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At least 19 recordsLinked to original sources
PubMed1987

Biosynthesis and processing of class II histocompatibility antigens.

The class II major histocompatibility antigens at the cell surface exist as heterodimers of alpha and beta subunits. During biosynthesis, these subunits are associated with a third chain, the invariant (I) or I chain. Association with the I chain occurs early in biosynthesis in the rough endoplasmic reticulum and persists during transport through the Golgi apparatus. One of the two alpha subunit N-linked oligosaccharides and the single beta subunit N-linked oligosaccharide are converted to the complex form during Golgi transit. In the human system, both I chain N-linked oligosaccharides can also be processed to the complex form, and at least two O-linked oligosaccharides can be added to the I chain. At some point during transit to the cell surface, class II antigens associate with a proteoglycan bearing chondroitin sulfate side chains. Complexes containing alpha, beta and I chain subunits and the associated proteoglycan accumulate in human B-cell lines treated with the ionophore monensin, an inhibitor of Golgi transport, suggesting that this may be a biosynthetic intermediate in class II antigen transport and assembly. Prior to cell surface expression of class II antigens, the exocytic pathway which they follow intersects the endocytic route, followed by certain ligands internalized by receptor-mediated endocytosis. The I chain appears to dissociate from mature class II alpha, beta dimers prior to their cell surface expression but following the intersection of the exocytic and endocytic pathways.

Animals↗
PubMed1992

Quantitative regional variation in the expression of major histocompatibility class II antigens in enterocytes of the mouse small intestine.

The qualitative and quantitative expression of major histocompatibility class II antigens was investigated in the absorptive epithelium of the duodenum, jejunum, and ileum from mice of C3H/He (H-2k haplotype) and C57BL/6 (H-2b haplotype) strains by peroxidase-antiperoxidase labelling and image analysis. Immunohistochemical labelling revealed that the expression of class II antigens was greatest in the ileum and decreased proximally towards the duodenum. The villus epithelium of the duodenum showed a granular staining pattern in the apices of some cells. In the jejunum, an increased expression was demonstrated in the apical and basal cytoplasm of all cells covering the villus. Cells at the tip of the villus, in addition, showed staining of the lateral surfaces. Ileal enterocytes demonstrated the most intense immunostaining appearing in the cytoplasm and along baso-lateral surface membranes. Quantitative analyses confirmed that a highly significant (p less than 0.0001) difference in expression of class II antigens occurred in the three regions of the small intestine, which corroborated the qualitative findings. This regional variation of class II molecules by the absorptive epithelium may influence regional differences in antigen presenting functions and immune responsiveness to ingested antigens.

Animals↗
PubMed1999

Expression of major histocompatibility class II antigens on polymorphonuclear neutrophils in patients with Wegener's granulomatosis.

BACKGROUND: Wegener's granulomatosis is a systemic inflammatory disease of unknown etiology. Many studies suggest that autoimmune reactions are involved, and there is good evidence for the participation of immunocompetent cells. In that context, we examined the activation of polymorphonuclear neutrophils (PMNs) of patients with Wegener's granulomatosis. METHODS: In a prospective study, the expression on the surface of PMNs of CD64 and of the major histocompatibility class II (MHC II) antigen was measured by cytofluorometry in whole blood. The expression of those antigens was correlated to disease activity. RESULTS: Up to 15% of the peripheral PMNs of patients with active disease expressed MHC II. Follow-up studies showed that expression correlated closely with disease activity and that it decreased rapidly under immunosuppressive therapy. Expression of CD64 was seen in approximately 50% of the patients, regardless of disease activity. CONCLUSION: MHC II expression on PMNs might serve as a novel diagnostic marker for active disease and appears to be suitable for monitoring immunotherapy. Moreover, our data provide evidence that PMNs, which are normally MHC II negative, acquire MHC II antigens in the course of disease and may be an unrecognized function within the afferent limb of the immune response.

Anti-Inflammatory Agents↗
PubMed1987

Gamma interferon, but not Mycobacterium leprae, induces major histocompatibility class II antigens on cultured rat Schwann cells.

