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PubMed1995

Cooperativity between the J and S elements of class II major histocompatibility complex genes as enhancers in normal and class II-negative patient and mutant B cell lines.

The class II major histocompatibility complex genes all contain in their proximal promoters three cis-elements called S, X, and Y that are conserved in both sequence and position, and a fourth element, J, conserved in sequence but not in position. J, X, and Y and, to some extent, S, have been shown to be functionally important in regulation of expression of these genes. In the present study, a protein factor that binds cooperatively to the S plus J elements of the promoter of the class II major histocompatibility complex gene DPA has been detected. Moreover, functional cooperativity between S and J in activation of the enhancerless -40 interferon-beta (-40 IFN-beta) promoter has been demonstrated. Finally, the latter assay appears to subdivide complementation group A of class II negative human B cell lines that includes both mutants generated in vitro and cells from patients with the bare lymphocyte syndrome (type II). In three of these cell lines, the enhancerless -40 IFN-beta promoter containing the S plus J elements was functionally active, while in the others it was inactive.

B-Lymphocytes↗

PubMed1997

An isotype-specific activator of major histocompatibility complex (MHC) class II genes that is independent of class II transactivator.

Patients with one type of major histocompatibility complex class II combined immunodeficiency have mutations in a gene termed class II transactivator (CIITA), which coordinately controls the transcription of the three major human class II genes, HLA-DR, -DQ, and -DP. However, the experimentally derived B-lymphoblastoid cell line, clone 13, expresses high levels of HLADQ in the absence of HLA-DR and HLA-DP, despite its mapping by complementation analysis to this group. It was possible that one of the clone 13 CIITA alleles bore a mutation that allowed HLA-DQ, but not HLA-DR or -DP transcription. Alternatively, another factor, distinct from CIITA, might control HLA-DQ expression. We report here that ectopic expression of CIITA cDNAs derived by reverse transcriptase polymerase chain reaction from clone 13 do not restore expression of HLA-DQ in another CIITA-deficient cell line, RJ2.2.5. In addition, no CIITA protein is detectable in clone 13 nuclear extracts. In contrast, somatic cell fusion between clone 13 and RJ2.2.5 restored expression of the HLA-DQ haplotype encoded by the RJ2.2.5 DQB gene. Taken together, these data demonstrate the existence of an HLA-DQ isotype-specific trans-acting factor, which functions independently of CIITA.

Blotting, Western↗

PubMed1998

Modulation of natural killer cell cytotoxicity in human cytomegalovirus infection: the role of endogenous class I major histocompatibility complex and a viral class I homolog.

Natural killer (NK) cells have been implicated in early immune responses against certain viruses, including cytomegalovirus (CMV). CMV causes downregulation of class I major histocompatibility complex (MHC) expression in infected cells; however, it has been proposed that a class I MHC homolog encoded by CMV, UL18, may act as a surrogate ligand to prevent NK cell lysis of CMV-infected cells. In this study, we examined the role of UL18 in NK cell recognition and lysis using fibroblasts infected with either wild-type or UL18 knockout CMV virus, and by using cell lines transfected with the UL18 gene. In both systems, the expression of UL18 resulted in the enhanced killing of target cells. We also show that the enhanced killing is due to both UL18-dependent and -independent mechanisms, and that the killer cell inhibitory receptors (KIRs) and CD94/NKG2A inhibitory receptors for MHC class I do not play a role in affecting susceptibility of CMV-infected fibroblasts to NK cell-mediated cytotoxicity.

Antigens, Viral↗

PubMed1998

Human leukocyte antigen class I- and class II-restricted cytotoxic T lymphocyte responses to measles antigens in immune adults.

The study of cytotoxic T cell (CTL) responses to measles polypeptides in persons with different HLA frequencies will provide information for the design of new vaccines. Peripheral blood mononuclear cells derived from African blacks and Caucasians were stimulated with measles virus-infected autologous cells and tested in a standard 51Cr-release assay against autologous B cells infected with vaccinia virus recombinants expressing measles virus antigens. The proportion of subjects who generated CTL to the fusion, hemagglutinin, and nucleoprotein antigens was 43%, 38%, and 28%, respectively. The use of HLA-mismatched targets showed killing to be restricted by both HLA class I and class II antigens, although CD8-mediated class I cytotoxicity predominated. Measles vaccine boosted CTL responses in subjects with low initial activity. These data suggest that the fusion and hemagglutinin proteins are important targets for the measles CTL response.

