially harmful NK cell clones and, at the same time, it leads to production of IFN-gamma, an antiviral cytokine able to amplify immune responses.

Antigens, CD↗
PubMed1997

Amnion epithelial cells, in contrast to trophoblast cells, express all classical HLA class I molecules together with HLA-G.

PROBLEM: The expression of the non-classical HLA-G gene has been shown at the protein level on trophoblast-derived embryonic tissue, like the extravillous cytotrophoblast. However, the presence of HLA-G on embryoblast-derived cells is currently controversial. The amnion epithelium is an embryoblast-derived cell layer covering the amnion cavity and is the main source for the amnion fluid. METHOD: The expression of HLA class I molecules was investigated by immunohistochemical, biochemical, and molecular biological methods in amnion membranes and amnion fluid. RESULTS: Immunohistochemically, HLA-C and occasionally also-B molecules as well as HLA-A and/or -G molecules have been identified on amnion epithelial cells. These results were extended by Western blotting with purified amnion epithelial cells where HLA-B and/or -C, HLA-A and HLA-G antigens have been detected. As expected HLA-G mRNA was detected in amino epithelial cells. Furthermore, classical HLA molecules as well as HLA-G were found in amnion fluid. CONCLUSION: These results show that the amnion epithelium frequently expresses classical HLA class I molecules as well as HLA-G. The expression of HLA-G antigens on amnion epithelial cells and their presence in the amnion fluid, which is continually ingested by the fetus, may be particularly relevant for the induction of peripheral tolerance.

Amnion↗
PubMed2003

HLA class I expression in bladder carcinomas.

HLA class I molecules are frequently lost in a large variety of human carcinomas, possibly because of T-cell immune selection of major histocompatibility complex class I deficient tumor variants. We report that this phenomenon is also a frequent event in bladder carcinomas. Of a total of 72 bladder carcinomas, 72% of the tumors had at least one alteration in HLA class I expression. These altered HLA class I phenotypes were classified as total HLA class I loss (25%; phenotype I); HLA-A or/and HLA-B locus-specific loss (12%; phenotype III); and HLA class I allelic loss (35%; phenotype II or IV). Comparison of histopathological parameters with HLA class I expression showed a statistically significant relationship with the degree of differentiation and tumor recurrence.

Carcinoma↗
PubMed1991

T-cell malignancies with mature phenotypes: altered cell cycle regulation by HLA class I molecules.

Soluble anti-HLA class I monoclonal antibodies (MoAbs) modulate normal T-lymphocyte proliferation induced via the CD3/Ti and the CD2 pathway, but do not induce proliferation of normal T lymphocytes in the absence of additional mitogenic stimuli. In this report, we show that anti-HLA class I MoAbs induce DNA synthesis in peripheral blood mononuclear cells from a patient with a CD4+CD8+T-prolymphocytic leukemia (T-PLL) and from a patient with a CD4-CD8+ T-chronic lymphocytic leukemia (T-CLL), in the absence of detectable additional mitogenic stimuli. Proliferation of leukemic T cells is induced by both whole Igs and Fab' fragments of anti-HLA class I MoAbs, arguing in favor of their direct interactions with the proliferating cells as the mechanism underlying the mitogenic effect. This interpretation is also supported by the ability of anti-HLA class I MoAbs to induce proliferation of leukemic T-cell preparations, depleted of accessory cells. DNA synthesis in T-CLL and T-PLL cells is preceded by expression of G1-specific messenger RNAs, ie. c-myc, 2F1, Tac, and interferon-gamma, in activated cells. Cell proliferation is inhibited by the protein kinase C inhibitor H7, indicating that activation of this enzyme is required for the mitogenic effect of anti-HLA class I MoAbs. The latter inhibit the proliferation of T-CLL cells as well as that of normal T cells stimulated with anti-CD3 MoAbs and enhance that of both types of cells stimulated with anti-CD2 MoAbs. In addition, anti-HLA class I MoAb Q6/64 in combination with anti-CD2 MoAb 9.6 or MoAb 9-1 induces proliferation of leukemic T cells to a greater extent than the individual MoAbs, but is not mitogenic for normal T cells. Anti-HLA class I MoAbs restore the cytolytic activity of T-CLL cells that is lost after 5 days of incubation of control medium, suggesting that HLA class I antigens may mediate a signal contributing to the activation state. The present results indicate that leukemic T-cell proliferation can be triggered via HLA class I molecules and suggest a potential role for these antigens in the in vivo growth of malignant clones.

