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PubMed1989

A gamma-interferon-induced factor that binds the interferon response sequence of the MHC class I gene, H-2Kb.

Transcription of class I genes of the major histocompatibility complex (MHC) can be induced by interferons. Treatment of HeLa cells with interferon-gamma induces a DNA-binding factor, IBP-1, specific for a site within the interferon response sequence (IRS) of the H-2Kb promoter. The mol. wt of IBP-1, as estimated by photoactivated protein-DNA crosslinking analysis, is approximately 59 kd. Point-mutation of this binding site abolishes IBP-1 interaction and the ability of the MHC promoter to respond to interferon. Induction of this binding activity is rapid and closely parallels the previously reported time course of transcriptional activation of endogenous MHC class I genes. Treatment of cells with cycloheximide, a protein synthesis inhibitor, blocked the induction of the DNA-binding activity. An oligonucleotide derived from the virus- and double-stranded RNA-inducible promoter of the interferon-beta 1 gene is able to bind IBP-1. Sequences similar to the IBP-1 binding site are found upstream of many interferon-responsive genes.

Animals↗
PubMed2006

Expressed MHC class II genes in sea otters (Enhydra lutris) from geographically disparate populations.

The major histocompatibility complex (MHC) is central to maintaining the immunologic vigor of individuals and populations. Classical MHC class II genes were targeted for partial sequencing in sea otters (Enhydra lutris) from populations in California, Washington, and Alaska. Sequences derived from sea otter peripheral blood leukocyte mRNAs were similar to those classified as DQA, DQB, DRA, and DRB in other species. Comparisons of the derived amino acid compositions supported the classification of these as functional molecules from at least one DQA, DQB, and DRA locus and at least two DRB loci. While limited in scope, phylogenetic analysis of the DRB peptide-binding region suggested the possible existence of distinct clades demarcated by geographic region. These preliminary findings support the need for additional MHC gene sequencing and expansion to a comprehensive study targeting additional otters.

Alaska↗
PubMed1993

Regulation of MHC class I and beta 2-microglobulin gene expression in human neuronal cells. Factor binding to conserved cis-acting regulatory sequences correlates with expression of the genes.

MHC class I molecules are coexpressed with beta 2-microglobulin (beta 2-M) on many somatic cells. However, these proteins are normally not present on cells of the central nervous system (CNS). Cells derived from human neuroblastomas were used as a model for investigating the molecular basis for the paucity of MHC class I and beta 2-M gene expression in neural cells and for the induction of these genes by two cytokines, IFN-gamma, and TNF-alpha. These cytokines independently increased MHC class I and beta 2-M cell surface expression on the neuroblastoma cell lines. IFN-gamma or TNF-alpha also increased MHC class I and beta 2-M steady-state RNA levels and the expression of MHC class I and beta 2-M CAT reporter constructs transiently transfected into the neuroblastoma cell lines, indicating that the cytokines acted by increasing the transcription of these genes. MHC class I and beta 2-M genes share two conserved regulatory elements, an NF kappa B-like site and the IFN consensus sequence, that act as a constitutive enhancer and an IFN-responsive element, respectively. Low MHC class I and beta 2-M gene expression in these cells was accounted for by undetectable to low factor binding activity specific for the above regulatory elements of these genes. TNF-alpha increased factor binding activity specific for the NF kappa B-like elements and IFN-gamma increased factor binding activity specific for the IFN consensus sequence elements of the MHC class I and beta 2-M genes, but not vice versa. Taken together, our results indicated that IFN-gamma and TNF-alpha increased MHC class I and beta 2-M gene expression in the neuroblastoma cell lines by inducing factor binding to the regulatory elements present in both genes.

Base Sequence↗
PubMed2000

Natural variation in immune responsiveness, with special reference to immunodeficiency and promoter polymorphism in class II MHC genes.

This review deals with natural selection operating on heterozygotes as a key factor controlling (a) the frequency of immunodeficiencies, and (b) promoter polymorphism in MHC class II genes. The known difference in frequency distribution of X-linked and autosomal deficiencies lend support to this possibility, and suggest that the frequency of neonatal defect may rise as old-established equlibria between entry and exit of deleterious mutations change. MHC class II gene promoters differ in their capacity to favor Th1 (or reciprocally Th2) responses, thus suggesting that promoter polymorphism is sustained by the greater flexibility in response that this confers on heterozygotes.

