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PubMed2005

Genomic characterization of MHC class I genes of the horse.

The availability of a contig of bacterial artificial chromosome (BAC) clones spanning the equine major histocompatibility complex (MHC) made possible a detailed analysis of horse MHC class I genes. Prior to this study, only a single horse MHC class I gene had been sequenced at the genomic level. Although many ( approximately 60) MHC class I cDNA sequences had been determined and published, from this information, it was not possible to determine how many class I loci are expressed in horses or to assign individual sequences to allelic series. In this study, 15 MHC class I genes were identified in BAC subclones and fully sequenced. Because the BAC library donor horse had been bred for homozygosity at the MHC, these 15 genomic clones represent distinct MHC class I genes and pseudogenes and not alleles at a smaller number of loci. For five of the genes, cDNA sequences from these loci had previously been identified. Two additional expressed class I genes were discovered, bringing the known total of different equine MHC class I genes (loci) expressed as mRNA to seven. Expression of all seven loci was detected by reverse transcriptase-polymerase chain reaction in adult, fetal, and placental tissues. The remaining eight genes were designated as pseudogenes. This work resulted in moderate expansion of the horse MHC BAC contig length, and the remaining gap was shortened. The information contained in these equine MHC class I sequences will permit comparison of MHC class I genes expressed across different horse MHC haplotypes and between horses and other mammalian species.

Alleles↗

PubMed1998

Description of two Mhc-C-related sequences in the New World monkey Saguinus oedipus.

Two new Mhc class I partial exon 1, intron 1, exon 2, intron 2 and partial exon 3 DNA sequences from the New World monkey Saguinus oedipus (Saoe) are described. These two sequences show certain Mhc-C sequence-specific changes. The only difference between these two new sequences is a productive substitution at position 152 [GCG (Ala)-->GAG (Glu)]. This change occurs in a position which in Mhc classical class I molecules affects the interaction between the peptide and the T-cell receptor. A dendrogram with Mhc sequences from different loci and different species was constructed, which clearly shows that these two new sequences cluster closer to Mhc-C sequences than to others. These data suggest that the new sequences may be related to the Mhc-C locus, and they have been named Mhc-Saoe-CR*01 and -CR*02. However, they share only a few of the conserved residues (from gorilla to human) of Mhc-C sequences, which suggests that the relationships with an ancestor of the Mhc-C lineage are very distant or that these two sequences are products of convergent evolution to perform a C locus related function. Furthermore, in the fragment of DNA sequenced, there is a loss of two invariant residues conserved in antigen-presenting molecules from reptiles to humans; thus, it is unlikely that these two Mhc-C-like sequences have an antigen-presenting function, or even that they are two alleles of a pseudogene; however, the G + C percentage (86.1%) at the third base of codons approaches that of an expressed gene in Saoe. It is concluded that Mhc molecules with C-locus characteristics existed in primates 50 million years ago and that this does not support a more recent origin of Mhc-C genes.

Alleles↗

PubMed1988

1987 Philip Levine award lecture. MHC haplotypes in biology and medicine.

(1) The MHC genes or genes within or near the MHC region are involved in the immune response. The polymorphism of the MHC loci can be used as markers for immune response because the recognition of antigens involves their interaction with the MHC antigens. Specific portions of an antigen bind to the polymorphic region of class II molecules. Identification of an MHC class II molecule with a peptide results in a lack of an immune response as a result of self-tolerance. Similarities, but not identity of these molecules, result in immune responses restricted by the variable region of the MHC (class II molecule). This also explains a high repertoire of alloreactive T-cells. (2) By virtue of their restriction of the immune response to foreign antigens that cross-react with self-antigen, the MHC genes or genes within or near the MHC region show an association with the autoimmune diseases. (3) Several alleles encoded by different MHC loci are found nonrandomly associated at the population level. The resulting haplotypes could predict identity of segments of chromosome 6 among unrelated persons. (4) Matching of nonrandomly associated alleles (extended haplotypes) can serve potentially for selection of donors for allotransplantation, especially of bone marrow. (5) Several diseases associated with alleles of the class II MHc loci, and at least in the case of the lack of response to hepatitis B vaccine, have been shown to be more significantly associated with extended haplotypes. In such cases, the extended haplotypes may contain a susceptibility MHC allele of a known MHC locus or may contain a susceptibility gene of a yet undiscovered locus.

