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PubMed2001

Mammalian expression cloning of two human trophoblast suppressors of major histocompatibility complex genes.

PROBLEM: Human trophoblasts suppress interferon-gamma (IFN-gamma)-simulated expression of major histocompatibility complex (MHC) class II genes and thereby protect the conceptus from maternal immune attack. The mechanism of this suppression is poorly understood. METHOD OF STUDY: IFN-gamma-responsive HeLa cells were stably transfected with trophoblast cDNA expression libraries and screened by negative immunoselection with an antibody to HLA-DR. RESULTS: Two suppressor cDNAs were isolated. One encoded the untranslated RNA trophoblast STAT utron (TSU), which blocked STAT1 nuclear translocation and can theoretically form triplex RNA-DNA at the class II transactivator gene promoters. The other encoded the N-terminal 28 residues of chorionic somatomammotropin (hCS). TSU-related genes were detected in human and macaque but not in mouse, genomic DNA. CONCLUSIONS: The genetics of two human trophoblast MHC suppressors suggest that these functions have been gained in human placenta in recent evolutionary history. TSU and hCS play critical roles in suppression of MHC genes, which may lead to silencing by DNA methylation.

Amino Acid Sequence↗
PubMed1992

Peptides presented to the immune system by the murine class II major histocompatibility complex molecule I-Ad.

Between 650 and 2000 different peptides are associated with the major histocompatibility complex class II molecule I-Ad. Sequences for nine of these were obtained by a combination of automated Edman degradation and tandem mass spectrometry. All of the peptides are derived from secretory or integral membrane proteins that are synthesized by the antigen-presenting cell itself. Peptides were 16 to 18 residues long, had ragged NH2-and COOH-termini, and contained a six-residue binding motif that was variably placed within the peptide chain. Binding data on truncated peptides suggest that the peptide binding groove on class II molecules can be open at both ends.

Amino Acid Sequence↗
PubMed1990

Presentation of exogenous antigen with class I major histocompatibility complex molecules.

Soluble antigens (Ags) in the extracellular fluids are excluded from the class I major histocompatibility complex (MHC)-restricted pathway of Ag presentation in most cells. However, an exogenous Ag can be internalized, processed, and presented in association with class I MHC molecules on specialized Ag-presenting cells (APCs). These APCs express class II molecules and can simultaneously present exogenous Ags to both class I and class II MHC-restricted T cells. These APCs may be important participants in the regulation of host immune responses. This APC activity may explain several phenomena of cytotoxic T lymphocyte (CTL) priming in vivo and might be exploited for eliciting CTL responses to protein vaccines.

Animals↗
PubMed1994

Susceptibility of major histocompatibility complex (MHC) class I- and MHC class II-deficient mice to Cryptosporidium parvum infection.

Major histocompatibility complex (MHC) class I-deficient and MHC class II-deficient mice lack functional CD8 T cells and CD4 T cells, respectively. These mice were evaluated for infection following oral administration of 10(7) Cryptosporidium parvum oocysts. MHC class II-deficient (but not MHC class I-deficient) mice dosed with C. parvum oocysts at 3 to 5 days of age remained infected 8 weeks postexposure. MHC class II-deficient mice exposed to C. parvum oocysts at 5 to 6 weeks of age were significantly more susceptible to infection than control mice (P < 0.0001).

Animals↗
PubMed1997

Efficient repression of endogenous major histocompatibility complex class II expression through dominant negative CIITA mutants isolated by a functional selection strategy.

Major histocompatibility complex class II (MHC-II) molecules present peptide antigens to CD4-positive T cells and are of critical importance for the immune response. The MHC-II transactivator CIITA is essential for all aspects of MHC-II gene expression examined so far and thus constitutes a master regulator of MHC-II expression. In this study, we generated and analyzed mutant CIITA molecules which are able to suppress endogenous MHC-II expression in a dominant negative manner for both constitutive and inducible MHC-II expression. Dominant negative CIITA mutants were generated via specific restriction sites and by functional selection from a library of random N-terminal CIITA deletions. This functional selection strategy was very effective, leading to strong dominant negative CIITA mutants in which the N-terminal acidic and proline/serine/threonine-rich regions were completely deleted. Dominant negative activity is dependent on an intact C terminus. Efficient repression of endogenous MHC-II mRNA levels was quantified by RNase protection analysis. The quantitative effects of various dominant negative CIITA mutants on mRNA expression levels of the different MHC-II isotypes are very similar. The optimized dominant negative CIITA mutants isolated by functional selection should be useful for in vivo repression of MHC-II expression.

