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M A Yui

Publications and source records attributed to M A Yui.

At least 19 recordsLinked to original sources
PubMed2001

A new regulatory region of the IL-2 locus that confers position-independent transgene expression.

Although the promoter/enhancer of the IL-2 gene mediates inducible reporter gene expression in vitro, it cannot drive consistent expression in transgenic mice. The location and existence of any regulatory elements that could open the IL-2 locus in vivo have remained unknown, preventing analysis of IL-2 regulation in developmental contexts. In this study, we report the identification of such a regulatory region, marked by novel DNase-hypersensitive sites upstream of the murine IL-2 promoter in unstimulated and stimulated T cells. Inclusion of most of these sites in an 8.4-kb IL-2 promoter green fluorescent protein transgene gives locus control region-like activity. Expression is efficient, tissue specific, and position independent. This transgene is expressed not only in peripheral T cells, but also in immature thymocytes and thymocytes undergoing positive selection, in agreement with endogenous IL-2 expression. In contrast, a 2-kb promoter green fluorescent protein transgene, lacking the new hypersensitive sites, is expressed in only a few founder lines, and expression is dysregulated in CD8(+) cells. Thus, the 6.4 kb of additional upstream IL-2 sequence contains regulatory elements that provide integration site independence and differential regulation of transgene expression in CD8 vs CD4 cells.

3' Untranslated Regions↗
PubMed1996

Production of congenic mouse strains carrying NOD-derived diabetogenic genetic intervals: an approach for the genetic dissection of complex traits.

Insulin-dependent (Type 1) diabetes (IDD) in the NOD mouse is inherited as a complex polygenic trait making the identification of susceptibility genes difficult. Currently none of the non-MHC IDD susceptibility genes in NOD have been identified. In this paper we describe the congenic mouse approach that we are using for the dissection of complex traits, such as IDD. We produced a series of six congenic strains carrying NOD-derived diabetogenic genomic intervals, which were previously identified by linkage analysis, on a resistant background. These congenic strains were produced for the purpose of characterizing the function of each of these genes, alone and in combinations, in IDD pathogenesis and to allow fine mapping of the NOD IDD susceptibility genes. Histological examination of pancreata from 6 to 8-month-old congenic mice reveals that intervals on Chromosomes (Chrs) 1 and 17, but not 3, 6, and 11, contain NOD-derived genes that can increase the trafficking of mononuclear cells into the pancreas. Insulitis was observed only very rarely, even in older congenic mice, indicating that multiple genes are required for this phenotype. These results demonstrate the utility of this congenic approach for the study of complex genetic traits.

Animals↗
PubMed1994

Pivotal role of colony stimulating factor-1 in lupus nephritis.

Spontaneous autoimmune renal injury in MRL-lpr mice shares many features of human lupus nephritis. We noted a prominent increase of macrophages (M phi) in the glomerulus of MRL-lpr mice. Since colony stimulating factor-1 (CSF-1) regulates M phi growth and is a potent chemoattractant, we explored the possibility that there was an increase in CSF-1 in MRL-lpr mice. We detected a biphasic increase in circulating CSF-1 in MRL-lpr mice as compared to congenic MRL- ++ mice other strains with the lpr gene, and normal mice. There was an increase in CSF-1 steady state mRNA transcripts in the kidney but not in the liver, lung or bone marrow. By in situ hybridization our studies identified the glomeruli as the predominant source of renal CSF-1. Enhanced CSF-1 is expressed by the mesangial cells at the same time (4 weeks of age) that M phi begin to accumulate in the glomeruli, well in advance of the loss of renal function. We have isolated pure populations of glomerular M phi in culture from MRL-lpr mice. These glomerular M phi require CSF-1 to survive and proliferate. Therefore, these data suggest that CSF-1 is increased in the glomerulus prior to the influx and accumulation of M phi. We propose that CSF-1 expression in the kidney is pivotal in the attraction and accumulation of M phi and in turn responsible for initiating tissue destruction.

Animals↗
PubMed1991

Increased macrophage colony-stimulating factor in neonatal and adult autoimmune MRL-lpr mice.

