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PubMedDate not supplied

Cytomegalovirus infection amplifies class I major histocompatibility complex expression on cultured human endothelial cells.

Cytomegalovirus infection, a common complication in immunosuppressed graft recipients, bears an adverse impact on graft survival. Cytomegalovirus enhances the expression of the monotypic determinants of the class I major histocompatibility complex molecule by the endothelium, possibly rendering the endothelial cells more immunogenic and prone to attack by the allogeneic lymphocytes. In the present study, we focused on the effect of cytomegalovirus on the endothelial cell expression of different class I genes, on the relation between the extent of endothelial cell infection and the class I effect, and on the time course of the class I changes induced by the cytomegalovirus infection. Cytomegalovirus infection of primary cultures of human umbilical vein endothelial cells augmented the expression of the A2, A3, and B7 class I major histocompatibility complex genes when compared with uninfected cells. beta 2 microglobulin upregulation by the infected cells paralleled the changes in specific class I expression; this effect was significant only after 7 days after infection. Double immunocytochemical staining and fluorescence-activated cell sorter analysis revealed that the class I enhancement was uniform throughout the umbilical vein endothelial cell monolayer and not restricted to the cells that expressed cytomegalovirus early or late antigens. Ultraviolet-inactivated supernatants from infected umbilical vein endothelial cell did not increase class I expression on uninfected cells. In conclusion, cytomegalovirus might affect graft survival by amplifying the changes in class I expression beyond the sites of viral replication.

Antibody Specificity↗
PubMed1996

Chromosomal localization of the proteasome Z subunit gene reveals an ancient chromosomal duplication involving the major histocompatibility complex.

Proteasomes are the multi-subunit protease thought to play a key role in the generation of peptides presented by major histocompatibility complex (MHC) class I molecules. When cells are stimulated with interferon gamma, two MHC-encoded subunits, low molecular mass polypeptide (LMP) 2 and LMP7, and the MECL1 subunit encoded outside the MHC are incorporated into the proteasomal complex, presumably by displacing the housekeeping subunits designated Y, X, and Z, respectively. These changes in the subunit composition appear to facilitate class I-mediated antigen presentation, presumably by altering the cleavage specificities of the proteasome. Here we show that the mouse gene encoding the Z subunit (Psmb7) maps to the paracentromeric region of chromosome 2. Inspection of the mouse loci adjacent to the Psmb7 locus provides evidence that the paracentromeric region of chromosome 2 and the MHC region on chromosome 17 most likely arose as a result of a duplication that took place at an early stage of vertebrate evolution. The traces of this duplication are also evident in the homologous human chromosome regions (6p21.3 and 9q33-q34). These observations have implications in understanding the genomic organization of the present-day MHC and offer insights into the origin of the MHC.

Amino Acid Sequence↗
PubMed1986

Intracellular transport blockade caused by disruption of the disulfide bridge in the third external domain of major histocompatibility complex class I antigen.

The third external domain of major histocompatibility class I antigens has a highly conserved disulfide bridge between cysteine-203 and cysteine-259. To elucidate the functional significance of this disulfide bridge, we have produced a mutant H-2Ld gene by site-directed mutagenesis in which the codon for cysteine-203 is changed to a codon for serine, which is unable to form a disulfide bridge. The mutant H-2Ld gene was introduced into mouse L cells and its expression has been studied. No measurable expression of the H-2Ld antigen was detected on the cell surface of the transformants by antibody-binding assays. However, a large quantity of the mutant H-2Ld antigen was found in the cytoplasm of the transformants as observed by immunoprecipitation of metabolically labeled lysate and by immunocytochemistry of membrane-permeabilized cells, using an antibody specific for the first external domain of the H-2Ld antigen. The mutant antigen was glycosylated and associated, at least in part, with beta 2-microglobulin. Subcellular fractionation experiments indicated that the transport of the antigen was blocked between the endoplasmic reticulum and the plasma membrane. It is concluded that structural integrity of the third external domain is a prerequisite for intracellular transport of class I antigens. On the basis of these findings we suggest that the domain structure containing the disulfide bridge serves as a signal structure necessary for receptor-mediated intracellular transport and that this requirement is the evolutionary basis for high conservation of similar structures present throughout the immunoglobulin supergene family.

Animals↗
PubMed1992

Structural analysis of the human interferon gamma receptor: a small segment of the intracellular domain is specifically required for class I major histocompatibility complex antigen induction and antiviral activity.