Antibodies, Monoclonal↗
PubMed2005

Ultrasensitive detection and phenotyping of CD4+ T cells with optimized HLA class II tetramer staining.

HLA class I tetramers have revolutionized the study of Ag-specific CD8+ T cell responses. Technical problems and the rarity of Ag-specific CD4+ Th cells have not allowed the potential of HLA class II tetramers to be fully realized. Here, we optimize HLA class II tetramer staining methods through the use of a comprehensive panel of HIV-, influenza-, CMV-, and tetanus toxoid-specific tetramers. We find rapid and efficient staining of DR1- and DR4-restricted CD4+ cell lines and clones and show that TCR internalization is not a requirement for immunological staining. We combine tetramer staining with magnetic bead enrichment to detect rare Ag-specific CD4+ T cells with frequencies as low as 1 in 250,000 (0.0004% of CD4+ cells) in human PBLs analyzed directly ex vivo. This ultrasensitive detection allowed phenotypic analysis of rare CD4+ T lymphocytes that had experienced diverse exposure to Ag during the course of viral infections. These cells would not be detectable with normal flow-cytometric techniques.

Amino Acid Sequence↗
PubMed1989

Complete nucleotide sequence of a unique HLA class I C locus product expressed on the human choriocarcinoma cell line BeWo.

We have used Northern blot analysis to detect mRNA from class I HLA genes in the human choriocarcinoma cell line BeWo, which has been previously shown to express an atypical HLA class I molecule, in the absence of HLA A and B. Hybridization was seen with three class I DNA probes, the strongest being seen with the probe pC800, which corresponds to an 800-bp section of the Cw3 gene. We have made cDNA libraries from BeWo cells and screened for positive clones by using class I DNA probes. Of the clones isolated, we determined the complete sequence of one and partial sequence of five shorter clones. They all code for an identical C locus-related product, which does not correspond to published C locus sequences.

Amino Acid Sequence↗
PubMed2004

HLA class II profile and distribution of HLA-DRB1 and HLA-DQB1 alleles and haplotypes among Lebanese and Bahraini Arabs.

The gene frequencies of HLA class II alleles were studied in 95 healthy Lebanese Arab and 72 healthy Bahraini Arab subjects. Our aim was to establish the genetic relationship between Bahraini and Lebanese Arabs in terms of HLA class II gene and haplotype frequencies and to compare these results with frequencies for other countries with populations of Caucasian and non-Caucasian descent. Subjects were unrelated and of both sexes, and HLA-DRB1 and -DQB1 genotyping was done by the PCR sequence-specific primer technique. Comparative analysis of the HLA-DR and -DQ alleles revealed differences in the allelic distribution among Bahraini and Lebanese subjects. Analysis of the 25 HLA-DRB1 alleles that have been investigated showed that the DRB1*040101 and DRB1*110101 alleles were more frequent among Lebanese, whereas DRB1*030101 and DRB1*160101 alleles were more frequent among Bahrainis. Similarly, of the seven HLA-DQB1 alleles analyzed, the presence of DQB1*0201 was more frequent among Bahrainis, whereas DQB1*030101 was more frequent among Lebanese. The DRB1*160101-DQB1*050101 (0.1318 versus 0.0379%) and DRB1*030101-DQB1*0201 (0.1202 versus 0.0321%) haplotypes were more frequent among Bahrainis, while the DRB1*110101-DQB1*030101 (0.3142 versus 0.1198%) and DRB1*040101-DQB1*0302 (0.1416 versus 0.0278%) haplotypes were more frequent in Lebanese subjects. Furthermore, a high prevalence of the DRB1*040101-DRB1*110101-DQB1*0302-DQB1*030101 (12.63 versus 1.35%, P = 0.015) and the homozygous DRB1*110101-DRB1*110101-DQB1*030101-DQB1*030101 (7.37 versus 0.00%, P = 0.046) genotypes was seen among Lebanese, and DRB1*070101-DRB1*160101-DQB1*0201-DQB1*050101 (6.76 versus 0.00%, P = 0.034) was seen more frequently among Bahraini subjects. Our results underline significant differences between these two populations in HLA class II distribution, provide basic information for further studies of major histocompatibility complex heterogeneity among Arabic-speaking countries, and serve as a reference for further anthropological studies.