Abnormal macrophages in MRL-lpr mice are implicated in the pathogenesis of autoimmune disease. These mice die of lupus nephritis by 5 to 6 months of age. This study reports that MRL-lpr mice have an increased level of circulating macrophage colony-stimulating factor (M-CSF) detectable as early as 1 week of age. Macrophage colony-stimulating factor decreased between 2 and 4 months and then steadily increased beginning at 4 months of age. In contrast, M-CSF was not detected in sera from congenic MRL-++ mice, normal C3H/FeJ mice, two other mouse strains with the lpr gene (B6-lpr and C3H-lpr), or another lupus model, the NZB/W mouse. These observations indicate that the lpr gene alone is not responsible for inducing this growth factor, and elevated M-CSF is not required for all forms of murine lupus. The entire source of serum M-CSF is not clear. The unique T cells regulated by the lpr gene are not responsible for the increased serum M-CSF levels, as no M-CSFs could be detected in supernatants from cultured lymph nodes from MRL-lpr mice, and the steady-state levels of M-CSF mRNA in lymph nodes and spleens in MRL-lpr, C3H-lpr mice and in their respective congenic strains were similar. The steady-state M-CSF mRNA transcripts in liver, lung, and bone marrow in MRL-lpr, MRL-++, and C3H/FeJ mice were also similar. Macrophage colony-stimulating factor transcripts were clearly elevated in the kidneys of MRL-lpr mice, suggesting a renal source of circulating M-CSF. The increase of M-CSF might be responsible for the increased numbers and enhanced functions of macrophages, which in turn cause tissue destruction in MRL-lpr mice.

Animals↗
PubMed1990

MHC class II, antigen presentation and tumor necrosis factor in renal tubular epithelial cells.

Proximal tubular (PT) epithelial cells express MHC class II (Ia) antigens in immunologically-mediated renal injury. To study the role of PT as accessory cells, we generated several murine PT-like epithelial cell lines by transformation with origin-defective SV40 DNA. These transformed cell lines display typical alkaline phosphatase and gamma-glutamyl-transpeptidase enzyme activity, proliferation to epidermal growth factor (EGF) and sodium-dependent glucose uptake. Clonal lines of transformed tubular cells from both normal C3H/FeJ and autoimmune MRL-lpr mice do not constitutively express Ia antigens or mRNA for class II. However, stimulation with recombinant interferon-gamma(rIFN-gamma) induces Ia mRNA and surface product in the cell lines. These Ia-positive cells can process and present hen egg-white lysozyme (HEL) to antigen-specific Iak-restricted T cell hybrids. Unstimulated tubular cells do not express detectable IL-1 alpha, IL-1 beta, TNA-alpha, or IL-6 mRNA. However, stimulation with IL-1 alpha or LPS induces TNF-alpha transcripts. We conclude that these cell lines have characteristics most consistent with a proximal tubular origin. They also bear characteristics of accessory cells such as processing and presentation of antigen and TNF-alpha gene expression. We speculate that PT have the capacity to participate in the pathogenesis of immune renal injury.

Cell Line↗
PubMed1989

Tumor necrosis factor and IL-1 in New Zealand Black/White mice. Enhanced gene expression and acceleration of renal injury.

TNF and IL-1 are potent immunologic and inflammatory cytokines. We have previously reported increased levels of mRNA for TNF alpha and IL-1 beta in MRL-lpr mice with lupus nephritis. To determine whether the increased levels of TNF and IL-1 mRNA are a more general feature of mice with lupus nephritis we studied cytokine gene expression in female NZB x NZW F1 (NZB/W) mice by Northern blot analysis. Enhanced steady state levels of mRNA for TNF alpha and IL-1 beta, but not IL-1 alpha, were detected in the renal cortices of animals with lupus nephritis. To determine whether administration of TNF or IL-1 would accelerate renal injury and mortality, we injected murine rTNF alpha or rIL-1 alpha i.p. into female NZB/W or C3H/FeJ mice at two doses, 2.0 micrograms or 0.2 micrograms, three times weekly for 2 or 4 mo beginning at 2 or 4 mo of age. Administration of the lower dose of each cytokine accelerated renal disease and mortality rate when treatment was initiated at 4 mo of age. At the higher dose, neither cytokine promoted disease. Treatment administered from 2-4 mo of age did not accelerate renal disease. This observation suggests that in order to cause renal injury, these cytokines must interact with other pathologic features present in these animals after 4 mo of age. These findings support the hypothesis that TNF and IL-1 can contribute to nephritis in murine models of lupus. Taken together with previously published data, we propose that TNF and IL-1 have differential dose effects on renal disease. The dose of TNF and IL-1 and the stage of disease activity dictate the pathogenic action of these cytokines.