Animals↗
PubMed2006

MHC class II genes in Mexican patients with idiopathic dilated cardiomyopathy.

The purpose of the present study was to evaluate the relationship between class II major histocompatibility complex (MHC) genes (HLA-DR and HLA-DQB) and the genetic susceptibility to idiopathic dilated cardiomyopathy (IDC) in Mexican patients. The HLA-DR and DQB alleles were analyzed in 53 patients with IDC and 99 ethnically matched healthy controls using the polymerase chain reaction-sequence specific oligonucleotides (PCR-SSO) technique. IDC patients showed increased frequencies of HLA-DR4 (pC=0.02, OR=1.87), HLA-DQB1*0301 (pC=0.02, OR=1.92) and HLA-DQB1*0302 (pC=0.02, OR=1.87) when compared to healthy controls. On the other hand, IDC patients also showed decreased frequencies of HLA-DR11 allele (pC=0.03, OR=0.26) and HLA-DQB1*0201 (pC=0.04, OR=0.41). These data suggest that variation in class II HLA alleles could be a genetic factor involved in the susceptibility to IDC of the Mexican Mestizo population.

Cardiomyopathy, Dilated↗
PubMed2006

Proceedings of the SMBE Tri-National Young Investigators' Workshop 2005. MHC Class I genes in the Tuatara (Sphenodon spp.): evolution of the MHC in an ancient reptilian order.

The major histocompatibility complex (MHC) is an extremely dynamic region of the genome, characterized by high polymorphism and frequent gene duplications and rearrangements. This has resulted in considerable differences in MHC organization and evolution among vertebrate lineages, particularly between birds and mammals. As nonavian reptiles are ancestral to both mammals and birds, they occupy an important phylogenetic position for understanding these differences. However, little is known about reptile MHC genes. To address this, we have characterized MHC class I sequences from the tuatara (Sphenodon spp.), the last survivor of an ancient order of reptiles, Sphenodontia. We isolated two different class I cDNA sequences, which share 93% sequence similarity with each other but are highly divergent from other vertebrate MHC genes. Southern blotting and polymerase chain reaction amplification of class I sequences from seven adult tuatara plus a family group indicate that these sequences represent at least two to three loci. Preliminary analysis of variation among individuals from an island population of tuatara indicates that these loci are highly polymorphic. Maximum likelihood analysis of reptile MHC class I sequences indicates that gene duplication has occurred within reptilian orders. However, the evolutionary relationships among sequences from different reptilian orders cannot be resolved, reflecting the antiquity of the major reptile lineages.

Amino Acid Sequence↗
PubMed1994

Polymorphism of bovine MHC class I genes. Joint report of the Fifth International Bovine Lymphocyte Antigen (BoLA) Workshop, Interlaken, Switzerland, 1 August 1992.

The objectives of the Fifth International BoLA Workshop were to: standardize nomenclature, compare typing methods, and characterize BoLA haplotypes. The workshop was based on the distribution of blood samples (cells) from 60 selected cattle to 14 laboratories. Results for the class I (BoLA-A) region are presented in this paper while results for the class II regions are presented in a separate report. Thirty-six of the 50 previously established serological class I specificities were represented in the cell panel. However, only 30 specificities could be confirmed. Two specificities, A16 and A32, were upgraded from provisional, workshop (w) specificities to BoLA-A locus specificities and three new specificities, w51(w28), w52 and w53(w28), were defined. The 39 specificities distinguished 30 class I haplotypes in the 60 animals. Class I isoelectric focusing proved to be a useful adjunct to the serology. Isoelectric focusing confirmed several serologically defined splits and detected splits of A15(A8), A18(A6) and A22(w49) that had not been detected by serology. Subsequently, serological support for splits of A15(A8) and A22(w49) was found.

Animals↗
PubMed2005

Rapid expansion of killer cell immunoglobulin-like receptor genes in primates and their coevolution with MHC Class I genes.

