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 1,513 records · Page 84Linked to original sources

PubMed2005

Imbalance of NKG2D and its inhibitory counterparts: how does tumor escape from innate immunity?

NK cells form a first line of defence against pathogens or host cells that are stressed or cancerous. NK cells express surface receptors that receive signals from the environment and determine their response to foreign or malignant cells. The effector functions of NK cells are regulated by integrated signals across the array of stimulatory and inhibitory receptors engaged upon interaction with target cell surface ligands. NKG2D is a peculiar activating receptor that is expressed as a disulphide-linked homodimer by all NK cells, alphabeta CD8(+) T cells, gammadeltaT cells and murine macrophages. It not only activates NK cells but also delivers co-stimulatory signals to CD8(+) T cells and gammadeltaT cells. The ligands of NKG2D are induced by cellular stress and are specifically expressed by some tumor cells. Recent studies reveal that the expression of MIC and ULBP on human tumor cells is sufficient to overcome the inhibitory effects of MHC class I expression on NK cell killing and indicate that NKG2D provides first line surveillance against stressed or abnormal cells that have been induced to express one of its ligands. However, malignant tumors develop means to control the expression of activating versus inhibitory receptors on immune cells and their ligands on tumor cell themselves in favor of tolerance. Modulating the balance between activating and inhibitory signals through NK cell receptors on NK cells may open a new approach to NK cell-based biotherapy for cancer and infectious diseases.

Animals↗

PubMed2006

Potent protective cellular immune responses generated by a DNA vaccine encoding HSV-2 ICP27 and the E. coli heat labile enterotoxin.

A mouse model was employed to evaluate protective cellular immune responses induced by an immediate early antigen of HSV-2. Particle-mediated DNA vaccination of mice with a DNA plasmid-encoding ICP27 resulted in the induction of ICP27-specific IFN-gamma and TNF-alpha production in Balb/c mice, but little protection to intranasal challenge with wild type HSV-2. However, when the DNA vaccine was supplemented with as little as 50ng of a vector encoding the A and B subunits of the Escherichia coli heat labile enterotoxin (LT), animals were profoundly protected from morbidity and mortality. The ICP27+LT-mediated protection was correlated with a large increase in ICP27-specific IFN-gamma and TNF-alpha production but cytokine-specific monoclonal antibody treatment at the time of challenge showed that protection was mediated predominantly by IFN-gamma. Furthermore, depletion of T cell subsets prior to infectious challenge demonstrated that removal of either CD8+ or CD4+ T cells impaired protection with CD8+ T cells appearing to play a direct effector role. These data demonstrate that augmented cellular immune responses resulting from LT vector plus antigen vector administration to the skin are biologically significant, leading to enhanced protection against mucosal pathogenic challenge.

Amino Acid Sequence↗

PubMed2003

Memory T cells and vaccines.

T lymphocytes play a central role in the generation of a protective immune response in many microbial infections. After immunization, dendritic cells take up microbial antigens and traffic to draining lymph nodes where they present processed antigens to naïve T cells. These naïve T cells are stimulated to proliferate and differentiate into effector and memory T cells. Activated, effector and memory T cells provide B cell help in the lymph nodes and traffic to sites of infection where they secrete anti-microbial cytokines and kill infected cells. At least two types of memory cells have been defined in humans based on their functional and migratory properties. T central-memory (T(CM)) cells are found predominantly in lymphoid organs and can not be immediately activated, whereas T effector-memory (T(EM)) cells are found predominantly in peripheral tissue and sites of inflammation and exhibit rapid effector function. Most currently licensed vaccines induce antibody responses capable of mediating long-term protection against lytic viruses such as influenza and small pox. In contrast, vaccines against chronic pathogens that require cell-mediated immune responses to control, such as malaria, Mycobacterium tuberculosis (TB), human immunodeficiency virus (HIV) and hepatitis C virus (HCV), are currently not available or are ineffective. Understanding the mechanisms by which long-lived cellular immune responses are generated following vaccination should facilitate the development of safe and effective vaccines against these emerging diseases. Here, we review the current literature with respect to memory T cells and their implications to vaccine development.

Animals↗

PubMed2000

Genetic differences in the Chlamydia trachomatis tryptophan synthase alpha-subunit can explain variations in serovar pathogenesis.

The human pathogen Chlamydia trachomatis is an obligate intracellular bacterium, characterized by a developmental cycle that alternates between the infectious, extracellular elementary bodies and intracellular, metabolically active reticulate bodies. The cellular immune effector interferon gamma (IFN-gamma) inhibits chlamydial multiplication in human epithelial cells by induction of the tryptophan degrading enzyme indoleamine 2,3 dioxygenase. IFN-gamma causes persistent C. trachomatis serovar A infections with atypical reticulate bodies that are unable to redifferentiate into elementary bodies and show diminished expression of important immunogens, but not of GroEL. However, the sensitivity to IFN-gamma varies among serovars of C. trachomatis. In our previous study significant IFN-gamma-specific, but tryptophan reversible, induction of proteins in C. trachomatis A and L2 with molecular masses of approximately 30 and 40 kDa was observed on 2D-gels. The 30-kDa protein from C. trachomatis L2 migrated with a significantly lower molecular weight in C. trachomatis A. In this paper we include C. trachomatis B, C and D in our investigations and identify the proteins as alpha- and beta-subunits of the chlamydial tryptophan synthase using matrix-assisted laser desorption/ionization mass spectrometry. DNA sequencing of the trpA genes from C. trachomatis A and C shows that the TrpA in these serovars is a 7.7-kDa truncated version of C. trachomatis D and L2 TrpA. The truncation probably impairs the TrpA activity, thus elucidating a possible molecular mechanism behind variations in the pathogenesis of C. trachomatis serovars.

