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PubMed2002

The class II transactivator requires brahma-related gene 1 to activate transcription of major histocompatibility complex class II genes.

The class II transactivator (CIITA) is the key regulator of major histocompatibility complex (MHC) class II gene transcription. We demonstrate here that CIITA requires the ATPase subunit of an hSWI/SNF complex, brahma-related gene 1 (BRG-1), to activate transcription. When introduced into a cell line lacking BRG-1, CIITA was unable to activate cellular MHC class II genes. Reexpression of the wild-type but not an ATP-binding-deficient BRG-1 protein in this cell line restored the ability of CIITA to transactivate transcription of MHC class II genes. Interestingly, when the activity of CIITA was assayed in the BRG-1-deficient cell line by using a plasmid-based reporter assay, BRG-1 was not required for transcriptional activation, suggesting that the chromatin structure on the plasmid is such that BRG-1 is not necessary. Coimmunoprecipitation experiments were performed to determine if BRG-1 and CIITA proteins associate with each other in cells. We found that the two proteins coimmunoprecipitate and that amino acids 1 to 140 of CIITA are sufficient for binding. Taken together, these data suggest that BRG-1 and, very likely, an hSWI/SNF complex are required for transcription of MHC class II genes. The complex is likely recruited to MHC class II promoters, at least in part, by interaction with CIITA.

Adenosine Triphosphatases↗
PubMed1989

Class inequality in health. A methodological study of two measures of social class in relation to sickness insurance diagnoses.

Measures of social class, if related to different class concepts, should differ in external consistency. External consistency depends on the character of the dependent variable. Two measures of social class are here used for independent variables, the socio-economic classification, the official index of Sweden, and a structural class concept. For dependent variables, ICD diagnose chapters, directly and in a simple grouping, are used on a material from health insurance authorities. Class inequality is measured both as to size and direction, by Gini-index and rank-order correlation, respectively. Separate analyses are made for the whole material, men and women, and doctor certified absence days. Results show clear differences between the class measures for diagnoses more closely associated to work conditions, while the measures coincide in other cases.

Absenteeism↗
PubMed2001

The Smad3 protein is involved in TGF-beta inhibition of class II transactivator and class II MHC expression.

TGF-beta is a immunoregulatory cytokine that inhibits class II MHC expression in a variety of cell types. Previous studies have shown that the class II MHC transactivator (CIITA), a master regulator that controls class II MHC expression, is targeted by TGF-beta for repression of IFN-gamma-induced class II MHC expression in astrocytes. The mechanism(s) underlying the TGF-beta inhibitory effect is not understood. In this study, we demonstrate that TGF-beta inhibition of CIITA expression occurs at the transcriptional level, and that both constitutive and IFN-gamma-induced human CIITA type IV promoter activity is inhibited by TGF-beta. TGF-beta does not affect the signaling events that mediate IFN-gamma activation of CIITA expression; i.e, TGF-beta does not inhibit IFN-gamma-induced STAT-1alpha phosphorylation and/or DNA binding ability, nor is IFN-gamma induction of IFN regulatory factor affected. The inhibitory effect of TGF-beta on the type IV CIITA promoter is mediated through a promoter region within 80 bp from the transcription start site. Elimination of TGF-beta inhibition of class II MHC and CIITA expression in Smad3-deficient astrocytes, as well as restoration of the inhibitory effect by overexpression of the Smad3 protein, demonstrates that Smad3 is essential in mediating TGF-beta inhibition of CIITA and class II MHC expression.

5' Untranslated Regions↗
PubMed2004

MHC class II molecules play a role in the selection of autoreactive class I-restricted CD8 T cells that are essential contributors to type 1 diabetes development in nonobese diabetic mice.

Development of autoreactive CD4 T cells contributing to type 1 diabetes (T1D) in both humans and nonobese diabetic (NOD) mice is either promoted or dominantly inhibited by particular MHC class II variants. In addition, it is now clear that when co-expressed with other susceptibility genes, some common MHC class I variants aberrantly mediate autoreactive CD8 T cell responses also essential to T1D development. However, it was unknown whether the development of diabetogenic CD8 T cells could also be dominantly inhibited by particular MHC variants. We addressed this issue by crossing NOD mice transgenically expressing the TCR from the diabetogenic CD8 T cell clone AI4 with NOD stocks congenic for MHC haplotypes that dominantly inhibit T1D. High numbers of functional AI4 T cells only developed in controls homozygously expressing NOD-derived H2(g7) molecules. In contrast, heterozygous expression of some MHC haplotypes conferring T1D resistance anergized AI4 T cells through decreased TCR (H2(b)) or CD8 expression (H2(q)). Most interestingly, while AI4 T cells exert a class I-restricted effector function, H2(nb1) MHC class II molecules can contribute to their negative selection. These findings provide insights to how particular MHC class I and class II variants interactively regulate the development of diabetogenic T cells and the TCR promiscuity of such autoreactive effectors.