Allergy and Immunology↗

PubMed1996

Regulation of MHC class II genes: lessons from a disease.

Precise regulation of major histocompatibility complex class II (MHC-II) gene expression plays a crucial role in the control of the immune response. A major breakthrough in the elucidation of the molecular mechanisms involved in MHC-II regulation has recently come from the study of patients that suffer from a primary immunodeficiency resulting from regulatory defects in MHC-II expression. A genetic complementation cloning approach has led to the isolation of CIITA and RFX5, two essential MHC-II gene transactivators. CIITA and RFX5 are mutated in these patients, and the wild-type genes are capable of correcting their defect in MHC-II expression. The identification of these regulatory factors has furthered our understanding of the molecular mechanisms that regulate MHC-II genes. CIITA was found to be a non-DNA binding transactivator that functions as a molecular switch controlling both constitutive and inducible MHC-II expression. The finding that RFX5 is a subunit of the nuclear RFX-complex has confirmed that a deficiency in the binding of this complex is indeed the molecular basis for MHC-II deficiency in the majority of patients. Furthermore, the study of RFX has demonstrated that MHC-II promoter activity is dependent on the binding of higher-order complexes that are formed by highly specific cooperative binding interactions between certain MHC-II promoter-binding proteins. Two of these proteins belong to families of which the other members, although capable of binding to the same DNA motifs, are probably not directly involved in the control of MHC-II expression. Finally, the facts that CIITA and RFX5 are both essential and highly specific for MHC-II genes make possible novel strategies designed to achieve immunomodulation via transcriptional intervention.

Animals↗

PubMed1997

An immunocytochemical study of MHC class I expression on human Langerhans cells and melanocytes.

Classical MHC class I glycoproteins (HLA-A, B, and C) present endogenous cytosolic peptide antigen fragments to CD8-positive T-cells. CD8-positive T-cell recognition and destruction of virus-infected cells are dependent on adequate cellular MHC class I expression. Constitutive MHC class I expression is ubiquitous, but known to be deficient on specific differentiated cell types which include hepatocytes, neurones, chondrocytes and myocytes. Although enabling assessment of MHC class I expression on individual cells, limitations of immunocytochemistry were encountered with this assessment on Langerhans cells and melanocytes. These dispersed intraepidermal cells were obscured by adjacent keratinocytes in sections immunostained for MHC class I glycoproteins. Initiatives designed to resolve the issue have included immunoelectron microscopy, cell culture techniques, and animal bone marrow chimera models. Despite the elegance of these techniques, the issue of MHC class I expression on Langerhans cells and melanocytes remains unresolved. In this immunocytochemical study, an alternative strategy was based upon the recognized deficiency of epithelial MHC class I expression within pilosebaceous adnexal units. Langerhans cells and melanocytes were therefore studied within this microenvironment of deficient MHC class I expression, using monomorphic and polymorphic MHC markers. Langerhans cells and melanocytes were demonstrated within pilosebaceous units of scalp skin by immunocytochemistry. Differentiation markers OKT6 (CD1a) and TMH1 defined Langerhans cells and melanocytes, respectively. Monomorphic MHC markers W6/32 and TAL IB5 defined invariant epitopes of HLA class I and II, respectively. Polymorphic MHC class I markers defined the HLA-Bw4 and HLA-Bw6 supertypic determinants. Constitutive MHC class I expression was shown to be deficient on Langerhans cells and melanocytes.

