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PubMed1991

Independent gene duplications, not concerted evolution, explain relationships among class I MHC genes of murine rodents.

It has been claimed that class I MHC loci are homogenized within species by frequent events of interlocus genetic exchange ("concerted evolution"). Evidence for this process includes the fact that certain rat class I loci (including RT1.A) located centromeric to class II and class III are more similar to each other than to the mouse K locus (also centromeric to class II/class III). However, a phylogenetic analysis showed that the rat RT1.A locus is in fact orthologous to the mouse K1 pseudogene (also centromeric to class II/class III). Thus, two independent events of translocation of genes centromeric to class II/class III have occurred in the history of the murine rodents, at least one of which (involving the ancestor of RT1.A and K1) occurred prior to the divergence of rat and mouse. It was also found that the rat nonclassical class I gene RT.BM1 is orthologous to the mouse nonclassical gene 37d. These results argue that interlocus genetic exchange does not occur at a rate sufficient to cause within-species homogenization of class I MHC loci.

Animals↗
PubMed2004

Comparative genomics of the Mill family: a rapidly evolving MHC class I gene family.

Mill (MHC class I-like located near the leukocyte receptor complex) is a novel family of class I genes identified in mice that is most closely related to the human MICA/B family. In the present study, we isolated Mill cDNA from rats and carried out a comparative genomic analysis. Rats have two Mill genes orthologous to mouse Mill1 and Mill2 near the leukocyte receptor complex, with expression patterns similar to those of their mouse counterparts. Interspecies sequence comparison indicates that Mill is one of the most rapidly evolving class I gene families and that non-synonymous substitutions occur more frequently than synonymous substitutions in its alpha 1 domain, implicating the involvement of Mill in immune defenses. Interestingly, the alpha 2 domain of rat Mill2 contains a premature stop codon in many inbred strains, indicating that Mill2 is not essential for survival. A computer search of the database identified a horse Mill-like expressed sequence tag, indicating that Mill emerged before the radiation of mammals. Hence, the failure to find Mill in human indicates strongly that it was lost from the human lineage. Our present work provides convincing evidence that Mill is akin to the MICA/B family, yet constitutes a distinct gene family.

Amino Acid Sequence↗
PubMed2005

Haplotype characterization of transcribed ovine major histocompatibility complex (MHC) class I genes.

The ovine major histocompatibility complex (MHC) remains poorly characterized compared with those of other livestock species. Molecular genetic analysis of the bovine MHC has revealed considerable haplotype and allelic diversity that earlier serological analysis had not detected. To develop cellular and molecular tools to support development of vaccines against intracellular pathogens of sheep, we have undertaken a molecular genetic analysis of four distinct ovine MHC haplotypes carried by two heterozygous Blackface rams. We have identified 12 novel class I transcripts and used a class I sequence-specific genotyping system to assign each of these transcripts to individual haplotypes. Using a combination of phylogenetic analysis, haplotype and transcript expression data, we identified at least four distinct polymorphic class I MHC loci, three of which appear together in a number of combinations in individual haplotypes. The haplotypes were further characterized at the highly polymorphic Ovar-DRB1 locus, allowing selection of the progeny of the two founder rams for the establishment of an MHC-defined resource population.

Amino Acid Sequence↗
PubMed1990

The regulation of exogenous and endogenous class I MHC genes in a human tumor cell line, K562.

Previous studies have implied the existence of a trans-dominant intracellular repressor able to down-regulate the expression of the entire family of class I MHC genes in the genome of the K562 erythroleukemia cell line. This study demonstrates, however, that the transfection of human or murine class I genes into K562 cells leads to the cell surface expression of the transfected MHC gene product in all situations, even when several kilobases of 5' flanking sequence were included in the transfected genes. The endogenous cellular class I MHC genes remained repressed in the transfected cells. These findings suggest that repression of class I MHC gene expression in K562 may not be mediated predominantly by a trans-dominant repressor of MHC gene expression; rather, other more complex regulatory influences might exist.

Gene Expression Regulation↗
PubMed2005

Evolution by recombination and transspecies polymorphism in the MHC class I gene of Xenopus laevis.