Animals↗
PubMed1992

Overlapping epitopes that are recognized by CD8+ HLA class I-restricted and CD4+ class II-restricted cytotoxic T lymphocytes are contained within an influenza nucleoprotein peptide.

Viral epitopes that are recognized by both HLA class I-restricted and class II-restricted T cells have been defined for a type A influenza virus nucleoprotein (NP) peptide. CD8+ and CD4+ CTL lines have been generated against a synthetic peptide encompassing residues 335 to 349 of NP that are restricted by HLA-B37 and HLA-DQw5, respectively. Both of these CTL populations were capable of specifically lysing influenza A virus-infected targets, indicating that a naturally processed NP peptide(s) was being mimicked by the NP (335-349) peptide. Amino acid residues that are critical for recognition of this NP determinant in the context of HLA-B37 and HLA-DQw5 were investigated by the use of panels of truncated and alanine-substituted NP peptides. The results demonstrate that: 1) truncations in the amino- or carboxy-terminal ends differentially affect CD8+ and CD4+ CTL recognition; 2) the NP (335-349) sequence contains two octapeptide epitopes that share a core of six amino acid residues (NP 338-343); and 3) alanine substitutions at five of these residues abrogated recognition by at least one of the CD8+ and CD4+ CTL lines. Thus, these class I- and class II-restricted CTL lines recognize similar but distinct epitopes, and different structural features of the NP peptide are required for presentation by HLA-B37 and HLA-DQw5. Comparison of the amino acid sequences of the NP peptide presented by HLA-B37 and HLA-DQw5 with other peptides known to be presented by both class I and class II molecules revealed a common motif among these peptides.

Amino Acid Sequence↗
PubMed1990

Transfection into mouse L cells of genes encoding two serologically and functionally distinct bovine class I MHC molecules from a MHC-homozygous animal: evidence for a second class I locus in cattle.

w10 and KN104 are distinct class I major histocompatibility complex (MHC) serological specificities present in Boran (Bos indicus) cattle. Although these specificities are commonly expressed together, they may also be expressed independently. To establish whether w10 and KN104, when expressed together, are on the same or different molecules, and whether a second class I MHC locus exists in cattle, genomic DNA from an animal homozygous for a haplotype encoding the w10 and KN104 specificities was transfected into thymidine kinase-deficient mouse L cells (Ltk- cells), and the transfected cells were screened with monoclonal antibodies (mAb) specific for the w10 or KN104 allospecificities. Two different populations of transfectants were identified: the cells of one population reacted only with w10-specific mAb, whereas those of the other population were recognized only by the KN104-specific mAb. Alloreactive cytotoxic T lymphocytes (CTL) also distinguished between the two populations. Two CTL clones, shown to be restricted by the KN104 specificity, killed only those L cells expressing molecules recognized by the KN104-reactive mAb. Of eight CTL clones which recognized class I molecules associated with the w10 specificity, four killed the L cells expressing the w10 specificity. The remaining four clones did not kill either population of transfectants. Finally, immunoprecipitation studies revealed that both populations express full-length bovine class I MHC molecules. These results demonstrate that the w10 and KN104 specificities are on distinct class I molecules. As the genes encoding these molecules were derived from a MHC-homozygous animal, the findings also provide strong evidence that there are at least two classical class I loci in cattle.

Animals↗
PubMed1987

Parasite-accessory cell interactions in murine leishmaniasis. II. Leishmania donovani suppresses macrophage expression of class I and class II major histocompatibility complex gene products.