Hair Follicle↗

PubMed2000

Identification and characterization of the antigen presenting cell in rat autoimmune myocarditis: evidence of bone marrow derivation and non-requirement for MHC class I compatibility with pathogenic T cells.

In the rat, autoimmune myocarditis can be produced by the infusion of activated myosin peptide specific, CD4(+), class II restricted, effector T cells. Whether antigen presenting cells (APCs), which interact with these effector T cells in the heart, are a fixed population of cells (resident dendritic, macrophage, or endothelial cells), or a dynamic bone marrow derived population has not yet been demonstrated in vivo. To study this question, bone marrow chimeras were generated using inbred Brown Norway (BN) rats, which are resistant to autoimmune myocarditis, and transplanting them after lethal irradiation with (LewisxBN) F1 bone marrow. BN rats differ at both MHC loci from the susceptible inbred Lewis rats. Two months after bone marrow transplantation, chimeric animals received Lewis T cells specific for a myocarditogenic peptide antigen. To characterize the cardiac APCs, immunohistochemistry using a battery of antibodies including Lewis-specific and broadly reactive antibodies for both MHC class I and class II, was performed on chimeric hearts, with and without infused Lewis T cells, and non-transplanted BN control hearts.All chimeric rats infused with allogeneic (Lewis), anti-cardiac myosin peptide effector T cells displayed the lesions of myocarditis. Myocarditis was not present in non-transplanted BN controls given either Lewis or F1 derived myocarditogenic T cells, nor in chimeric animals which did not receive myocarditogenic T cells, thus excluding graft vs host disease as the explanation for the inflammation in chimeric hearts with myocarditis. Marrow derived cells expressing both Lewis class I and class II MHC molecules were demonstrated on perivascular cells in the myocardium of all chimeric animals, and on infiltrating cells in chimeric animals with myocarditis. Cells expressing Lewis-specific MHC antigens were not detected in the non-transplanted BN controls. Furthermore, immunohistochemistry using broadly reactive antibodies demonstrated MHC class II on perivascular cells with a dendritic morphology in all hearts but not on endothelial cells or cardiac myocytes. These results support the hypothesis that in vivo, cardiac APCs which result in MHC class II restricted, T cell induced myocarditis are a dynamic bone marrow derived population and not a fixed population. In order to address the potential requirement of MHC class I for the initiation of autoimmune myocarditis, myocarditogenic T cells derived from either Lewis or DA(RP) rats were infused into a member of the other strain. These strains share common MHC class II genes but differ at the MHC class I loci. Myocarditis identical to that produced in the syngeneic animal was successfully transferred by the MHC class I mismatched T cells, but only after the recipient animal's native immune system was mildly suppressed. These results further support the primary role for professional antigen presentation via MHC class II restriction to the effector T cells at the initiation of autoimmune myocarditis in the heart.Together, these experiments confirm that activated effector T cells, in order to produce myocarditis, require MHC class II compatible APCs in the heart, that these APCs are bone marrow derived, and will endogenously take up and present local antigens in the target organ after bone marrow reconstitution.

Adoptive Transfer↗

PubMed1991

The relationship between MHC restricted and allospecific T cell recognition.

