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PubMed2004

17beta-Estradiol inhibits class II major histocompatibility complex (MHC) expression: influence on histone modifications and cbp recruitment to the class II MHC promoter.

Major histocompatibility complex (MHC) class II proteins are important for the initiation of immune responses and are essential for specific recognition of foreign antigens by the immune system. Regulation of class II MHC expression primarily occurs at the transcriptional level. The class II transactivator protein is the master regulator that is essential for both constitutive and interferon-gamma-inducible class II MHC expression. Estrogen [17beta-estradiol (17beta-E2)] has been shown to have immunomodulatory effects. In this study, we show that 17beta-E2 down-regulates interferon-gamma inducible class II MHC protein levels on brain endothelial cells, as well as other cell types (astrocytes, fibrosacroma cells, macrophages). The inhibitory effects of 17beta-E2 on class II MHC expression are not due to changes in class II transactivator mRNA or protein levels, rather, 17beta-E2 mediates inhibition at the level of class II MHC gene expression. We demonstrate that 17beta-E2 attenuates H3 and H4 histone acetylation and cAMP response element binding protein-binding protein association with the class II MHC promoter, suggesting that 17beta-E2 inhibits class II MHC expression by a novel mechanism involving modification of the histone acetylation status of the class II MHC promoter.

Acetylation↗

PubMed1986

The role of class II MHC molecules in the activation of class I-reactive T cell hybridomas.

To examine the role of Ia molecules in T cell responses to allo-class I major histocompatibility antigens, a series of allo-class I-reactive T cell hybridomas was established. Of 134 T cell hybridomas obtained from the fusion of C3H/HeJm or B10.HTT T cells stimulated with C57BL/6 splenocytes, nine T cell hybridomas were reactive to class I antigens and 126 T cell hybridomas were reactive to class II antigens. Six of the nine IL 2-producing T cell hybridomas were further analyzed: five mapped to H-2Kb and the other mapped to H-2Db. Three of these T cell hybridomas, HTB-157.7, HTB-176.10, and HTB-177.2, could react to the EL-4 cell line that expresses H-2Kb and H-2Db class I antigens but lacks class II I-Ab molecules. Furthermore, the activation of these three T cell hybridomas with C57BL/6-derived splenocytes was not blocked by either anti-I-A or anti-L3T4 antibody. In contrast, the other three T cell hybridomas, CB-127.6, CB-221.7, and HTB-102.7, failed to react with EL-4 but reacted with the LB cell line which expresses class I (H-2Kb, H-2Db) and class II (I-Ab) molecules. Although class II molecules were required for activation of the latter clones, there was no apparent I-A allele specificity, suggesting that a relatively nonpolymorphic Ia determinant was involved. The activation of the three latter T cell hybridoma clones with C57BL/6 splenocytes could be blocked completely by either anti-I-A or anti-L3T4 antibody. The data are interpreted in terms of possible T cell receptor models for recognition of class I with nonpolymorphic class II determinants.

Animals↗

PubMed1989

Physical association between MHC class I and class II molecules detected on the cell surface by flow cytometric energy transfer.

The physical association of HLA class I and class II Ag in the membranes of PGF and JY lymphoblastoid cell lines was studied using flow cytometric energy transfer. This technique measures the proximity of cell surface molecules in the nm range and provides a distribution histogram of the average proximity of molecules on each cell of a population. HLA Ag were labeled with mAb conjugated to fluorescein, serving as donor, or tetramethylrhodamine, serving as acceptor molecules. Significant fluorescence energy transfer was detected between various combinations of class I and class II molecules indicating that these molecules are within 10 nanometers of each other. Specifically, energy transfer was observed between class I molecules and DR, DQ, or DP class II HLA molecules. In addition, energy transfer between all combinations of DR, DQ, and DP molecules was observed. No transfer was observed among class I molecules or among DR or among DP molecules. Among DQ molecules, subpopulations transferred fluorescence energy to each other. The close contact measured between class I and class II Ag correlates with previous reports of cocapping and may reflect an immunologically significant interaction or the reported tendency of class I Ag to associate with other cell surface receptors, including growth factor receptors. The energy transfer between fluorescent antibodies to class II Ag suggests the existence of heterodimers formed from the different locus products, as well as possible quaternary surface interactions between alpha/beta complexes from separate loci.

