SEARCH · PubMed Health

Results for “pathogen effectors”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,045 records · Page 58Linked to original sources

PubMed1991

Antigen-specific tolerance induced by autoimmunization with photoinactivated syngeneic effector cells.

Development of a protocol that could invoke specific suppression of an undesired immune response, while sparing normal immune competence, would be of great clinical value. This report demonstrates that multiple infusions of splenocytes sensitized in vivo to sheep red blood cells (SRBC) and photoinactivated in vitro with 8-methoxypsoralen and ultraviolet A light can render a syngeneic recipient selectively unresponsive to subsequent challenge with this antigen. Mice treated in this fashion did not develop a T cell-mediated delayed type hypersensitivity (DTH) reaction to SRBC. In contrast, control mice exposed to nonimmune splenocytes pretreated in an identical manner developed a normal DTH response to SRBC, thereby demonstrating that drug and light in the absence of effector T cells were not suppressive. Inhibition of the DTH response was antigen specific, since animals rendered unresponsive to SRBC developed a normal DTH response to chicken red blood cells. Cell transfer experiments demonstrated that unprimed recipients of splenocytes from mice rendered unresponsive to SRBC could not mount a DTH reaction when challenged. Moreover, this procedure can also suppress established immunity to that antigen. The use of photoinactivated syngeneic antigen-reactive effector cells as immunosuppression agents suggests that this method may be clinically useful in inhibiting pathogenic antigen-specific immunologic reactions.

Animals↗

PubMed1994

Interactions between respiratory epithelial cells and cytokines: relationships to lung inflammation.

Epithelial cells lining respiratory airways can participate in inflammation in a number of ways. They can act as target cells, responding to exposure to a variety of inflammatory mediators and cytokines by altering one or several of their functions, such as mucin secretion, ion transport, or ciliary beating. Aberrations in any of these functions can affect local inflammatory responses and compromise pulmonary defense. For example, oxidant stress can increase secretion of mucin and depress ciliary beating efficiency, thereby affecting the ability of the mucociliary system to clear potentially pathogenic microbial agents. Recent studies have indicated that airway epithelial cells also can act as "effector" cells, synthesizing and releasing cytokines, lipid mediators, and reactive oxygen species in response to a number of pathologically relevant stimuli, thereby contributing to inflammation. Many of these epithelial-derived substances can act locally, affecting both neighboring cells and tissues, or, via autocrine or paracrine mechanisms, affect structure and function of the epithelial cells themselves. Studies in our laboratories utilized cell cultures of both human and guinea pig tracheobronchial and nasal epithelial cells, and isolated human nasal epithelial cells, to investigate activity of respiratory epithelial cells in vitro as sources of cytokines and inflammatory mediators. Primary cultures of guinea pig and human tracheobronchial and nasal epithelial cells synthesize and secrete low levels of IL-6 and IL-8 constitutively. Production and release of these cytokines increases substantially after exposure to specific inflammatory stimuli, such as TNF or IL-1, and after viral infection.

Animals↗

PubMed2001

Strict control of human immunodeficiency virus type 1 replication by a genetic switch: Tet for Tat.

Live-attenuated human immunodeficiency virus type 1 (HIV-1) variants have shown great promise as AIDS vaccines, but continued replication can lead to the selection of faster-replicating variants that are pathogenic. We therefore designed HIV-1 genomes that replicate exclusively upon addition of the nontoxic effector doxycycline (dox). This was achieved by replacement of the viral TAR-Tat system for transcriptional activation by the Escherichia coli-derived Tet system for inducible gene expression. These designer "HIV-rtTA" viruses replicate in a strictly dox-dependent manner both in a T-cell line and in primary blood cells, and the rate of replication can be fine-tuned by simple variation of the dox concentration. These HIV-rtTA viruses provide a tool to perform genetics, e.g., selection and optimization experiments, with the E. coli-derived Tet reagents in a eukaryotic background. Furthermore, such viruses may represent improved vaccine candidates because their replication can be turned on and off at will.

Bacterial Proteins↗

PubMed1988

Induction of activated lymphocyte killing by bacteria associated with periodontal disease.