The existence in the mature T cell repertoire of a high precursor frequency of cells which recognise allogeneic MHC molecules appears to contradict the well-established dogma of positive selection for self MHC restriction. In order to explore the possibility that alloreactive cells are derived from a fraction of the repertoire that is not self-MHC-restricted, the contribution of in vivo-primed T cells to "primary" alloresponses was investigated. Peripheral blood T cells were separated into virgin and memory populations by sorting for low and high levels of LFA-3 expression, and their proliferative responses to MHC incompatible stimulator cells was quantitated. The results demonstrated that approximately half of a "primary" alloresponse is contributed by previously primed T cells that, by definition, must be self-MHC restricted. Furthermore it was possible to define the original MHC-restricted antigen specificity of two T cell clones raised against the allospecific HLA-DR1 from a DR4Dw4/DRw13DW19 responder. The emerging consensus view that anti-MHC alloreactive T cells, like antigen-specific T cells, are specific for MHC/peptide complexes, and have a parental self-MHC restriction, begs a structural explanation. Comparison of multiple DR beta 1 domain sequences reveals that DR molecules fall into groups that have extensive homology in the residues on the beta 1 domain alpha-helix that are predicted to point up towards the T cell receptor (histotopic), and thus to determine MHC restriction. Given that the DR alpha chain is invariant this creates the possibility that anti-DR allorecognition can mimic self-restricted recognition. Within these groups of histotopically similar DR products there are multiple differences in the peptide-binding residues that lie on the inner aspects of the alpha-helix or on the floor of the antigen-binding groove. As a consequence, it is predicted that a different array of endogenous peptides will be bound, due to determinant selection. Thus, allorecognition within these groups may result from the recognition of endogenous peptides that are bound by stimulator but not by responder MHC products, seen in a self-restricted manner. In combinations where histotopic similarity does not exist, allorecognition may be best explained by the chance occurrence of a receptor selected for intermediate affinity for thymically expressed MHC molecules having a higher affinity for an allogeneic histotope. Such a receptor would have been deleted in a thymus expressing the allospecificity, but would be perceived as "safe" in the absence of this MHC product.

Antigen-Antibody Reactions↗

PubMed2002

Rat nigral xenografts survive in the brain of MHC class II-, but not class I-deficient mice.

We have examined the role of the indirect pathway of antigen recognition and T cells in neural xenografts rejection by using major histocompatibility complex (MHC) class II-deficient mice as xenograft recipients. Dissociated embryonic ventral mesencephalic tissue from Sprague-Dawley rats was stereotaxically injected as a cell suspension into the striatum of MHC class II-deficient adult mice as well as MHC class I-deficient and wild-type mice as controls. All of the MHC class II-deficient mice had surviving grafts in the striatum 4 weeks post-grafting. In contrast, only a few of the MHC class I-deficient mice exhibited very small grafts and none of the wild-type mice had any surviving grafts. The mean number of surviving transplanted dopamine neurons in the MHC class II-deficient group was significantly larger than that observed in the other two groups. Moderate levels of MHC class I antigen expression were seen in the transplantation sites of some animals in the MHC class II-deficient group. No helper or cytotoxic T cells were observed infiltrating into the graft sites of this group. However, there were markedly increased levels of expression of MHC class I and class II antigens, and a number of T cells infiltrating in the graft sites in both the MHC class I-deficient and wild-type groups. These results show that rat embryonic nigral tissue can survive transplantation in the brain of the MHC class II-deficient mice for at least 4 weeks without any overt signs of rejection, suggesting that the indirect pathway of foreign antigen recognition mediated by host MHC class II molecules and helper T cells plays an important role in the rejection responses to intracerebral xenografts.

Animals↗

PubMed1998

Analysis of graft-versus-host disease (GVHD) and graft rejection using MHC class I-deficient mice.