Adult↗

PubMed1992

Interferon-alpha/beta, pentoxifylline, and caffeine synergize with interferon-gamma to induce major histocompatibility complex class I expression on a constitutively class I-negative murine tumor cell line.

The constitutively class I-negative tumor cell line, Kgv, expresses H-2Dk in response to interferon-gamma (IFN-gamma), but not in response to IFN-alpha/beta, tumor necrosis factor, or lymphotoxin. H-2Dk expression was not induced on Kgv cells by the methylxanthines, pentoxifylline (PTX) and caffeine, which modulate class I expression on cells that constitutively express class I molecules. Treatment of Kgv cells with either IFN-alpha/beta, PTX, caffeine, or dibutyryl cAMP and a concentration of IFN-gamma insufficient by itself to induce Dk expression resulted in the induction of Dk expression. Since PTX and caffeine are cAMP-specific phosphodiesterase inhibitors, it is possible that the effects of PTX, caffeine, and dibutyryl cAMP involve a cAMP-dependent mechanism. We conclude that concentrations of IFN-gamma insufficient to induce Dk expression on Kgv cells may be capable of rendering the Dk gene responsive to signals that, in the absence of IFN-gamma treatment, have no effect on Dk expression.

Animals↗

PubMed2002

Comparative analysis of the CD8(+) T cell repertoires of H-2 class I wild-type/HLA-A2.1 and H-2 class I knockout/HLA-A2.1 transgenic mice.

HHD transgenic mice which express HLA-A2.1 monochain molecules in a H-2 class I(-) context have an improved capacity to develop HLA-A2.1-restricted cytotoxic T lymphocyte (CTL) responses as compared with classical A2.1/K(b) transgenic mice, which express heterodimeric HLA-A2.1 molecules in a H-2 class I wild-type context. A detailed TCR analysis of HLA-A2.1-restricted CD8(+) T cells educated and mobilized in both strains of mice was undertaken. Focusing on TCR beta chains, comparative PCR analysis of naive and immune CD8(+) T cell repertoires were performed. In spite of lower cell surface expression of HLA class I molecules and lower overall number of CD8(+) T cells, HHD mice educate a qualitatively normally diversified CD8(+) T cell repertoire and mobilize a larger variety of CD8(+) T cells in response to HLA-A2.1-restricted antigens compared with A2.1/K(b) mice. These observations provide the molecular bases accounting for the fact that HHD mice represent the most versatile animal model currently available for preclinical studies of HLA-A2.1-restricted CTL responses.

Amino Acid Sequence↗

PubMed1996

Diploid expression of human leukocyte antigen class I and class II molecules on spermatozoa and their cyclic inverse correlation with inhibin concentration.

A diploid expression of class I and class II human leukocyte antigens (HLA) has been found in purified spermatozoa by using double fluorescence labeling cytofluorometry and relevant monoclonal antibodies; this expression has been confirmed for the first time by the analysis of specific HLA mRNA and metabolic 35S labeling followed by immunoprecipitation, which demonstrates an active ongoing translation of HLA proteins in germinal cells. Long-living mRNA coming from diploid germinal cells may be translated to HLA molecules in spermatozoa. This translation is controlled (or at least inversely correlated) by a testicular hormone (inhibin) in a cyclic fashion. Remarkably, serum levels of inhibin, synthesized by Leydig and Sertoli cells, follow a 12- to 13-day cycle, with a peak level at Day 6; this is probably controlled by FSH (not cyclic in males) and other testicular and/or unknown hormones. Peak levels of inhibin concur with the lower density and percentage of spermatozoa expressing both HLA class I and II molecules (close to 3% by cytofluorometry); lowest levels of inhibin coincide with the highest numbers (35-40%) of spermatozoa positive for both HLA molecules and a higher surface density. These observations could put to an end a disconcerting and long-lasting controversy on the expression/non-expression of HLA antigens on spermatozoa. The possibility that HLA-bearing spermatozoa are more capacitated for fertilization than those that do not bear HLA, and the implications of our results on male fertility control are also discussed.