Adolescent↗
PubMed1993

Unfolded HLA class I alpha chains and their use in an assay of HLA class-I-peptide binding.

Unfolded HLA class I alpha chains were isolated from B-cell lysates by alkaline denaturation and subsequent gel filtration and used for the detection of HLA class-I-peptide binding. Binding to specific peptides in the presence of excess beta 2-microglobulin induced the unfolded alpha chains to refold and acquire a conformation that is specific to folded alpha chains. This conformational change was measured by a specific RIA that involves inhibition of the binding of 125I-labeled HLA-A2 alpha/beta dimers and rabbit anti-HLA-B7 serum absorbed with beta 2-microglobulin. This assay procedure does not require labeling of either test peptides or test class I proteins and does not seem to have specificity degeneracy. It is applicable to the detection of peptide binding by all HLA class I allelic proteins. Evaluation of the assay conditions and HLA allelic specificity of the peptide binding defined by the use of synthetic peptides are described here, including the technical details, specificity, and reproducibility.

Alleles↗
PubMed1991

Association of high sensitization to the structure of HLA class I alleles.

Some HLA Class I alleles or groups of alleles can be explained by exclusive residues which may explain their structural uniqueness. However, many sera are directed to alleles whose structural uniqueness is explained only by a combination of nonexclusive residues. A program implementing a combinatorial search algorithm was developed to analyze serological data by associating the primary structure of specific alleles to reaction patterns of broad multispecific sera. The method determines the residue or residues whose associated alleles best describe the serum specificity. The raw data reaction patterns direct the search, which utilizes known primary sequence information of HLA Class I alleles. Three-hundred highly positive sera from parous females were analyzed; 74 were highly correlated to the A locus and 125 to the B locus. Some of the remaining sera were associated with multiple loci. Reorganization methods were applied to the data. Clusters of residues associated with certain alleles focus attention on specific locations on the HLA Class I molecule. These regions may be included in, or in close proximity to, the serological determinant. Serological descriptions of certain broad specific sera have been termed "public epitopes." Specificities associated with distinct conserved regions of the Class I molecule offer a molecular basis for many public epitopes. Similar reaction patterns to 3 serologically allelic regions were found in pregnancy allosera, monoclonal antibodies, and transplant recipient sera. The correlated areas were: positions 166 and 167 of the alpha 2 domain alpha helix on the A locus, positions 79-83 of the alpha 1 domain alpha helix on the A locus, and positions 80-83 on the A and B loci.

Alleles↗
PubMed1999

Inefficient protection of human TAP-deficient fibroblasts from autologous NK cell-mediated lysis by cytokines inducing HLA class I expression.

We studied HLA class I expression and susceptibility to lysis of activated autologous NK cells in normal and TAP-deficient fibroblasts. These cells were cultured in the presence or absence of cytokines known to increase the surface expression of HLA class I molecules. All the cytokines tested (IFN-alpha, IFN-gamma, TNF-alpha and IFN-gamma + TNF-alpha) increased the expression of HLA class I molecules on fibroblasts after 48-h culture, but on TAP-deficient cells this expression remained very low as compared to that of normal cells. In the presence of IFN-alpha, IFN-gamma or IFN-gamma + TNF-alpha, normal target cells became resistant to lysis by autologous NK cells, whereas this effect was much less pronounced in the case of TAP-deficient fibroblasts. Addition of an anti-HLA class I mAb to fibroblasts treated with cytokines increased lysis of normal but not of TAP-deficient cells. These results suggest that activated TAP-deficient NK cells are strongly cytotoxic to normal autologous cells and that these cells cannot be efficiently protected by cytokines inducing HLA class I expression. Thus, in human TAP deficiency, activated NK cells may contribute to the progressive lung degradation which characterizes the clinical course of these patients.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

HLA class I gene, antigen and haplotype frequencies in New Zealand Maori and Europeans.