GVHD is a major complication in allogeneic bone marrow transplantation (BMT). MHC class I mismatching increases GVHD, but in MHC-matched BMT minor histocompatibility antigens (mH) presented by MHC class I result in significant GVHD. To examine the modification of GVHD in the absence of cell surface MHC class I molecules, beta2-microglobulin-deficient mice (beta2m(-/-)) were used as allogeneic BMT recipients in MHC- and mH-mismatched transplants. Beta2m(-/-) mice accepted MHC class I-expressing BM grafts and developed significant GVHD. MHC (H-2)-mismatched recipients developed acute lethal GVHD. In contrast, animals transplanted across mH barriers developed indolent chronic disease that was eventually fatal. Engrafted splenic T cells in all beta2m(-/-) recipients were predominantly CD3+alphabetaTCR+CD4+ cells (15-20% of all splenocytes). In contrast, CD8+ cells engrafted in very small numbers (1-5%) irrespective of the degree of MHC mismatching. T cells proliferated against recipient strain antigens and recognized recipient strain targets in cytolytic assays. Cytolysis was blocked by anti-MHC class II but not anti-CD8 or anti-MHC class I monoclonal antibodies (MoAbs). Cytolytic CD4+ T cells induced and maintained GVHD in mH-mismatched beta2m(-/-) mice, supporting endogenous mH presentation solely by MHC class II. Conversely, haematopoietic beta2m(-/-) cells were unable to engraft in normal MHC-matched recipients, presumably due to natural killer (NK)-mediated rejection of class I-negative cells. Donor-derived lymphokine-activated killer cells (LAK) were unable to overcome graft rejection (GR) and support engraftment.

Animals↗

PubMed2002

Absence of donor MHC antigen expression ameliorates chronic kidney allograft rejection.

BACKGROUND: In previous studies, we have demonstrated that a subset of mouse kidney allografts has prolonged survival without any immunosuppressive treatment. Chronic rejection (CR) develops in these long surviving grafts. The pathologic features of CR in this model are similar to CR in human kidney grafts. METHODS: To explore the role of donor major histocompatibility complex (MHC) antigens in the development of CR, we performed vascularized kidney transplants using kidneys from donor mice that lack expression of both MHC class I and II antigens (MHC-/-). RESULTS: Survival was significantly improved in recipients of MHC-/- allografts. This enhanced survival was associated with higher glomerular filtration rate (GFR) in MHC-/- allografts (4.92 +/- 0.54 cc/min/kg) compared to controls (2.19 +/- 0.63 cc/min/kg; P = 0.004). The typical histologic features of CR were markedly reduced in MHC-/- allografts. Semiquantitative histopathological scores for MHC-/- grafts (13.3 +/- 2.1) were significantly lower than in control allografts (19.0 +/- 1.0; P = 0.04). Along with this improvement in structural abnormalities, significantly fewer CD4+ T (38.3 cells/mm(2) vs. 75.0 cells/mm(2); P = 0.008), CD8+ T cells (38.7 vs. 96 cells/mm(2), respectively; P = 0.008) and macrophages (60 vs. 134 cells/mm(2), respectively; P = 0.04) infiltrated MHC-/- allografts compared to controls. The levels of intragraft cytokine mRNA expression also were reduced in MHC-/- allografts compared to control allografts. Finally, serum alloantibodies were virtually undetectable in recipients of MHC-/- kidney allografts. CONCLUSIONS: Cell surface expression of donor MHC antigens promotes the development of CR. Donor antigen expression promotes the accumulation of infiltrating cells in the graft and the development of donor specific alloantibodies. Abrogation of these responses is associated with improved graft survival and reduced CR in MHC-/- grafts.

Animals↗

PubMed2006

The quantitative assessment of MHC II on thymic epithelium: implications in cortical thymocyte development.

The dynamics of MHC II expression in various thymic stromal compartments was investigated. By including MHC II in flow cytometry in addition to the cortical CDR1, medullary UEA-1 and pan-epithelial G8.8 markers, thymic stromal compartments were subdivided into at least six different populations. The total level of surface and cytoplasmic MHC II from fresh cortical thymic epithelial cells (cTECs) of normal mouse was as high as MHC II levels in medullary thymic epithelial cells (mTECs). MHC II levels as well as the percentages and cycling status of thymic epithelial cell populations expressing MHC II were not static during post-natal development, suggesting quantitative flexibility in presenting signals to the developing thymocytes. Although there was no evidence found for regulation of surface MHC II levels by TCR or by IFN-gamma, the absence of class II transactivator reduced both the level of MHC II expression and the number of MHC II+ cells. Surprisingly, MHC II molecules were found to form distinct focal aggregates on the surface of cTEC but not mTEC using high-resolution analysis by confocal microscopy. Moreover, these aggregates were formed independent of TCR or TCR-bearing cells in the thymus. These aggregates could potentially generate a functional unit containing a much higher local MHC II concentration to yield a higher avidity interaction. We discuss possible mechanisms for positive selection by weak interactions in the presence of such preformed MHC II aggregate units in cTEC.

