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PubMed1986

[Immunohistologic analysis of chronic obstructive sialadenitis. I. Changes in the expression of antigens of the major histocompatibility complex].

In the course of electrolyte sialadenitis progressing towards obstructive sialadenitis, changes in the epithelial expression of antigens of the major histocompatibility complex (MHC) occur even before morphological alterations and inflammatory cells can be detected. Class I antigens are enhanced and induced, and Class II antigens are induced. These changes begin focally. Only the expression of HLA-A,B,C and -DR in acinar epithelium is linked to the close vicinity of lymphohistiocytic infiltrates. In later stages of the disease the foci tend to fuse and antigenic changes are pronounced in areas of fibrosclerosis and parenchymal atrophy. The altered MHC antigen expression induced by chronical saliva congestion probably represents an important part of the postulated "immunoreaction in the duct epithelium" supposedly giving rise to this type of immunosialadenitis.

Adult↗
PubMed1984

Orientation of loci within the human major histocompatibility complex by chromosomal in situ hybridization.

We have determined the localization and orientation of two genetic probes within the human major histocompatibility complex by chromosomal in situ hybridization. Our data indicate that a cloned genomic probe cross-hybridizing to HLA-A, -B, and -C heavy chain loci is homologous to sequences located on chromosome 6 at band p21.3 while a subclone of the genomic HLA-DR alpha-chain gene corresponding to the nonpolymorphic p34 protein is homologous to sequences in band 6p21.1. Our data suggest that this technique may permit the estimation of map distances between linked gene loci, assuming a uniform frequency of map units in the human genome. The relative positions of these genes was confirmed in a mother and son carrying a chromosome rearrangement involving 6p and 14p in which the sequences hybridizing to a DR alpha-chain genomic clone were found at the distal end of the 6p--chromosome [der(6)] while the sequences hybridizing to the HLA-A, -B, -C alpha-chain probe were found in the 14p+ chromosome [der(14)].

Chromosome Mapping↗
PubMed2005

Sequence of the canine major histocompatibility complex region containing non-classical class I genes.

We have sequenced a segment of 150,102 nucleotides of canine major histocompatibility complex (MHC) DNA, corresponding to the junction of the class I and class III regions. The distal portion contained five class III genes including two tumor necrosis factor genes and the proximal portion contained five genes or pseudogenes belonging to the class I region. The order of the class III region genes was conserved as in the porcine and human MHC regions. The order of the class Ib loci from the proximal side outwards was DLA-53, DLA-12a, DLA-64, stress-induced phosphoprotein-1, followed by DLA-12. Only DLA-64 and DLA-12 display an overall predicted protein sequence compatible with the expression of membrane-anchored glycoproteins. The other class 1b loci do not appear to be functional by sequence analysis. In all, these 10 genes spanned 24% of the total sequence. The remaining 76% comprised of a number of non-coding and repetitive DNA elements including long interspersed nuclear element (LINE) fragments, short interspersed nuclear elements (SINE), and microsatellites.

Animals↗
PubMed1978

Primary structure of murine major histocompatibility complex alloantigens: amino acid sequence studies of the cyanogen bromide fragments of the H-2Kb glycoprotein.

Radiochemical microtechniques have been used in the amino acid sequence analysis of five major CNBr fragments of the glycoprotein specified by the murine major histocompatibility complex gene H-2k(b). These fragments have been tentatively aligned and represent the NH(2)-terminal 80% of the intact molecule. All amino acids except Asp, Asn, and Gln have been assigned in 128 out of 149 possible positions in the NH(2)-terminal portions of each of these fragments. These assignments, which represent approximately 50% of the total sequence from these fragments, are listed below in the order of their alignment in the intact H-2K(b) molecule: IIIn, -PHSLRYFVTAVSRP(G)L(G)(E)PRYM; IIIa, EVGYV--TEFVRF-S-AE(A)PRYEPR(A)--M; Ib, E-EGPEYWERET-KAK(G)-E-SFR--LRTLL(G)YY--TK; Ia, AALITK-KWE-AGEAERLRAYLEGTC-E-L; Ic, ELVETRPAG-GTF-KWAS-VVPLGKE-YY(T). The unassigned positions represented by dashes in the above sequences may be tentatively assigned as Asp, Asn, or Gln. The NH(2)-terminal sequence obtained for the H-2K(b) molecule was compared to the limited sequence information available for other major histocompatibility complex gene products. An 84% homology (16 of 19 residues) to the H-2K(q) and H-2K(k) molecules, which are identical to one another in the positions compared, was observed. A similar comparison with 28 of the 31 NH(2)-terminal residues of HLA-B7 indicated 68% homology. Furthermore, significant homology was observed between H-K(b) and HLA-B7 in a region of glycosylation, which occurs between positions 85 and 100 in the two molecules.

