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PubMed1996

Identification of a transcription factor that binds to the S box of the I-A beta gene of the major histocompatibility complex.

Class II genes of the MHC show a striking homology upstream of the transcription start site that is composed of three conserved sequences (S, X and Y boxes, each separated by 15-20 bp). The presence of the S-box sequence in the mouse MHC class II gene I-A Beta was examined for its influence on the expression of this gene. Deletion or mutation of the S box decreased the induction of chloramphenicol acetyltransferase (CAT) activity in B lymphocytes by 32%. In macrophages, deletion or mutation of the S box abolished interferon-gamma (IFN-gamma) inducibility of CAT activity. Using a gel-retardation assay, we have identified a nuclear factor whose binding site overlaps the 7-mer conserved sequence of the S box. This factor is present in lymphocytes, macrophages, mastocytes and fibroblasts. Surprisingly, binding of this nuclear factor to DNA was induced by IFN-gamma in bone-marrow-derived macrophages, but not in macrophage-like cell lines. The binding site for this factor was defined by DNase I footprinting and partially purified by using an affinity column containing double-stranded oligonucleotides containing a sequence of the S box. A prominent protein of 43 kDa was found that bound specifically to the S-box sequence.

Animals↗
PubMedDate not supplied

Marsupial MHC class II beta genes are not orthologous to the eutherian beta gene families.

The major histocompatibility complex (MHC) class II DRB, DQB, DPB, and DOB gene clusters are shared by different eutherian orders. Such an orthologous relationship is not seen between the beta genes of birds and eutherians. A high degree of uncertainty surrounds the evolutionary relationship of marsupial class II beta sequences with eutherian beta gene families. In particular, it has been suggested that marsupials utilize the DRB gene cluster. A cDNA encoding an MHC class II beta molecule was isolated from a brushtail possum mesenteric lymph node cDNA library. This clone is most similar to Macropus rufogriseus DBB. Our analysis suggests that all known marsupial beta-chain genes, excluding DMB, fall into two separate clades, which are distinct from the eutherian DRB, DQB, DPB, or DOB gene clusters. We recommend that the DAB and DBB nomenclature be reinstated. DAB and DBB orthologs are not present in eutherians. It appears that the marsupial and eutherian lineages have retained different gene clusters following gene duplication events early in mammalian evolution.

Amino Acid Sequence↗
PubMed1989

The class II genes of the rat MHC.

Genes that encode class II Ag from the MHC of the rat, the RT1 region, have been isolated as a series of cosmid clones. The cosmids define two clusters, each of which contains three identifiable sequences; one homologous to alpha-chain and two to beta-chain genes. Both the serologically identified rat class II Ag have been expressed in mouse L cell fibroblasts after the introduction of each alpha-chain gene along with a beta-chain gene from the same cluster. There are substantial homologies to the I region of the mouse H-2 complex in the presence, location, orientation, and expression of the six identified sequences from the rat RT1, supporting the view that the overall organization of the two gene complexes has remained conserved since the species separated.

Animals↗
PubMed2003

Novel mechanisms of class II major histocompatibility complex gene regulation.

Class II MHC molecules present processed peptides from exogenous antigens to CD4+ helper T lymphocytes. In so doing, they are central to immunity, driving both the humoral and cell mediated arms of the immune response. Class II MHC molecules, and the genes encoding them, are expressed primarily in cells of the immune system (B cells, thymic epithelial cells, activated T cells and professional antigen presenting cells). The expression is also under developmental control. Research over the past 20 years have provided a clear understanding of the cis-elements and transcription factors that regulate the expression of Class II MHC genes. Perhaps the most critical advance has been the discovery of CIITA, a non- DNA binding activator of transcription that is a master control gene for class II gene expression. Current research is focused on understanding the situations where class II MHC gene expression occurs in a CIITA-independent pathway, and the molecular basis for this expression. Finally, significant emphasis is being placed on targeting class II MHC transcription factors to either inhibit or stimulate the immune response to transplanted tissue or in cell based vaccines. This communication outlines recent advances in this field and discusses likely areas for future research.

Animals↗
PubMed2003

Frequent segmental sequence exchanges and rapid gene duplication characterize the MHC class I genes in lemurs.