Burkitt Lymphoma↗
PubMed1999

Reduced phosphorylation of p50 is responsible for diminished NF-kappaB binding to the major histocompatibility complex class I enhancer in adenovirus type 12-transformed cells.

Reduced cell surface levels of major histocompatibility complex class I antigens enable adenovirus type 12 (Ad12)-transformed cells to escape immunosurveillance by cytotoxic T lymphocytes (CTL), contributing to their tumorigenic potential. In contrast, nontumorigenic Ad5-transformed cells harbor significant cell surface levels of class I antigens and are susceptible to CTL lysis. Ad12 E1A mediates down-regulation of class I transcription by increasing COUP-TF repressor binding and decreasing NF-kappaB activator binding to the class I enhancer. The mechanism underlying the decreased binding of nuclear NF-kappaB in Ad12-transformed cells was investigated. Electrophoretic mobility shift assay analysis of hybrid NF-kappaB dimers reconstituted from denatured and renatured p50 and p65 subunits from Ad12- and Ad5-transformed cell nuclear extracts demonstrated that p50, and not p65, is responsible for the decreased ability of NF-kappaB to bind to DNA in Ad12-transformed cells. Hypophosphorylation of p50 was found to correlate with restricted binding of NF-kappaB to DNA in Ad12-transformed cells. The importance of phosphorylation of p50 for NF-kappaB binding was further demonstrated by showing that an NF-kappaB dimer composed of p65 and alkaline phosphatase-treated p50 from Ad5-transformed cell nuclear extracts could not bind to DNA. These results suggest that phosphorylation of p50 is a key step in the nuclear regulation of NF-kappaB in adenovirus-transformed cells.

Adenoviruses, Human↗
PubMed2000

Clinical course of patients with major histocompatibility complex class II deficiency.

The clinical course of 10 children who have been diagnosed with major histocompatibility complex (MHC) class II deficiency (bare lymphocyte syndrome) in the UK over the past eight years is described. They have had a generally poor prognosis, with only two of the 10 still alive despite eight attempts at bone marrow transplantation in six patients. Overwhelming viral infection was the predominant cause of death. Alternative transplant strategies or novel therapies are required for these patients.

Bone Marrow Transplantation↗
PubMed2002

High glucose levels increase major histocompatibility complex class I gene expression in thyroid cells and amplify interferon-gamma action.

Increased major histocompatibility complex (MHC) class I gene expression in target tissues may be relevant to the pathogenesis of autoimmune diseases. In this study, we questioned whether high glucose levels might increase MHC class I levels and thereby contribute to autoimmune complications. We used thyrocytes in continuous culture, because there is an increased incidence of autoimmune thyroiditis in type 2 diabetics and because transcriptional regulation of MHC class I is well studied in these cells. Northern analysis and flow cytometry showed that 20 and 30 mM D-glucose up-regulated MHC class I expression and that the glucose effect was additive to and independent of interferon-gamma. The effect was specific, because L-glucose did not modify class I expression. The glucose acted transcriptionally, requiring both enhancer A and a cAMP-response element-like element located in the hormone-sensitive region of the MHC class I 5'flanking region. These elements are different from those activated by interferon-gamma. High glucose levels increase formation of the MOD-1 complex with enhancer A; MOD-1 is a heterodimer of fra-2 and the p50 subunit of NF-kappaB. Both TSH and insulin are required for full expression of the glucose activity in thyrocytes. The glucose effect is partially blocked by wortmannin, suggesting involvement of the PI3K signal system. The data support the possibility that high serum glucose levels in type 2 diabetic patients may increase MHC class I levels in target tissues and contribute to autoimmune complications of the disease.

Animals↗
PubMed1992

Acceptance of class II major histocompatibility complex disparate skin grafts associated with suppressor cells and elevated Langerhans cell numbers.

