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At least 829 records · Page 46Linked to original sources
PubMed1998

The RFX complex is crucial for the constitutive and CIITA-mediated transactivation of MHC class I and beta2-microglobulin genes.

In type III bare lymphocyte syndrome (BLS) patients, defects in the RFX protein complex result in a lack of MHC class II and reduced MHC class I cell surface expression. Using type III BLS cell lines, we demonstrate that the RFX subunits RFX5 and RFXAP are crucial for constitutive and CIITA-induced MHC class I and beta2m transactivation. Similar to MHC class II, the promoters of MHC class I and beta2m contain an S-X-Y region of which the X1 box is crucial for constitutive and CIITA-induced MHC class I and beta2m transactivation. Thus, the RFX complex is part of a regulatory pathway linking the transactivation of MHC class I and II and their accessory genes.

Amino Acid Sequence↗
PubMed1995

Contrast between class I and class II MHC-mediated differentiation of a CD4+CD8+ T cell line: implications for lineage commitment.

Experiments in transgenic mice have demonstrated that thymocyte differentiation into the mature CD4+ helper or CD8+ cytotoxic T cell lineage is ultimately dependent upon the specificity of the TCR for class II or class I MHC molecules respectively. However, the initial mechanistic events involved in this process remain unclear. To address this issue, we have expressed a TCR specific for an ovalbumin peptide and the Kb class I MHC molecule in the DPK CD4+CD8+ precursor T cell line. This cell line originally expressed a TCR specific for a pigeon cytochrome c peptide and class II MHC molecules and has been shown previously to differentiate into CD4+CD8- cells upon recognition of antigen in vitro or thymic epithelial cells in vivo. Surprisingly, we find that recognition of either class I or class II MHC by these cells initiates differentiation into the CD4+ lineage and induces down-regulation of recombination associated genes. Unlike recognition of class II MHC, however, recognition of class I MHC does not induce full maturation. These results support a model in which (i) commitment to the CD4 lineage occurs prior to positive selection and (ii) CD4 lineage commitment is associated with a requirement for activation by a class II MHC-specific TCR in order to complete differentiation.

Animals↗
PubMed1999

Locus specificity of polymorphic alleles and evolution by a birth-and-death process in mammalian MHC genes.

We have conducted an extensive phylogenetic analysis of polymorphic alleles from human and mouse major histocompatibility complex (MHC) class I and class II genes. The phylogenetic tree obtained for 212 complete human class I allele sequences (HLA-A, -B, and -C) has shown that all alleles from the same locus form a single cluster, which is highly supported by bootstrap values, except for one HLA-B allele (HLA-B*7301). Mouse MHC class I loci did not show locus-specific clusters of polymorphic alleles. This was considered to be because of either interlocus genetic exchange or the confusing designation of loci in different haplotypes at the present time. The locus specificity of polymorphic alleles was also observed in human and mouse MHC class II loci. It was therefore concluded that interlocus recombination or gene conversion is not very important for generating MHC diversity, with a possible exception of mouse class I loci. According to the phylogenetic trees of complete coding sequences, we classified human MHC class I (HLA-A, -B, and -C) and class II (DRB1) alleles into three to five major allelic lineages (groups), which were monophyletic with high bootstrap values. Most of these allelic groups remained unchanged even in phylogenetic trees based on individual exons, though this does not exclude the possibility of intralocus recombination involving short DNA segments. These results, together with the previous observation that MHC loci are subject to frequent duplication and deletion, as well as to balancing selection, indicate that MHC evolution in mammals is in agreement with the birth-and-death model of evolution, rather than with the model of concerted evolution.

Alleles↗
PubMed2001

Genomic organization of the mammalian MHC.