Antibodies, Monoclonal↗

PubMed1985

In vivo treatment of neonatal mice with anti-I-A antibodies interferes with the development of the class I, class II, and Mls-reactive proliferating T cell subset.

In this study we investigated the effect of monoclonal anti-I-A Ab treatment of neonatal mice on the development of alloreactive class I-specific, class II-specific, and Mls-specific T cell proliferative responses. Responses to both class I and class II alloantigens, as well as to Mls antigens, were nearly abrogated at the end of the 2- to 3-wk in vivo treatment period in both the thymus and the spleen. Development of suppressor cells could be excluded as the cause of the observed defect. Diminished responsiveness could not be restored by the addition of IL 2-containing supernatant, suggesting that the reduced T cell proliferative response in anti-I-A-treated mice is due to defective or absent MHC-specific T cell precursors. Furthermore, generation of alloreactive class I-specific proliferative responses was dependent on self-class II recognition, thus providing an explanation for the absence of class I-specific proliferating T cells. Finally, a non-Ia-restricted T cell response, i.e., Con A-induced proliferation, was not affected by anti-I-A Ab treatment. It was previously reported that neonatal anti-Ia Ab treatment results in reduced Ia-antigen expression in the thymus, and that the development of the class I-specific CTL precursors proceeds undisturbed in these mice. The present results extend these findings and suggest that in vivo development of class II-restricted T cells is dependent on interaction with Ia-encoded products on cells either in the thymus or at other sites where T cells undergo development. Moreover, these results demonstrate that in vivo development of the alloreactive class II-specific T cell repertoire is dependent on development of self-class II recognition.

Animals↗

PubMed1988

Class II antigen-specific murine cytolytic T lymphocytes (CTL). II. Genuine class II specificity of Lyt-2+ CTL clones.

Class II-specific allogeneic cytolytic T lymphocytes (CTL) consist of two types of cells, i.e., Lyt-2+L3T4- and Lyt-2-L3T4 T cells. The Lyt-2+L3T4- class II-specific CTL population constitutes a conspicuous exception to the general correlation observed between the class of major histocompatibility complex antigen recognized and the type of accessory molecules expressed by T cells. In order to examine the specificity of such an exceptional T cell population, CTL clones were established by limiting dilution of a bulk CTL line developed in an I region incompatible combination of mouse strains, B10.QBR anti-B10.MBR. These CTL lines showed single genetic specificity indicating their clonal nature with respect to CTL activities. Lyt-2+L3T4- (2+4-), Lyt-2-L3T4+ (2-4+) and Lyt-2-L3T4- (2-4-) clones were obtained. Among many CTL clones showing a spectrum of genetic specificities, 2+4- and 2-4+ clones with apparent I-Ak-specificity, were studied further and four lines of evidence confirmed their class II specificity: 1) genes encoding the target antigen for these CTL clones were mapped within the I-A subregion by simple genetics; 2) an I-Ak-specific monoclonal antibody readily blocked specific cytolysis by these clones; 3) the clones failed to react with cells expressing mutated I-Ak antigens; and 4) a B cell tumor transfected with alpha- and beta-chain genes of I-Ak was specifically lysed by these CTL clones. These data therefore establish the existence of Lyt-2+ CTL with genuine class II specificity. All 2-4+ CTL were sensitive to the blocking effect of an antibody to L3T4, whereas none of the 2+4- class II-specific CTL were sensitive to blocking by an anti-Lyt-2 antibody, indicating that class II-specific CTL with "wrong phenotype" is not dependent on the function of the accessory molecule. Besides true class II-specific CTL clones, 2+4- clones with a spectrum of genetic specificities were obtained, including clones recognizing a combination of an I-Ak product and the Kb molecule. Two 2-4- clones were also specific for the combination of Kb + I-Ak. These clones most likely recognize an allogeneic class II antigen in the context of a class I antigen and therefore would more appropriately be included in the class I-restricted T cell population.