Class II major histocompatibility complex (MHC) molecules are only present on Langerhans cells (LC) in normal murine epidermis. Depletion of this antigen with the chemical carcinogen dimethylbenzanthracene (DMBA) causes I-E disparate B10.A(2R) congenic tail skin to be accepted permanently when grafted onto B10.A(4R) recipients. Adoptive transfer of spleen cells from these recipients into naive syngeneic hosts inhibited the ability of the host mice to reject untreated B10.A(2R) tail skin grafts. Hence DMBA-treated LC depleted I-E disparate skin grafts activate suppressor cells which did not inhibit BALB/c mice from rejecting a B10.A(2R) tail skin graft. In contrast, the tobacco derived carcinogen benzo(a)pyrene (BP) increased the number of epidermal LC but had no effect on either class I or class II MHC disparate skin graft survival time. This confirms that the number of class II MHC-positive LC is critical for the initiation of skin graft rejection; when the threshold level is attained graft rejection proceeds at a maximal rate that cannot be enhanced by raising the number of LC. The tolerant skin grafts had increased numbers of LC; this was not observed in syngeneic grafts and therefore may be related to the active suppression of immunity.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2003

[Cloning and biological activities of riboenzymes against major histocompatibility complex class II transactivator].

OBJECTIVE: To investigate the cloning and biological activities of riboenzymes against major histocompatibility complex (MHC) class II transactivator (CIITA) so as to explore the feasibility of using hammerhead riboenzyme to create immune tolerance. METHODS: Three riboenzymes against MHC CIITA were synthesized and their activities were evaluated in vitro. Rz464, the riboenzyme with a better digestion effect, was inserted into the vector pIRES2-EGFP (then called pRz464). Human B lymphoma cells of Daudi line were cultured and transfected with pRz464 (then called pRz464-D). Cultured Daudi cells transfected with riboenzyme without the ability against CIITA (Rz-D) were used as control group. The expressions of classic MHC CIITA (HLA-DR, DP, and DQ) on the surface of Daudi cells before and after transfection were examined by flow cytometry. RESULTS: The expressions of HLA-DR, DP, and DQ on the surface of cultured Daudi cells (Rz-D) were 97.9 +/- 0.8%, 94.3 +/- 1.1%, and 54.4 +/- 3.1% respectively. The expressions of HLA-DR, DP, and DQ were inhibited by 88.4%, 83.5%, and 93.4% respectively on the surface of pRz464-D cells. CONCLUSION: The hammerhead riboenzyme Rz464 inhibits the expression of CIITA mRNAs, thus inhibiting the expression of MHC II molecules. It may be used in antigen-specific tolerance induction in allo-transplantation.

Cloning, Molecular↗
PubMed1992

Absence of expression of class II major histocompatibility complex determinants on keratinocytes in bullous pemphigoid.

Aberrant expression of class II products of the major histocompatibility complex (HLA-D locus antigens) occurs on keratinocytes in several inflammatory dermatoses and on thyroid epithelial cells in autoimmune thyroiditis. The functional significance of aberrant HLA-D expression is unclear but it has been hypothesized that epithelial cells bearing these determinants may act as antigen-presenting cells for autoantigens. The aim of the present study was to investigate the pathogenesis of bullous pemphigoid using immunohistochemical methods to determine whether the HLA-D locus antigens are aberrantly expressed on keratinocytes in lesional and uninvolved skin. A panel of monoclonal antibodies to each of the HLA-D subregions (DR, DP and DQ) and to Langerhans cells was used. Epidermal expression of the HLA-D locus antigens was similar in patients and controls, and there was no significant increase in expression in lesional skin compared with uninvolved skin in six out of nine patients. In three out of nine patients slight enhancement of epidermal HLA-D expression in lesional epidermis corresponded to increased Langerhans cells rather than expression on keratinocytes. HLA-D locus antigens are absent from keratinocytes in bullous pemphigoid skin and aberrant expression of these determinants cannot therefore be implicated in antigen presentation.

HLA-D Antigens↗
PubMed1992

Regulation of major histocompatibility complex class II gene expression on bovine bronchial epithelial cells.