Complex interactions occur among host defense cells during bacterial infection. Bacteria and bacterial products may enhance or inhibit the effector and regulatory activity of human lymphocytes. Accordingly, we tested the ability of human periodontal pathogens to activate peripheral blood lymphocytes using standard chromium-release assays to measure lymphocyte-mediated cytolysis. Human adherent-cell depleted peripheral blood lymphocytes (PBL) with the addition of glutaraldehyde-fixed bacteria at a 5:1 bacteria:lymphocyte ratio were incubated at 37 degrees C for 24 hr in RPMI 1640 medium. Six of eight bacteria tested significantly augmented lymphocyte killing of the natural killer (NK) cell-sensitive human erythroleukemia cell line K562. E. corrodens, representing activating bacteria, was also able to induce the killing of NK-resistant targets (M14, Raji), comparable with induction by interleukin-2. Lipopolysaccharides extracted from A. actinomycetemcomitans strains, when incubated with PBL, were able to enhance cytotoxicity without the presence of whole bacteria. A majority of cytotoxicity was mediated by NK cells bearing Leu-11 and NKH-1 markers.

Actinobacillus↗

PubMed2005

Pathogenic autoantibodies in lupus nephritis.

Lupus nephritis is a major complication of systemic lupus erythematosus (SLE) and is associated with a high rate of morbidity and mortality. While many different immunologic and nonimmunologic factors contribute to disease expression in lupus nephritis, a large body of evidence suggests that the production of anti-DNA antibodies and the formation of glomerular immune deposits are important initial events in the pathogenesis of the disease. This review will summarize our current understanding of the differences between pathogenic and nonpathogenic autoantibodies, the mechanisms by which these autoantibodies induce renal injury and the effector mechanisms which are subsequently activated by the deposited autoantibodies that ultimately lead to the expression of the different lupus lesions.

Antibodies, Antinuclear↗

PubMed2002

Viral binding proteins as antibody surrogates in immunoassays of cytokines.

Cytokines are pivotal to a balanced innate or cell-mediated immune response, can be indicative of disease progression and/or resolution, and are being evaluated as therapeutics. There is a need to purify and/or to measure key cytokines rapidly with accuracy, precision, and sensitivity. The current assay technologies, which are based on RT-PCR, immunoassays, or bioassays, are limited in their use in the clinic, in particular because of the long time (1-3 h) required to carry out the assays. An alternative approach explored here is the use of pathogen-encoded cytokine-binding proteins, which have Kd in the nanomolar range. It is anticipated that pathogens have evolved binding proteins, antagonists, and/or specific neutralizing phenotypes directed against key signaling and effector molecules involved in the multifaceted host defense system. Thus, by screening the genomes of a wide range of microbial agents, we would expect to find coding sequences for binding proteins for the most important cytokines. Consistent with this view is the identification of poxvirus genes encoding binding activities for TNF type I and type II interferons, interleukin (IL)-1beta, IL-18, and beta-chemokines. These high-affinity receptors have the potential to act as surrogate antibodies in a number of applications in cytokine quantification and purification and could be potentially useful reagents to complement the existing panel of anti-cytokine, monoclonal, polyclonal, or engineered antibodies that are currently available.

Antibodies↗

PubMed2005

The mammalian innate immune system: potential targets for drug development.

The innate immune system is the oldest mammalian defence against invading micro-organisms and provides the first line of defence against them, however until recently a detailed understanding of its complexity has been lacking. This review describes recent advances that have been made in understanding the components of the innate immune system, including the pathogen sensing mechanisms, receptor and intracellular signalling pathways, linkage to the acquired immune system, and effectors of the innate immune response. These discoveries have created an opportunity for the development of novel drugs through the identification of targets for rational drug design. The opportunity for the development of novel anti-inflammatory and antimicrobial drugs through modulation of pro-inflammatory or antimicrobial signals within the innate immune system, are discussed. A more detailed understanding of the effectors of the innate immune system is providing an opportunity for the design of effector mimetics as novel antimicrobial drugs. The innate immune system is providing the basis for much-needed alternative approaches to controlling infection and inflammation in human medicine.

Animals↗

PubMed2003

Selective unresponsiveness to conformational B cell epitopes of the myelin oligodendrocyte glycoprotein in H-2b mice.

Autoantibodies directed against conformation-dependent epitopes of the extracellular domain of the myelin oligodendrocyte glycoprotein (MOG(Igd)) play a major role in the immunopathogenesis of demyelination in experimental autoimmune encephalomyelitis. We now demonstrate that one or more genes encoded within the MHC selectively censor the ability of H-2(b) mice to mount this conformation-dependent autoantibody response, while leaving T and B cell responses to linear MOG(Igd) epitopes intact. This novel form of selective B cell unresponsiveness discriminates between pathogenic and nonpathogenic Ab responses to MOG and determines whether or not Ab-dependent effector mechanisms play an important role in the pathogenesis of MOG-induced experimental autoimmune encephalomyelitis in the mouse.

Amino Acid Sequence↗

PubMed2005

Adhesion molecules in human dendritic cells.