Animals↗

PubMed1995

TAP associates with a unique class I conformation, whereas calnexin associates with multiple class I forms in mouse and man.

To define the rules governing de novo assembly of the trimeric class I complex, we have identified the class I folding/assembly intermediates associated with calnexin or TAP, using both human and mouse cell lines. To better characterize the class I H chain structure associated with TAP, mouse mAb that distinguish open (64-3-7+) vs folded (30-5-7+) Ld heavy (H) chains were used. We report here that open forms of Ld are uniquely and specifically associated with TAP and that the conformational change in the class I H chain coincident with peptide binding induces TAP release. Chimeric Ld/Q10 displayed TAP association, demonstrating that soluble class I molecules can bind TAP. As previously reported, beta 2m was found to be required for H chain association with TAP. Interestingly, beta 2m was associated with TAP in the human class I-negative cell line LCL 721.221, suggesting that beta 2m can bind to TAP before class I H chain. In contrast to TAP, which binds a specific class I conformation, calnexin was detected in association with multiple forms of both mouse and human class I. Most significantly, we show for the first time that beta 2m-assembled forms of human as well as mouse class I molecules interact with calnexin. Based on these findings, we propose a model for the sequential assembly of class I heterotrimers and their respective interactions with TAP and calnexin.

ATP-Binding Cassette Transporters↗

PubMed1993

Human cytomegalovirus down-regulates HLA class I expression by reducing the stability of class I H chains.

Human CMV (HCMV) infection leads to an almost complete inhibition of expression of MHC class I proteins. After infection with HCMV, the biosynthesis of HLA class I molecules was examined in human lung fibroblasts and in mouse fibroblasts transfected with genes encoding the human class I H chain HLA-B27 and human beta 2-microglobulin (beta 2m). In both cell types, we observed a large decrease in steady state levels specific for human class I H chains--both free H chains and those complexed with beta 2m. In the mouse cells transfected with HLA class I, infection did not affect levels and assembly of mouse class I H chains with human beta 2m. The effect of HCMV infection on class I expression is insensitive to phosphonoacetic acid, suggesting the involvement of immediate early or early viral proteins. Pulse-chase analysis showed that the low steady state level of class I H chains in HCMV-infected cells is not the result of a reduced rate of synthesis. Rather, we observed accelerated degradation of class I H chains, regardless of their association with beta 2m. We conclude that HCMV reduces human MHC class I protein levels by interference with the stability of class I H chains.

Animals↗

PubMed1998

Rejection of allogeneic and syngeneic but not MHC class I-deficient tumor grafts by MHC class I-deficient mice.

The ability of TAP1-/-, beta2m-/-, and TAP1/beta2m-/- mice to mount rejection responses against allogeneic, syngeneic, and MHC class I-deficient tumor grafts was examined. The results demonstrate a potent ability of TAP1-/- and beta2m-/- as well as TAP1/beta2m-/- mice to reject allogeneic tumors. In contrast to published data, rejection of syngeneic MHC class I-expressing tumors was also observed. This response was specific for the MHC class I-deficient mice, since wild-type mice did not reject syngeneic MHC class I-positive tumors under identical experimental conditions. The rejection response of syngeneic tumors required preimmunization of the mice and was MHC class I specific at the level of priming as well as at the level of the tumor target. Finally, MHC class I-deficient tumor grafts were accepted in MHC class I-deficient mice while similar grafts were rejected in wild-type mice. In summary, while MHC class I-deficient mice have retained a capacity to reject allogeneic tumors. they have gained an ability to reject syngeneic MHC class I-positive tumors and lost the ability to reject MHC class I-negative tumors. The present results are discussed in relation to the role of MHC class I molecules in selecting functional CD8+ T and NK cell repertoires, and the development of cell-mediated immunity.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1991

Homotypic aggregation of human cell lines by HLA class II-, class Ia- and HLA-G-specific monoclonal antibodies.