In the present study, we examined the modulation of MHC class II and class I gene products on BALB/c macrophages infected with the obligate intracellular protozoan Leishmania donovani. Our findings indicated that this organism suppressed macrophage expression of both classes of MHC antigens. These effects varied somewhat, depending on whether cells were in the basal state or were stimulated with interferon-gamma. Thus, class II density on interferon-gamma-treated infected macrophages was suppressed by as much as 90%, relative to lymphokine-stimulated control cells. Induction of H-2K and H-2D by lymphokine treatment of infected macrophages was also markedly reduced. In the basal (non-lymphokine-treated) state, infected cells also showed reduced expression of H-2K and H-2D, but not I-A or I-E. The latter result was related to minimal levels of class II molecules on normal, in vitro cultured macrophages. Suppression of MHC gene products correlated with both the duration and intensity of leishmania infection and could not be overcome by increasing doses of interferon-gamma. Culture of cells under conditions of cyclooxygenase inhibition completely abolished elevated synthesis of prostaglandin E2 by infected macrophages and augmented their responsiveness to lymphokine induction of class II antigens by 60 to 80%. These results indicate that L. donovani is capable of subverting a critical macrophage accessory function required for the induction of T lymphocyte immunity. This mechanism could account, at least in part, for defective parasite-specific cell-mediated immunity seen during infections with this protozoan.

Animals↗
PubMed1989

Rheumatoid T lymphocyte MHC class II expression: in vitro stimulation produces normal MHC class II expression, independent of proliferation.

MHC Class II mediated immune responses, such as tuberculin PPD, are often subnormal in rheumatoid arthritis (RA). We investigated peripheral blood T lymphocyte proliferation and Class II expression after stimulation with phytohemagglutinin, OKT3 and tuberculin PPD, using double label immunofluorescence and flow cytometry. No difference was found in the percentage of Class II positive T lymphocytes or intensity of fluorescence of Class II between matched controls and patients with RA. A disparity between Class II expression and proliferation was noted, particularly in the 50% of patients with RA with poor proliferation to PPD, who showed normal Class II expression, indicating that these 2 functions are under separate control.

Adult↗
PubMed1988

The effect of class and collection labels on cardinality, class-inclusion, and number conservation tasks.

3 experiments were carried out to assess Markman's hypothesis that the organizational principles underlying collection concepts facilitate children's performance on cognitive tasks requiring part-whole comparisons. In Experiment 1, the effect of class/collection labels on both cardinality and class-inclusion tasks was assessed. 32 3- and 4-year-olds from 2 populations (suburban middle class and inner-city working class) received both tasks. An additional 32 kindergarten and first-grade children from the 2 populations received the class-inclusion task. For cardinality, there was no difference in performance as a function of label. A facilitative effect of the collection label was found for class inclusion. Experiment 2 assessed the effect of class/collection labels on 28 nursery school children's demonstration of number conservation. Experiment 3 extended the age range and examined the effect of label on 56 kindergartners' and first graders' performance on number conservation. Both experiments failed to replicate Markman's findings. The results of the 3 experiments indicate that the facilitative effect of collection labels appears to be specific to the class-inclusion task. In light of these failures to replicate and the considerable variation in cognitive level among preschoolers, it is suggested that Markman's findings of a facilitative effect of collection labels on conservation and cardinality problems may have resulted from the use of small sample sizes and between-subject designs.

Attention↗
PubMed1986

Expression of MHC class II antigens in human B-cell leukaemia, and increased levels of class II antigens and DR-specific mRNA after stimulation with 12-O-tetradecanoyl phorbol-13-acetate.

Cells from the peripheral blood of B-cell chronic lymphocytic leukaemia (CLL) patients were examined serologically for the expression of cell surface MHC class II antigens with monoclonal antibodies (mAbs) specific for the products of HLA-DP, -DQ and -DR genes, and mRNAs from the cells of three patients were analysed with a cDNA probe specific for DR beta chain genes. In 12 cases of CLL studied by indirect immunofluorescence and FACS analysis, a variable proportion of cells failed to express detectable levels of HLA-DP and HLA-DQ antigens at the cell surface, although greater than 90% of the cells had detectable expression of HLA-DR antigens. In all cases, greater than 90% of the cells expressed MHC class I antigens and the majority of cells reacted with the Leu-1 (CD5) mAb. Cells from different patients expressed variable levels of MHC class II antigens, and this was reflected in the finding of variable levels of mRNA detectable with the cDNA probe. Culture of cells with the phorbol ester 12-O-tetradecanoyl phorbol-13-acetate (TPA) induced much increased levels of expression of MHC class II antigens. HLA-DP and -DQ antigens were expressed on greater than 90% of the cells in all cases studied after culture of the cells with TPA, and MHC class II specific mRNA transcripts were correspondingly increased. In a single case of plasma cell leukaemia studied, MHC class II antigens were not detectable at the cell surface and their expression was not induced after culture of the cells with TPA.