Induction and increased expression of major histocompatibility complex (MHC) class II antigens in tissues that do not normally express class II antigens is thought to be important in the pathogenesis of allograft rejection and may also be important in the pathogenesis of obliterative bronchiolitis in lung allografts. We hypothesized that MHC antigen expression on bronchial epithelial cells, particularly MHC class II expression, is regulated by immune mediators in a manner similar to the regulation of antigen expression by lymphoid cells. With an in vitro system of bovine bronchial epithelial cells, we evaluated the effects of both a lymphokine-containing supernatant and recombinant tumor necrosis factor-alpha on MHC class II expression. Immunofluorescence and flow cytometry demonstrated markedly increased MHC class II surface antigen expression on the bronchial epithelial cells after exposure to the lymphokine-containing supernatant. Tumor necrosis factor-alpha had no effect on MHC class II surface antigen expression. Immunosuppressant drugs altered the cellular responses to lymphokines in a manner similar to that of lymphoid cells. Dexamethasone suppressed the induction of MHC class II antigens at both the surface antigen and messenger RNA transcript levels. Cyclosporine did not have a consistent effect on the surface expression of class II antigens, but it did inhibit the messenger RNA transcript levels. These suppressive effects have implications for the therapy of airway disorders associated with lung and bone marrow transplantation.

Animals↗
PubMed1986

Antibodies reactive with class II antigens encoded for by the major histocompatibility complex inhibit human B cell activation.

Although class II antigens encoded by genes in the major histocompatibility complex (MHC) are important as recognition structures for immunoregulatory cell interactions, the precise functional role of these molecules in the biological responses of B lymphocytes is unknown. In the studies described here, we have examined the effects of six monoclonal antibodies reactive with human class II MHC antigens on B cell activation and proliferation. Peripheral blood IgM+ B cells purified by fluorescence-activated cell sorter (FACS) techniques were stimulated with anti-mu antibodies, protein A-bearing Staphylococcus aureus (SAC), or in T cell-dependent activation cultures. The B cell proliferative responses induced by these stimuli were inhibited 68 to 90% by low concentrations (1 to 5 micrograms/ml) of antibodies reactive with class II MHC antigens. Antibodies specific for DR and DQ antigens were both effective inhibitors of B cell proliferation. This inhibition was not due to the binding of antibody to B cell Fc-IgG receptors, because IgM and IgG anti-class II antibodies were equally potent as inhibitors. When responses of B cells fractionated on the basis of cell size by forward angle light scatter were analyzed, anti-DR and anti-DQ antibodies inhibited the proliferation of small, resting IgM+ cells induced by T-independent as well as T-dependent stimuli. Activation-dependent increases in B cell size and RNA synthesis were similarly inhibited. In contrast, the responses of large B cells (that had been preactivated in vivo) to T cell-derived B cell growth factors were not affected by anti-class II antibodies. These data suggest that class II MHC molecules do not serve merely as cellular interaction structures but also directly participate in early events of the B cell activation cascade that precede cell enlargement or increased RNA synthesis. After activation and expression of receptors for growth factors, however, B cell class II MHC antigens no longer mediate signals required for mitogenesis.

Adult↗
PubMed1993

Aberrant biosynthesis and transport of class I major histocompatibility complex molecules in cells transformed with highly oncogenic human adenoviruses.

The expression of class I major histocompatibility complex antigens on the surface of cells transformed by adenovirus 12 (Ad12) is generally very low. The absence of class I antigens correlates with the high oncogenicity of this virus. In primary embryonal fibroblasts from transgenic mice that express both endogenous H-2 genes and a miniature swine class I gene (PD1), Ad12-mediated transformation results in complete suppression of cell surface expression of class I antigens, but only 50% of the cell lines tested demonstrated decreased steady state levels of class I mRNA. The complete absence of cell surface class I antigens is accompanied by decreased levels of newly synthesized class I molecules. Those molecules that are immunoprecipitated by class I-specific antibodies are assembled with beta 2-microglobulin, but their transport through the Golgi is inefficient. The biosynthesis of both the endogenous H-2K, H-2D, and the transgene product, PD1, is similarly altered in the transformed cells. The results suggest that Ad12 transformation is associated with both reduced synthesis rate and inefficient transport of class I molecules to the cell surface. This might be a general mechanism by which virus-infected or -transformed cells escape immune surveillance.

Adenoviruses, Human↗
PubMed1997

Expression of major histocompatibility complex class I antigens in the demyelinating twitcher CNS and PNS.