AIM: To determine class I HLA gene, antigen and haplotype frequencies for New Zealand Maori and Europeans. METHODS: Statistical analysis was performed using accumulated data from Maori (n = 576) and European (n = 1747) parentage studies. RESULTS: HLA class I gene, antigen and haplotype frequencies are as tabulated. Significant statistical differences were shown to exist between New Zealand Maori, New Zealand Europeans and Europeans. Gene frequencies of HLA A1, 3, 9, 11, 19 and HLA B7, 8, 12, 16, 22, and 40 differed significantly between New Zealand Maori and New Zealand European data. Gene frequencies of HLA A1 and B12 differed significantly between New Zealand European and European data. CONCLUSIONS: This HLA frequency data can be used for calculating more reliable indices of paternity or for determining the potential availability of matched organs for transplantation, as well as for anthropological studies. The data may also be useful in forensic investigations.

Europe↗
PubMed1999

Molecular characterization of HLA class I in Colombians carrying HLA-A2: high allelic diversity and frequency of heterozygotes at the HLA-B locus.

Polymerase chain reaction using sequence-specific oligonucleotide probes (PCR-SSOP) typing was used to analyze HLA class I A, B and C alleles in three different Colombian populations. Fifty-nine samples were from Hispano-American Mestizos living in the urban areas of Cali (referred to here as Aso population). Forty-four and thirty samples were from the African Black populations of Zacarias (Zac) and Punta Soldado (PS), respectively. Samples were selected for expression of HLA-A2 by monoclonal antibody staining and allele-specific hybridization, and their HLA-A2 subtype distribution has been reported previously. Although only a limited number of samples was analyzed, the data suggest the existence of a remarkable degree of HLA class I polymorphism in the populations studied, with representatives of most serological classes. Despite their common African origin, the populations Zac and PS, both resident in malaria endemic regions, showed some striking differences in allelic distribution for all three class I loci. Furthermore, the samples from Aso and PS, but not Zac, showed a low percentage of blank alleles at the HLA-B locus (0 and 0.4%, respectively), suggesting the possibility of a heterozygote advantage for HLA-B alleles in Colombian populations.

Alleles↗
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↗
PubMed1992

DNA typing of HLA class II genes in B-lymphoblastoid cell lines homozygous for HLA.

The HLA class II genotypes were determined in the B-lymphoblastoid cell lines selected for the Tenth International Histocompatibility Workshop. The HLA class II genes were determined by the PCR-SSOP method using the reagents provided by the Eleventh Histocompatibility Workshop. Additional studies have been performed for further characterization of HLA class II polymorphism on these cell lines. It is observed that several cell lines have HLA class II haplotypes with the same DRB1, DQA1 and DQB1 alleles on both haplotypes but different alleles at the other class II loci, confirming that these cell lines are not truly HLA class II-homozygous. Other cell lines carried HLA class II haplotypes which were only different at the DRB1 gene. These results suggest double recombination events or gene conversion-like events in generation of HLA DR, DQ haplotypes. These cell lines provide an important tool as references for HLA DNA typing.

Alleles↗
PubMed2001

HLA class I genotyping including HLA-B*51 allele typing in the Iranian patients with Behçet's disease.