The Human Genome Project transformed the quest of more than 50 years to understand the major histocompatibility complex (Mhc). The sequence of the Mhc from human and mouse, together with a large amount of sequence and mapping information from several other species, allows us to draw general conclusions about the organization and origin of this crucial part of the immune system. The Mhc is a mosaic of stretches formed by conserved and nonconserved genes. Surprisingly, of the approximately 3.6-Mb Mhc, the stretches that encode the class I and class II genes, which epitomize the Mhc, are the least conserved part, whereas the approximately 1.7-Mb stretches that encode at least 115 other genes are highly conserved. We summarize the available data to answer the questions (a) What is the Mhc? and (b) How can we define it in a general, not species-specific, way? Knowing what is essential and what is incidental helps us understand the fundamentals of the Mhc, and defining the species differences makes the model organisms more useful.

Animals↗
PubMed2001

Making the animal model for AIDS research more precise: the impact of major histocompatibility complex (MHC) genes on pathogenesis and disease progression in SIV-infected monkeys.

Experimentally infected rhesus monkeys serve as an indispensable animal model to assess the pathogenesis, to validate therapy approaches and to develop vaccination strategies against viral diseases such as AIDS threatening the human population. Upon infection with simian immunodeficiency virus (SIV), a retrovirus closely related to the human immunodeficiency virus (HIV), macaques develop clinical manifestations similar to those of HIV-infected humans. As in humans, the disease course is variable. Polymorphic genes of the major histocompatibility complex (MHC) are required for the initiation and regulation of a specific immune response and represent a major host factor accounting for the differential outcome of infection. During the last few years, our understanding of the structure and function of the rhesus macaque MHC has increased substantially. Functional studies have led to the identification of specific SIV and HIV peptide epitopes presented by rhesus macaque MHC molecules. The subsequent development of MHC class I tetramers has allowed further insight into the cellular immune response following SIV-infection. Detailed studies demonstrated that viral escape mutants are generated during the acute and chronic phase of infection and explain why control of viral replication ultimately fails. Furthermore, particular MHC haplotypes which influence disease progression have been discovered. Thus, MHC-typing can have a prognostic potential. The further elucidation of the rhesus macaque MHC and the search for other relevant genes will remain an important task for future research and will stimulate all immunologically-related investigations in macaques.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Function of the MHC.

The major histocompatibility complex (MHC) was discovered originally as a genetic locus controlling rapid rejection of tissue grafts. Subsequently, study of antibody responses in vivo and T-cell responses in vitro to MHC antigens identified the presence of a number of closely linked loci within the MHC. Immune response (Ir) genes also mapped to the MHC. The discovery of MHC restriction and the molecular identification of MHC genes and their products has led to a unified theory of the principal function of MHC molecules to act as guidance molecules for T-cell responses. Additional functions are suggested by their association with cell surface receptors.

Animals↗
PubMed2003

MHC class I-deficient metastatic tumor variants immunoselected by T lymphocytes originate from the coordinated downregulation of APM components.

Previous reports from our group indicated that the MHC class I phenotype of metastatic lung colonies produced by a mouse fibrosarcoma tumor clone (B9) were, depending on the immune status of the host, MHC class I negative in immunocompetent mice and MHC class I positive in immunodeficient athymic nude/nude mice. Now we report the identification of the molecular alterations responsible for the changes of MHC class I molecules in both situations. Metastatic nodes were analyzed for the mRNA level of H-2 class I and beta2-microglobulin genes, and several gene components of the major histocompatibility complex (MHC) class I antigen-processing machinery (APM). These included the genes coding for the low-molecular-weight proteins LMP2, LMP7, LMP10, the transporter associated with antigen processing (TAP-1, TAP-2), and calnexin, calreticulin, tapasin, PA-28-alpha, PA-28-beta, ERP-59 and ER-60. Analyses with RT-PCR showed that TAP-1, TAP2, LMP-2, LMP7, LMP10, tapasin and calnexin mRNA specific for these genes was absent in metastases produced in immunocompetent mice. In contrast, similar techniques with mRNA preparations obtained from metastatic nodes from immunodeficient mice showed that the mRNA expression level of these genes was highly positive. Interestingly, the MHC class I-positive or negative phenotypes of the metastatic colonies correlated with in vivo immunogenicity. H-2 positive metastasis grew more slowly than the H-2 negative ones when injected intrafootpat in syngeneic immunocompetent animals and were finally rejected. These results provide evidence of the role of T cells in immune surveillance against tumors and identify a mechanism targeted by antitumor T lymphocytes to generate MHC class I-negative tumor escape variants.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

Changes in NF-kappa B and ISGF3 DNA binding activities are responsible for differences in MHC and beta-IFN gene expression in Ad5- versus Ad12-transformed cells.

