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Biomedical subjects

B Fleischer

Publications and source records attributed to B Fleischer.

At least 163 records · Page 9Linked to original sources
PubMed1991

An evolutionary conserved mechanism of T cell activation by microbial toxins. Evidence for different affinities of T cell receptor-toxin interaction.

The enterotoxins produced by Staphylococcus aureus are the most potent mitogens known. They belong to a group of distantly related mitogenic toxins that differ in other biologic activities. In this study we have compared the molecular mechanisms by which these mitogens activate human T lymphocytes. We used the staphylococcal enterotoxins A to E, the staphylococcal toxic shock syndrome toxin, the streptococcal erythrogenic toxins A and C (scarlet fever toxins, erythrogenic toxins (ET)A, ETC), and the soluble mitogen produced by Mycoplasma arthritidis. We found that all these toxins can activate both CD4+ and CD8+ T cells and require MHC class II expression on accessory and target cells. However, T cells could be activated in the absence of class II molecules if the toxins ETA or SEB were co-cross-linked on beads together with anti-CD8 or anti-CD2 antibodies. Enterotoxins, toxic shock syndrome toxin and scarlet toxins stimulate a major fraction of human T cells, and show preferential, but not exclusive, stimulation of T cells carrying certain TCR V beta. In contrast, the mitogen of M. arthritidis, a pathogen for rodents stimulates only a minority of human T cells but activates a major fraction of murine T cells. Analysis of human T cell clones expressing V beta 5 or V beta 8 TCR showed that these clones responded also to those toxins that did not stimulate V beta 5+ and V beta 8+ T cells in bulk cultures. These results indicate that different TCR bind to these toxins with different affinities and that the specificity of the TCR-V beta-toxin interaction is quantitative rather than qualitative in nature. Taken together our findings suggest that these toxins use a common mechanism of T cell activation. They are functionally bivalent proteins crosslinking MHC class II molecules with variable parts of the TCR. Besides V beta, other parts of the TCR must be involved in this binding. The finding that murine T cells responded more weakly to the toxins produced by the human-pathogenic bacteria than to the Mycoplasma mitogen could indicate that the toxins have been adapted to the host's immune system in evolution.

Animals↗
PubMed1991

Evidence for T cell receptor-HLA class II molecule interaction in the response to superantigenic bacterial toxins.

The staphylococcal enterotoxins and related microbial T cell mitogens stimulate T cells by cross-linking variable parts of the T cell receptor (TcR) with MHC class II molecules on accessory or target cells. In this report we describe that a given combination of T cell, accessory cell (AC) and toxin can be non-stimulatory. However, the same T cell can respond to the same toxin on another AC and the same AC can present the same toxin to another T cell. This indicates that in the complex formed between TcR, toxin and class II molecule an interaction between TcR and class II molecule takes place.

Antigen-Presenting Cells↗
PubMed1991

Synovial fluid-derived Yersinia-reactive T cells responding to human 65-kDa heat-shock protein and heat-stressed antigen-presenting cells.

Humoral and cellular immune reactions to heat-shock proteins have been implicated in the pathogenesis of arthritis. Heat-shock proteins occur in bacteria as well as all eukaryotes and have been highly conserved during evolution. Cross-reactivity between bacterial and human heat-shock proteins induced at the site of inflammation may underlie the pathogenesis of some forms of arthritis. In order to test this hypothesis, we raised and cloned a Yersinia-specific T cell line from the synovial fluid lymphocytes of a patient with Yersinia-induced reactive arthritis. From this line we obtained a CD4+ T cell clone that proliferated in response to Yersinia antigens and both to the mycobacterial and the human 65-kDa heat-shock protein. This T cell clone also proliferated in response to autologous heat-stressed antigen-presenting cells as well as to synovial fluid mononuclear cells from the inflamed joint, thus showing true autoreactivity against endogenously synthetized self-antigen. These results demonstrate the induction of an autoimmune T cell response by a natural bacterial infection and support the important role of heat-shock proteins in the pathogenesis of immune-mediated arthritis.