It is well known that Behçet's disease (BD) is strongly associated with human leukocyte antigen (HLA) B51 in many ethnic groups. However, there has been no published report as yet with respect to this association among the Iranian people. Furthermore, since it is now known that the B51 antigen can be encoded by 21 alleles, B*5101-B*5121, we performed HLA-B*51 allele typing as well as HLA class I genotyping of 48 Iranian patients with this disease. As a result, the frequency of the B*51 allele was significantly higher (62.1%) in the patient group as compared with the ethnically matched control group (31.8%) (Pc=0.067, R.R.=3.51). In the genotyping of B*51 alleles, 33 out of the 36 B*51-positive patients possessed B*5101 and the remaining 3 carried B*5108. This study revealed that Iranian patients with BD also had a strong association with HLA-B51. In addition, this significantly high incidence of HLA-B*51 was found to be caused by an increase in both the HLA-B*5101 and HLA-B*5108 alleles. However, there was no significant difference in the HLA-B*51 allelic distribution between the patient and control groups.

Alleles↗
PubMed2004

Distribution of HLA class I altered phenotypes in colorectal carcinomas: high frequency of HLA haplotype loss associated with loss of heterozygosity in chromosome region 6p21.

HLA class I loss or down-regulation is a widespread mechanism used by tumor cells to avoid tumor recognition by cytotoxic T lymphocytes, and thus favor tumor immune escape. Multiple mechanisms are responsible for these HLA class I alterations. In different epithelial tumors, loss of heterozygosity (LOH) at chromosome region 6p21.3, leading to HLA haplotype loss, occurs in 6-50% of all cases depending on the tumor entity. In this paper we report the frequency of LOH at 6p21 in 95 colorectal carcinomas (CRC) previously analyzed for altered HLA class I expression with immunohistological techniques. We used PCR microsatellite amplification of selected STR markers located on Chromosome 6 to identify LOH with DNA from microdissected tumor tissues and the surrounding stroma. Sequence-specific oligonucleotide analysis was performed in microdissected stroma and tumor cells for HLA typing, and to detect HLA haplotype loss. A high frequency (40%) of HLA haplotype loss was found in CRC. Eight tumors showed microsatellite instability. We sometimes observed two or more mechanisms responsible for HLA alteration within the same HLA-altered phenotype, such as LOH and HLA class I total loss. In 25 tumors (26%) no HLA class I alteration could be identified. These data are potentially relevant for CRC patients undergoing T-cell-based immunotherapy.

Chromosomes, Human, Pair 6↗
PubMed2004

Gains and losses of HLA class II (DR) and CD4 in atypical hyperplasia, carcinoma in situ and infiltrating ductal carcinoma of the breast.

AIM: Breast cancer is a frequent cause of death among women with gynaecologic malignancies despite the introduction of combination chemotherapy. There is therefore a need for new therapeutic strategies for patients with breast cancer, such as cellular immunotherapy. In this immunohistochemical study we analyzed the epithelial expression of major histocompatibility complex (MHC) class II (HLA-DR) on atypical and malignant primary mammary epithelial cells, as well as the magnitude of the stromal T lymphocytes (T4 subset) at the tumor site. EXPERIMENTAL DESIGN: The study was carried out retrospectively in tumor tissue from 82 patients with mammary lesions (31 cases of atypical ductal hyperplasia -ADH-, 12 cases of ductal carcinoma in situ -DCIS- and 39 cases of infiltrating ductal carcinoma not otherwise specified -IDC-NOS). Medullary carcinomas were not included in our investigation. Material used had been formalin fixed and paraffin embedded. RESULTS: HLA class II (DR) was expressed in 20 of 31 ADHs (64.5%), in 4 of 12 DCISs (33.3%), and in 10 of 39 IDC-NOSs (25.6%). CD4 was expressed in 9 of 31 ADHs (29%), in 5 of 12 DCISs (42%), and in 26 of 39 IDC-NOSs (67%). CONCLUSIONS: The results showed decreased epithelial expression of HLA class II (DR) and increased stromal expression of CD4, as the lesion progressed to malignancy. Gradual loss of epithelial HLA class II expression might be a manifestation of cellular differentiation from the atypical form versus the malignant one, signaling simultaneously a selective effect on the response capacity of the immune system.

Adult↗