Major histocompatibility complex (MHC) class II molecules have been implicated in cell adhesion in two ways. In addition to the well-established role of class II antigens in low-affinity adhesion provided by interactions between class II and CD4, recent data indicated that class II may also induce adhesion between T and B cells by activating the CD18/CD11a (LFA-1) adhesion pathway. Here we report that monoclonal antibodies (mAb) against HLA-DR (L243, p4.1, HB10a, VI15) and certain broad class II reacting mAb (TU35, TU39), but not anti-DQ (TU22, Leu-10) mAb, induced homotypic aggregation of human class II-positive monocytic (I937) and T leukemic (HUT78) tumor cell lines and Epstein-Barr virus (EBV) transformed B-lymphoid cell lines (EBV-LCL). Class II-negative cell lines (U-937 and the EBV-LCL mutant line 616) were not induced to aggregate. An HLA-G-transfected EBV-LCL, 221-AGN, but not the class I-negative parental line, 221, showed homotypic aggregation in response to an HLA-G specific mAb (87G) and a broad reacting class I-specific mAb (IOT2). Both cell lines responded with aggregation to anti-class II mAb (TU35). The anti-class I mAb, W6/32, had no effect on all cell lines tested and two anti-beta 2-microglobulin mAb had variable, weak effects. The aggregation response was an active, temperature-sensitive process which was almost totally abrogated by azide and by cytochalasins B and E, but unaffected by colchicine, EDTA, aphidicolin, actinomycin D and protein tyrosine kinase inhibitors (genistein, herbimycin A). Serine/threonine protein kinase inhibitors (staurosporin, H7) partly inhibited the aggregation responses. There was no strict correlation between induction of aggregation and epitope density. FcR were not involved in the aggregation response, since F(ab')2 fragments of anti-DR mAb, L243, were as effective as the whole antibody. The aggregation was not influenced by mAb against accessory molecules previously shown to be involved directly or indirectly in homotypic aggregation [CD11a (LFA-1)/CD18/CD54 (ICAM-1), CD58 (LFA-3)/CD2, BB1/CD28, CD43, and CD44]. In conclusion, these data provide further evidence that HLA molecules are implicated in a novel, cellular aggregation phenomenon involving the cytoskeleton.

Antibodies, Monoclonal↗

PubMed1998

Rate-dependence of antiarrhythmic and proarrhythmic properties of class I and class III antiarrhythmic drugs.

Rate or frequency-dependence is a characteristic property of antiarrhythmic drugs belonging to the Vaughan William classes I and III. The rate-dependence of class I drugs (i.e., increasing blockade of fast Na(+)-channels with faster rates) results from periodical drug binding to Na(+)-channel sites which are preferably available in the activated and/or inactivated channel states (use-dependence). With respect to their binding and unbinding kinetics, class I drugs can be subdivided into three groups (group 1-group 3) which differ in their block-frequency relations as well as in their onset kinetics of channel blockade. These properties can serve as predictors of the anti- and proarrhythmic potential of class I drugs. Class III drugs (blockers of potassium channels) are mostly characterized by reverse rate-dependence (loss of class III action at faster rates). However, this property cannot be attributed to reverse use-dependence, i.e., binding to channels in the rested state. It is more likely due to different rate-dependent contributions of the two components of the delayed rectifier potassium current to repolarization, when the rapidly activating, the rectifying component IKr is specifically blocked by class III drugs, while the slowly activating component IKs remains unchanged. In spite of their reverse rate-dependence, class III drugs exert an antifibrillatory effect when fibrillation is induced by frequent stimulation. This can be attributed to the slow time course of the decline (offset kinetics) of the class III effect accompanying a sudden increase in frequency. Proarrhythmic effects of class III drugs result from the delay in repolarization that may favor the development of early afterdepolarizations. The proarrhythmic potential of class III drugs is species dependent and is favored if the contribution of IKr to the repolarization phase of the action potential is comparatively large.