Adult↗
PubMed1991

T lymphocyte-stimulating microbial toxins as "superantigens".

Infectious pathogens generally have to cope with the host's adaptive immune system, i.e., T and B lymphocytes. Common evasion mechanisms in this complex interaction are antigenic variations, the escape to immunologically priviledged sites or the use of immunosuppressive mechanisms. Many bacteria and other microorganisms eleborate soluble factors or toxins that act suppressively on cells of the immune system, such as pore-forming molecules or proteins that interfere with the function of G proteins. Gram-positive cocci and a mycoplasma have developed an extremely potent mechanism of T cell stimulation by closely mimicking recognition of specific antigen. From the functional similarity to antigen recognition and the multiclonal activation of T cells the designation "superantigens" has been suggested for these molecules.

Animals↗
PubMed1991

Stimulation of human T cells by microbial 'superantigens'.

The enterotoxins and the TSST of S. aureus, the erythrogenic toxins A and C of S. pyogenes and a still uncharacterized exoprotein of M. arthritidis belong to a family of exotoxins that have in common a potent mitogenic activity for T lymphocytes of several species. These proteins stimulate CD4+ and C8+ T cells, as well as a fraction of gamma delta TCR-bearing T cells by cross-linking variable parts of the T cell antigen receptor with MHC class II molecules on accessory or target cells. They are functionally bivalent molecules having distinct interaction sites for variable parts of the TCR and for nonpolymorphic parts of the MHC class II molecule. For alpha beta TCR-bearing T cells the V beta is the dominant site of interaction with the toxins. However, there is only a preferential but not exclusive stimulation of T cells carrying a certain V beta, because T cell clones carrying e.g. V beta 5 or V beta 8 can respond also to those toxins that do not stimulate V beta 5+ and V beta 8+ T cells in bulk cultures. Therefore, different TCR bind to these toxins with different affinities and the specificity of the TCR-toxin interaction is quantitative rather than qualitative in nature. Murine T cells respond to the mitogen of M. arthritidis that is a natural pathogen for mice and rats much better than to the toxins of the human pathogenic bacteria, whereas the opposite is true for human T cells. This could indicate that the toxins have been adapted to the host's immune system in evolution. The T cell-stimulating activity contributes to the pathogenesis of the respective diseases.

Antigens, Bacterial↗
PubMed1991

Human asialoglycoprotein receptor as an autoantigen in chronic hepatitis.

ASGPR may play a role in the pathogenesis of autoimmune chronic liver diseases. Several lines of evidence support this hypothesis. Antibodies to rabbit ASGPR could be found in various inflammatory liver diseases. In contrast, ASGPR preparations derived from human liver (h-ASGPR) were recognized predominantly by sera from patients with ai-CAH. Moreover, anti-h-ASGPR showed a close correlation to the inflammatory activity of ai-CAH both in terms of prevalence (88% in histologically proven active diseases), immunoglobulin class (IgM antibodies restricted to active inflammation) and behavior during treatment. Anti-h-ASGPR secretion could also be found in vitro, when PBL of patients were stimulated in cell culture. Anti-h-ASGPR antibodies did not correlate with a subgroup of ai-CAH; they also occurred in nearly 15% of patients with PBC. Other inflammatory liver diseases, as well as nonhepatic autoimmune disorders, seldom exhibited anti-h-ASGPR (less than 5%). Additionally, PBL and T-cell clones obtained from liver biopsies in patients with ai-CAH and PBC responded to h-ASGPR. Liver-infiltrating T cells were predominantly of CD4 phenotype and HLA class II restricted. Thus, the human ASGPR has been shown to represent a common target for humoral and cellular autoimmune response in chronic hepatitis probably contributing to disease induction or perpetuation.

Animals↗
PubMed1991

Clonal analysis of liver-infiltrating T cells in patients with LKM-1 antibody-positive autoimmune chronic active hepatitis.