Antibodies, Monoclonal↗

PubMed1984

Acceptance of cardiac allografts by lethally irradiated rats repopulated with syngeneic bone marrow. Role of class I and class II alloantigens.

LEW rats (RT1l) that are lethally irradiated and repopulated with syngenic bone marrow accept WF (RT1u) cardiac allografts. If bone marrow repopulation is delayed for two days after irradiation and operation, grafts containing passenger leukocytes (nonperfused grafts) are generally rejected, but perfused grafts, which have fewer passenger leukocytes, are accepted. If bone marrow is given on the same day as irradiation and surgery, then both perfused and nonperfused grafts are accepted. The difference in acceptance of grafts by recipients that are repopulated on day 0 as opposed to day 2 depends on class II alloantigens, because grafts that are similar to LEW for class II antigens are not rejected by day-2-repopulated recipients. Also, the acceptance of totally major histocompatibility complex (MHC)-mismatched cardiac allografts by day-0-repopulated recipients is influenced by a radiation-resistant host cell. Splenectomy of the irradiated and repopulated recipient prevents tolerance induction unless syngeneic irradiated spleen cells are returned to the recipient. Thus class II alloantigen disparities appear to be a major barrier to tolerance induction in the system of total body irradiation and syngeneic bone marrow reconstitution, although proper timing of bone marrow administration can minimize rejection of completely MHC-mismatched grafts.

Animals↗

PubMed2000

Human cytomegalovirus blocks interferon-gamma stimulated up-regulation of major histocompatibility complex class I expression and the class I antigen processing machinery.

Interferon-gamma stimulates major histocompatibility complex (MHC) class I antigen processing and presentation by inducing the expression of major histocompatibility complex class I heavy chains, beta2-microglobulin, the transporter associated with antigen processing, and components of the proteasome complex. We demonstrate that this effect of interferon-gamma on the major histocompatibility complex class I pathway is inhibited in human cytomegalovirus-infected fibroblasts and endothelial cells. This is the result of a direct human cytomegalovirus/cell interaction leading to a block in interferon-gamma signal transduction beginning at early times after infection and peaking at 72 hr after infection. These observations suggest a novel level of herpesvirus interference with antigen processing: protection of infected cells from the immunoregulatory effects of interferon-gamma. Thus protected, human cytomegalovirus persists and may exacerbate graft rejection or lead to fulminant infection in the immunocompromised transplant recipient.

Antigen Presentation↗

PubMed1988

Immune response to H-2 class I antigens on platelets. II. Specific decrease of H-2 class I-specific antibody response induced by treatment with allogeneic platelets.

Mice pretreated with injections of allogeneic platelets were found to mount a decreased antibody response upon challenge by lymphocytes of the same donor strain. This decrease was mediated by platelets themselves, and not by leucocytes and red cells contaminating the platelet suspension. It affected specifically antibodies reactive with H-2 class I antigens present on donor platelets. This phenomenon may be related to the lack of class II or some non-H-2 antigens on platelets, and/or to properties of their class I antigens (soluble molecules adsorbed from the plasma). These findings emphasize the potential usefulness of purified platelet transfusions preceding organ transplantation in man.

Animals↗

PubMed1997

Triplet repeat polymorphism within the NOTCH4 gene located near the junction of the HLA class II and class III regions in narcolepsy.