The expression of the major histocompatibility complex Class I antigens (Class I) was investigated in the nervous system of twitcher (C57BL/6J-twi), a murine model of Krabbe disease in humans. Class I mRNA expression was low in wild type and in twitcher mice prior to the onset of demyelination. However, immunoreactivity for Class I antigens was demonstrated in the spindle-shaped cells in the sciatic nerve and in ramified microglia, endothelial cells and Bergmann glia. In twitcher, transcription of Class I mRNA increased significantly with the progression of demyelination and Mac-1+ macrophages/microglia express Class I immunoreactivity. Class I immunoreactivity was also found in CD3+ T-cells that were scattered in demyelinating lesions. CD8+ or CD4+ cells were also found in the demyelinating area. The results of this study indicate that immunoreactivity to Class I antigens is detected in certain cells even in the wild-type mice and that Class I expression is enhanced in the twitcher nervous system paralleling the progression of demyelination. Expression of MHC molecules in non-immunological demyelinating disease such as twitcher may suggest a role of Class I molecules in the progression of demyelination. Alternatively, the expression may be a non-specific cellular response to the breakdown of myelin.

Animals↗
PubMed2001

An immunoelectron-microscopic study of class II major histocompatibility complex molecule-expressing macrophages and dendritic cells in experimental rat periapical lesions.

Previous studies have demonstrated that heterogeneous populations of class II major histocompatibility complex (MHC) molecule-expressing non-lymphoid cells, ultrastructurally classified as macrophages and dendritic cell (DC) cell-like cells, comprise the major immune cell population in experimental periapical lesions in rat molars. In this study, the temporal changes in relative proportions of the two types of cells were examined, on the hypothesis that they are involved in different aspects of the pathogenesis of the lesions. The lesions were induced by making surgical pulp exposures in mandibular first molars of 5-week-old Wistar rats. Observation periods were set at 0 (normal), 3, 14, 28, and 56 days. Non-lymphoid cells immunoreactive to OX6 (reactive to class II MHC molecules) were classified as macrophages and DC cell-like cells according to their ultrastructure, and the frequencies of the two types of cells were assessed at each time-point. ED1 (reactive to nearly all macrophages and DCs) was also used to identify macrophages and DC cell-like cells. At 3 days, most OX6+ cells and ED1+ cells in the periapical tissue had the ultrastructural appearance of newly recruited macrophages. At 14 days, when the lesion was actively expanding, there were significantly more OX6+ macrophages than OX6+ DC cell-like cells (P<0.01). However, at 28 days, when lesion expansion had ceased, DC cell-like cells significantly outnumbered OX6+ macrophages (P<0.01); this remained constant at 56 days. Cell-to-cell contact between OX6+ non-lymphoid cells and OX6- lymphocytes, suggesting a functional interaction, was most frequently seen at 28 days. These results support the notion that class II MHC molecule-expressing macrophages play some part in the initial lesion expansion, and suggest that DC cell-like cells may primarily be involved in immune defence against perpetuated antigenic challenges following lesion stabilization.

Animals↗
PubMed1982

Identification of the class I genes of the mouse major histocompatibility complex by DNA-mediated gene transfer.

DNA-mediated gene transfer was used to identify cloned class I genes from the major histocompatibility complex of the BALB/c mouse. Three genes encoding the transplantation antigens H-2 Kd, Dd and Ld were identified as well as genes encoding the Qa-2,3 and two TL differentiation antigens. As many as 10 putative novel class I genes were detected by the association of their gene products with beta 2-microglobulin. Alloantiserum prepared to one of the novel antigens was used to demonstrate the expression of the previously undetected antigen on spleen cells of various inbred, congeneic, and recombinant congeneic strains of mice.

Animals↗
PubMed1999

Major histocompatibility complex (MHC) class II polymorphism and paternity in the monogamous Hypogeomys antimena, the endangered, largest endemic Malagasy rodent.

Sequence variation at a major histocompatibility complex (MHC) class II gene was examined in Hypogeomys antimena, a monogamous endemic rodent of Madagascar. The study was conducted throughout its remaining geographical range (20 x 40 km) by direct sequencing and single-strand conformation polymorphism (SSCP). The objectives of the study were: (i) to investigate levels of polymorphism in the MHC complex of a highly endangered species that experienced a severe reduction in population size; and (ii) to investigate the genetic mating system by assessing the frequency of extra-pair paternity (EPP) as EPP might have important consequences to increase gene flow and, therefore, genetic variability within a population. The amplified gene segment had a very low variability (only two alleles) in H. antimena compared with other mammalian species. The alleles segregated consistently with Mendelian expectations in families. No case of EPP was found. The present data suggest no difference between the social and the genetic mating system.

Animals↗