Autoantibodies against microsomal antigen of liver and kidney (LKM-1) are diagnostic markers for a subgroup of autoimmune chronic active hepatitis (AI-CAH). Cytochrome P450dbl, now classified as cytochrome P450 IID6, is the major antigen of LKM-1 antibodies. Immunohistological studies suggest that hepatic injury in AI-CAH is mediated by liver-infiltrating T cells. In the present study the specificity and function of liver-infiltrating T cells was analysed at the clonal level. Phenotypical characterization of 189 T cell clones isolated from four liver biopsies of LKM-1 antibody-positive patients showed an enrichment of CD4+ CD8- T cell clones proliferated specifically in the presence of recombinant human LKM-1 antigen (rLKM). This reaction was restricted to autologous antigen-presenting cells and to HLA class II molecules. In order to see whether rLKM was also recognized by peripheral blood T lymphocytes (PBL) we tested the proliferative response of PBL from several individuals. PBL from three of the four patients with LKM-1 antibody-positive AI-CAH proliferated to rLKM, whereas no response was seen with PBL from patients with LKM-1 antibody-negative chronic liver diseases and from healthy blood donors. These data demonstrate that the LKM-1 antigen is recognized by liver-infiltrating T cells in LKM-1 antibody-positive AI-CAH. For further functional characterization, liver-derived T cell clones were tested for their cytotoxic activity. In the presence of phytohaemagglutinin 24 out of 26 CD4- CD8+ but also 20 out of 63 CD4+ CD8- T cell clones lysed autologous as well as allogenic EBV-transformed B cell lines or K562 cells. Five CD4- CD8+ T cell clones lysed autologous but not allogenic B cell lines spontaneously in a HLA class I-restricted manner. Although the antigen specificity of these clones is still unknown the data show the presence of autoreactive T cells at the site of inflammation that could contribute in the pathogenesis of AI-CAH.

Adolescent↗
PubMed1991

A comprehensive worksite smoking control, discouragement, and cessation program.

The effectiveness of a comprehensive program of worksite smoking control, discouragement, and cessation was compared with a program of smoking cessation alone. Two comparable oil refineries served as the research sites. Outcome variables consisted of employee self-reported smoking rate assessed by the use of a smoking questionnaire and unobtrusive observations of smoking behavior before and after the intervention. One company was randomly assigned to the comprehensive program of smoking control, discouragement, and cessation while the other company only received smoking cessation. Humorous antismoking posters emphasizing the benefits of quitting smoking were distributed throughout the first worksite and changed every 2 weeks. Large banners stating "Go SmokeFree" were also placed at all locations to this plant and left up for the duration of the study. Three weeks after the initiation of the smoking discouragement program at one refinery, a group smoking cessation program was begun at both plants. At a 5-month follow-up, participants in the smoking cessation treatment at the plant receiving the comprehensive program achieved a 5-month abstinence rate of 43% in comparison with a rate of 21% at the refinery receiving only smoking cessation.

Adult↗
PubMed1991

Demonstration of virus-specific cytotoxic T lymphocytes in liver tissue in hepatitis A--a model for immunopathological reactions.

The pathogenetic mechanism leading to liver tissue injury in hepatitis caused by hepatitis A virus is unclear. We have randomly established T cell clones from liver biopsies from 4 patients with hepatitis A. A total of 578 clones was phenotypically analyzed. Whereas during the acute phase of disease CD8+ clones dominated over CD4+ clones, from a biopsy taken late after onset of clinical syndromes more CD4+ than CD8+ clones were obtained. Interestingly, in a patient with a second exacerbation of the disease, more than 20% of all clones had the CD3+ WT31- CD4- CD8- gamma delta TCR+ phenotype. Variable IFN-gamma production was observed with all types of T cell clones. All CD8+ clones had cytotoxic activity, and approximately 60% of all CD8+ clones showed specific cytotoxicity against autologous fibroblasts infected with hepatitis A virus but not with herpes simplex, adeno- or enteroviruses. These results show that the liver injury in hepatitis A is not caused by a viral cytopathogenic effect but is due to an immunopathological reaction of sensitized cytotoxic T lymphocytes against infected hepatocytes. In addition, these studies show an enrichment of CD4-8- alpha beta T cell receptor negative T lymphocytes at the site of an inflammation and suggest a role of these cells in an antiviral reaction.