Mutations of the human interferon gamma (IFN-gamma) receptor intracellular domain have permitted us to define a restricted region of that domain as necessary for both induction of class I major histocompatibility complex antigen by IFN-gamma and protection against encephalomyocarditis virus. This region consists of five amino acids (YDKPH), all of which are conserved in the human and murine receptors. Tyr-457 and His-461 are essential for activity. Approximately 80% of the amino acids of the intracellular domain of the receptor is not required for major histocompatibility complex class I antigen induction or for antiviral protection against encephalomyocarditis virus. The observation that there was no protection by IFN-gamma against vesiculostomatitis virus indicates that other factors, in addition to chromosome 21 accessory factor(s), are required to generate the full complement of transduction signals from the human IFN-gamma receptor.

Amino Acid Sequence↗
PubMed2004

The S box of major histocompatibility complex class II promoters is a key determinant for recruitment of the transcriptional co-activator CIITA.

Tightly regulated expression of major histocompatibility complex (MHC) class II genes is critical for the immune system. A conserved regulatory module consisting of four cis-acting elements, the W, X, X2 and Y boxes, controls transcription of MHC class II genes. The X, X2, and Y boxes are bound, respectively, by RFX, CREB, and NF-Y to form a MHC class II-specific enhanceosome complex. The latter constitutes a landing pad for recruitment of the transcriptional co-activator CIITA. In contrast to the well defined roles of the X, X2, and Y boxes, the role of the W region has remained controversial. In vitro binding studies have suggested that it might contain a second RFX-binding site. We demonstrate here by means of promoter pull-down assays that the most conserved subsequence within the W region, called the S box, is a critical determinant for tethering of CIITA to the enhanceosome complex. Binding of CIITA to the enhanceosome requires both integrity of the S box and a remarkably stringent spacing between the S and X boxes. Even a 1-2-base pair change in the native S-X distance is detrimental for CIITA recruitment and promoter function. In contrast to current models, binding of RFX to a putative duplicated binding site in the W box is thus not required for either CIITA recruitment or promoter activity. This paves the way for the identification of novel factors mediating the contribution of the S box to the activation of MHC class II promoters.

Base Sequence↗
PubMed1992

Reptilian class I major histocompatibility complex genes reveal conserved elements in class I structure.

The polymerase chain reaction was used to isolate clones with class I major histocompatibility complex sequences from fish (carp), amphibian (axolotl), and two species of reptile (lizard and snake). The lizard and snake clones were used to isolate class I cDNA clones. All the sequences showed the expected evolutionary relatedness. The carp and axolotl clones and one lizard cDNA clone lacked the first cysteine in the alpha 3 domain which in other class I heavy chains forms an intradomain disulfide bond. A small number of amino acid residues are conserved in the class I heavy chain sequences from all five classes of vertebrates. In the first two domains they are symmetrically clustered and contribute to intra- and interdomain contacts. None of these invariant residues are at peptide-binding, T-cell receptor-interacting, or CD8-binding positions.

Amino Acid Sequence↗
PubMed1987

Class II genes of the human major histocompatibility complex. Evolution of the DP region as deduced from nucleotide sequences of the four genes.

The DP region of the human major histocompatibility complex contains two alpha genes and two beta genes. The DP alpha 1 and beta 1 genes encode the expressed DP histocompatibility antigen molecule, while the DP alpha 2 and beta 2 genes are inactive in the haplotypes examined. Here we present the sequence of the two DP beta genes and of the expressed DP alpha 1 gene. Nucleotide sequence comparisons reveal a considerably greater degree of similarity between the two beta genes than between the two alpha genes. We propose that a duplication giving rise to the DP alpha gene pair evolutionarily preceded the corresponding DP beta gene duplication. We also propose, based on the orientation of other class II gene pairs, that the original DP molecule was encoded by the DP beta 1 and DP alpha 2 genes. At some stage during the evolution of the DP region both of the two pseudogenes appear to have been expressed.

Amino Acid Sequence↗
PubMed1986

Insulin-dependent diabetes mellitus is associated with genes that map to the right of the class I RT1.A locus of the major histocompatibility complex of the rat.

Previous studies have demonstrated that the presence of at least one u-haplotype of the rat major histocompatibility complex (MHC), RT1, is a necessary but not sufficient condition for the development of overt diabetes mellitus. The present studies were undertaken to determine which portion of the RT1 gene complex is necessary for the occurrence of diabetes. We crossed hooded diabetic rats (RT1.AuBuDu) with PVGr8 rats (RT1.AaBuDu). F1 animals were mated to give 82 F2 animals and backcrossed with the hooded diabetics to produce 41 backcross animals. Diabetes occurred in animals with all three possible RT1.A genotypes. The diabetes was similar to that seen in BB rats and in hybrid strains developed from them. An immunoregulatory defect was marked by decreased percentage of peripheral blood lymphocytes staining with w3/25 monoclonal antibody, by an increased percentage of peripheral blood lymphocytes binding a mouse ascites control protein, and by decreased responsiveness of peripheral blood lymphocytes to stimulation by concanavalin A. We conclude that the u-allele of the class I A-locus gene product is not necessary for susceptibility to the development of diabetes in the rat. Therefore, either genes coding for the class II products of the u-haplotype or genes in linkage disequilibrium with these genes and mapping to the right of the A locus provide the permissive condition. Furthermore, the data suggest, but do not prove, that the u-haplotype derived from a strain remote from the BB rat can confer this susceptibility to the development of diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Specific prolongation of skin graft survival following retroviral transduction of bone marrow with an allogeneic major histocompatibility complex gene.