In order to investigate the possible role of Schwann cells in immune reactions, and in particular their involvement in the response to infection with Mycobacterium leprae, it was determined under what conditions Schwann cells express major histocompatibility complex class II (MHC class II) antigens, since these molecules are thought to have a key role in antigen presentation during cellular immune responses. In situ and in vitro preparations from newborn and adult rat sciatic nerves were used as a model system to examine this question. Schwann cells in dissociated cell cultures did not express immunohistochemically detectable amounts of MHC class II antigens. Teased nerve preparations from the sciatic nerves of healthy adult rats showed no detectable immunolabelling of either myelin-forming or non-myelin-forming Schwann cells. When dissociated Schwann cell cultures derived from the sciatic nerves of either neonatal or adult rats were treated with 10, 50 or 100 units of gamma interferon, MHC class II antigens were detectable on the surface of some Schwann cells 48 h after addition of the interferon. By 72 h, 32.29 +/- 3.9% of Schwann cells in the cultures from neonatal rats and 53.32 +/- 5.4% of Schwann cells in cultures from adult rats, identified by the presence of intracellular S-100, were clearly MHC class II-positive, especially at doses of 50 and 100 units per ml of gamma interferon. Some, but not all, of the fibroblastic cells were very weakly MHC class II-positive. Infection of the cultures with Mycobacterium leprae did not induce MHC class II antigen expression in either Schwann cells or fibroblasts.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1985

Genetic complexity and expression of human class II histocompatibility antigens.

The genes encoding nearly all of the serologically defined class II antigens of the major histocompatibility complex have been isolated. Three class II loci have been studied in great detail. The DR region contains a single alpha gene and 3 beta chain genes, 1 of which is a pseudogene. The DR alpha chain gene has been linked to a DR beta gene which encodes a beta protein which contains the serological determinant MT3. A second cosmid cluster contains 2 beta genes, 1 of which encodes the DR4 allospecificity. The identification of these genes has been made by the comparison of amino terminal sequences of DR molecules obtained from a DR4 cell line and the deduced protein sequences of the beta 1 exons from cosmid and phage clones. A conserved element including the promoter and signal sequence is found at the 5' end of each of the 3 DR beta genes. Additionally, this element occurs three more times in the DR region, raising the question of whether additional beta chain genes might be found. The DQ region contains 2 pairs of genes, 1 of which encodes the DQ antigen. The 2nd pair of genes, called DX alpha and beta, appears to be capable of expressing a DQ-related product, although, to date, there is no evidence for its expression. The DP region also contains 2 pairs of genes. One pair encodes the DP antigen while the 2nd alpha-beta pair is shown to be composed of pseudogenes. The location of polymorphic regions in these genes and aspects of their relationship to the serology, evolution, and function of the class II MHC are discussed. The control of expression of class II genes by gamma-interferon has been examined. The promoters of class II genes are characterized by two conserved sequences common to all alpha and beta chain genes as well as by conserved sequences specific for either alpha or beta chain genes. In addition to studies of expression by DNA-mediated gene transformation, a system for the gene transfer of MHC antigens utilizing transmissible retrovirus vectors is described. Retrovirus vectors have been used to transmit DR alpha, DR beta, and the invariant chain (gamma) sequences to recipient cells with resultant expression of these proteins.

Alleles↗
PubMed1986

Factors involved in decreased detection of class II histocompatibility antigens on blood mononuclear cells from transplanted patients receiving immunosuppressive drugs.

Class II histocompatibility antigens were assessed by complement-dependent cytotoxicity on B enriched mononuclear cells and on purified monocytes isolated from the peripheral blood of renal patients before and after transplantation. After transplantation, a significant decrease of detection of DR alloantigens (cytotoxicity score before transplantation 3 +/- 0.1; after transplantation 0.95 +/- 0.1; p less than 0.001) was found. A similar defect was observed both on B enriched frozen cells and on purified monocytes isolated during the post-transplant period. Nevertheless, antigens could be adequately detected by a sensitive microabsorption method and by a procedure involving preincubation of mononuclear cells at 37 degrees C for 3 h followed by B cells enrichment by rosetting. The 37 degrees C induced reexpression could be inhibited by 10 micrograms/ml cycloheximide and by 50 microM monensin. No difference was found in the magnitude either of decreased expression or of temperature-induced reexpression between patients treated by CyS-Pred and those receiving Aza-Pred. It is concluded that transplanted recipients disclose a reversible defect of the expression of class II histocompatibility antigens probably related to perturbation of various steps of intracellular biosynthesis and traffic of these molecules.

Antibodies, Monoclonal↗
PubMed1995

Activated rat T cells synthesize and express functional major histocompatibility class II antigens.