Antigens, CD↗
PubMed1991

Mitogenic toxins as MHC class II-dependent probes for T cell antigen receptors.

The enterotoxins produced by Staphylococcus aureus (SE) are prototypes of a group of microbial exoproteins that share a potent mitogenic activity for T lymphocytes of several species. These exoproteins use a very effective novel mechanism of T lymphocyte stimulation. For stimulation of all types of T cells (CD4+, CD8+ as well as gamma delta TCR+) the presence of allogeneic or xenogeneic MHC class II molecules on accessory or target cells is required. This requirement is reflected by a selective binding of the toxins to MHC class II molecules. The toxins stimulate preferentially but not exclusively alpha beta TCR+ T cells carrying certain TCR V beta s. A current model suggests that the toxins are functionally bivalent molecules, crosslinking variable parts of the TCR with MHC class II molecules on the accessory or target cells. Of all T cell mitogens the toxins thus most closely simulate T cell recognition of specific antigen. The differential pattern of reactivity of human and murine T cells with various toxins suggests that the toxins have been adapted to the host's immune system in evolution.

Enterotoxins↗
PubMed1991

[Stimulation of the immune system by microbial "superantigens"].

The enterotoxins and the toxic-shock-syndrome toxin-1 of Staphylococcus aureus, the erythrogenic toxins of Streptococcus pyogenes as well as a still uncharacterized exoprotein of Mycoplasma arthritidis belong to a family of exotoxins, that have in common a potent mitogenic activity for T lymphocytes of several species. These proteins stimulate CD4(+)- and CD8+ T-lymphocytes by cross-linking the T-cell-antigen receptor with MHC-class-II molecules on accessory or target cells. They are functionally bivalent molecules having distinct interaction sites for variable parts of the T-cell receptor and for nonpolymorphic parts of MHC-class-II molecules. Due to their preferential action on T cells expressing certain V beta-parts of the T-cell receptor the designation "superantigens" has been proposed. The mechanism of T-cell stimulation has apparently been conserved in evolution and has been adapted to the host's T-cell-receptor repertoire. The T cells stimulating activity apparently contributes to the pathogenesis of certain infectious diseases. Noteworthy, mice express endogenous "superantigens" that have similar properties.

Animals↗
PubMed1990

Relationship between enterotoxic- and T lymphocyte-stimulating activity of staphylococcal enterotoxin B.

The enterotoxins produced by Staphylococcus aureus cause a gastrointestinal intoxication probably via their action on intramucosal neuronal cells. Staphylococcal enterotoxins are also the most powerful mitogens known, activating CD3+ T lymphocytes of several species in a clonally variable and MHC class II-dependent fashion. We examined a possible relationship between enterotoxic and mitogenic activity of staphylococcal enterotoxin serotype B (SEB). We used a monoclonal anti-Id directed against the combining site of an anti-SEB mAb. This anti-Id failed to elicit an enteric response by itself but could block the enteric response in monkeys to a 6000-fold excess of SEB. The anti-Id was mitogenic, however, for human and monkey T cells, triggering a fraction of CD4+ and CD8+ T cells. Not all SEB-reactive T cells were activated by the anti-Id. The anti-Id bound to T cells with a similarly low affinity as did SEB. Additional evidence for a separation of enterotoxic and mitogenic activity comes from studies with carboxymethylated SEB. Although this modified SEB had lost its enterotoxic activity, it was as mitogenic as the unmodified molecule. These results support the notion that the enteric reaction to SEB is not mediated via its effect on T lymphocytes. We conclude that SEB and anti-Id might bind to a common structure of different receptors on T cells and target cells in the intestinal mucosa, probably peripheral sensory neurons.

Animals↗
PubMed1990

The T cell triggering molecule Tp103 is associated with dipeptidyl aminopeptidase IV activity.