Animals↗

PubMed1994

The role of infectious disease, inbreeding and mating preferences in maintaining MHC genetic diversity: an experimental test.

In house mice, and probably most mammals, major histocompatibility complex (MHC) gene products influence both immune recognition and individual odours in an allele-specific fashion. Although it is generally assumed that some form of pathogen-driven balancing selection is responsible for the unprecedented genetic diversity of MHC genes, the MHC-based mating preferences observed in house mice are sufficient to account for the genetic diversity of MHC genes found in this and other vertebrates. These MHC disassortative mating preferences are completely consistent with the conventional view that pathogen-driven MHC heterozygote advantage operates on MHC genes. This is because such matings preferentially produce MHC-heterozygours progeny, which could enjoy enhanced disease resistance. However, such matings could also function to avoid genome-wide inbreeding. To discriminate between these two hypotheses we measured the fitness consequences of both experimentally manipulated levels of inbreeding and MHC homozygosity and heterozygosity in semi-natural populations of wild-derived house mice. We were able to measure a fitness decline associated with inbreeding, but were unable to detect fitness declines associated with MHC homozygosity. These data suggest that inbreeding avoidance may be the most important function of MHC-based mating preferences and therefore the fundamental selective force diversifying MHC genes in species with such mating patterns. Although controversial, this conclusion is consistent with the majority of the data from the inbreeding and immunological literature.

Animals↗

PubMed1994

MHC antigen presentation on the surface of hepatocytes: modulation during and after hypoxic stress.

Presentation and recognition of MHC antigen on the surface of cells is the basic process of initiating rejection and distinguishing "self and not self". This is considered to begin when a transplanted organ is reperfused with the blood of the recipient. In this study, the modulation of MHC I antigen presentation during preservation was investigated in a cell culture model using primary hepatocyte cultures of male Wistar rats. By incubation with different preservation solutions used in clinical transplantation, expression of the MHC antigen was observed during cold hypoxia. Primary hepatocyte cultures were isolated from male Wistar rats by a modified Seglen technique and seeded to glass slides, thus obtaining monolayer cultures. After 1 day of resting the cultures were incubated under different conditions using Krebs Henseleit solution (KH), Euro-Collins solution (EC), HTK solution of Bretschneider (HTK) and University of Wisconsin solution (UW) as incubation media. The conditions of incubation were warm normoxia (37 degrees C, pO2 100 mm Hg) and cold hypoxia (4 degrees C, pO2 < 0.1 mm Hg), which is the main condition of organ preservation. Incubation time was 6 h. Before starting the incubation reference cultures were fixed and every 60 min several cultures were withdrawn from the experiment and fixed also. MHC expression was studied by staining the cultures with monoclonal antibodies against rat MHC class I and class II. As expected, MHC class II was not present on the surface of hepatocytes, while MHC class I was demonstrated on the controls as well as on the cultures that were incubated using KH and EC independent of temperature and hypoxia or normoxia. At the end of the incubation they were still positive but not as strong as in the beginning. During incubation using HTK and UW, MHC I was not detectable at all phases of the experiment. In conclusion, hypoxic stress did not completely eradicate MHC I expression in rat hepatocytes, while the composition of the preservation medium may result in a hepatocyte surface negative for MHC I. Hydroxyethylstarch may be the substance in UW that covers the MHC antigen, while in HTK, mannitol or the histidine complex may play the same role. MHC negativity of the cells of a preserved transplant is another reason for the benefit of UW or HTK.