Amino Acid Sequence↗
PubMed2003

Major histocompatibility complex class I is downregulated in Marek's disease virus infected chicken embryo fibroblasts and corrected by chicken interferon.

The major histocompatibility complex (MHC) is a part of the immune system which presents epitopes of intracellular antigens on the cell surface. MHC molecules have receptor-ligand binding affinities with T lymphocytes, permitting the latter to detect foreign intracellular infectious agents. Some pathogens, such as herpesviruses, have developed strategies of evading the host response by MHC. This pressure on the immune system brought, in turn, improvements in the antigen-presenting pathway, for example through the effect of interferon (IFN), which can upregulate MHC expression. The main objective of this work was on the one hand, to determine the abilities of three strains of Marek's disease virus (MDV), a chicken herpesvirus, in interfering with the expression of MHC class I molecules in chicken embryo fibroblasts. On the other hand, we analyzed the ability of IFN to reinstate this important immune capability to the infected cells. Our results show that only an oncogenic serotype 1 strain of MDV (RB1B) was able to markedly decrease MHC class I expression, and that addition of IFN reversed this MDV effect.

Animals↗
PubMed1994

Combination of cyclosporine and splenectomy suppresses interleukin-6 production and major histocompatibility complex class II expression and prolongs cardiac xenograft survival.

Although untreated Lewis rat recipients will reject a transplanted hamster heart in 3 days, accommodation of heart xenografts can be induced by treatment with cyclosporine and splenectomy, improving graft survival to greater than 50 days. Both humoral and cellular arms of the immune system may be involved in the mechanisms responsible for the prolongation of graft survival. Our objective was to study the impact of cyclosporine and splenectomy on the deposition of antibodies, complement, or both within the graft. We also compared the cellular component of inflammation in treated recipients with that in untreated controls. Inbred male Lewis rats given cyclosporine 15 mg/kg per day were splenectomized 2 days after they had received heterotopic heart transplants from Golden Syrian hamsters. Recipients of syngeneic grafts or untreated xenografts served as controls. Plasma interleukin-6 activity was measured in a standard proliferation assay with 7TD1 hybridoma cells. Deposition of immunoglobulin M, immunoglobulin G, and complement in heart tissue was evaluated by immunofluorescence. Cells infiltrating the graft that expressed major histocompatibility complex class II antigens were identified by immunohistochemical staining with OX6 antibodies. In xenograft recipients receiving immunosuppression, interleukin-6 activity, immunoglobulin M and complement deposition were significantly reduced, graft infiltration was mild, and cardiac function was good compared with the results in those without treatment 3 and 10 days after implantation. Inflammatory cells expressing major histocompatibility complex class II antigens were significantly reduced in immunosuppressed xenograft recipients (2.8 +/- 0.4 cells/high power field) compared with those in xenogeneic controls (9.5 +/- 0.6 cells/high power field; p < 0.0005). The significant decrease in deposition of humoral components (immunoglobulin M and complement), interleukin-6 plasma levels, and expression of major histocompatibility complex class II antigens by inflammatory cells within the nonrejecting grafts suggests that the synergistic benefit of cyclosporine and splenectomy depends on the attenuation of both cellular and humoral mechanisms of xenograft rejection.

Animals↗
PubMed1979

Selective expression of antibody classes and contact sensitivity affected by genes in the major histocompatibility complex.

This report describes IgM, IgG and IgE antibody and contact sensitivity responses of strains of mice congenic at the major histocompatibility complex (MHC) to skin painting with picryl chloride or oxazolone. B10 had low responses of all classes to picryl chloride. This was also reflected by the DNA synthesis occurring in their draining lymph nodes after painting. B10BR were high responders to picryl chloride for all classes but B10A and B10D2 were high responders for all classes except IgE. This presents evidence that genes in the MHC can selectively control antibody classes. The contact sensitivity response of the congenics to oxazolone confirmed the low previously described responsiveness of B10 mice. Antibody responses to oxazolone (agglutinin and reagin) were low for all congenics with B10 backgrounds.

Agglutinins↗
PubMed2001

Human antibodies to major histocompatibility complex alloantigens mediate lysis and neutralization of HIV-1 primary isolate virions in the presence of complement.