Dendritic cells are bone marrow-derived professional antigen-presenting cells that link innate and adaptive immunity, and they are essentially involved in the initiation of primary immune responses and in the establishment of peripheral tolerance. The existence of distinct functional states and subsets of dendritic cells is critical for the generation of pathogen-specific immune responses without the risk of autoimmunity or chronic inflammation. To fulfil their effector tasks in tissues and lymph nodes, dendritic cells must engage in multiple adhesive and migratory events. The molecular dissection of these adhesive interactions may provide new potential therapeutic targets to modulate immune responses and to improve current dendritic cell-based therapeutic cancer vaccines.

Animals↗

PubMed1997

Interleukin-10-mediated T cell apoptosis during the T helper type 2 cytokine response in murine Schistosoma mansoni parasite infection.

The pathogenesis of infection with the helminth parasite Schistosoma (S) mansoni in mice has been reported to involve a T helper (Th)1 to Th2 cytokine switch, associated with a pathogenic granulomatous response to parasite eggs and to a global defect in Th1-cell effector functions. Here we report that the Th2 cytokine response, which begins 6 weeks after infection, at the time of parasite egg laying (i) does not occur in the context of a genuine Th1 to Th2 cytokine switch, but is associated with a persistent capacity of Th1 (or Th0) cells to secrete IL-2 and IFN-gamma in response to T cell receptor (TCR) stimulation; (ii) is associated, in vitro, with spontaneous death by apoptosis of a significant fraction of the CD4 and CD8 T cells, which is greatly enhanced by TCR stimulation; and (iii) is associated, in vivo, with numerous and large clusters of apoptotic cells in the spleen and in the inflammatory infiltrates surrounding the parasite egg deposits in the liver. The in vitro addition of antibodies to the Th2 cytokine IL-10 had both a preventive effect on TCR-induced T cell apoptosis and an enhancing effect on TCR-induced T cell secretion of Th1 cytokines. Taken together, these findings suggest that the downregulation of Th1-cell-mediated effector functions in S. mansoni-infected mice may not be related to a lack of Th1 cell production, but to a process of IL-10-mediated and activation-induced premature T cell death, that include Th1 (or Th0) cells. Further identification of mechanisms involved in the regulation of T cell apoptosis has implications for the understanding of the pathogenesis of immunosuppression associated with chronic infectious diseases.

Animals↗

PubMed1998

Cellular and molecular mechanisms for induction of mucosal immunity.

The epithelial glycoprotein called secretory component (SC) is quantitatively the most important receptor of the immune system because it is responsible for external transport of locally produced polymeric IgA (pIgA) to generate remarkably large amounts of secretory IgA. Antibodies of this type constitute the major mediators of specific humoral immunity. Transmembrane SC belongs to the Ig supergene family and functions as a common pIg receptor, also translocating pentameric IgM externally to form secretory IgM. The B cells responsible for mucosal production of Ig polymers are initially stimulated in organized mucosa-associated lympho-epithelial structures, particularly the Peyer's patches in the distal small intestine; from these inductive sites they migrate ("home") as memory cells to exocrine tissues all over the body. Mucous membranes are thus furnished with secretory antibodies in an integrated way, ensuring a variety of specificities at every secretory effector site. There is currently great interest in exploiting this integrated or "common" mucosal immune system for oral vaccination against pathogenic infectious agents and also to induce tolerance in T cell-mediated auto-immune diseases. However, much remains to be learned about mechanisms for antigen uptake and processing necessary to elicit stimulatory or suppressive mucosal immune responses in humans. Moreover, evidence is emerging for the existence of considerable regionalization with regard to functional links between inductive sites and effector sites of mucosal immunity.

Animals↗

PubMed1999

The paradigm of type 1 and type 2 antigen-presenting cells. Implications for atopic allergy.