The patterns of major histocompatibility complex (MHC) evolution involve duplications, deletions, and independent divergence of loci during episodes punctuated by natural selection. Major differences in MHC evolution among taxa have previously been attributed to variation in linkage patterns of class I and class II MHC genes. Here we characterize patterns of evolution in the MHC class Ia gene of Xenopus laevis in terms of polymorphism, recombination, and extent of transspecies polymorphism. We also compare these patterns to see if a correlation exists with linkage or separation of the MHC class I and class II regions as seen in amphibians and teleost fishes. In X. laevis, we find high levels of polymorphism. Also, genetic exchange is relatively frequent and occurs in intron II, reshuffling allelic forms of exons 2 and 3. Evolutionary relationships among class I alleles show an intermingling of alleles from divergent Xenopus species rather than a species-specific clustering. Results indicate that the patterns of evolution are similar to those found in salmonid fishes and are different from the mode of evolution seen in primates. Similar patterns of class Ia evolution in salmonid fishes and X. laevis suggest that nonlinkage of class I and class II regions alone is insufficient to explain some patterns of MHC evolution in salmonids.

Animals↗
PubMed1992

Transcription of class II MHC gene by interferon-gamma in FRTL-5 cells.

The intracellular mechanism by which interferon-gamma induces the expression of class II major histocompatibility complex (MHC) antigen in nonlymphoid cells is not clear. The effect of recombinant rat interferon-gamma (IFN-gamma), and cycloheximide on the expression of class II MHC gene was studied using the techniques of immunocytochemical staining and northern blot analysis. IFN-gamma induced de novo transcription of class II MHC gene and class II MHC antigen expression on the cell surface. Cycloheximide did not inhibit IFN-gamma-induced class II MHC antigen expression in a dose-dependent manner indicating translational blockade. These results suggest that IFN-gamma induces class II MHC antigen expression via de novo transcription of class II MHC gene leading to synthesis of new class II MHC molecule.

Animals↗
PubMed1986

Human MHC class III genes, Bf and C4. Polymorphism, complotypes and association with MHC class I genes in the Finnish population.

Electrophoretically detected genetic polymorphism of human MHC class III genes, factor B (Bf) and complement C4A and C4B, was studied in the Finnish population. Bf alleles were determined in a panel of sera from 70 unrelated individuals. The common Bf alleles, Bf*S and Bf*F, had frequencies of 73% and 26%, respectively. Only in 1 individual was another allele, Bf*F1, detected. The frequencies of the C4A and C4B alleles were based on studies of 254 unrelated individuals. In this panel, five different alleles were detected at the C4A locus and four at the C4B locus. At both loci an allele without a gene product, i.e. a 'null' allele, was observed with high frequency, 11% for C4A 'null' and 17% for C4B 'null'. The association of complotypes to HLA haplotypes was analyzed in 70 chromosomes. The most common combination, defined by class I and class III alleles, was HLA-B7-S31 (13%), followed by HLA-B35-F20 (8.4%) and HLA-B8-S03 (7.1%). Some HLA-B specificities, for example B15, B27 and B40, were associated with a variety of complotypes. The importance of complotyping in HLA genetics is discussed.

Complement C4↗
PubMed1994

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

Polymorphism of the bovine DRB, DQA, DQB, DYA, DOB and DIB genes was investigated using restriction fragment length polymorphism (RFLP) analysis, isoelectric focusing (IEF), class II serology and polymerase chain reaction (PCR) based typing techniques. The simultaneous application of multiple typing techniques and the characterization of multiple genes resulted in a greatly enhanced picture of the bovine class II regions. Thirty-eight class IIa (DR-DQ) and 5 class IIb (DYA-DOB-DIB) haplotypes were defined. It was found that IEF types were associated with DRB3 polymorphism defined by DRB3 PCR-RFLP and DRB3 microsatellite PCR. Serologically defined polymorphism was associated with distinct molecular/IEF motifs and, therefore, DR and DQ specificities could be tentatively distinguished. Although the DR and DQ genes are tightly linked, neither DR nor DQ typing defined all of the class IIa region polymorphism. Furthermore, even the most powerful DRB3 typing technique, DRB3 PCR-RFLP, failed to detect all expressed DRB3 polymorphism. All detected DRB3 polymorphism could, however, be distinguished with a combination of two molecular techniques: DRB3 PCR-RFLP and DRB3 microsatellite PCR. RFLP typing with transmembrane probes detected significantly less polymorphism than typing with cDNA or exon probes. However, the transmembrane probes were useful because they were locus specific. The presence of only 5 of 12 possible class IIb haplotypes was unexpected and indicates that the DYA, DOB and DIB genes are tightly linked.