In the present report, we studied the presence and functional significance of major histocompatibility complex (MHC) class II antigen on rat T cells. Most rat T-cell lines cultured in vitro were found to be MHC class II+. Also, these T-cell lines were shown to synthesize MHC class II molecules. Immunohistochemical and flow cytometric double stainings for T-cell receptor (TCR) and MHC class II showed that in vivo as well a large proportion of T cells was MHC class II+. The immunohistochemical staining of spleen sections enabled us to characterize the MHC class II+ and MHC class II- T cells. It was shown that resting T cells in vivo were MHC class II-. In contrast, activated T cells, as determined by their localization in the marginal zone of the spleen, proved to be MHC class II+. Finally, T-cell clones were found to be able to present peptidic antigens, but could only poorly present more complex exogenous antigens, probably due to inefficient uptake of such antigens. These features would endow activated rat T cells with the capacity to present cell-specific self-proteins, such as TCR, to regulatory CD4+ MHC class II-restricted T cells, as was described by our group elsewhere.

Animals↗
PubMed1985

Specificity of monoclonal antibodies directed against human and murine class II histocompatibility antigens as analyzed by binding to HLA-deletion mutant cell lines.

The specificity of 70 monoclonal anti-Ia monoclonal antibodies (MoAbs) (18 mouse allo-induced and 52 rodent anti-human) was studied with a panel of 17 HLA-deletion mutants that were derived from a single parent line and vary in expression of Ia antigens due to deletion of different subregions of HLA. MoAb binding was analyzed both by ELISA and flow microfluorometry. Characterization of the MoAbs with respect to specificity for products of subregions of a DR1-DC1-SB2 haplotype revealed great complexity. Many antibodies were quite specific for DR-linked determinants (26 MoAbs), DC-linked determinants (5 MoAbs), or determinants indistinguishable from SB (4 MoAbs). However, many MoAbs bound to products of more than one subregion: DR + SB (+/- weak DC) (22 MoAbs); DR + DC (3 MoAbs); or DR + DC + SB (1 MoAb). Furthermore, a number of the MoAbs bound unequally to products of the two HLA haplotypes analyzed, particularly among those recognizing DC1-linked determinants and the murine alloinduced MoAbs. Finally, despite strong structural homologies of murine I-A to human DC and murine I-E to human DR, the intraspecies cross-reactions of MoAbs do not closely follow that pattern. These data: (1) illustrate the usefulness of HLA-deletion mutant cell lines for analysis of the specificity of MoAbs and for delineation of HLA subregions; (2) demonstrate the great diversity of MoAbs specific for class II molecules and the high frequency of MoAbs that bind to products of more than one Ia subregion, particularly DR and SB. In view of such complexity, many (perhaps most) MoAbs cannot be relied on to unambiguously identify products of a particular Ia subregion, without extensive characterization.

Animals↗
PubMed1986

Cell surface expression of class II histocompatibility antigens occurs in the absence of the invariant chain.

The invariant chain is a glycoprotein transiently associated with the alpha and beta subunits of class II antigens of the major histocompatibility complex during their transport to the cell surface. An expression assay with cDNA clones transfected into simian COS cells was used to test whether the invariant chain is required for assembly and transport of human class II antigens. COS cells do not express detectable levels of RNA from the endogenous invariant chain gene. Cell surface expression of the DP, DQ, and DR antigens was observed in COS cells transfected with the respective alpha and beta chain cDNA clones. Analysis of RNA from the transfected cells showed that the human genes were transcribed in COS cells and that the endogenous simian class II and invariant chain genes were not induced. Cotransfections with an invariant chain cDNA clone did not alter the levels of class II antigens at the cell surface. Biosynthetic labeling and immunoprecipitation demonstrated that the invariant chain cDNA was expressed into a protein which associated with DR alpha and beta chains. Efficient expression of DR antigen in absence of invariant chain was also observed at the surface of a human fibroblast line stably transfected with DR alpha and beta cDNA. This study demonstrates that expression of all three human class II antigens can be achieved with cDNAs cloned in expression vectors. Furthermore, cell surface expression of class II major histocompatibility complex antigens can occur in absence of invariant chain. The postulated role of the invariant chain in class II antigen transport to the cell surface must be reevaluated. The invariant chain may rather be involved in functional properties of class II molecules such as antigen presentation.