Tp103 is a 103-kDa T cell activation molecule that defines an alternative activation signal for human T lymphocytes. It is absent from or present in only low amounts on resting T cells but is expressed strongly after activation. Cross-linking of Tp103 via a mAb CB.1 leads to triggering of functional activities in preactivated CD3+ T lymphocytes. By using mAb CB.1 in immunohistology we found that Tp103 is expressed in epithelial cells of various tissues, such as kidney, prostate, epidermis and on endothelia of liver, spleen, lungs, and most vessels, and in bile duct canaliculi in the liver. We found a carcinoma cell line expressing Tp103 and could precipitate a 110-kDa molecule from the surface of these cells. We considered several known molecules of similar distribution and molecular mass for identity with Tp103 and show here that Tp103 is probably identical to the proteolytic enzyme dipeptidyl aminopeptidase IV. When we purified Tp103 by affinity chromatography, typical dipeptidyl aminopeptidase IV activity copurified with Tp103. On activated T cells the enzymatic activity associated with Tp103 is expressed on the outside of the cell. We show that mAb CB.1 recognizes the same molecule as the anti-CD26 mAb anti-Ta1. The anti-Ta1 mAb was found to have T cell-activating activity too, but to differ in its requirements for triggering of T lymphocytes.

Antibodies, Monoclonal↗
PubMed1990

Activation of MHC class I-restricted CD8+ CTL by microbial T cell mitogens. Dependence upon MHC class II expression of the target cells and V beta usage of the responder T cells.

The T cell response to microbial T cell mitogens (MTM) such as enterotoxins from Staphylococcus aureus (SE) and the soluble mitogen from Mycoplasma arthritidis, resemble the minor lymphocyte stimulatory locus (Mls) response in several aspects. An important feature of the Mls response is it restriction to CD4+ cells. This study demonstrates that in contrast to Mls, the MTM response includes both CD4+ and CD8+ subsets. Both CD4+ and CD8+ cells expanded in IL-2 after stimulation with SEB showed preferential expression of T cell receptors bearing V beta 8 domains. Mouse and human target cells could be lysed in the presence of MTM both by MTM-stimulated CD8+ lymphocytes and by MHC class I-restricted CTL clones of defined Ag specificity. MTM-induced lysis required the expression of MHC class II, but not class I Ag, on the target cells. Inhibition studies of SEB and Ag-dependent cytolysis by CTL clones underlined the crucial role of CD3 and LFA-1 in both instances, but showed CD8 dependence only for AG-dependent cytolysis. Together these findings suggest important differences between the putative MTM-mediated interaction of TCR with MHC molecules and the classical TCR/MHC interaction involved in MHC-restricted Ag recognition.

Animals↗
PubMed1990

The human hepatic asialoglycoprotein receptor is a target antigen for liver-infiltrating T cells in autoimmune chronic active hepatitis and primary biliary cirrhosis.

Autoantibodies to the human hepatic asialoglycoprotein receptor have been found in nearly 50% of the sera of patients with autoimmune chronic active hepatitis and in 15% of patients with primary biliary cirrhosis. In this study we demonstrate that the human hepatic asialoglycoprotein receptor is also a target antigen for T cell-mediated immune responses. Peripheral blood lymphocytes of 37% (7 of 19) of patients with autoimmune chronic active hepatitis and 33% (2 of 6) of patients with primary biliary cirrhosis showed a proliferative response to highly purified human hepatic asialoglycoprotein receptor, whereas no proliferation was found with peripheral blood lymphocytes of patients with chronic viral hepatitis (0 of 13) and healthy blood donors (0 of 4). Moreover, we isolated T-cell clones from liver biopsy samples of two patients with autoimmune chronic active hepatitis and two patients with peripheral blood lymphocytes. Between 2.8% and 14.3% of these clones showed a specific proliferative response to purified human hepatic asialoglycoprotein receptor. The response was restricted to autologous antigen-presenting cells and could be blocked by monoclonal antibodies against human leukocyte antigen-DR molecules. The response of T cells to the human hepatic asialoglycoprotein receptor did not require the lectinlike activity of the asialoglycoprotein receptor. Thus the human hepatic asialoglycoprotein receptor could be identified as a major target antigen of humoral and cellular immune reactions in autoimmune-mediated liver diseases.

Adult↗