Animals↗
PubMed1994

Evidence for retinoblastoma protein (RB) dependent and independent IFN-gamma responses: RB coordinately rescues IFN-gamma induction of MHC class II gene transcription in noninducible breast carcinoma cells.

The class II major histocompatibility (MHC) genes encode cell surface heterodimers that present processed antigen to CD4 positive T-cells. The class II genes are expressed constitutively on B-cells and can be induced by IFN-gamma on a variety of other cell types. Because the class II genes are aberrantly expressed on many mesenchymal tumors, which are frequently defective for the retinoblastoma tumor suppressor protein (RB), we investigated the role of RB in the regulation of HLA-DR and -DP. The RB defective breast carcinomas cell line, MDA-468-S4 (S4), as well as S4 subclones reconstituted with RB coding sequences under the control of a zinc inducible promoter, were treated with IFN-gamma and examined for DR and DP expression. Surface DR is not inducible in S4 cells, but inducibility is rescued by RB. DP is only slightly inducible in S4, but inducible to a much higher level in the RB positive subclones of S4. IFN-gamma induction of DR and DP mRNAs are correspondingly dependent on RB. IFN-gamma receptors are present on S4 cells, and the guanylate binding protein and ICAM-1 genes respond to IFN-gamma, ruling out the possibility that all IFN-gamma signal transduction pathways are defective in S4 cells. These data indicate RB regulates the coordinate response of class II genes to IFN-gamma. Possible roles for RB in this process are discussed, as well as the role of the class II-noninducible phenotype in tumor rejection.

Breast Neoplasms↗
PubMed2002

Evidence for an ancient selective sweep in the MHC class I gene repertoire of chimpanzees.

MHC class I molecules play an essential role in the immune defense against intracellular infections. The hallmark of the MHC is its extensive degree of polymorphism at the population level. However, the present comparison of MHC class I gene intron variation revealed that chimpanzees have experienced a severe repertoire reduction at the orthologues of the HLA-A, -B, and -C loci. The loss of variability predates the (sub)speciation of chimpanzees and did not effect other known gene systems. Therefore the selective sweep in the MHC class I gene may have resulted from a widespread viral infection. Based on the present results and the fact that chimpanzees have a natural resistance to the development of AIDS, we hypothesize that the selective sweep was caused by the chimpanzee-derived simian immunodeficiency virus (SIVcpz), the closest relative of HIV-1, or a closely related retrovirus. Hence, the contemporary chimpanzee populations represent the offspring of AIDS-resistant animals, the survivors of a HIV-like pandemic that took place in the distant past.

Animals↗
PubMed1988

Limited polymorphism of both classes of MHC genes in four different species of the Balkan mole rat.

We analyzed the restriction fragment length polymorphism of class I and class II MHC genes in DNA from 20 individuals belonging to the four different species of the complex of species of Balkan mole rats Spalax leucodon captured at four different localities in Yugoslavia. All populations were tested with four restriction enzymes and one conserved mouse probe for each of the two classes of MHC genes. The probes employed detect either limited polymorphism of class I genes or lack of polymorphic bands containing class II genes. Of the two other subterranean rodents that have been studied, four karyotype forms of the Israeli mole rat show polymorphism in both classes of MHC genes similar to the one found in all other mammals (Nizetić et al. 1985), and the Syrian hamster shows limited polymorphism of class I genes and high polymorphism of class II genes (McGuire et al. 1985). Balkan mole rats belong to a new group in this respect, different from all mammals studied so far, since they apparently show limited polymorphism of both classes of MHC genes.

Animals↗
PubMed1998

Structure of MHC class I and class II cDNAs and possible immunodeficiency linked to class II expression in the Mexican axolotl.

Despite the fact that the axolotl (Ambystoma spp. a urodele amphibian) displays a large T-cell repertoire and a reasonable B-cell repertoire, its humoral immune response is slow (60 days), non-anamnestic, with a unique IgM class. The cytotoxic immune response is slow as well (21 days) with poor mixed lymphocyte reaction stimulation. Therefore, this amphibian can be considered as immunodeficient. The reason for this subdued immune response could be an altered antigenic presentation by major histocompatibility complex (MHC) molecules. This article summarizes our work on axolotl MHC genes. Class I genes have been characterized and the cDNA sequences show a good conservation of non-polymorphic peptide binding positions of the alpha chain as well as a high diversity of the variable amino acids positions, suggesting that axolotl class I molecules can present numerous antigenic epitopes. Moreover, class I genes are ubiquitously transcribed at the time of hatching. These class I genes also present an important polylocism and belong to the same linkage group as the class II B gene; they can be reasonably considered as classical class Ia genes. However, only one class II B gene has been characterized so far by Southern blot analysis. As in higher vertebrates, this gene is transcribed in lymphoid organs when they start to be functional. The sequence analysis shows that the peptide binding region of this class II beta chain is relatively well conserved, but most of all does not present any variability in the beta 1 domain in inbred as well as in wild axolotls, presuming a limited antigenic presentation of few antigenic epitopes. The immunodeficiency of the axolotl could then be explained by an altered class II presentation of antigenic peptides, putting into question the existence of cellular co-operation in this lower vertebrate. It will be interesting to analyze the situation in other urodele species and to determine whether our observations in axolotl represent a normal feature in urodele amphibians. But already two different models in amphibians, Xenopus and axolotl, must be considered in our search for understanding immune system and MHC evolution.