Animals↗

PubMed2005

Impact of MHC class II incompatibility on localization of mononuclear cell infiltrates to the bronchiolar compartment of orthotopic lung allografts.

Chronic pathological changes in transplanted lungs are unique because they center on the airways. We examined the relative role of MHC class I and II antigens in causing bronchial pathology in orthotopic lung transplants to rats maintained on cyclosporin A (CsA). Transplants mismatched for MHC class II antigens had significantly more peri-bronchiolar infiltrates than MHC class I incompatible transplants. No significant increase in infiltrates was found in lung transplants incompatible for MHC class I plus II antigens compared to MHC class II antigens alone. Immunohistochemistry demonstrated that MHC class II antigen expression was confined to macrophages in MHC class I incompatible transplants, but was upregulated on bronchial epithelium in transplants with MHC class II incompatibilities. Vascular endothelium was notably devoid of MHC class II antigen expression in all transplants. However, both peri-bronchial and peri-vascular infiltrates were frequently cuffed by alveolar macrophages and type II pneumocytes that expressed MHC class II antigens. PCR analysis demonstrated that IFN-gamma and regulated on activation, normal T cells expressed and secreted (RANTES) were upregulated in MHC class II incompatible transplants. Thus, MHC class II incompatible orthotopic lung transplants in rats maintained on CsA immunosuppression undergo a bronchiolcentric upregulation of alloantigens.

Animals↗

PubMed1997

Capture and processing of exogenous antigens for presentation on MHC molecules.

Class I and class II MHC molecules bind peptides during their biosynthetic maturation and provide a continuously updated display of intracellular and environmental protein composition, respectively, for scrutiny by T cells. Receptor-mediated endocytosis, phagocytosis, and macropinocytosis all contribute to antigen uptake by class II MHC-positive antigen-presenting cells. Capture of antigenic peptides by class II MHC molecules is facilitated because antigen catabolism and class II MHC maturation take place in the same compartments or in communicating compartments of the endosome/lysosome system. These class II MHC-rich, multivesicular endosomes receive incoming antigen and can support not only antigen processing and class II MHC peptide loading but also the export of peptide/class II MHC complexes to the cell surface. A balance between production and destruction of antigenic peptides is achieved by the activity of local proteases and may be influenced by binding of antigen to other proteins both prior to the onset of processing (e.g. antibodies) and during antigen unfolding (e.g. MHC molecules). T cell determinants that can be released for MHC binding without a substantial processing requirement may be able to utilize a distinct minor population of cell surface class II MHC molecules that become available during peripheral recycling. Although peptides derived from exogenous protein sources are usually excluded from presentation on class I MHC molecules, recent evidence shows that this embargo may be lifted in certain professional antigen-presenting cells to increase the spectrum of antigens that may be displayed on class I MHC.

Animals↗

PubMed2006

Regulation of antisense RNA expression during cardiac MHC gene switching in response to pressure overload.

Hypertension has been shown to cause cardiac hypertrophy and a shift in myosin heavy chain (MHC) gene expression from the faster alpha- to slower beta-MHC isoform. The expression of the beta- and alpha-MHC pre-mRNAs, mRNAs, as well as the newly discovered antisense beta-RNA were analyzed in three regions of the normal control (NC) and 12-day pressure-overloaded (AbCon) hearts: the left ventricle apex, left ventricle base, and the septum. The RNA analyses in the AbCon heart targeted both the 5' and the 3' ends of each RNA molecule. beta-MHC mRNA expression significantly increased relative to control in all three regions, regardless of the target site (5' or 3' end). In contrast, beta-MHC pre-mRNA expression in the AbCon heart depended on the site of the measurement (5' vs. 3' end). For example, whereas the pre-mRNA did not change when targeted at the 3' end (last intron), it increased significantly in the AbCon heart when measurement targeted the 5' end (2nd intron) of the 25-kb molecule. Analyses of the antisense beta-RNA revealed that its expression in the AbCon heart was significantly decreased relative to control regardless of its measurement site. A negative correlation was observed between the beta-mRNA expression and the antisense beta-RNA (P < 0.05), suggesting an inhibitory role of antisense RNA on the sense beta-MHC gene expression. In contrast, a positive correlation was observed between the antisense beta-RNA and the alpha-MHC pre-mRNA (P < 0.05). This latter observation along with the alpha-MHC gene position relative to that of the beta-antisense suggest that the alpha-MHC sense and beta-antisense transcription are coregulated likely via common intergenic regulatory sequences. Our results suggest that the increased beta-MHC expression in the AbCon heart not only is the result of increased beta-MHC transcription but also involves an antisense beta-RNA regulation scheme. Although the exact mechanism concerning antisense regulation is not clear, it could involve modulation of both transcriptional activity of the beta-MHC gene and posttranscriptional processing.