Action Potentials↗

PubMed1991

Class II radical hysterectomy shows less morbidity and good treatment efficacy compared to class III.

Treatment of 102 patients with cancer of the cervix by class II and III radical hysterectomy was reviewed to compare the operative morbidity and efficacy of class II radical hysterectomy for select cases. Of the 102 patients, 21 had a class II hysterectomy, whereas 81 patients had a class III hysterectomy. The class II operation was performed for those subjects in whom invasive cancer beyond microinvasion could not be excluded after a cone biopsy. The mean age and weight of women having class II and III radical hysterectomies were nearly identical (41.1 and 40.6 years, respectively, and 66 and 65 kg, respectively). However, the mean operative time (3.8 and 4.7 hr, respectively; P = 0.001) and postoperative hospital stay (7.3 and 9.2 days, respectively; P = 0.001) were lower for class II than for class III hysterectomies. No fistulas or recurrent cancer developed following class II hysterectomy, and no patients had metastatic cancer in the nodes or parametrium. Among the 81 women undergoing class III hysterectomy, there were 3 fistulae and 3 recurrences. We conclude that the lesser morbidity, including shorter operative time and shorter postoperative hospital stay and excellent cancer control of the class II radical hysterectomy and lymphadenectomy, recommend the operation for selected early cancers of the cervix especially when a question concerning depth of invasion exists after cone biopsy.

Adult↗

PubMed1989

Interleukin 2 production by alloantigen-stimulated CD4+ and CD8+ human T cell subsets: frequency of HLA class I or class II-reactive precursor cells and clonal specificity of activated T cells.

A recently developed limiting dilution (LD) method was used to analyze the frequency and specificity of IL2-producing cells within alloantigen-stimulated human CD4+ and CD8+ T cell subsets. Cell sorter-separated CD4+ and CD8+ responder cells were cocultured under LD conditions with HLA class I and/or class II different Epstein Barr virus (EBV)-transformed lymphoblastoid cells line (LCL) stimulator cells in the absence of additional factors. After 3 days, IL2 in cell-free culture supernatants was measured by a colorimetric assay on IL2-dependent murine CTLL cells. Under these conditions, one out of 200-500 CD4+ and one out of 300 to 1000 C8+ T cells produced IL2 when stimulated by HLA class I and class II disparate LCL. By using selected responder and stimulator cells differing only in HLA class I (A, B, C) or class II (DR) antigens, it was found that CD4+ T cells produced IL2 in response to HLA class II antigens, while CD8+ T cells produced IL2 in response to HLA class I antigens. Surprisingly, high frequencies of IL2-secreting CD4+ T cells were noted in certain HLA-DR-identical responder-stimulator combinations. To investigate whether HLA class II antigens other than DR (i.e., DQ or DP) activate CD4+ cells to IL2 secretion, we analyzed a set of HLA-A,B,C and -DR,DQ-identical responder-stimulator cells which differed only in DP antigens. In several of these instances, we measured high frequencies (f = 1/1000 to 1/2000) of HLA-DP-reactive CD4+ IL2 producers, while the frequencies in LD cultures stimulated with autologous LCL were low (f = 1/10,000 to 1/30,000). The specificity of alloantigen-activated IL2-secreting T cells was assayed by restimulation with the original or HLA-mismatched third-party LCLs. CD4+ responder cells could be efficiently and specifically restimulated to IL2 production after a resting period of 3 to 4 days, while CD8+ cells were refractory to restimulation under these conditions. Together these data demonstrate that: 1) CD4+ and CD8+ cells are stimulated to IL2 production by HLA class II and class I antigens, respectively; 2) alloantigen-activated CD4+ IL2 producers are highly specific for stimulating HLA antigens as shown by a split culture and restimulation approach; and 3) significant numbers of CD4+ IL2-producing T cells can be activated by selected HLA-DR-identical, DP-different stimulator cells.