Ambystoma mexicanum↗
PubMed1998

Inhibition of VLA-4 and up-regulation of TIMP-1 expression in B16BL6 melanoma cells transfected with MHC class I genes.

The effect of MHC class I gene transfection on the metastatic properties of B16BL6 melanoma cells was investigated. BL6-8 melanoma cells transfected with H-2Kb or H-2Kd, but not H-2Dd or H-2Ld, genes showed a dramatic reduction in their ability to generate experimental metastases in immunosuppressed CB6F1 mice. This observation suggested that some changes in the metastatic phenotype may have been induced in the H-2K- transfected melanoma cells. Analyses of adhesive and invasive properties of BL6-8 melanoma cells transfected with H-2 class I genes have been performed. We found that the loss of metastatic properties in the H-2Kb or H-2Kd gene-transfected melanoma cells was associated with reduced adherence to endothelial cells, laminin and collagen IV, decreased ability to form homotypic cell aggregates and with a complete loss of VLA-4 integrin expression. In addition, BL6-8 melanoma cells transfected with H-2K genes demonstrated reduced ability to invade Matrigel that paralleled up-regulation of TIMP-1 expression. Incubation of untransfected BL6-8 clone or B16F1 cells with 5-azacytidine similarly resulted in up-regulation of TIMP-1, suggesting that the changes in methylation of TIMP-1 gene could be responsible for TIMP-1 expression in the H-2K-transfected BL6-8 melanoma cells. Transfection of BL6-8 cells with the H-2Dd/Ld genes did not affect their adhesive and invasive properties. Previously we reported that reduction in the metastatic properties of the H-2Kb transfected cells was associated with alterations in cell surface carbohydrates with appearance of alpha-galactosyl epitopes and reduction in cell surface sialylation. The present data indicate that, in addition to changes in cell surface carbohydrates, reduction in adhesive properties and up-regulation of TIMP-1 may be responsible for the observed loss of metastatic potential of BL6-8 cells transfected with the H-2K genes.

Animals↗
PubMed1999

A mechanism for selective induction of 2'-5' oligoadenylate synthetase, anti-viral state, but not MHC class I genes by interferon-beta in neurons.

Interferon-inducible expression of major histocompatibility class I genes has previously been found to be quantitatively and functionally deficient in neurons compared to other somatic cells or other neural cell types including astrocytes. This deficiency is a key component of neuronal immunoprivilege during viral infections of the CNS. To the contrary, in the present study, induction of functional antiviral state by IFN-beta in neurons compared to astrocytes was found to be highly efficient with respect to both viral replication and protection from cytopathic effects. A candidate antiviral state gene found to be efficiently induced in neurons by IFN-beta was the 2'-5'-oligoadenylate synthetase (OAS) gene. Unlike MHC class I genes, induction of OAS was comparable in neurons and astrocytes indicating differential expression in these neural cell types. Analysis of OAS gene promoter activity indicated that induction of the OAS gene by IFN-beta was dependent on a region containing the interferon stimulated responsive element (ISRE). In contrast, a construct containing the MHC class I-ISRE responsible for induction by IFN-beta in astrocytes was not responsive to IFN-beta in neurons. Therefore, transcription factor binding to the OAS- and MHC-ISREs was analyzed. While the OAS and MHC Class I site bound equal amounts of the transcriptional repressor IRF-2, the OAS-ISRE preferentially interacted with the transcriptional activator ISGF3 in response to IFN-beta. Further, unlike neurons, upregulation of MHC class I genes in astrocytes was related to binding of IRF-1 instead of IRF-2 to the MHC-ISRE. It is proposed that selective activation of anti-viral state genes compared to MHC class I genes by IFN-beta in neurons is mediated by preferential induction and binding of ISGF3 to anti-viral state gene ISREs but not the MHC-ISRE.