Antibodies, Monoclonal↗
PubMed1981

Significance of class 1 and class 2 major histocompatibility complex antigens: help to allogeneic K and D antigens does not involve I recognition.

The significance of the dichotomy of MHC antigens was investigated. It was determined that primed helpers directed against allogeneic class 1 antigens (K and D in the mouse) were not restricted to syngeneic class 2 antigens (I in the mouse). Furthermore, the generation of helper T cell-replacing factor by stimulation with K or D antigens was not blocked by Ia antibodies that were effective in blocking the same factors generated in response to I region MHC antigens. It is concluded that class 2 antigens are not recognized during the response of helpers to class 1 antigens, and it is suggested that class 1 and class 2 molecules can perform reciprocal functions.

Animals↗
PubMed1995

DMA and DMB are the only genes in the class II region of the human MHC needed for class II-associated antigen processing.

Previous studies have shown that homozygous mutations between the LMP2 and DNA loci in the human MHC cause class II molecules to be abnormally conformed and unstable in the presence of SDS at low temperature, and impede class II-associated Ag processing and presentation. These abnormalities result from impaired ability to form intracellular class II/peptide complexes that predominate in normal cells. We show in this work that this defect results from deficient expression of either the DMA or the DMB gene. Human B-LCL.174 (DR3) cells, which have a deletion of all known expressible genes in the class II region, express transgene-encoded HLA-DR3, but have the abnormalities. Transfer of cosmid HA14, which contains the DMA and DMB genes, into .174 (DR3) cells restored normal DR3 conformation, stability in 0.4% SDS at 0 degree, and ability to process and present tetanus toxoid, but only when both DMA and DMB mRNAs were present. The requirement for both genetic expressions in engendering normal phenotypes was confirmed by transferring the cloned genes into .174 (DR3) cells separately or together. Because normal phenotypes were fully restored in transferent cells expressing DMA plus DMB, other genes in the approximately 1-mb homozygous class II region deletion in .174 (DR3) cells either do not participate in or are dispensable for apparently normal production of intracellular class II/peptide complexes. The properties of DM-deficient EBV-transformed B lymphoblastoid cell lines (LCLs) suggest ways of identifying humans in whom DM deficiency contributes to congenital immunodeficiency and malignancy.

Antigen Presentation↗
PubMed1997

Up-regulation of cytokine mRNA, adhesion molecule proteins, and MHC class II proteins in salivary glands of TGF-beta1 knockout mice: MHC class II is a factor in the pathogenesis of TGF-beta1 knockout mice.

Mice homozygous for a disrupted TGF-beta1 allele develop multiple lymphoproliferative disorders similar to those seen in the pseudolymphoma of Sjögren's syndrome. At 2 wk of age, these TGF-beta1 mutant mice begin to develop wasting syndrome and die at around 4 to 5 wk of age. We studied salivary glands from symptomatic mutant mice >14 days of age. Reverse transcriptase-PCR analysis showed up-regulation of proinflammatory cytokine genes such as IL-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-10, and IFN-gamma in these mutant mice. Enhanced expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule (VCAM-1), and MHC class II as well as CD4-positive T lymphocyte infiltration was detected by immunostaining. To elucidate the role of MHC class II, salivary glands from TGF-beta1/MHC class II double knockout mice were used to investigate the expression of adhesion molecules and MHC class II. In spite of the existence of basal intercellular adhesion molecule-1 expression on vessels, there was neither MHC class II expression, enhanced vascular cell adhesion molecule-1 expression, nor lymphocytic infiltration in the salivary glands. These results suggest that MHC class II plays a significant role in the pathogenesis of TGF-beta1 mutant mice. Although the mechanism that initiates multiple inflammatory diseases in these mice remains unclear, the context reported here would provide insight into the immunopathology of Sjögren's syndrome.

Animals↗
PubMed1997

In vitro and in vivo evidence for high frequency of I-Ab-reactive CD4+ T cells in HLA-DQ or HLA-DRA transgenic mice lacking endogenous MHC class I and/or class II expression.