Antigens, Differentiation, T-Lymphocyte↗

PubMed2003

Dose and time changes in liver alcohol dehydrogenase (ADH) activity during acute alcohol intoxication involve not only class I but also class III ADH and govern elimination rate of blood ethanol.

BACKGROUND: The elimination rate of blood ethanol usually depends on the activity of liver alcohol dehydrogenase (ADH). During acute alcohol intoxication, however, it is unclear how liver ADH activity changes with dose and time and what the involvement is of the two major isozymes of liver ADH: the classically known class I ADH and the very high Km class III ADH. We investigated dose- and time-wise changes in liver ADH activity and the contents of both ADHs by administering ethanol to mice, and analyzed the relationship among these ADH parameters to assess the contributions of these ADHs to liver ADH activity and ethanol metabolism in vivo. METHODS: Mice were given ethanol doses of 0, 1, 3 or 5 g/kg body weight and killed 0.5, 1, 2, 4, 8 or 12 h after administration. The elimination rate of blood ethanol was calculated from the regression line fitted to the blood ethanol curve. The liver ADH activity of crude extract was conventionally measured with 15 mM ethanol as a substrate. The liver class I and class III ADH contents were determined by enzyme immunoassay. These three ADH parameters were statistically analyzed. RESULTS: The change in liver ADH activity depended on both dose and time (P<0.001 by two-way ANOVA, n=74), but the change in the class I content depended on dose alone (P<0.0001). The class III content depended on both dose and time (P<0.001) with a time course similar to that of liver ADH activity for each dose. The sum of the class I and class III contents exhibited a higher correlation with liver ADH activity (r=0.882, P<0.0001) than the class I content alone did (r=0.825). The mean liver ADH activity during ethanol metabolism for each dose correlated significantly with the elimination rate of blood ethanol (r=0.970, P<0.0001). CONCLUSION: Liver ADH activity changes dose and time dependently during acute alcohol intoxication and governs the elimination rate of blood ethanol through the involvement not only of class I but also of class III ADH.

Alcohol Dehydrogenase↗

PubMed1996

Pea formaldehyde-active class III alcohol dehydrogenase: common derivation of the plant and animal forms but not of the corresponding ethanol-active forms (classes I and P).

A plant class III alcohol dehydrogenase (or glutathione-dependent formaldehyde dehydrogenase) has been characterized. The enzyme is a typical class III member with enzymatic parameters and substrate specificity closely related to those of already established animal forms. Km values with the pea enzyme are 6.5 microM for NAD+, 2 microM for S-hydroxymethylglutathione, and 840 microM for octanol versus 9, 4, and 1200 microM, respectively, with the human enzyme. Structurally, the pea/human class III enzymes are closely related, exhibiting a residue identity of 69% and with only 3 of 23 residues differing among those often considered in substrate and coenzyme binding. In contrast, the corresponding ethanol-active enzymes, the long-known human liver and pea alcohol dehydrogenases, differ more (47% residue identities) and are also in functionally important active site segments, with 12 of the 23 positions exchanged, including no less than 7 at the usually much conserved coenzyme-binding segment. These differences affect functionally important residues that are often class-distinguishing, such as those at positions 48, 51, and 115, where the plant ethanol-active forms resemble class III (Thr, Tyr, and Arg, respectively) rather than the animal ethanol-active class I forms (typically Ser, His, and Asp, respectively). Calculations of phylogenetic trees support the conclusions from functional residues in subgrouping plant ethanol-active dehydrogenases and the animal ethanol-active enzymes (class I) as separate descendants from the class III line. It appears that the classical plant alcohol dehydrogenases (now called class P) have a duplicatory origin separate from that of the animal class I enzymes and therefore a paralogous relationship with functional convergence of their alcohol substrate specificity. Combined, the results establish the conserved nature of class III also in plants, and contribute to the molecular and functional understanding of alcohol dehydrogenases by defining two branches of plant enzymes into the system.