The gene family of killer cell immunoglobulin-like receptors (KIRs) in primates provides the first line of defense against virus infection and tumor transformation. Interacting with MHC class I molecules, KIRs can regulate the cytotoxic activity of natural killer (NK) cells and distinguish the tumor and virus infected cells from normal body cells. Phylogenetic analysis and comparison of domain structures identified three major groups of KIR genes (group I, II, and III genes). These groups of KIR genes, generated by a series of gene duplications, have acquired different MHC-binding specificity. Inference of ancestral KIR sequences suggested that the functional divergence of group I genes from group II genes occurred by positive selection at the MHC-binding sites after duplication. Our evolutionary study has shown that group I genes diverged from group II genes about 17 million years ago (Mya) apparently after separation of hominoids from Old World (OW) monkeys. Around the same time, gene duplication generating the class I MHC-C locus appears to have occurred. These findings suggest that KIR and MHC class I genes have coevolved as an interacting system. The KIR gene family has experienced a rapid expansion in primate species. The rate of expansion of this gene family seems to be one of the highest among all hominoid gene families. The KIR gene family is also subject to birth-and-death evolution.

Amino Acid Sequence↗
PubMed1991

Analysis of MHC class I gene expression in adult bone marrow and fetal liver of the BALB/c mouse.

The BALB/c mouse has at least 29 class I genes encoded in the Qa, Tla, and Hmt (histocompatibility dependent on a maternally transmitted factor) regions of the MHC. The pattern of expression of these class Ib MHC genes is not well characterized, although some of their products such as the serologically detectable Qa-2 and TL Ag are expressed mainly in lymphoid and hematopoietic tissues. In this study, the expression pattern of BALB/c class I genes has been analyzed in adult bone marrow and fetal liver. cDNA libraries were synthesized from these tissues, and isolated class I cDNA clones were characterized by hybridization with oligonucleotide probes and by nucleotide sequence analysis. Of the 29 total class Ib genes, transcripts of five including Q6d, Q7d, T9c, T10c, and the 37 gene were isolated from the bone marrow cDNA library. Four of these can encode proteins; the sequence of the T10c gene demonstrates it is most likely a pseudogene. A non-overlapping set of three class Ib cDNA clones was obtained from the fetal liver, including T13c, the Thy 19.4 gene, and a previously uncharacterized class I gene provisionally designated as FL 57.2. Although the majority of H-2Dd cDNA clones that were analyzed lack introns, many of the class Ib cDNA clones contain intron sequences. This suggests that the expression of some of these genes may be regulated at the level of RNA splicing. The T13c gene encodes the thymus leukemia Ag in BALB/c mice. We have confirmed that the T13c gene is expressed in fetal liver by flow cytometric analysis of cells stained with anti-TL mAb.

Animals↗
PubMed1984

Expression of the MHC class III genes.

The second (C2) and fourth (C4) components of complement and factor B (B) are coded for by genes within the major histocompatibility complex (MHC). These proteins are synthesized in liver and in extrahepatic mononuclear phagocytes. The isolation of complementary DNA probes corresponding to each of these proteins now permits analysis of the molecular mechanisms controlling expression of the class III MHC genes. Genetic control of C4 gene expression has been examined in two model systems. A defect in post transcriptional processing of C4-specific RNA accounts for a failure to generate mature C4 mRNA in homozygous deficients of a C4 deficient guinea-pig strain. On the other hand, a quantitative difference in the amounts of mature C4 liver mRNA accounts for the genetic variation in C4 levels observed among several mouse strains. The maturation of monocytes to macrophages results in changes in biosynthesis of the MHC class III products; for example, a significant increase in rate of secretion of C2 and B is noted in human monocytes during the first 3 d in culture and the proportion of C2-producing cells is greater in freshly isolated macrophages than in monocytes. Macrophages demonstrate selective increases in factor B and C2 mRNA characteristic of specific tissues. In the guinea-pig macrophage, C4 gene expression is regulated by a selective feedback mechanism induced by extracellular native C4. The C4 binds to the macrophage cell surface mediating a change in transcription or, less likely, a change in stability of C4 mRNA. Regulation of C4 synthesis in the mouse macrophage is accomplished by mechanisms that are independent of this feedback control but the murine cells also display separate mechanisms for regulation of C4 and factor B-specific mRNA levels. Resident and elicited macrophages from either mouse or guinea-pig differ with respect to expression of the class III MHC gene products. These studies form the basis for evaluating the molecular regulation of inflammation, maturation of mononuclear phagocytes and the genetic variants and deficiencies of complement proteins.