A polymorphic (CTG)n microsatellite repeat was found in the signal peptide domain of the NOTCH4 gene located near the junction of the class II and class III regions of the human major histocompatibility complex. This gene belongs to a multigene family of NOTCH originally identified as a differential factor of neuronal cells. To ascertain whether the NOTCH4 gene is involved in the development of neurogenic disease, narcolepsy, which is known to be tightly associated with HLA-DR15, this microsatellite polymorphism of the (CTG)n repeat was analyzed in Japanese patients with narcolepsy One allele, 9 repetitions of CTG (Leu) was significantly increased in the patient group. However, the significant increase of this allele in the patient group could be explained by a strong linkage disequilibrium with the HLA class II alleles, DRB1*1501, DQA1*0102 and DQB1*0602, which were more strongly associated with the disease. These results suggest that the (CTG)n repeat polymorphism in NOTCH4 does not primarily determine the susceptibility to narcolepsy.

Alleles↗

PubMed1995

Evolution of Mhc class II polymorphism: the rise and fall of class II gene function in primates.

The substitution rate at the codons implicated at ARS of Mhc class II genes has previously been shown to be heavily biased towards nonsynonymous substitutions, indicative of positive selection for polymorphism. Based on our analysis of the number of synonymous changes at codons outside putative ARS in primates, the average age of the polymorphism at class II loci was found to increase in the following order: DPB1, DRB3, DRB5, DRB1, DRB4, DQB1, DQA1. For DRB loci, nonsynonymous changes were found to exceed synonymous changes at HLA-DRB1, DRB3 and DRB5, while no evidence of deviations from equal rates of synonymous and nonsynonymous substitutions were found for DRB6. The pattern of substitutions at the DRB loci of most Catarrhini species indicates constant positive selection at ARS codons over the evolutionary period examined. An exception to the relatively stable selection pattern between species exhibited by most loci is the appearance of polymorphism under positive selection at DRB4 only in the regular chimpanzee. The ds/dn ratios for DQA1 and DQB1 alleles are lower than for the most polymorphic DRB genes. Since the dn/ds ratio of ARS codons may be positively correlated to the ds for non-ARS codons, at least for DQB1, caution must be exercised in interpreting the low ratio for the DQ genes as an indication of weaker selection. The DQA1 allelic lineages show different dn/ds ratios, consistent with the hypothesis that the lineages are constrained from evolving in relation to the diversity of the interacting DQB1 alleles. In contrast to all other class II loci, DPB1 appears to have been subjected to strong positive selection only in the human lineage, and may represent the most conspicuous example of an Mhc locus acquiring an altered function in antigen presentation.

Animals↗

PubMed1989

Rabbit major histocompatibility complex. III. Multiple class II DR beta genes and restriction fragment length polymorphism of the class II alpha and beta genes.

Several class II alpha and beta chain genes of the rabbit MHC have been cloned and classified into three distinct subregions, R-DP, R-DQ and R-DR, based on their homology to the corresponding HLA-DP, -DQ and -DR genes. The organization of the rabbit MHC class II genes has now been studied in greater detail by analysing genomic DNA of an inbred III/J strain and several other RLA-D homozygous rabbits, with DNA probes derived from cloned R-DR beta genes. Eight previously cloned R-DR beta genes were shown to be allelic forms of five R-DR beta loci. Genomic blot analyses of DNA from seven rabbits homozygous for different RLA haplotypes revealed that the germline contains a total of approximately seven class II beta genes, one DQ beta, one DP beta and five DR beta. Extensive allelic polymorphism was identified by RFLP analysis using DQ and DR probes; limited RFLP was observed with DP probes. RFLP analyses allowed us to distinguish two haplotypes which had not been previously distinguished by MLR. Such RFLP analyses will be useful for identifying MHC 'compatible' rabbits for various immunobiological studies, including transplantation.

Animals↗

PubMed1984

Cellular localization of class I (HLA-A, B, C) and class II (HLA-DR and DQ) MHC antigens on the epithelial cells of normal human jejunum.

HLA class I and class II (HLA-DR (human I-E equivalent) and DQ (human I-A equivalent] antigens were localized by immunofluorescence technique on thin frozen sections of normal human jejunum using a panel of monomorphic monoclonal antibodies. HLA class I (A, B and C) and HLA-DR molecules were found in the basolateral membrane of enterocytes; HLA-DR were also detected in a patchy distribution in the apical part of enterocytes; HLA-DQ molecules (the human equivalent of the murine I-A molecular subset) were not detected on normal enterocytes. All three molecules were detected on the membrane of lymphocytes and monocytes present in the lamina propria.