Engrafted allogeneic hematopoietic cells have a unique capacity to induce a state of donor-specific transplantation tolerance across major histocompatibility complex barriers. This state allows permanent acceptance of donor-type organ grafts, with otherwise normal immunocompetence. We hypothesized that introduction of allogeneic MHC genes into autologous bone marrow which is then returned to recipient mice might similarly induce specific tolerance to products of the introduced MHC genes, without the risk of graft-vs-host disease. We demonstrate here that the introduction of MHC class I Kb cDNA by retrovirus-mediated gene transfer into B10.AKM (Kk) hematopoietic cells confers specific hyporesponsiveness to allogeneic skin grafts expressing Kb.

Amino Acid Sequence↗
PubMed1998

Potent T cell activation with dimeric peptide-major histocompatibility complex class II ligand: the role of CD4 coreceptor.

The interaction of the T cell receptor (TCR) with its cognate peptide-major histocompatibility complex (MHC) on the surface of antigen presenting cells (APCs) is a primary event during T cell activation. Here we used a dimeric IEk-MCC molecule to study its capacity to activate antigen-specific T cells and to directly analyze the role of CD4 in physically stabilizing the TCR-MHC interaction. Dimeric IEk-MCC stably binds to specific T cells. In addition, immobilized dimeric IEk-MCC can induce TCR downregulation and activate antigen-specific T cells more efficiently than anti-CD3. The potency of the dimeric IEk-MCC is significantly enhanced in the presence of CD4. However, CD4 does not play any significant role in stabilizing peptide-MHC-TCR interactions as it fails to enhance binding of IEk-MCC to specific T cells or influence peptide-MHC-TCR dissociation rate or TCR downregulation. Moreover, these results indicate that dimerization of peptide-MHC class II using an IgG molecular scaffold significantly increases its binding avidity leading to an enhancement of its stimulatory capacity while maintaining the physiological properties of cognate peptide-MHC complex. These peptide-MHC-IgG chimeras may, therefore, provide a novel approach to modulate antigen-specific T cell responses both in vitro and in vivo.

Animals↗
PubMed1984

Restriction fragment polymorphisms in the major histocompatibility complex of diabetic BB rats.

DNA isolated from diabetic BB (BB/Hagedorn) rats was examined for restriction fragment length differences within the major histocompatibility complex (MHC) as compared with nondiabetic (W-subline) BB rats. Polymorphisms were detected using a mouse class I MHC gene as probe. Specifically, a 2-kb BamHI fragment was present in all the nondiabetic rats examined, but absent in the diabetic rats. Similar polymorphisms were observed with various other restriction enzymes, particularly XbaI, HindII, and SacI. There were no polymorphisms detected using either a human DR-alpha (class II antigen heavy chain) or a human DC-beta (class II antigen light chain) gene as probes. These results indicate that the BB rat diabetic syndrome may be linked to differences in class I MHC genes.

Animals↗
PubMed1990

Regulation of self-major histocompatibility complex reactive human T-cell clones.

The proliferative response of human T-lymphocyte clones, (TLC) specific for self-major histocompatibility complex (MHC) products either alone or associated with PPD epitopes are inhibited in vitro by dexamethasone (DEX) and by a non-specific inhibitory factor(s) (nsINH) produced by PPD-activated T-cells. The inhibiting effect has been investigated by preincubating autoreactive and PPD-specific TLC with nsINH or DEX. Results obtained indicate that T-lymphocytes are the target of these two immunoregulatory molecules. Moreover, the addition of exogenous recombinant interleukin 2 (rIL-2) substantially reverses the inhibition observed in both nsINH- or DEX-treated cultures.

Antigens, Bacterial↗
PubMed1994

Pulsed field gel electrophoretic analysis of the rat major histocompatibility complex class III region shows extensive inter-species conservation.

Using pulsed field gel electrophoresis (PFGE), we have examined the rat major histocompatibility complex (MHC) for the presence of a number of new class III region genes recently identified in the human MHC. We find homologous genes to the human G1, G2, G4, G7a, G9, G9a, G10, G13, G15, and G18 genes, but not the G8 gene in the rat genome, and show that these are linked to the rat TNF-alpha and C4/Slp loci. A long-range restriction map has been constructed on the basis of a PFGE analysis which demonstrates extensive co-linearity in the positions of the homologous sequences in the region between the C4/Slp and TNF loci in the rat MHC when compared with that of the human MHC class III region.