Optimal clearance of the various pathogen types encountered by the human body requires the selective activation of particular cellular and/or humoral immune responses. The orchestration of the types of effector responses is directed by Th cells through the production of type 1 (Th1 cell-associated) and type 2 (Th2 cell-associated) cytokines. The way in which the Th cell cytokine profile is matched to the type of invading pathogen, and why these profiles sometimes derail and lead to disease, is not well understood. Here, we will discuss the concept that antigen-presenting cells (APC) provide Th cells not only with antigen and costimulatory signals, but also with a polarizing signal (signal 3). This signal can be mediated by many APC-derived factors, but IL-12 and PGE2 seem to be of major importance. The Th2-biased responses in atopic allergy appeared to be associated with monocytes with a decreased IL-12/PGE2 ratio and, consequently, with the down-regulation of type 1 cytokine production in Th cells. As for Th cells, APC can be functionialy polarized. In vitro experiments with monocyte-derived dendritic cells (DC) showed that the presence of IFN-gamma during activation of immature DC primes for mature DC with the ability of high IL-12 production and, consequently, a Th1-driving capacity (APC1 or DC1). In contrast, PGE2 primes for a low IL-12 production ability and a Th2-driving capacity (APC2 or DC2). These findings suggest that pathogens provoke either Th1- or Th2-cell development by inducing the production of a certain pattern of inflammatory DC-polarizing mediators (e.g. IFN-gamma and PGE2) at the site of infection. The type of immune polarization will not only depend on the type of pathogen, but also varies with the type of infected tissue, i.e. that different tissues produce different mediators in response to the same pathogen. In the case of atopic allergy, this concept implies that the Th2-cell bias may be related to low levels of cross-regulatory infections, to Th1 cell-inducing pathogens, or to an aberrant function of stromal cells in peripheral tissues.

Animals↗

PubMed2002

Multiple mechanisms compensate to enhance tumor-protective CD8(+) T cell response in the long-term despite poor CD8(+) T cell priming initially: comparison between an acute versus a chronic intracellular bacterium expressing a model antigen.

We evaluated CD8(+) T cell responses against the dominant CTL epitope, OVA(257-264), expressed by an acute (Listeria monocytogenes (LM) OVA) vs a chronic pathogen (Mycobacterium bovis bacillus Calmette-Guérin (BCG) OVA) to reveal the influence on CD8(+) T cell memory and consequent protection against a challenge with OVA-expressing tumor cells. Infection with lower doses of both pathogens resulted in stronger bacterial growth but weaker T cell memory indicating that memory correlates with pathogen dose but not with bacterial expansion. The CD8(+) T cell response induced by LM-OVA was helper T cell-independent and was characterized by a rapid effector response followed by a rapid, but massive, attrition. In contrast, BCG-OVA induced a delayed and weak response that was compensated for by a longer effector phase and reduced attrition. This response was partly dependent on CD4(+) T cells. CD8(+) T cell response induced by BCG-OVA, but not LM-OVA, was highly dependent on pathogen persistence to compensate for the weak initial CD8(+) T cell priming. Despite a stronger initial T cell response with LM-OVA, BCG-OVA provided more effective tumor (B16OVA) control at both local and distal sites due to the induction of a persistently activated acquired, and a more potent innate, immunity.

Animals↗

PubMed2003

Chemokine-mediated recruitment of NK cells is a critical host defense mechanism in invasive aspergillosis.

Invasive aspergillosis is a severe pneumonia that is usually fatal despite currently available therapy. The disease disproportionately afflicts immunocompromised patients, indicating the critical importance of the immune status of the host in this infection, but the defense mechanisms against this pathogen remain incompletely understood. In the current study, we hypothesized that the chemokine ligand monocyte chemotactic protein-1, also designated CC chemokine ligand-2 (MCP-1/CCL2) is necessary for effective host defense against invasive aspergillosis in immunocompromised hosts. We found a rapid and marked induction of MCP-1/CCL2 in the lungs of neutropenic mice with invasive aspergillosis. Neutralizing MCP-1/CCL2 resulted in twofold greater mortality and greater than threefold increase in pathogen burden in the lungs. Neutralization of MCP-1/CCL2 also resulted in reduced recruitment of NK cells to the lungs at early time points, but did not affect the number of other leukocyte effector cells in the lungs. Ab-mediated depletion of NK cells similarly resulted in impaired defenses against the infection, resulting in a greater than twofold increase in mortality and impaired clearance of the pathogen from the lungs. These data establish MCP-1/CCL2-mediated recruitment of NK cells to the lungs as a critical early host defense mechanism in invasive aspergillosis and demonstrate NK cells to be an important and previously unrecognized effector cell in this infection.

Animals↗

PubMed2002

Cytotoxic T lymphocytes: all roads lead to death.

Cytotoxic T lymphocytes (CTLs) provide potent defences against virus infection and intracellular pathogens. However, CTLs have a dark side--their lytic machinery can be directed against self-tissues in autoimmune disorders, transplanted cells during graft rejection and host tissues to cause graft-versus-host disease, which is one of the most serious diseases related to CTL function. Although this duplicitous behaviour might seem contradictory, both beneficial and detrimental effects are the result of the same effector proteins. So, an understanding of the mechanisms that are used by CTLs to destroy targets and a knowledge of pathogen immune-evasion strategies will provide vital information for the design of new therapies.