Changes in MHC class I expression are frequently observed in tumors, which represents at least one mechanism by which tumor cells escape immune surveillance. MHC class I expression is often suppressed in type 12 adenovirus (Ad12)-transformed rodent cells, but is highly induced in Ad5-transformed cells. This difference helps to explain why Ad12 but not Ad5 can induce tumors in immunocompetent syngeneic rats. In this report we demonstrate that only Ad5- but not Ad12-transformed rodent fibroblasts constitutively express beta-IFN which results in ISGF3 factor induction, and stimulation of MHC class I expression. Furthermore, we demonstrate that in contrast to Ad12-transformed cells, Ad5-transformed cells show constitutive levels of nuclear NF-kappa B-like DNA binding activity. This is of particular interest since both the beta-IFN and the MHC class I promoters contain an NF-kappa B DNA binding site. Thus, high levels of MHC class I expression in Ad5-transformed cells are due to a combinatorial stimulation of two cis-regulatory sequences of the MHC class I promoter: the NF-kappa B binding site and the interferon stimulated response element (ISRE), which binds the ISGF3 factor complex. The failure of Ad12-transformed cells to activate this pathway explains their low levels of MHC class I expression and their greater oncogenicity.

Adenoviruses, Human↗
PubMed1995

Downregulation of MHC class I expression due to interference with p105-NF kappa B1 processing by Ad12E1A.

We have previously demonstrated that expression of major histocompatibility complex (MHC) class I genes is repressed in baby rat kidney cells transformed by early region 1 of oncogenic adenovirus type 12 (Ad12E1). Reduced expression of MHC class I antigens contributes to the escape of Ad12-transformed cells from T-cell-mediated immune surveillance and to tumour induction. In this study, we show that repression of MHC class I expression by Ad12E1A is mediated via the H2TF1 element of the MHC class I promoter. This element binds NF kappa B and KBF1, two factors which play a major role in the regulation of MHC class I expression in vivo. In extracts from Ad12E1-transformed cells, binding of KBF1 and NF kappa B to the H2TF1 element is decreased. This is caused by reduced production of p50-NF kappa B1, the 50 kDa subunit shared by KBF1 and NF kappa B, due to interference with p105-NF kappa B1 processing by Ad12-13S-E1A protein. Overexpression of the p105-NF kappa B1 cDNA, or of a truncated p105-NF kappa B1 cDNA that codes for p50-NF kappa B1, restores MHC class I expression in Ad12E1-transformed cells. These data demonstrate that downregulation of MHC class I expression in Ad12E1-transformed cells is due to interference with processing of p105-NF kappa B1 by the Ad12-13S-E1A protein.

Adenoviridae↗
PubMed1999

Anti-TNF antibody modulates cytokine and MHC expression in cardiac allografts.