Animals↗
PubMed1989

Enhanced MHC class II expression in renal proximal tubules precedes loss of renal function in MRL/lpr mice with lupus nephritis.

Enhanced MHC class II (Ia) antigen expression is a common feature of autoimmunity. The authors investigated the occurrence of renal Ia expression in MRL/MpJ-lpr/lpr (MRL/lpr) mice with lupus nephritis. By immunoperoxidase staining, normal C3H/FeJ and the congenic strain MRL/MpJ-+/+ express Ia in mononuclear cells in the interstitium only, whereas MRL/lpr with nephritis have abundant Ia expression in proximal tubules (PT), mainly towards the basolateral membrane, and in the characteristic perivascular infiltrates. To a lesser extent, enhanced Ia expression is also observed in the interstitium and in the glomerular mesangium. By Northern blot analysis, the increase in Ia surface determinants correlates with an increased steady-state level of class II mRNA for both I-A and I-E. Ia expression on PT starts focally at around 2-months of age, often in proximity to vascular infiltrates, and precedes overt glomerulo-nephritis and proteinuria. Enhanced class II expression is not restricted to the kidney. MRL/lpr have also increased interstitial class II antigen expression in liver, lung, and spleen compared with normal C3H/FeJ mice. Thus, MRL/lpr mice have enhanced systemic Ia expression, but Ia antigen expression is particularly prominent in PT and may play a key role in the initiation and progression of lupus nephritis.

Animals↗
PubMed1988

Increased tumor necrosis factor and IL-1 beta gene expression in the kidneys of mice with lupus nephritis.

Because TNF and IL-1 can initiate immunologic and inflammatory events alone or synergistically, a local increase in the levels of one or both of these cytokines in vivo may cause irreparable tissue damage. The purpose of this study was to evaluate local TNF and IL-1 beta gene expression in vivo in the kidneys of MRL-Ipr mice with autoimmune lupus nephritis. TNF mRNA was detected in the renal cortex of MRL-Ipr mice but was not present in the cortex of normal congenic MRL-++ or C3H/FeJ mice. MRL-Ipr mice with lupus nephritis expressed higher amounts of TNF mRNA compared with MRL-Ipr mice prior to disease. In addition, freshly isolated, unstimulated glomeruli from MRL-Ipr mice with nephritis were found to secrete detectable levels of TNF, whereas glomeruli from MRL-++ mice did not. IL-1 beta mRNA, present in the renal cortex of C3H/FeJ, MRL-++, and young MRL-Ipr mice with normal kidneys, was also more abundantly expressed in MRL-Ipr mice with nephritis. Cultured macrophages from glomeruli of mice with nephritis were found to express TNF and IL-1 beta mRNA and product. These macrophages are prominent only in MRL-Ipr mice with renal disease and are the likely source of increased gene expression for both cytokines.

Animals↗
PubMed1988

Novel and enhanced IL-1 gene expression in autoimmune mice with lupus.

IL-1 is a pleiotropic factor encoded for by at least two genes, alpha and beta, and capable of eliciting a broad set of immunologic and inflammatory events. MRL/MP-lpr (MRL-lpr) mice are an appealing model for studies of renal injury inasmuch as disease in this strain is spontaneous, rapid, predictable, and regulated by the lpr gene. Infiltration of macrophages and the proliferation of the glomerular mesangial cells are prominent features of renal disease. Because both mesangial cells and macrophages can synthesize IL-1, the purpose of this study was to determine whether enhanced IL-1 gene expression is associated with lupus nephritis in the MRL-lpr mouse model. Glomerular macrophages, abundant in the kidneys of MRL-lpr mice but rarely present in the kidney of congenic MRL/MP-++(MRL-++) mice, were isolated and cultured and found to express a 10-fold increase in both IL-1 alpha and IL-1 beta mRNA transcripts as compared with MRL-++ and MRL-lpr mesangial cells. IL-1 alpha was not detected in the total RNA extracted from freshly excised kidney, whereas IL-1 beta transcripts were detected in both the renal cortex of MRL-lpr as well as MRL-++ animals. A previously undetected truncated 1200 nucleotide IL-1 beta transcript together with the conventional 1600 nucleotide IL-1 beta transcript was found in kidneys from MRL-lpr and was abundantly expressed in glomeruli of MRL-lpr mice with lupus nephritis. Isolated glomeruli from MRL-lpr mice with nephritis produce IL-1, whereas in normal glomeruli from MRL-++ and C3H/FeJ mice this cytokine was not detected. Glomerular macrophages and mesangial cells cultured from MRL-lpr mice with nephritis both secrete IL-1. These studies indicate that IL-1 beta gene expression and IL-1 protein are increased in the kidneys of autoimmune mice with lupus nephritis and is generated, at least in part, by glomerular macrophages. We speculate that an alteration in IL-1 beta gene expression may be responsible for causing a cascade of events leading to acute and chronic renal injury.