Animals↗

PubMed2004

Comparative analysis of locus of enterocyte effacement pathogenicity islands of atypical enteropathogenic Escherichia coli.

The pathogenicity of enteropathogenic Escherichia coli (EPEC) is linked to the locus of enterocyte effacement, or LEE, encoding a type III secretion system (T3SS) that directly transfers bacterial effector proteins into eukaryotic cells. Atypical diffusely adhering EPEC (DA-EPEC) strains that harbor homologues of the LEE but lack the EPEC adherence factor plasmid have been increasingly associated with outbreaks of diarrhea. In this study, we have completely sequenced and functionally characterized LEE pathogenicity islands derived from the clinical DA-EPEC isolates 3431 (O8:H-) and 0181 (O119:H9:K61). LEE3431 and LEE0181 exhibit genetic organization analogous to that of the prototype LEE(E2348/69). Genes constituting the T3SS apparatus are highly conserved. However, LEE-encoded effector proteins exhibit major differences. Transfer and functional expression of LEE0181 in an E. coli XL1 blue MR background demonstrated that LEE0181 contains all the information for signal transduction and pedestal formation.

Amino Acid Sequence↗

PubMed2002

The classical pathway is the dominant complement pathway required for innate immunity to Streptococcus pneumoniae infection in mice.

The complement system is an important component of the innate immune response to bacterial pathogens, including Streptococcus pneumoniae. The classical complement pathway is activated by antibody-antigen complexes on the bacterial surface and has been considered predominately to be an effector of the adaptive immune response, whereas the alternative and mannose-binding lectin pathways are activated directly by bacterial cell surface components and are considered effectors of the innate immune response. Recently, a role has been suggested for the classical pathway during innate immunity that is activated by natural IgM or components of the acute-phase response bound to bacterial pathogens. However, the functional importance of the classical pathway for innate immunity to S. pneumoniae and other bacterial pathogens, and its relative contribution compared with the alternative and mannose-binding lectin pathways has not been defined. By using strains of mice with genetic deficiencies of complement components and secretory IgM we have investigated the role of each complement pathway and natural IgM for innate immunity to S. pneumoniae. Our results show that the proportion of a population of S. pneumoniae bound by C3 depends mainly on the classical pathway, whereas the intensity of C3 binding depends on the alternative pathway. Furthermore, the classical pathway, partially targeted by the binding of natural IgM to bacteria, is the dominant pathway for activation of the complement system during innate immunity to S. pneumoniae, loss of which results in rapidly progressing septicemia and impaired macrophage activation. These data demonstrate the vital role of the classical pathway for innate immunity to a bacterial pathogen.

Animals↗

PubMed1986

Assays for complement activation.

Complement is a major biologic mediation system that functions in host defense against microorganisms and other pathogens and also aids in the elimination of damaged and abnormal cells. This is accomplished by its ability to mediate the destruction of pathogens and altered cells directly through cytolytic and cytotoxic properties, as well as indirectly by its ability to augment the actions of various effector cells, which in turn destroy or inactivate these substances. Its second major action in vivo is the production of an acute inflammatory response that, by altering blood-vessel permeability, contracting smooth muscles, and promoting an influx of leukocytes, aids in the localization of the injurious process responsible for complement activation and retards its spread and dissemination throughout the body. The actions of the activated complement system upon pathogens and altered cells, as well as its phlogistic properties, are the direct consequence of the actions of complement protein-protein complexes, enzymes, peptides, and cleavage products on the activator, on biologic membranes, and on various effector and other tissue cells. Complement activation is a frequent phenomenon in infectious diseases, autoimmune diseases, and many other conditions having an inflammatory component. Because of the importance of this system in contributing to the resolution of the disease process, monitoring of the status of the system in patients is frequently indicated. Monitoring of the complement status is also appropriate in numerous other diseases, such as those with an inflammatory component, in which complement activation occurs secondarily but in which it is frequently responsible for confining the injurious process and aiding in its resolution. A number of techniques are available to assess the status of the complement system in samples obtained from patients. Among these are a group of newer tests that specifically detect complement activation. They quantitate activation-dependent complement cleavage products, antigenic changes, or protein-protein complexes. These tests are quantitative, highly sensitive, and extremely specific; furthermore, most can be employed with samples obtained from patients. Because all of the biologic actions of the complement system require complement activation, such newer activation-specific assays permit the precise evaluation of the status of this system in human diseases. Further extension of their use to additional patients and other disease complexes will undoubtedly increase the understanding of the biologic importance of the complement system in human disease processes.

Complement Activation↗