Antigens, Differentiation, B-Lymphocyte↗
PubMed1986

Class II histocompatibility antigen expression in human melanocytes transformed by Harvey murine sarcoma virus (Ha-MSV) and Kirsten MSV retroviruses.

Human melanocytes infected with Ki-MSV or Ha-MSV, but not amphotropic MuLV, undergo a series of transformation-related changes that are characteristic of malignant melanoma. These are (a) expression of Ia antigens, in particular DP, DQ, and DR class II histocompatibility gene products, (b) a transformed morphology and ability to grow in soft agar, and (c) a 5-10-fold increase in the cell surface expression of GD3 ganglioside. However, other characteristics of melanoma, such as independence from specific growth factors and loss of adenosine deaminase binding protein were not observed. We conclude that viral ras oncogenes initiate early transformation events in melanocytes, and that Ia antigen expression is a transformation marker in this system.

Cell Division↗
PubMed1993

Immunoelectronmicroscopical demonstration of major histocompatibility class II antigen: expression on endothelial and perivascular cells but not Schwann cells in human neuropathy.

A pre-embedding technique for identifying major histocompatibility (MHC) class II antigen with monoclonal antibody LN3 at the electron microscope level by immunogold silver enhancement was applied to sections from 12 human nerve biopsies. Many perivascular mononuclear cells in the epineurium, perineurium and endoneurium expressed MHC class II antigen and had the morphological appearance of macrophages. Cell processes expressing MHC class II antigen extended throughout the endoneurium, often close to Schwann cells. No MHC class II expression was identified on myelinating or non-myelinating Schwann cells. The endothelial cells of epineurial blood vessels expressed MHC class II antigen on their luminal surfaces more often and more strongly than those of the endoneurial vessels. These observations indicate that perivascular cells in both the endoneurium and perineurium commonly express the molecules necessary to present antigen to CD4+ T lymphocytes, but Schwann cells do not.

Adult↗
PubMed1991

Tetraethylammonium, a K+ channel blocker, inhibits interferon-gamma-induced major histocompatibility class II antigen (Ia) expression and DNA synthesis in rat astrocytes.

Astrocytes play an important role in antigen presentation to T lymphocytes by their ability to express major histocompatibility class II (Ia) antigen upon exposure to a number of agents, including interferon-gamma (IFN-gamma). Astrocytes have been shown to express a variety of voltage-sensitive ion channels including voltage-sensitive K+ channels. The function(s) of these channels in astrocyte functions is not clearly understood. In this investigation, we examined: (1) the comparative effects of mouse, rat, and human recombinant IFN-gamma (rIFN-gamma) on the induction of Ia antigen and DNA synthesis in rat astrocytes; (2) the effect of tetraethylammonium (TEA), a K+ channel blocker, on rat IFN-gamma-induced Ia expression and DNA synthesis in rat astrocytes. Our data show that all INF-gamma induce DNA synthesis in rat astrocytes but only rat and mouse and not the human IFN-gamma will induce Ia expression. TEA in a dose-dependent manner inhibited both Ia expression and DNA synthesis in rat astrocytes. The concentration kinetics of TEA with regard to maximum inhibition of Ia and DNA synthesis were different. Furthermore, these inhibitory effects were not a result of toxic or nonspecific effect of TEA on astrocytes as demonstrated by viability data and lack of any effect of tetramethylammonium, an analogue of TEA, that does not block K+ ion channels. These data suggest a role of K+ channels in Ia expression and DNA synthesis, therefore in immunological functions of astrocytes.

Animals↗
PubMed1992

Stromal macrophages of the choroid plexus situated at an interface between the brain and peripheral immune system constitutively express major histocompatibility class II antigens.

Using immunocytochemistry we have shown that there is a population of macrophages within the stroma of the choroid plexus of rats and mice which expresses high levels of major histocompatibility complex Class II antigens. In whole mount preparations of the choroid plexus, the morphology and regular distribution of these cells is similar to the Langerhans cells of the skin. These cells reside at an important interface between the central nervous system and the peripheral immune system and their possible role in immune-mediated diseases of the central nervous system is discussed.

Animals↗
PubMed1997

Induction of major histocompatibility class II antigen on microglial cells in postnatal and adult rats following intraperitoneal injections of lipopolysaccharide.