Animals↗

PubMed1999

Donor MHC and adhesion molecules in transplant arteriosclerosis.

Transplant-associated arteriosclerosis remains an obstacle to long-term graft survival. To determine the contribution to transplant arteriosclerosis of MHC and adhesion molecules from cells of the donor vasculature, we allografted carotid artery loops from six mutant mouse strains into immunocompetent CBA/CaJ recipients. The donor mice were deficient in either MHC I molecules or MHC II molecules, both MHC I and MHC II molecules, the adhesion molecule P-selectin, intercellular adhesion molecule (ICAM)-1, or both P-selectin and ICAM-1. Donor arteries in which ICAM-1, MHC II, or both MHC I and MHC II were absent showed reductions in neointima formation of 52%, 33%, and 38%, respectively, due primarily to a reduction in smooth muscle cell (SMC) accumulation. In P-selectin-deficient donor arteries, neointima formation did not differ from that in controls. In donor arteries lacking both P-selectin and ICAM-1, the size of the neointima was similar to that in those lacking ICAM-1 alone. In contrast, neointima formation increased by 52% in MHC I-deficient donor arteries. The number of CD4-positive T cells increased by 2.8-fold in MHC I-deficient arteries, and that of alpha-actin-positive SMCs by twofold. These observations indicate that ICAM-1 and MHC II molecules expressed in the donor vessel wall may promote transplant-associated arteriosclerosis. MHC I molecules expressed in the donor may have a protective effect.

Animals↗

PubMed1992

Expression of type-specific MHC isoforms in rat intrafusal muscle fibers.

Myosin heavy chain (MHC) expression by intrafusal fibers was studied by immunocytochemistry to determine how closely it parallels MHC expression by extrafusal fibers in the soleus and tibialis anterior muscles of the rat. Among the MHC isoforms expressed in extrafusal fibers, only the slow-twitch MHC of Type 1 extrafusal fibers was expressed along much of the fibers. Monoclonal antibodies (MAb) specific for this MHC bound to the entire length of bag2 fibers and the extracapsular region of bag1 fibers. The fast-twitch MHC isoform strongly expressed by bag2 and chain fibers had an epitope not recognized by MAb to the MHC isoforms characteristic of developing muscle fibers or the three subtypes (2A, 2B, 2X) of Type 2 extrafusal fibers. Therefore, intrafusal fibers may express a fast-twitch MHC that is not expressed by extrafusal fibers. Unlike extrafusal fibers, all three intrafusal fiber types bound MAb generated against mammalian heart and chicken limb muscles. The similarity of the fast-twitch MHC of bag2 and chain fibers and the slow-tonic MHC of bag1 and bag2 fibers to the MHC isoforms expressed in avian extrafusal fibers suggests that phylogenetically primitive MHCs might persist in intrafusal fibers. Data are discussed relative to the origin and regional regulation of MHC isoforms in intrafusal and extrafusal fibers of rat hindlimb muscles.

Aging↗