Cellular proteins, including major histocompatibility complex (MHC) class I and class II antigens, are incorporated into the membrane of HIV-1 when virions bud from infected cells. Experiments were performed to determine whether human sera that contained MHC class I and/or class II antibodies would lyse or neutralize a primary isolate of HIV. These results demonstrate that in the presence of complement, sera from some alloimmunized persons mediated significant anti-viral activity against an HIV primary isolate. Both lysis and neutralization of virus were observed. The antiviral effects were complement dependent because heat inactivation eliminated most anti-viral effects. Antiviral activity mediated by sera containing MHC alloantibodies in the presence of complement was > or = activity due to sera from HIV-infected persons as reported in this and a previous study. High levels of antibodies to both MHC class I and class II were present in sera that mediated the highest levels of anti-viral activity. Absorption of serum with platelets (which express class I but not class II antigens) substantially reduced their lytic activity. These studies suggest that MHC antibodies mediate potent anti-viral effects on primary isolates of HIV and support the possibility that deliberately alloimmunizing humans might protect against HIV infection.

Antibodies↗
PubMed2001

Oxidative stress induces the expression of the major histocompatibility complex in murine tumor cells.

The effect of t-butyl hydroperoxide (t-BOOH) on the induction of the Major Histocompatibility Complex (MHC) class I genes has been studied in two cell clones (B9 and G2) of the methylcholanthrene-induced murine fibrosarcoma GR9. These two clones were selected based on their different biological and biochemical behavior specially related to their tumor induction capability when injected into a BALB/c mouse. t-BOOH (0.125 mM) induced the expression of H-2 molecules in both cell clones. In B9 cell clone, in which MHC basal expression is very low or absent, t-BOOH significantly induced H-2Kd, H-2Dd and H-2Ld molecules. In G2 cell clone the expression of MHC class I genes was also enhanced by the xenobiotic, the effect being especially significant on the H-2Ld molecule which is not expressed under basal conditions. H-2 molecules expression was accompanied by the activation of the transactivator factor NF kappa B. These results suggest that oxidative stress may modulate the antigen expression of tumor cells and thus the immune response of the host organism. Basal levels of oxidative parameters, such as anti-oxidant enzymes, malondialdehyde (MDA) and the DNA damaged base 8-hydroxy-2'-deoxyguanosine (8-OHdG), showed differences between the two fibrosarcoma cell clones.

3T3 Cells↗
PubMed1994

Role of methylation in placental major histocompatibility complex antigen expression and fetal loss.

The purpose of this study was to determine the role of gene methylation on major histocompatibility complex (MHC) antigen expression in the rat placenta, specifically: 1) the constitutive suppression of labyrinthine class I genes and of all class II genes, 2) genomic imprinting of class I genes, and 3) the amount of fetal loss in relationship to gene methylation. Placentas from all four mating combinations, or a subset thereof, of the inbred DA and WF strains of rats were studied simultaneously through 1) molecular assessment of their levels of methylation at various stages of pregnancy and changes in methylation after treatment with 5-azacytidine and 2) immunohistochemical determination of their MHC class I and class II antigen expression. Treatment with 5-azacytidine caused demethylation of both class I and class II genes, the level depending upon the method of administration of the drug. Treatment with 5-azacytidine did not, however, alter the expression of either the class I or class II antigens. Hence, demethylation is not involved in the constitutive suppression of labyrinthine class I genes or that of all placental class II genes, and it is not involved in the genomic imprinting of placental class I genes. The effect of 5-azacytidine on fetal loss is due to its direct cellular effects and not to an immunological mechanism.

Animals↗
PubMed2004

Expression of Major Histocompatibility Complex class I and II in a case of Neospora caninum myositis in a dog.

Neosporosis was diagnosed in a 2-month-old dog by indirect immunofluorescence antibody test (IFAT) and confirmed by means of histopathology and immunohistochemistry. The associated myositis was characterized by Major Histocompatibility Complex expression on some muscle fibres. This finding indicates an immunological activation, of the muscle cells that, acquiring Major Histocompatibility Complex expression, may, in some way, contribute to antigen presentation. A possible role of these glycoproteins in the pathogenesis of Neospora-associated myositis is discussed.

Animals↗
PubMed2005

Accessory molecules in the assembly of major histocompatibility complex class I/peptide complexes: how essential are they for CD8(+) T-cell immune responses?