Animals↗
PubMed1987

Polyclonal activation of salmonid B lymphocytes.

The process of in vitro polyclonal activation of coho salmon (Oncorhynchus kisutch) lymphocytes was examined with respect to the induction of mitogenesis, total immunoglobulin production, and the production of specific antibodies or plaque forming cells. These studies demonstrate that antigen specific stimulation of antibody production is not linked to mitogenic activity, or total immunoglobulin production, while the polyclonal activation of specific antibody production is closely linked to these functions. Stimulation of immunoglobulin production by phytohemagglutinin suggests that this mitogen may not be limited to T cell activation in salmonids or, alternatively, it may induce the production of lymphokines capable of polyclonally activating B cells. Further, fetal calf serum was found to cause production of large amounts of immunoglobulin in vitro without antigenic stimulation.

Animals↗
PubMed1987

Vibrio anguillarum antigen stimulates mitogenesis and polyclonal activation of salmonid lymphocytes.

An antigen preparation of Vibrio anguillarum, a salmonid pathogen, acts as a potent in vitro mitogenic stimulator of splenic and pronephric (anterior kidney) lymphocytes from coho salmon (Oncorhynchus kisutch), chinook salmon (O. tshawytscha) and rainbow trout (Salmo gairdneri). This antigen (VA) is comparable in its mitogenic activity to Concanavalin A (Con A), Escherichia coli lipopolysaccharide (LPS), and phytohemagglutinin (PHA). VA gives peak mitogenic responses in coho five days after initiation of cell culture. VA also appears to be a nonspecific polyclonal activator as determined by the generation of plaque forming cells to trinitrophenyl (TNP) and fluorescein (FI) haptenic determinants. Chemical characterization is limited, but it appears that Vibrio LPS could be responsible for these activities.

Animals↗
PubMed1987

Widespread antigenic cross-reactivity between plasma proteins of a gastropod, and its trematode parasite.

Evidence obtained earlier with immunofluorescence and immunoelectron microscopy was interpreted to imply molecular mimicry of the host Biomphalaria glabrata by the parasite Schistosoma mansoni. Using Western Blotting, we find that "mimicry" is due to widespread shared epitopes. Furthermore, at least one individual plasma protein of B. glabrata shares epitopes with the majority of plasma proteins in the mollusc. The widespread antigenic determinants may be carbohydrates. Caution is warranted when antisera, raised in mammals against heterogeneous invertebrate extracts, are used to screen for related antigenic determinants.

Animals↗
PubMed1986

Echinostoma paraensei: hemocytes of Biomphalaria glabrata as targets of echinostome mediated interference with host snail resistance to Schistosoma mansoni.

Earlier in vivo work by Lie et al. (1977) indicated that the innate resistance of the 10R2 strain of Biomphalaria glabrata to PR1 Schistosoma mansoni could be interfered with if the snails were infected previously with another trematode, Echinostoma paraensei. We have studied this interference phenomenon using in vitro methods in an attempt to understand its mechanistic basis. Hemolymph, derived from 10R2 snails infected with E. paraensei for 14-28 days, killed 25% of S. mansoni sporocysts in vitro, significantly less (P less than 0.001) than the 90% killing rate observed with hemolymph from uninfected, control 10R2 snails. Hemolymph from the infected 10R2 snails and from schistosome susceptible M line snails did not differ significantly (P greater than 0.1) in their relative inability to kill S. mansoni sporocysts in vitro. The defect in sporocyst killing exhibited by echinostome infected 10R2 snails was traced to the cellular, rather than the humoral, component of the hemolymph. Preparations containing uninfected 10R2 snail hemolymph and echinostome daughter rediae exhibited significantly less (P less than 0.001) killing of S. mansoni sporocysts than did controls containing only 10R2 hemolymph and S. mansoni sporocysts. Our results suggest that echinostome larvae release factors that interfere with the ability of B. glabrata hemocytes to kill S. mansoni sporocysts.