Major histocompatibility complex (MHC) class I genes have complicated and profound evolutionary histories. To reconstruct and better understand their histories, partial class I genes (exon 2-intron 2-exon 3) were sequenced in a sampling of prosimians (Strepsirhini, Primates). In total, we detected 117 different sequences from 36 Malagasy prosimians (lemurs) and 1 non-Malagasy prosimian (galago) representing 4 families, 7 genera, and 13 species. Unlike the MHC class II genes ( MHC-DRB), MHC class I genes show a generally genus-specific mode of evolution in lemurs. Additionally, no prosimian class I loci were found to be orthologous to HLA genes, even at highly conserved loci (such as HLA-E, HLA-F). Phylogenetic analysis indicates that nucleotide diversity among loci was very small and the persistence time of the polymorphisms was short, suggesting that the origin of the lemur MHC class I genes detected in this study was relatively recent. The evolutionary mode of these genes is similar to that of classic HLA genes, HLA-A, HLA-B, and HLA-C, in terms of their recent origin and rarity of pseudogenes, and differs from them with respect to the degree of gene duplications. From the viewpoint of MHC genes evolution, some interlocus sequence exchanges were apparently observed in the lemur lineage upon phylogenetic and amino acid motif analyses. This is also in contrast to the evolutionary mode of HLA genes, where intralocus exchanges have certainly occurred but few interlocus exchanges have taken place. Consequently, the gene conversion model for explaining the generation of the MHC diversity among different loci can be thought to play more important roles in the evolution of lemur MHC class I genes than in that of HLA genes.

Animals↗
PubMed1993

Major histocompatibility complex genes have an increased brain expression after scrapie infection.

We have examined the expression of the major histocompatibility complex (MHC) antigens and related genes in scrapie-infected hamster brain. Both the class I and the class II MHC genes as well as the class II-associated invariant chain were found to have an increased brain expression after scrapie infection. The increased expression of the class I complex was immunohistochemically localized primarily to neurons, though some astrocytes contained much smaller amounts of the class I complex. While there is no detectable immune response to scrapie infection, the possibility that increased MHC expression affords some defense against the scrapie agent is discussed.

Animals↗
PubMed1995

Human class II major histocompatibility complex gene transfer into murine neuroblastoma leads to loss of tumorigenicity, immunity against subsequent tumor challenge, and elimination of microscopic preestablished tumors.

Immunological recognition of transformed cells is critically important to limit tumor development and proliferation. Because established tumors have escaped immune recognition and elimination, novel strategies to enhance antitumor immunity have been developed. A unique approach has used the introduction of genes encoding major histocompatibility complex (MHC) antigens into tumor cells. Experiments in mice have shown that the expression of syngeneic class II MHC antigens in tumor cells completely abrogates tumorigenicity and induces tumor-specific immunity. In this study we sought to determine whether a more effective antitumor immune response would be generated by introducing xenogeneic class II MHC genes into tumor cells. To address this question we used recombinant retroviruses to express human class II MHC genes in a highly malignant murine neuroblastoma cell line, Neuro-2a. We found that normal mice inoculated with Neuro-2a expressing the human class II MHC antigen did not develop tumors and were immune to subsequent challenge with unmodified Neuro-2a cells. In addition, mice bearing small established Neuro-2a tumors were cured by vaccination with Neuro-2a expressing human class II MHC. We hypothesize that a similar approach using retroviral-mediated transduction of class II MHC genes into human tumor cells may be an effective alternative to current cancer treatment.

Adjuvants, Immunologic↗
PubMed2001

Lymphocyte antigens in sheep: linkage to the MHC class II DRB1 gene.

In this work a typing battery of sera was developed to test lymphocyte antigens in sheep. Eight antigens were detected in a Latxa sheep sample. The serological determination of these antigens is described. As some of the detected antigens segregated in close linkage with class II DRB1 SSCP patterns in two half-sib families, we can conclude that they are coded by genes located in the MHC. Gene frequencies were very similar in Latxa Mutur Gorria and Latxa Mutur Beltza, the two varieties of the Latxa breed. Although few animals were typed in the comparison with other typing sera, it seems that two of our sera clusters detect the same antigens as those detected by other research groups working in other breeds with their own typing batteries.