Tumor necrosis factor-alpha (TNF) is a multifunctional cytokine evoked in response to alloantigen stimulation and may be involved in lymphocyte activation, adhesion molecule expression, and regulation of MHC class II antigens. Anti-TNF treatment prolongs cardiac allograft survival. We investigated the role of anti-TNF in the regulation of MHC class II antigens and cytokine mRNA expression of TNF, interferon-gamma (IFN), IL-2, IL-4, and IL-10 in cardiac allografts to elucidate its immunological mechanism. These in vivo studies were conducted using a rat MHC mismatch Brown-Norway to Lewis (BN to LEW) heterotopic cardiac transplant model. In control untreated rats, allografts were rejected at 6.8 +/- 0.6 days. Allograft survival was significantly prolonged to 12.7 +/- 1.4 days with anti-TNF treatment. MHC class II expression, analyzed by indirect immunofluorescence cytometry, demonstrated that MHC class II-positive cells increased by 25% in spleens of untreated allografted rats compared to naive rats, while anti-TNF-treated allografted rats had a similar percentage of MHC II cells as naives. Further, naive, untransplanted rats and both anti-TNF and untreated, transplanted rats had heart and spleens harvested on Day 5 post-transplant. Cytokine mRNA expression was determined by semiquantitative RT-PCR. In heart and spleen cells from naives, TNF mRNA expression was undetectable or very weak. However, in rejecting allografts and spleen cells from untreated recipients, TNF expression was remarkably increased, while anti-TNF attenuated this TNF expression in both heart graft and spleen cells. Furthermore, IL-2, IL-10, and IFN expression were absent in naive hearts. However, in untreated allografts IL-2, IL-10, and IFN were strongly expressed, which was markedly decreased after anti-TNF treatment. Finally, IL-4 expression was found equally in naive hearts, untreated allografts, and anti-TNF-treated allografts. These results suggest that anti-TNF antibody treatment may not only neutralize TNF activity but also play a role in altering cytokine mRNA expression and MHC class II expression.

Animals↗
PubMed2005

Expression of MHC II genes.

Innate and adaptive immunity are connected via antigen processing and presentation (APP), which results in the presentation of antigenic peptides to T cells in the complex with the major histocompatibility (MHC) determinants. MHC class II (MHC II) determinants present antigens to CD4+ T cells, which are the main regulators of the immune response. Their genes are transcribed from compact promoters that form first the MHC II enhanceosome, which contains DNA-bound activators and then the MHC II transcriptosome with the addition of the class II transactivator (CIITA). CIITA is the master regulator of MHC II transcription. It is expressed constitutively in dendritic cells (DC) and mature B cells and is inducible in most other cell types. Three isoforms of CIITA exist, depending on cell type and inducing signals. CIITA is regulated at the levels of transcription and post-translational modifications, which are still not very clear. Inappropriate immune responses are found in several diseases, including cancer and autoimmunity. Since CIITA regulates the expression of MHC II genes, it is involved directly in the regulation of the immune response. The knowledge of CIITA will facilitate the manipulation of the immune response and might contribute to the treatment of these diseases.

B-Lymphocytes↗
PubMed1995

Allelic diversity at the Mhc-DP locus in rhesus macaques (Macaca mulatta).

Allelic diversity at the major histocompatibility complex class II DP locus of rhesus macaques was studied by sequencing exon 2 of Mamu-DPA1 and -DPB1 genes. The Mamu-DPA1 gene is apparently invariant, whereas the Mamu-DPB1 locus displays polymorphism. Here we report the characterization of 1 Mamu-DPA1 and 13 Mamu-DPB1 alleles which were compared with other available primate Mhc-DPA1 and -DPB1 sequences. As compared with Mhc-DRB and -DQB1, most codons for the contact residues in the antigen binding site of the primate Mhc-DPB1 gene have a relatively low degree of variation in encoding various types of amino acids. In contrast to Mhc-DRB and -DQB, the HLA- and Mamu-DPB1 sequences cluster in a species-specific manner in phylogenetic trees. Mhc-DPB1 polymorphisms, however, are inherited in a transspecies mode of evolution, as is demonstrated by the sharing of lineage members between closely related macaque species. The data demonstrate that the transspecies character of Mhc-DPB1 polymorphism was retained over much shorter periods of time as compared with its sister class II loci, Mhc-DQ and -DR.

Alleles↗
PubMed1992

Evolutionary relationships among the primate Mhc-DQA1 and DQA2 alleles.