Animals↗
PubMed1990

The regulation and expression of MHC class I genes.

The expression of mouse MHC class I genes and their products in vivo reveals complex patterns of regulation. Different promoter elements, which are required for gene activation or modulation in response to various external stimuli, have now been characterized as well as the proteins that bind to them. As described here by Brigitte David-Watine and colleagues, the picture that has gradually emerged from these in vitro studies is of an intricate interplay of transacting factors that ultimately lead to the fine tuning of MHC class I expression in vivo.

Adenoviridae↗
PubMed1986

Bone marrow-derived macrophage expression of endogenous and transfected class II MHC genes during differentiation in vitro.

C57BL/6 (H-2b) mice fail to express I-E molecules on the surface of their cells and thus are unable to respond to I-E-restricted antigens such as GL phi and cytochrome c. Previous experiments in our laboratory have involved developing a system for studying differentiation of bone marrow cells into mature macrophage to gain a better understanding of class II MHC gene expression and function. In this study, we have used this system to transfect the E alpha d gene (cosmid 17.2) into C57BL/6 bone marrow cells and subsequently observed I-E expression on bone marrow-derived macrophages (BMDM) after differentiation in vitro. By using a modified calcium phosphate protocol, we found that the optimal period for transfection of the bone marrow cells was after 2 days of culture in vitro. By using the anti-I-E monoclonal antibody (Ia.7) derived from hybridoma 14-4-4, we detected the I-E molecule on the surface of transfected macrophages by a radiobinding assay and immunoprecipitation. BMDM expressed the I-E product maximally at 5 days of differentiation, and expression then declined. Furthermore, we have found that the expression of the I-E molecule on transfected macrophage was dependent upon exposure to interferon-gamma. Expression of I-E molecules was also detected by the generation of an allogeneic response. Transfected BMDM were compared with (CB6)F1 BMDM for their ability to stimulate C57BL/6 T cells and they were found to be equally effective. By using these initial findings, we hope to further optimize the conditions for insertion and expression of class II MHC genes in bone marrow cells.

Animals↗
PubMed1992

The genes for MHC class II regulatory factors RFX1 and RFX2 are located on the short arm of chromosome 19.

RFX1 is a transacting DNA-binding regulatory factor involved in the control of MHC class II gene expression. RFX2 is a structurally very similar protein with identical DNA binding features. A member of the family of RFX factors is affected in an autosomal recessive disease, MHC class II deficient combined immunodeficiency (CID), caused by a defect in a trans-acting regulatory factor controlling MHC class II gene expression. In situ hybridization with 3H-labeled RFX1 cDNA has allowed us to identify two distinct targets on the short arm of chromosome 19 (19p13.1 and 19p13.2-p13.3). With the use of biotinylated genomic cosmid clones specific for RFX1 and RFX2, respectively, it was then possible to localize RFX1 at 19p13.1 and RFX2 at 19p13.2-p13.3. These two regulatory genes are thus assigned to a region of high gene density and RFX1 is close to another DNA-binding factor, LYL1.

Chromosome Mapping↗
PubMedDate not supplied

Identification, inheritance, and linkage of B-G-like and MHC class I genes in cranes.

We identified B-G-like genes in the whooping and Florida sandhill cranes and linked them to the major histocompatibility complex (MHC). We evaluated the inheritance of B-G-like genes in families of whooping and Florida sandhill cranes using restriction fragment patterns (RFPs). Two B-G-like genes, designated wcbg1 and wcbg2, were located within 8 kb of one another. The fully sequenced wcbg2 gene encodes a B-G IgV-like domain, an additional Ig-like domain, a transmembrane domain, and a single heptad domain typical of alpha-helical coiled coils. Patterns of restriction fragments in DNA from the whooping crane and from a number of other species indicate that the B-G-like gene families of cranes are large with diverse sequences. Segregation of RFPs in families of Florida sandhill cranes provide evidence for genetic polymorphism in the B-G-like genes. The restriction fragments generally segregated in concert with MHC haplotypes assigned by serological typing and by single stranded conformational polymorphism (SSCP) assays based in the second exon of the crane MHC class I genes. This study supports the concept of a long-term association of polymorphic B-G-like genes with the MHC. It also establishes SSCP as a means for evaluating MHC genetic variability in cranes.