Animals↗
PubMed1986

Primary in vitro stimulation of antibody production by rainbow trout lymphocytes.

Trinitrophenylated (TNP) forms of E. coli lipopolysaccharide (LPS) and keyhole limpet hemocyanin (KLH) were used to produce antigen specific plaque-forming cell (PFC) responses with rainbow trout (Salmo gairdneri) splenocytes from unprimed fish in vitro. The culture system that was developed is described and characterized with respect to the kinetics and dose responses for both the haptenated and unhaptenated forms of the carriers. The induction of the PFC response to TNP-LPS was inhibited with TNP-lysine. Exposure to graded levels of gamma-radiation demonstrated a low dose augmentation of the PFC response with both antigens. Antigen addition experiments reveal that both antigens appear to stimulate the same population of antibody-producing B lymphocytes.

Animals↗
PubMed1986

Interactions between the plasma proteins of Biomphalaria glabrata (Gastropoda) and the sporocyst tegument of Schistosoma mansoni (Trematoda).

The tegumental surface of Schistosoma mansoni sporocysts is the site of both nutritive and immunological interactions with haemolymph cells and plasma of Biomphalaria glabrata, the schistosome intermediate host. Within minutes of being placed in host plasma, sporocysts acquire plasma antigens, and within 3 h host plasma antigens are present on the surface at near steady state. Though a wide variety of peptides is acquired, there is selection. Furthermore, some differences occur in the peptides acquired from the plasma of susceptible and resistant strains of snail. Acquired antigens are rapidly processed, and are predominantly undetectable in tegumental extracts after a few hours. In contrast, rabbit antibody on sporocysts remains in situ for at least 48 h, so under some conditions there is stable expression of certain tegumental antigenic determinants. These data, obtained using antibodies to snail plasma antigens and to sporocyst tegumental antigens, are discussed in the light of current ideas on the cellular and molecular basis of susceptibility and resistance in this host-parasite system.

Adhesiveness↗
PubMed1985

Plasma components which mediate cellular defences in the gastropod mollusc Biomphalaria glabrata.

Blood plasmas from certain strains of Biomphalaria glabrata are known to have components which facilitate a hemocyte-effected cytotoxic response against encapsulated Schistosoma mansoni sporocysts. The possible identity of the factor(s) has been investigated. Sporocysts placed in snail plasma rapidly acquire a wide variety of host plasma antigens, at least some of which are displayed on the parasite surface. Plasmas from strains of snail resistant to the parasite agglutinate fixed sporocysts, while plasmas from susceptible strains fail to do so. Fixed sporocysts incubated in plasma bind selectively a subpopulation of plasma antigens; some are bound uniquely in resistant plasma. Another resembles a hemagglutinin from snail plasma. These and other recently acquired data are discussed in light of increasing evidence for defensive roles of multivalent lectins.

Agglutinins↗
PubMed1984

Schistosoma mansoni: agglutination of sporocysts, and formation of gels on miracidia transforming in plasma of Biomphalaria glabrata.

The resistance or susceptibility of Biomphalaria glabrata strains to strains of Schistosoma mansoni, the human blood fluke, are evidenced by the responses of snail hemocytes to sporocysts of the schistosome, both in vivo and in vitro. It is now reported that living sporocysts of the PR1 strain of S. mansoni agglutinate in the plasma of all tested strains of B. glabrata, in contrast to fixed sporocysts which agglutinate only in plasma from resistant snail strains. The agglutinating activity in resistant plasmas is not divalent cation dependent, and was not inhibited by the 26 carbohydrates and four amino acids tested. In addition, the observation that gelatinous deposits develop on transforming miracidia-sporocysts in B. glabrata plasmas is also reported. Both the agglutination and gel-formation phenomena may facilitate recognition of, and attacks on, sporocysts, thereby contributing to susceptibility and resistance in this host-parasite system.

Agglutination↗