The variation of the Mhc-DQA1 and DQA2 loci of ten different primate species (hominoids and Old World monkeys) was studied in order to obtain an insight in the processes that generate polymorphism of major histocompatibility complex (Mhc) class II genes and to establish the evolutionary relationships of their alleles. To that end nucleotide sequences of 36 Mhc class II DQA1 and seven DQA2 second exons were determined and phylogenetic trees that illustrate their evolutionary relationships were constructed. We demonstrate the existence of four primate Mhc-DQA1 allele lineages, two of which probably existed before the separation of the ancestors of the hominoids and Old World monkeys (approximately 22-28 million years ago). Mhc-DQA2 sequences were found only in the hominoid species and showed little diversity. We found no evidence for a major contribution of recombinational events to the generation of allelic diversity of the primate Mhc-DQA1 locus. Instead, our data suggest that the primate Mhc-DQA1 and DQA2 loci are relatively stable entities that mutated primarily as a result of point mutations.

Alleles↗
PubMed1993

Sequence and evolution of cattle MHC class I cDNAs: concerted evolution has not taken place in cattle.

To explore genetic mechanisms responsible for major histocompatibility complex (MHC) class I evolution in the artiodactyls, we cloned and sequenced MHC class I cDNAs from a Bos taurus bull heterozygous for cattle MHC (BoLA) class I serological specificities w2 and w30. Four unique cDNAs were found, indicating the presence of at least two MHC class I loci. Analysis of these four cDNAs and all previously published BoLA cDNA sequences suggested that there may be three cattle MHC class I loci. Additionally, comparison of all of the BoLA class I cDNAs to MHC class I cDNAs of other artiodactyls showed that some of the BoLA class I cDNAs were more similar to certain sheep cDNAs than they were to other cattle cDNAs. These data indicate that each BoLA class I locus has evolved independently after an ancestral gene duplication event and that inter-locus segmental exchange or concerted evolution has not occurred rapidly enough to cause extensive divergence between the orthologous MHC class I loci of sheep and cattle.

Amino Acid Sequence↗
PubMed1996

The RAG cell line defines a new complementation group of MHC class II deficiency.

We previously described RAG, a mouse adenocarcinoma cell line, as deficient for the induction of major histocompatibility (MHC) class II antigens by IFN-gamma, but responding normally for MHC class I antigen stimulation and anti-viral protection. We had established that the fusion of RAG with various human cell lines restored the induction of MHC class II antigens, whenever the human chromosome 16 was present in somatic cell hybrids. Here we show that the RAG cell line does not exhibit any induction by IFN-gamma of DMA, DMB, and the invariant chain (Ii) mRNAs, and that the induction is restored in somatic cell hybrids containing human chromosome 16. In order to define the gene (designated F16) affected in the RAG cells, we performed a complementation analysis by fusing RAG with previously described human cell lines defective for MHC class II antigen expression (e.g., BLS cell lines), and which belong to five different complementation groups. Our data show that the resulting somatic cell hybrids present an inducible expression of mouse MHC class II antigens, Ii, DMA, and DMB. Therefore, the RAG cell line represents a yet undescribed cellular mutant affected in the expression of MHC class II antigens. In addition, we demonstrate that MHC class II antigens can be constitutively expressed in the RAG cell line when transfected with the cDNA encoding human CIITA driven by the RSV LTR promoter. Since the complementation analysis assessed that F16 and CIITA are distinct, our data suggest that F16 is required for the expression of CIITA.

Animals↗
PubMed2005

Inter- and intralocus recombination drive MHC class IIB gene diversification in a teleost, the three-spined stickleback Gasterosteus aculeatus.