Amino Acid Sequence↗
PubMed2000

A 39-kb sequence around a blackbird Mhc class II gene: ghost of selection past and songbird genome architecture.

To gain an understanding of the evolution and genomic context of avian major histocompatibility complex (Mhc) genes, we sequenced a 38.8-kb Mhc-bearing cosmid insert from a red-winged blackbird (Agelaius phoeniceus). The DNA sequence, the longest yet retrieved from a bird other than a chicken, provides a detailed view of the process of gene duplication, divergence, and degeneration ("birth and death") in the avian Mhc, as well as a glimpse into major noncoding features of a songbird genome. The peptide-binding region (PBR) of the single Mhc class II B gene in this region, Agph-DAB2, is almost devoid of polymorphism, and a still-segregating single-base-pair deletion and other features suggest that it is nonfunctional. Agph-DAB2 is estimated to have diverged about 40 MYA from a previously characterized and highly polymorphic blackbird Mhc gene, Aph-DAB1, and is therefore younger than most mammalian Mhc paralogs and arose relatively late in avian evolution. Despite its nonfunctionality, Agph-DAB2 shows very high levels of nonsynonymous divergence from Agph-DAB1 and from reconstructed ancestral sequences in antigen-binding PBR codons-a strong indication of a period of adaptive divergence preceding loss of function. We also found that the region sequenced contains very few other unambiguous genes, a partial Mhc- class II gene fragment, and a paucity of simple-sequence and other repeats. Thus, this sequence exhibits some of the genomic streamlining expected for avian as compared with mammalian genomes, but is not as densely packed with functional genes as is the chicken Mhc.

Amino Acid Sequence↗
PubMed2000

MHC class I gene expression and regulation.

Major histocompatibility complex (MHC) is a conglomerate of genes that play an important role in recognition of self and nonself. These genes are under tight control. In this review we have discussed the transcription processes regulating MHC gene expression. Various biological or chemical modulators can modulate MHC gene expression. The promoter region of class I genes can be activated through several pathways. Hence, these genes are not typical "domestic" genes. Extensive studies on regulation of MHC class I expression, using transfection techniques and transgenic animal models, have resulted in identification of various cis-acting sequences involved in positive and negative regulation of class I genes. Work is in progress to identify the transacting proteins that bind to these sites and to delineate the mechanisms that regulate constitutive and inducible expression of class I genes in normal and diseased cells. It has been seen that various biological molecules (IFN, GM-CSF, IL-2) and other chemicals up-regulate the MHC expression. If the exact mechanisms are known by which the expression of class I genes is up regulated, the efforts can be made to balance the beneficial and toxic effects of biological molecules with one another, which may facilitate the use of combination of these molecules in subpharmacological doses (to eliminate toxicity) for early and better management of neoplastic diseases, as it is well-known that during malignancy MHC gene expression is down-regulated. In the future, the use of transgenic and knockout mice will be useful in acquiring a better understanding, which may further help in cancer therapy.

Animals↗
PubMed1993

Regulation of class II MHC gene expression by the inducible anti-sense RNA in transgenic mice.

We have established a gene regulatory system in mice by the inducible anti-sense RNA. We have generated transgenic mice carrying the anti-sense DNA composed of the class II MHC gene under the control of the human metallothionein IIa gene promoter. The detectable amount of anti-sense RNA was constitutively produced in spleen and bone marrow from transgenic mice and the amount in spleen was increased about fivefold by the stimulation of mice with heavy metal ions. We have previously reported that the reduction of class II MHC molecules on early B lineage cells by the anti-sense RNA results in delay of their development in the bone marrow culture. The early B cell development was slightly delayed in the culture from the transgenic mice. This delay was augmented in the culture by the addition of heavy metal ions in proportion to its concentration. These results suggest that the inducible anti-sense RNA reduces the expression of class II MHC molecules on B lineage cells.

Animals↗