Microglial cells, notably the ramified form, were induced to express major histocompatibility complex (MHC) class II antigen in postnatal and adult rats given intraperitoneal injections of lipopolysaccharide (LPS). The immunoreactive microglia which occurred in cell colonies or clusters were detected immunohistochemically with the monoclonal antibody OX-6. Some of the widely distributed MHC II positive cells were round or amoeboidic located preferentially in the perivascular area. In view of the widespread occurrence of microglial cells showing OX-6 immunoreactivity which is negligible in normal animals, it is suggested that the effect of LPS on microglia in vivo is a widespread phenomenon and is independent of age. It is suggested that the endotoxin not only triggers off the immunological potentiality of these cells but also elicits the entry of some mononuclear cells into the brain parenchyma.

Aging↗
PubMed1983

Organization of the transcriptional unit of a human class II histocompatibility antigen: HLA-DR heavy chain.

A total of 5724 base pairs of a recombinant phage DNA containing a human HLA-DR heavy chain gene including flanking regions has been analyzed. The regions corresponding to all the exons have been identified. The sites of initiation of transcription and polyadenylation have been determined. A large intron of 2399 base pairs separates the first exon containing the 5' untranslated region and the signal peptide from the second exon containing the N-terminal peptide domain.

Amino Acid Sequence↗
PubMed1997

Studies on the interaction of T-cells with major histocompatibility complex class II antigens.

1. Major histocompatibility complex class II antigens have the central role in the immune response of 'presenting' antigenic peptide to CD4+ T-cells. This interaction with a T-cell's receptor may result in activation, but, if recognition occurs without collateral molecular interactions which cause 'co-stimulation', these T-cells will be tolerized. 2. In the light of current interest in muscle cell transplantation, a transformed myoblast, TE671, phenotypically comparable to untransformed cells, transfected to express class II, was studied as a stable model of antigen presentation by muscle cells. These cells failed to activate T-cells but induced tolerance. 3. The DR alpha chain is unusual being the only non-polymorphic classical class II polypeptide, raising the question of its functional contribution. To this end, several single polypeptide constructs were generated with contributions from different class II alpha-chains. On this basis, it was established that DR alpha makes significant contributions to peptide binding and that its alpha 2 domain is also important in T-cell recognition, possibly through CD4 binding. 4. One implication of the lack of polymorphism of DR alpha may be that it has a wider range of pairing partners, possibly including beta chains of different isotypes. To address this, it is planned to use transfectants expressing only a mixed isotype pair to generate T-cell clones in vitro. These reagents would be useful tools to detect whether such mixed pairs exist physiologically. In this paper, the development of a system is described which will allow this question to be addressed.

Antigen Presentation↗
PubMed1990

Immunoprotective effect of a calcium channel blocker on macrophage antigen presentation function, major histocompatability class II antigen expression, and interleukin-1 synthesis after hemorrhage.

Hemorrhage induces a severe suppression of the immune system resulting in increased susceptibility to sepsis. Although studies indicate beneficial effects of calcium channel blockers on cell and organ functions after low-flow conditions, it remains unknown whether such agents have any effects on different immune responses after hemorrhage. To study this, C3H/HeN mice were bled to a mean blood pressure of 35 mm Hg and were maintained for 60 minutes, followed by resuscitation with their own shed blood and adequate fluid. The mice received either the water-soluble calcium channel blocker diltiazem (400 or 2400 micrograms/kg body weight) or saline solution (vehicle). Peritoneal macrophages were obtained by lavage 24 hours later. Antigen presentation was measured by coculturing peritoneal macrophages with the D10.G4.1 helper T-lymphocyte clone. Immune associated antigen (Ia) expression was determined by direct immunofluorescence. Interleukin (IL)-1, 6, and tumor necrosis factor-alpha (TNF) levels in peritoneal macrophage supernatants were measured by use of cytokine-specific cellular assays. Hemorrhage caused a significant decrease in peritoneal macrophage antigen presentation function, Ia expression, and IL-1 and IL-6 synthesis in the vehicle-treated group, whereas TNF levels were increased. However, both doses of diltiazem significantly improved peritoneal macrophage antigen presentation, Ia expression, and IL-1 synthesis. IL-6 synthesis was only increased with high doses of diltiazem, whereas both diltiazem doses decreased TNF production. These results indicate that the calcium channel blocker diltiazem can markedly improve macrophage functions after hemorrhage. The use of diltiazem might offer a new therapeutic modality in the treatment of immunosuppression and in decreasing the susceptibility to sepsis after hemorrhagic shock.

Animals↗