The mutational mechanism underlying the striking diversity in MHC (major histocompatibility complex) genes in vertebrates is still controversial. In order to evaluate the role of inter- and intragenic recombination in MHC gene diversification, we examined patterns of nucleotide polymorphism across an exon/intron boundary in a sample of 31 MHC class IIB sequences of three-spined stickleback (Gasterosteus aculeatus). MHC class IIB genes of G. aculeatus were previously shown to be under diversifying (positive) selection in mate choice and pathogen selection experiments. Based on recoding of alignment gaps, complete intron 2 sequences were grouped into three clusters using maximum-parsimony analysis. Two of these groups had >90% bootstrap support and were tentatively assigned single locus status. Intron nucleotide diversity within and among loci was low (p-distance within and among groups = 0.016 and 0.019, respectively) and fourfold lower than the rate of silent mutations in exon 2, suggesting that noncoding regions are homogenized by frequent interlocus recombination. A substitution analysis using GENECONV: revealed as many intergenic conversion events as intragenic ones. Recombination between loci may explain the occurrence of sequence variants that are particularly divergent, as is the case in three-spined stickleback, with nucleotide diversity attaining dN = 0.39 (peptide-binding residues only). For both MHC class II loci we also estimated the amount of intragenic recombination as population rate (4N(e)r) under the coalescent and found it to be approximately three times higher compared to point mutations (Watterson estimate per gene, 4N(e)mu). Nonindependence of molecular evolution across loci and frequent recombination suggest that MHC class II genes of bony fish may follow different evolutionary dynamics than those of mammals. Our finding of widespread recombination suggests that phylogenies of MHC genes should not be based on coding segments but rather on noncoding introns.

Animals↗
PubMed2004

The selection of tumor variants with altered expression of classical and nonclassical MHC class I molecules: implications for tumor immune escape.

Tumor immune escape variants can be identified in human and experimental tumors. A variety of different strategies are used by tumor cells to avoid recognition by different immune effector mechanisms. Among these escape routes, alteration of MHC class I cell surface expression is one of the mechanisms most widely used by tumor cells. In this review we focus our attention on the T-cell immune selection of MHC class I-deficient tumor variants. Different altered MHC class I phenotypes that originate from multiple molecular mechanisms can be identified in human tumors. MHC-deficient tumor clones can escape T-cell immune responses, but are in theory more susceptible to NK-cell-mediated lysis. In this context, we also review the controversial issue of the aberrant expression of nonclassical HLA class I molecules, particularly HLA-G, in tumors. This expression may be relevant in tumor cells that have lost the capacity to interact with NK inhibitory receptors-namely, those tumor cells with no HLA-B or HLA-C expression. Most published studies have not analyzed these possibilities and do not provide information about the complete HLA-A, HLA-B, or HLA-C molecule profiles of the tumors studied. In contrast, HLA-E has been reported to be expressed in some tumor cell lines with very low HLA-A, HLA-B, and HLA-C expression, suggesting that HLA-E may indeed, in some cases, play a role by inhibiting NK lysis of cells that otherwise would be destroyed by NK cells. Finally, we provide evidence that the status of the immune system in the tumor-bearing animal is capable of defining the MHC profile of the tumor cells. In other words, MHC class I-negative metastatic colonies are produced in immunocompetent animals, and MHC class I-positive colonies in T-cell immunodeficient individuals.

Animals↗
PubMed1999

Cancer immunotherapy by antisense suppression of Ii protein in MHC-class-II-positive tumor cells.

This study was aimed at creating a more effective tumor cell vaccine by suppressing Ii protein in the presence of MHC class II molecules within a cancer cell. Absence of the Ii protein, which normally blocks the antigenic-peptide-binding site of MHC class II molecules at synthesis in the endoplasmic reticulum, presumably increases the range of cancer-related epitopes presented to CD4+ helper T cells. Effective suppression of Ii protein was achieved with an antisense, phosphorothioate oligonucleotide, which was selected on the basis of (1) the RNase H activation assay, (2) an assay for Ii protein suppression, and (3) a test for potency with respect to the extent of base sequence ("sequence walking"). The SaI murine sarcoma, which is MHC-class-I+ and MHC-class-II-, Ii-protein-, upon transfection with genes for either interferon gamma or the MHC class II transactivator, came to express MHC class II molecules and Ii protein. In each line of transfected tumor cells, the antisense oligonucleotide profoundly suppressed Ii protein in 35%-55% cells, without affecting expression of MHC class II molecules. Inoculation of mice with such Ii-protein-suppressed tumor vaccine cells, after either formaldehyde fixation or X-irradiation, led to much greater protection against challenge with the parental SaI sarcoma than did inoculation with untreated cells. This approach to cancer cell vaccination can be applied in a wide range of human tumors.

Animals↗