Assembly of major histocompatibility complex (MHC) class I molecules in the endoplasmic reticulum is a highly coordinated process that results in abundant class I/peptide complexes at the cell surface for recognition by CD8(+) T cells and natural killer cells. During the assembly process, a number of chaperones and accessory molecules, such as transporter associated with antigen processing, tapasin, ER60, and calreticulin, assist newly synthesized class I molecules to facilitate loading of antigenic peptides and to optimize the repertoire of surface class I/peptide complexes. This review focuses on the relative importance of these accessory molecules for CD8(+) T-cell responses in vivo and discusses reasons that may help explain why some CD8(+) T-cell responses develop normally in mice deficient in components of class I assembly, despite impaired antigen presentation.

ATP-Binding Cassette Transporters↗
PubMed2001

G6b, a novel immunoglobulin superfamily member encoded in the human major histocompatibility complex, interacts with SHP-1 and SHP-2.

The G6b gene, located in the class III region of the human major histocompatibility complex, has been suggested to encode a putative receptor of the immunoglobulin superfamily. Genomic sequence information was used as a starting point to clone the corresponding cDNA. Reverse transcriptase polymerase chain reaction showed that expression of the gene is restricted to certain hematopoietic cell lines including K562, Molt 4, and Jurkat. Several splice variants were detected, varying only in their C-terminal parts. One of the potential membrane-bound isoforms contained two immunoreceptor tyrosine-based inhibitory motifs in its cytoplasmic tail. Four of the isoforms were expressed as epitope-tagged proteins in the cell lines K562 and COS-7. The two splice isoforms lacking the hydrophobic transmembrane segment were secreted from the cell. Glycosidase treatment of the four recombinant proteins provided evidence for N- and O-glycosylation. Immunofluorescence studies indicated that the spliced isoforms having a transmembrane segment were directed to the cell membrane. The G6b isoform containing two immunoreceptor tyrosine-based inhibitory motifs in its cytoplasmic tail was found to be phosphorylated on tyrosine residues after pervanadate treatment of cells and, subsequently, interacts with the SH2-containing protein-tyrosine phosphatases SHP-1 and SHP-2. Mutagenesis studies showed that phosphorylation of tyrosine 211 is critical for the interaction of G6b with SHP-1 and SHP-2.

Amino Acid Sequence↗
PubMed1984

The nucleotide sequence of the murine I-E beta b immune response gene: evidence for gene conversion events in class II genes of the major histocompatibility complex.

We have determined the DNA sequence of the murine I-E beta b immune response gene of the major histocompatibility complex (MHC) of the C57BL/10 mouse and compared it with the sequence of allelic I-E and non-allelic I-A genes from the d and k haplotypes. The polymorphic exon sequences which encode the first extracellular globular domain of the E beta domain show approximately 8% nucleotide substitutions between the E beta b and E beta d alleles compared with only approximately 2% substitutions for the intron sequences. This suggests that an active mechanism such as micro gene conversion events drive the accumulation of these mutations in the polymorphic exons. The fact that several of the nucleotide changes are clustered supports this hypothesis. The E beta b and E beta k genes show approximately 2-fold fewer nucleotide substitutions than the E beta d/E beta b pair. The A beta bm12, a mutant I-A beta b gene from the C57BL/6 mouse, has been shown to result from three nucleotide changes clustered in a short region of the beta 1 domain, which suggests that a micro gene conversion event caused this mutation. We show here that the E beta b gene is identical to the non-allelic A beta bm12 DNA sequence in the mutated region and suggest, therefore, that the E beta b gene was the donor sequence for this intergenic transfer of genetic information. Diversity in class II MHC genes appears therefore to be generated, at least in part, by the same mechanism proposed for class I genes: intergenic transfer of short DNA regions between non-allelic genes.

Alleles↗
PubMed1999

Monoclonal antibodies against maternal major histocompatibility complex class I molecules induce rapid abortion in mice.

PROBLEM: The role of antibodies against fetal or maternal antigens in maintaining or losing pregnancy is not clear. METHOD OF STUDY: Term-pregnant mice were injected with monoclonal antibodies against only fetal or fetal and maternal major histocompatibility complex class I molecules. The development of pregnancy was then followed. RESULTS: Antibodies against maternal, but not fetal, major histocompatibility complex class I molecules induced abortion in mice. The abortion occurred 6-8 hr after the administration of autoreactive antibodies. The abortion could only be induced after the formation of placenta. Antibodies against tumor necrosis factor-alpha could not prevent or postpone the abortion. Extensive bleeding has been detected in the placenta of aborting mice 3 hr after the administration of the antibodies. CONCLUSIONS: This study indicates that autoreactive antibodies present risk for pregnancy and that the damage leading to abortion induced by such antibodies most likely occurs at the maternal side of placenta.