Animals↗
PubMed1987

Regulation of the expression of class II genes of the human major histocompatibility complex in tumor cells.

The control of expression of human class II MHC genes has been studied in lymphoid and melanoma cells. Specific unmethylation of all restriction sites nearby the promoter regions has been detected in all cell lines and tissues studied, irrespective of their ability to express class II MHC products. The main functional role of DNA methylation appears, on the contrary, to be the regulation of a fraction of the nucleotide polymorphism of class II MHC genes. Constitutive expression of these genes can be modified by recombinant IFN-gamma and by the demethylating agent 5-azacytidine. Both the modifiers differentially regulate the levels of class II MHC and invariant chain products. In melanoma cells IFN-gamma derepresses transcription of a 1.2-Kb HLA-DR alpha mRNA, but does not affect the levels of a 0.8-Kb HLA-DR alpha specific mRNA. These molecular changes are triggered by IFN-gamma through a protein-synthesis-dependent pathway.

Azacitidine↗
PubMed2002

Murine NFX.1: isolation and characterization of its messenger RNA, mapping of its chromosomal location and assessment of its developmental expression.

We have previously isolated (by expression cloning) a human cDNA, termed NFX.1, encoding a nucleic acid-binding protein that interacts with the conserved X1 box cis-element first discovered in class II major histocompatibility complex (MHC) genes. Functional studies involving expression of NFX.1 and assessment of expression from class II reporter constructs and endogenous class II MHC genes indicated that the factor could repress transcription of class II MHC genes. Subsequent studies have extended the biological significance of the factor, indicating that it plays an important role in neuronal development. Indeed, the reiterated RING finger motifs in the central domain of the polypeptide strongly suggest that NF-XI is a probable E3 ubiquitin protein ligase, indicating that the protein may have multiple activities. Here we report the cloning of the mouse homologue of the human NfX.1 cDNA: m-Nfx.1. Comparison of the deduced primary sequence of mouse and human NFX.1 proteins shows very high homology and confirms that m-NFX.1 contains the conserved cysteine-rich DNA-binding motif first described in human NFX.1 (95% homology). Expression of MHC class II genes is substantially reduced following expression of m-NFX.1, which confirms that we have isolated the functional murine homologue of human NfX.1 cDNA. Further evidence comes from the mapping of m-Nfx.1 gene to the proximal region of mouse chromosome 4, a region syntenic to the location of human Nfx.1 (short arm of chromosome 9). Expression profiling shows that m-NFX.1 is expressed ubiquitously in both adult tissues and during development, supporting the hypothesis that it may have yet-undescribed roles in distinct biological processes.

Aging↗
PubMed1998

Polymorphism of the HLA class II loci in Siberian populations.

The populations that colonized Siberia diverged from one another in the Paleolithic and evolved in isolation until today. These populations are therefore a rich source of information about the conditions under which the initial divergence of modern humans occurred. In the present study we used the HLA system, first, to investigate the evolution of the human major histocompatibility complex (MHC) itself, and second, to reveal the relationships among Siberian populations. We determined allelic frequencies at five HLA class II loci (DRB1, DQA1, DQB1, DPA1, and DPB1) in seven Siberian populations (Ket, Evenk, Koryak, Chukchi, Nivkh, Udege, and Siberian Eskimo) by the combination of single-stranded conformational polymorphism and DNA sequencing analysis. We then used the gene frequency data to deduce the HLA class II haplotypes and their frequencies. Despite high polymorphism at four of the five loci, no new alleles could be detected. This finding is consistent with a conserved evolution of human class II MHC genes. We found a high number of HLA class II haplotypes in Siberian populations. More haplotypes have been found in Siberia than in any other population. Some of the haplotypes are shared with non-Siberian populations, but most of them are new, and some represent "forbidden" combinations of DQA1 and DQB1 alleles. We suggest that a set of "public" haplotypes was brought to Siberia with the colonizers but that most of the new haplotypes were generated in Siberia by recombination and are part of a haplotype pool that is turning over rapidly. The allelic frequencies at the DRB1 locus divide the Siberian populations into eastern and central Siberian branches; only the former shows a clear genealogical relationship to Amerinds.

Alleles↗