Cell Membrane↗

PubMed1992

The DNA-binding defect observed in major histocompatibility complex class II regulatory mutants concerns only one member of a family of complexes binding to the X boxes of class II promoters.

The X box of major histocompatibility complex class II promoters is essential for proper expression of class II genes. Here we show that two distinct protein-DNA complexes (A and B), which exhibit similar binding characteristics and identical contact points on the X box, can be formed. This suggests the existence of a family of related X box-binding factors. Complex B (and not complex A) is specifically affected in primary combined immunodeficiency, a congenital defect in class II gene regulation. RFX1, the first X box-binding protein cloned, encodes a functionally relevant factor present in complex A and not in complex B as originally suspected. This report also illustrates the need for caution in correlating specific cloned proteins with nuclear factors identified by DNA-binding assays, particularly when dealing with families of related proteins.

Base Sequence↗

PubMed2004

Human immunoglobulin selection associated with class switch and possible tolerogenic origins for C delta class-switched B cells.

Current paradigms of peripheral B cell selection suggest that autoreactive B cells are controlled by clonal deletion, anergy, and developmental arrest. We report that changes to the human antibody repertoire likely resulting from these mechanisms both for a well-characterized autoreactivity from antibodies encoded by the V(H)4-34 gene and for other hallmarks of an autoreactive repertoire are apparent mainly for class-switched B cells and not for IgM germinal center, IgM memory, or IgM plasma cells. Other possible indicators of autoreactivity found selected with immunoglobulin class include J(H)6 gene segment usage, increased frequency of B cells with long third hypervariable regions, and distal J(kappa) gene segment bias. Of particular interest is the finding that B cells with these same characteristics are selected into the lineage of B cells that have undergone the unusual class switch from constant region C mu to C delta (C delta-CS). The C delta-CS population also displays an increased frequency of charged amino acids localized to the complementarity-determining regions, further suggesting autoreactivity, and evidence is presented that these B cells had undergone extensive receptor editing. Thus, the C delta-CS lineage may be a "sink" for B cells harboring autoreactive specificities in normal humans. A model for a new tolerizing mechanism that could account for the C delta-CS lineage is presented.

Antibodies, Monoclonal↗

PubMed1991

Race or class or race and class: growing mortality differentials in the United States.

Recent statistics on increasing differences in mortality rates between blacks and whites in the United States are causing a great deal of concern. The reduction of this gap is an important national goal. Yet mortality differentials cannot be explained solely by race. We must also look at class, as do all Western nations other than the United States, when compiling health statistics. In the United States, how people live, get sick, and die depends not only on their race, sex, and age, but also on their class, whether measured by level of education, income, or occupation. Class differentials in mortality and morbidity are greater than race differentials. By focusing our attention on race differentials alone, we will not be able to understand why the health indicators of minorities in the United States are deteriorating.

Black or African American↗

PubMed2000

Methylation of class II trans-activator promoter IV: a novel mechanism of MHC class II gene control.

Inhibition of class II trans-activator (CIITA) expression prevents embryonic trophoblast cells from up-regulating MHC class II genes in response to IFN-gamma. This is thought to be one mechanism of maternal tolerance to the fetal allograft. The CIITA gene is regulated by four distinct promoters; promoter III directs constitutive (B cell) expression, and promoter IV regulates IFN-gamma-inducible expression. Using in vivo genomic footprinting, promoter-reporter analysis, Southern blot analysis, and RT-PCR, we have examined the cause of CIITA silencing in a trophoblast-derived cell line. We report here that methylation of promoter IV DNA at CpG sites in Jar cells prevents promoter occupancy and IFN-gamma-inducible transcription. The inhibition of CpG methylation in Jar cells by treatment with 5-aza-2'-deoxycytidine restores IFN-gamma inducibility to CIITA. This is the first description of an epigenetic mechanism involved in regulation of CIITA and MHC class II gene expression.

Antimetabolites, Antineoplastic↗