Abortion, Spontaneous↗
PubMed2006

Immune tolerance to self-major histocompatibility complex class II antigens after bone marrow transplantation: role of regulatory T cells.

The immune system undergoes rapid reconstitution after autologous or syngeneic bone marrow transplantation with the re-establishment of tolerance to self-antigens. Administration of drugs such as cyclosporine that inhibit thymic-dependent clonal deletion disrupts the reconstitution of the immune system. In the absence of a peripheral regulatory T cells eliminated by the preparative regimen, systemic autoimmunity with pathology similar to graft-versus-host disease often develops. Moreover, the resolution of autoaggression is dependent on the reconstitution of CD4+ regulatory T cells. This study examined the specificity and function of this regulatory population assessed ex vivo that plays a critical role in down-regulating the autoreactive T lymphocyte response in cyclosporine-induced syngeneic graft-versus-host disease. The results suggest that both the antigen-specific regulatory and pathogenic effector T cells recognize a common peptide antigen framework (CLIP, a peptide derived from the invariant chain) presented by major histocompatibility complex class II molecules. Analysis of the CD4+ T-cell compartment revealed two subsets of CLIP-reactive T cells that differentially require the N- and C-terminal flanking domain of this peptide. Regulatory function is associated with the cells that require the C-terminal flanking domain. This population expresses the Foxp3 nuclear transcription factor and plays a critical role in re-establishing tolerance to self-major histocompatibility complex class II antigens. In addition to suppressing the production of type 1 cytokines, these regulatory T cells can direct the apoptotic death of the pathogenic autoreactive lymphocytes. This study also suggests that the development of functional regulatory activity is an active response initiated by the presence of autoreactive lymphocytes that can present the target antigen (major histocompatibility complex class II CLIP) to the regulatory T cells. Moreover, this process can be mimicked by peptide antigen in the absence of the pathogenic effector lymphocytes leading to the development of functional regulatory T-cell activity.

Adoptive Transfer↗
PubMed1998

Co-trafficking of HFE, a nonclassical major histocompatibility complex class I protein, with the transferrin receptor implies a role in intracellular iron regulation.

The mechanism by which a novel major histocompatibility complex class I protein, HFE, regulates iron uptake into the body is not known. HFE is the product of the gene that is mutated in >80% of hereditary hemochromatosis patients. It was recently found to coprecipitate with the transferrin receptor (Feder, J. N., Penny, D. M., Irrinki, A., Lee, V. K., Lebron, J. A., Watson, N., Tsuchihashi, Z., Sigal, E., Bjorkman, P. J., and Schatzman, R. C. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 1472-1477; Parkkila, S., Waheed, A., Britton, R. S., Bacon, B. R., Zhou, X. Y., Tomatsu, S., Fleming, R.E. , and Sly, W. S. (1997) Proc. Natl. Acad. Sci. U. S. A. 94, 13198-13202) and to decrease the affinity of transferrin for the transferrin receptor (Feder et al.). In this study, HeLa cells were transfected with HFE under the control of the tetracycline-repressible promoter. We demonstrate that HFE and the transferrin receptor are capable of associating with each other within 30 min of their synthesis with pulse-chase experiments. HFE and the transferrin receptor co-immunoprecipitate throughout the biosynthetic pathway. Excess HFE is rapidly degraded, whereas the HFE-transferrin receptor complex is stable. Immunofluorescence experiments indicate that they also endocytose into transferrin-positive compartments. Combined, these results suggest a role for the transferrin receptor in HFE trafficking. Cells expressing HFE have modestly increased levels of transferrin receptor and drastically reduced levels of ferritin. These results implicate HFE further in the modulation of iron levels in the cell.

Cloning, Molecular↗
PubMed2001

Peptide generation in the major histocompatibility complex class I antigen processing and presentation pathway.

The bulk of antigens that are presented by major histocompatibility complex (MHC) class I molecules are processed in the cytosol. Therefore, the cellular protein degradation machinery is thought to play a major role in antigen processing. For example, there is clear evidence that the ubiquitin-proteasome pathway, the major proteolytic pathway in the cytosol, plays a role in the processing of class I-associated antigens. In addition, peptide chaperones must exist to properly target peptides to the transporter associated with antigen processing. Here, the author reviews some of the more important advances over the past year that further define the pathways of antigen breakdown in the cytosol. This includes a look at the distinctive roles of proteasomes versus immunoproteasomes, the isolation of peptide processing intermediates in the cytosol, and the role of defective ribosomal products. These findings highlight the importance of understanding basic cellular protein degradation pathways in antigen processing.

Animals↗