Alcohol Dehydrogenase↗

PubMed1993

Structurally related class I and class II receptor protein tyrosine kinases are down-regulated by the same E3 protein coded for by human group C adenoviruses.

Receptor tyrosine kinases (RTKs) are grouped into subcategories based on shared sequence and structural features. Human group C adenoviruses down-regulate EGF receptors, which are members of the class I family of RTKs, during the early stages of infection. Adenovirus appears to utilize a nonsaturable intracellular pathway since it causes EGF-R down-regulation even in cells that significantly overexpress EGF-R. Adenovirus-induced down-regulation is mediated by a small hydrophobic molecule coded for by the E3 early transcription region that has recently been localized to plasma membrane. Here we examine intracellular trafficking of other RTKs in adenovirus-infected cells, to better understand the molecular basis for the action of the E3 protein. Although p185c-neu, which is a class I RTK closely related to the EGF receptor, is down-regulated in cells expressing physiological concentrations of this molecule, it is not down-regulated in tumor cell lines that significantly overexpress p185c-neu. Cell surface receptors for insulin and IGF1, which are class II RTKs, are also reduced in cells expressing the E3 protein, although to a slightly lesser extent than the EGF receptor. Moreover, whereas EGF receptors are degraded between 3- and 9-h postinfection, insulin and IGF1 receptors are degraded between 6- and 12-h postinfection under identical conditions. In contrast to the class I and class II RTKs, there is no difference in the expression of the class III receptors for PDGF and aFGF in cells infected with a virus with an intact E3 region versus a virus mutant with an internal deletion in the relevant E3 gene. These results suggest that the E3 protein provides an internalization and degradative sorting signal for some class I and class II RTKs, although down-regulation of class II RTKs is somewhat less efficient. Molecular recognition of class I and class II RTKs during adenovirus infection may not be due strictly to amino acid structure, however, since EGF-R but not p185c-neu is down-regulated in cells where it is significantly overexpressed.

Adenovirus E3 Proteins↗

PubMed2006

Molecular characteristics of class 1 and class 2 integrons and their relationships to antibiotic resistance in clinical isolates of Shigella sonnei and Shigella flexneri.

OBJECTIVES: To analyse the gene cassettes and determine the roles of class 1 and class 2 integrons in antibiotic-resistant strains of Shigella sonnei (n=31) and Shigella flexneri (n=33). METHODS: Various molecular techniques, including PCR and Southern-blotting analysis, were used to analyse various markers of class 1 and class 2 integrons in these 64 S. sonnei and S. flexneri isolates collected in Hangzhou, China. The gene cassette arrays in integrons were identified by DNA sequencing and/or restriction fragment length polymorphism. Two genomic DNA fragments, one containing intI1 from a S. flexneri isolate that contains intI1 but lacks 3'-conserved region and another containing intI2 from a S. sonnei isolate, were cloned into pUC19 vectors and sequenced. The links between integron gene cassette arrays and antibiotic resistance were analysed. RESULTS: Class 2 integrons were present in 80.6% (25/31) of the S. sonnei isolates and 87.9% (29/33) of the S. flexneri isolates. All of these integron 2-positive isolates contained constant gene cassette arrays of dfrA1+sat1+aadA1 which confer resistance to trimethoprim and streptomycin. It was demonstrated that the class 2 integron was located in the Tn7 region inside the attTn7 locus downstream of glmS in Shigella. Class 1 integrons were found in 9.4% (6/64) of Shigella spp. isolates. An atypical class 1 integron without a 3'-conserved segment on the Shigella chromosome, termed Shigella atypical class 1 integron (SAI), was present in 84.9% (28/33) of S. flexneri isolates. The SAI contained two gene cassettes, bla(OXA30) and aadA1; however, the SAI conferred resistance to ampicillin, but not to streptomycin, in Escherichia coli host. The bla(OXA30) and aadA1 cassettes of the SAI seemed to be always coordinately excised or integrated. CONCLUSIONS: Multiple and complex mechanisms involving mobile genetic elements in class 1 and class 2 integrons and antibiotic resistance have been developed in the evolution of Shigella strains.