2',5'-Oligoadenylate Synthetase↗
PubMed1995

At least four MHC class I genes are transcribed in the horse: phylogenetic analysis suggests an unusual evolutionary history for the MHC in this species.

Nineteen horse MHC class I specificities have been serologically identified previously at a single locus (ELA-A), and two other specificities appear to be coded at other loci. Biochemical studies indicate that there are at least two expressed loci. In order to establish the number of transcribed horse MHC class I genes, we made a cDNA library from a heterozygous animal (ELA-A3/A7), and screened for positive clones using a bovine class I probe. More than 200 class I clones were isolated in this way, and so far seven unique full length sequences have been identified. All of the sequences are predicted to code for surface expressed, functional molecules. The number of different sequences identified demonstrate that at least four genes are transcribed, although variations in transmembrane length (which is generally conserved in class I loci) suggest that five genes could be represented. Evolutionary analysis of these sequences (and two additional sequences known to represent different horse class I loci) reveals no firm relationships, such that the division between the different loci cannot be discerned. These results suggest an unusual evolutionary history for the horse MHC, the precise nature of which may be revealed only following further cross-species comparisons.

Amino Acid Sequence↗
PubMed1990

Identification of sequences responsible for positive and negative regulation by E1A in the promoter of H-2Kbm1 class I MHC gene.

The mechanism of transcriptional regulation of the H-2Kbm1 major histocompatibility complex (MHC) class I gene by adenovirus type 12 E1A (Ad12-E1A) was studied in transfected rat embryonal fibroblasts. Results of long-term expression of the chloramphenicol acetyl transferase (CAT) gene placed under the control of the 5'-flanking region of the mouse MHC class I gene. H-2Kbm1, and the results of nuclear run-on transcription assays, yield evidence for both positive and negative regulation of H-2Kbm1 by E1A gene product. Deletion studies in the H-2Kbm1 promoter region revealed that a proximal 58 bp upstream sequence (-194 to -136, relative to the cap site) and a distal 316 bp sequence (-1837 to -1521) respectively contribute to positive and negative regulation mediated by the E1A gene product. Both regulatory elements of MHC class I gene promoter region are responsible for the differential expression of the H-2Kbm1 gene in Ad12 transformed cells. A nuclear factor binding to the negative element has been detected only in extracts derived from cells expressing Ad12-E1A.

Adenovirus Early Proteins↗
PubMed1991

Hyperexpression of interferon-gamma-induced MHC class II genes associated with reorganization of the cytoskeleton.

Class I and class II major histocompatibility complex (MHC) gene products are key recognition units in the induction and regulation of the immune response. Expression of class I and class II may be constitutive or inducible by cytokines such as interferon-gamma (IFN-gamma). A key step in the induction of MHC genes is recognition of IFN-gamma by its membrane receptor. The work described here examines the regulation of the occupied IFN-gamma receptor by the cytoskeleton. To do this the authors have used the fungal metabolites dihydrocytochalasin B (DHCB) and cytochalasin D (CD), substances that bind to actin filaments and thereby disrupt the cytoskeleton. The authors have studied the effect of DHCB and CD on IFN-gamma-induced MHC gene expression in 143 B cells, a human osteosarcoma-derived cell line. Herein the authors demonstrate that alterations in the cytoskeleton induced by DHCB and CD can lead to increases in IFN-gamma-induced MHC gene expression. Dihydrocytochalasin B added up to 3 hours after IFN-gamma results in a threefold to sixfold increase in levels of class II mRNA while producing minimal enhancement of class I gene expression. In contrast, glyceraldehyde-3-phosphate dehydrogenase mRNA expression was unaltered by IFN-gamma or by the cytochalasins. The increased amount of class II mRNA can be accounted for by a concomitant increase in transcription rate of this gene. Studies using 125I-IFN-gamma demonstrate that the occupied IFN-gamma receptor associates with a Triton X-100 insoluble fraction of 143 B cells and that DHCB and CD markedly inhibit this association. The results described here provide evidence that is consistent with the hypothesis that the activity of the occupied IFN-gamma receptor may be modulated by interactions with the cytoskeleton of the cell. This receptor may be one of a group of plasma membrane receptors that are sensitive to the action of cytochalasins after ligand binding.

B-Lymphocytes↗