Although T cells are educated to recognize foreign antigenic peptides in the context of self MHC molecules during their development in the thymus, peripheral T cells also recognize allo- and xeno-MHC molecules. The lower frequency of xeno-MHC-reactive T cells than that of allo-MHC-reactive T cells is often explained by the difference in the degree of homology between xeno- or allo-MHC and self MHC molecules, as well as by the species barrier of the molecules involved in immune recognition. To distinguish these two possibilities, we estimated the frequency of I-Ab-reactive CD4+ T cells selected by HLA-DQ or DR alpha E beta b molecules, using HLA-DQ6 and HLA-DRA transgenic C57BL/6 (B6) mice lacking endogenous MHC class I and/or class II molecules (DQ6A0/0 and DR alpha 30A0/0 beta 20/0). CD4+ lymph node T cells from DQ6A0/0 and DR alpha 30A0/0 beta 20/0 showed the strong proliferative response to I-Ab molecules. In addition, DQ6A0/0 and DR alpha 30A0/0 beta 20/0 rejected the skin graft from mice expressing I-Ab molecules irrespective of MHC class I expression, indicating that the CD4+ T cells recognizing I-Ab molecules are directly involved in this rejection. The estimated frequency of I-Ab-reactive CD4(+)CD8- thymocytes in DR alpha 30A0/0 beta 20/0 and DQ6A0/0 was comparable with that observed in the MHC class II-disparate strains. Our findings thus indicate that CD4+ T cells selected to mature on xeno-MHC class II molecules such as HLA-DQ6 or DR alpha E beta b, when these molecules are expressed in mice, recognize I-Ab molecules as allo-MHC class II, despite the less structural homology.

Animals↗
PubMed1985

A new class of cardiotonic agents: structure-activity correlations for natural and synthetic analogues of the alkaloid A new class of A new class of cardiotonic agents: structure-activity correlations for natural and synthetic analogues of the alkaloid pumiliotoxin B (8-hydroxy-8-methyl-6-alkylidene-1-azabicyclo[4.3.0]nonanes).

Pumiliotoxin B (PTX-B, 6-(6',7'-dihydroxy-2',5'-dimethyl-(E)-4'-octenylidene)-8-hydroxy-8 -methyl-1- azabicyclo-[4.3.0] nonane) increases the force of contractures of spontaneously beating guinea pig atrial strips by 3- to 5-fold with half-maximal effects at about 3 microM and increases rates of atrial contractions by 2- to 3-fold with half-maximal effects at about 6 microM. The presence of an axial 7-hydroxy substituent (PTX 339A) decreases the efficacy but not the potency of PTX-B as a positive inotropic agent while having only slight effects on activity as a positive chronotropic agent. The presence of an equatorial 7-hydroxy substituent (PTX 339B) greatly decreases efficacy and potency of PTX-B as a positive chronotropic and inotropic agent. Pumiliotoxin A which lacks the side-chain 7'-hydroxy group of PTX-B causes only a 2-fold increase in force of contracture at 54 microM while having minimal effects on rate. The presence of an axial 7-hydroxy substituent (PTX 323B' and 323B", epimeric at the 6'-hydroxy) markedly enhances positive inotropic and chronotropic effects of PTX-A. Another congener, PTX 251D with a 6-(2'-methylhexylidene) side chain, and a synthetic analogue with a 6-(6'-heptenylidene) side chain are cardiac depressants. Both lack hydroxyl groups in the side chain. The presence of an omega-1 hydroxy group in the side chain of PTX 251D yields an alkaloid (267C) with weak positive inotropic effects and minimal chronotropic effects. The presence of an axial 7-hydroxy group in the indolizidine ring of PTX 251D results in a compound (PTX 267A) with very weak positive inotropic effects while retaining the negative chronotropic effects of PTX 251D. A synthetic analogue with a 6-(7'-hydroxyheptylidene) side chain is a cardiac depressant even though it contains a side-chain hydroxyl corresponding in position to the 7'-hydroxyl of the side chain of PTX-B. The positive chronotropic and inotropic effects of pumiliotoxin B are reversed only by relatively high concentrations of the calcium channel blockers nifedipine and verapamil, suggesting that pumiliotoxin B may owe its cardiotonic activities to effects on internal mobilization of calcium.

Alkaloids↗