Ampicillin Resistance↗

PubMed1975

Shifts from IgG-2 class to IgG-1 class in CBA and C3H anti-BALB/c antibody.

With use of a recently developed method for determining relative levels of IgG-1 and IgG-2 class antibodies of a given specificity within an unfractionated serum, it has been possible to examine anti-BALB/c antibodies in the early and late part of an immunization with allogeneic spleen cells. At about 6 days after primary immunization of CBA or C3H mice with BALB/c spleen cells, suppressive antibodies can be measured in the sera of the animals. About half of these are attributable to IgM class, and this contribution decreases to zero by the 12th day. The remaining suppressive antibodies are of IgG-2 class and these increase in concentration until day 8 or 12, or begin to decline between day 8 and day 12. Anti-BALB/c antibodies of IgG-1 class have not yet appeared on day 6, but thereafter appear and increase in concentration. Thus, antibodies of IgG-1 class begin to appear after those of the IgG-2 class and may still be increasing after the IgG-2 class has stopped to increase in concentration, antibody of IgG-1 class is continuing to increase and may even continue to increase after IgF-2 class antibody has begun to decrease in concentration. Thus, the synthesis of IgG-1 class antibody begins later and continues later than that of IgG-2 class. The implications of this sequence for our data on various effects of anti-H-2 antibodies on retention of skin allografts are discussed.

Animals↗

PubMed1986

The effects of cyclosporine on the induction of donor class I and class II MHC antigens in heart and kidney allografts in the rat.

We have previously reported 5-30-fold increases in the expression of class I and class II major histocompatibility complex (MHC) antigens in rejecting heart and kidney allografts in the DA-to-PVG rat strain combination. We examine here the effects of immunosuppression with cyclosporine on the induction of donor class I and class II MHC antigens in heart and kidney allografts in this strain combination. Immunohistological studies and quantitative absorption analyses using monoclonal antibodies and assay systems specific for donor class I and class II MHC antigens were used throughout. Heart allografts in cyclosporine-treated rats were examined on day 3,5,7,9,11, and 14 after transplantation, and kidney allografts in cyclosporine-treated rats were examined at day 7. In addition, untreated heart and kidney isografts were studied at days 1,3,5, and 7 after grafting. Immunohistological studies on frozen sections showed that cyclosporine-treated heart and kidney allografts showed no induction of class II MHC antigens, in contrast to untreated heart and kidney allografts. Class I MHC antigen induction did occur in spite of cyclosporine-therapy, but at levels lower than those seen in untreated allografts. Moreover, the pattern and degree of class I induction in the cyclosporine-treated allografts resembled very closely those seen in isografts, and so this induction was, in all probability, a consequence of the transplantation procedure rather than of specific immune responses. We also noted, in the cyclosporine-treated heart allografts, that all donor interstitial dendritic cells had disappeared and been replaced by recipient interstitial dendritic cells by the end of the second week after grafting. In addition, there was no reduction in the class II antigen content of kidney allografts treated for 7 days with cyclosporine. The absence of class II antigen induction in allografts where rejection is effectively suppressed with cyclosporine might be of clinical value in the differential diagnosis between rejection and cyclosporine toxicity in renal transplantation, and between active and inactive cellular infiltrates in heart transplantation.

Animals↗