Animals↗
PubMed1981

Induced tolerance in F1 rats to anti-major histocompatibility complex receptors on parental T cells. Implications for self tolerance.

The immunogenicity of cell surface markers associated with specific anti-major histocompatibility complex (MHC) alloreactivity of rat peripheral T lymphocyte subpopulations has been demonstrated in the past by the ability of such cell populations to induce a profound and specific resistance to systemic graft-vs.-host (GVH) disease in adult rats. Our studies demonstrate that these specificity-associated anti-MHC parental strain T cell markers are also tolerogenic; if small numbers of parental strain T cells are administered to newborn F1 rats, they result in the specific inability to induce GVH resistance later on in adult life. Moreover, unlike normal animals, these F1 rats are extremely sensitive to systemic GVH disease caused by T cells from the original donor parental strain.

Animals↗
PubMed1987

Influence of the major histocompatibility complex (MHC) on the response to and expression of H-Y in rats.

The influence of the major histocompatibility complex (MHC) on the survival of H-Y-incompatible skin grafts in rats has been determined by challenging normal and previously sensitized females of various isogenic and congenic strains with male trunk or ear skin isografts. The MHC's influence on the potency of H-Y has also been evaluated by determining the survival of male parental strain ear skin grafts on sensitized (with F1 hybrid male cells) F1 hybrid females of two different MHC congenic strains. The results indicate that, as in mice, the MHC has a dual affect on H-Y; it is involved in determining the ability of females to respond to the antigen as well as influencing its potency.

Animals↗
PubMed1993

Ligation of major histocompatibility complex class II molecules mediates apoptotic cell death in resting B lymphocytes.

Class II major histocompatibility complex-encoded molecules expressed on the surface of primed B lymphocytes function as restriction elements for presentation of antigen to T lymphocytes, an interaction that ultimately leads to activation and differentiation of both cell types. The engagement of class II on a resting B cell, on the other hand, inhibits subsequent B-cell growth and activation. Our studies show that treatment of resting B lymphocytes with anti-class II antibodies, or with other agents (dibutyryl cAMP or isoproterenol) that increase intracellular levels of cAMP, results in the apoptotic death of most or all of the resting B cells. Conversely, treating cells with immobilized anti-immunoglobulin and interleukin 4, conditions known to prime cells, protects them from class II-mediated death and specifically from increases in nucleosomal fragments characteristic of apoptotic death. Freshly ex vivo activated B cells likewise are refractory to class II-mediated apoptosis. Treating B cells with anti-class II reagents causes an elevation of cAMP in resting, but not in activated, B cells. These results suggest that apoptotic death is a mechanism of prevention of nonspecific B-cell activation in the event that T-cell receptor and/or CD4 ligation of major histocompatibility complex class II occurs in the absence of antigen.

Animals↗
PubMed1992

Evolutionary stability of transspecies major histocompatibility complex class II DRB lineages in humans and rhesus monkeys.

Sequence analysis of rhesus monkey (Macaca mulatta) polymorphic second exon of major histocompatibility complex class II DRB subregion genes demonstrates the existence of at least 34 alleles. Some of these rhesus monkey alleles are very similar (or nearly identical) to HLA-DRB alleles. These data demonstrate that members of the lineages for Mhc-DRB1*03, -DRB1*04, -DRB1*10, and the loci of Mhc-DRB3, -DRB4, -DRB5, and -DRB6 predate speciation of man and rhesus monkey and were already present 25 million years ago. Calculation of evolutionary rates suggests that the various allele lineages have differential stabilities. Furthermore, the data indicate that distinct species may not have inherited or lost transspecies Mhc-DRB lineages in evolution, because several allele lineages in rhesus monkeys appear to be absent in humans and vice versa.

Alleles↗
PubMed1993

cDNA cloning and characterization of the protein encoded by RD, a gene located in the class III region of the human major histocompatibility complex.

The RD gene, initially defined in the mouse, has been mapped between the Bf and C4A genes in the human major histocompatibility complex class III region. Using the mouse cDNA as a probe, we isolated and sequenced human RD cDNA clones. The composite nucleotide sequence consisted of 1301 nucleotides, excluding a poly(A) tail at the 3' end. It contained a single open reading frame encoding a polypeptide of 380 amino acid residues with a calculated molecular mass of 42274 Da. The most striking structural feature of the deduced amino acid sequence is a region consisting entirely of 24 tandem repeats of an Arg-Asp (or Glu) dipeptide. The human RD cDNA was expressed in Escherichia coli as a fusion protein with glutathione S-transferase and used to produce antisera in rabbits. Western blot analysis and immunoprecipitation of lysates of biosynthetically labelled HeLa cells indicated that RD is a 44 kDa nuclear protein.

Amino Acid Sequence↗