Amino Acid Sequence↗

PubMed2006

Renal Toll-like receptors: recent advances and implications for disease.

Toll-like receptors (TLRs) are proteins that recognize specific molecular patterns of pathogens. They can also interact with a variety of endogenous ligands. When stimulated, TLRs initiate a cascade of signaling events leading to the production of a myriad of cytokines and effector molecules. Early investigations extensively characterized TLRs on cells of the innate immune system. More recently, TLRs have been found to reside in organs such as the heart, lungs, intestines, liver and kidneys. The role of these TLRs is not fully understood and is the subject of intensive current research. The available information indicates that renal TLRs have the potential to interact with exogenous and endogenous ligands, thereby influencing kidney function in health and disease. Here, we present an overview of what is currently known about renal TLRs, and discuss the potential implications for further research and clinical practice.

Animals↗

PubMed1999

Structure-activity analysis of synthetic autoinducing thiolactone peptides from Staphylococcus aureus responsible for virulence.

The synthesis of virulence factors and other extracellular proteins responsible for pathogenicity in Staphylococcus aureus is under the control of the agr locus. A secreted agr-encoded peptide, AgrD, processed from the AgrD gene product, is known to be an effector of self-strain activation and cross-strain inhibition of the agr response. Biochemical analysis of AgrD peptides isolated from culture supernatants has suggested that they contain an unusual thiol ester-linked cyclic structure. In the present work, chemical synthesis is used to confirm that the mature AgrD peptides contain a thiolactone structure and that this feature is absolutely necessary for full biological activity. The AgrD synthetic thiolactone peptides exhibited biological activity in vivo in a mouse protection test. Structure-activity studies have allowed key aspects of the peptide structure involved in the differential activation and inhibition functions to be identified. Accordingly, we propose a model for activation and inhibition of the agr response in which the former, but not the latter, involves specific acylation of the agr transmembrane receptor, AgrC.

Abscess↗

PubMed2002

Cellular and cytokine immunoregulation in patients with chronic obstructive pulmonary disease and bronchial asthma.

BACKGROUND: Different forms of chronic airway inflammation may involve diverse pathogenic elements. In general, deficient defence response is a feature of chronic obstructive pulmonary disease (COPD), whereas distorted immunoregulatory mechanisms lead to development of asthmatic symptoms. In addition to diverse effector mechanisms, the cellular and humoral elements participating in the development of immune response may appear to be different in COPD and bronchial asthma (BA) patients. AIMS: To evaluate the immunoregulatory properties of T cells and monocytes in cultures of peripheral blood mononuclear cells (PBMC) and to determine the chosen cytokine profiles in COPD and BA patients. METHODS: The microcultures of PBMC from COPD and BA patients were assessed for the T-cell response to mitogens, saturation of interleukin (IL)-2 receptors, T-cell suppressive activity and monokine influence on lymphocyte proliferation. Concomitantly, the cytokine (IL-1beta, interleukin-1 receptor antagonist, tumour necrosis factor-alpha, IL-4, IL-6, IL-8) concentrations were determined in the serum, the broncho-alveolar lavage fluid and in the culture supernatants. RESULTS: The T-lymphocyte reactions (response to phytohaemagglutinin, IL-2 receptor saturation, suppressive activity) were lower in BA patients than in COPD patients. Reversely, the immunogenic activity of monocytes (IL-1beta versus IL-1ra production) was higher in BA patients than in COPD patients. The highest values of cytokine concentrations were found in the culture supernatants. The concentrations of tumour necrosis factor-alpha, IL-4, IL-6 and IL-8 were significantly higher and the concentration of IL-1ra was lower in BA patients than in COPD patients. CONCLUSION: The assessments of cellular immunoregulatory properties and cytokine profiles in the cultures of blood mononuclear cells may prove helpful for diagnostic and therapeutic discrimination between BA and COPD patients.

Adult↗

PubMed2004

The SPI2-encoded SseA chaperone has discrete domains required for SseB stabilization and export, and binds within the C-terminus of SseB and SseD.

SseA, a key Salmonella virulence determinant, is a small, basic pI protein encoded within the Salmonella pathogenicity island 2 and serves as a type III secretion system chaperone for SseB and SseD. Both SseA partners are subunits of the surface-localized translocon module that delivers effectors into the host cell; SseB is predicted to compose the translocon sheath and SseD is a putative translocon pore subunit. In this study, SseA molecular interactions with its partners were characterized further. Yeast two-hybrid screens indicate that SseA binding requires a C-terminal domain within both partners. An additional central domain within SseD was found to influence binding. The SseA-binding region within SseB was found to encompass a predicted amphipathic helix of a type participating in coiled-coil interactions that are implicated in the assembly of translocon sheaths. Deletions that impinge upon this putative coiled-coiled domain prevent SseA binding, suggesting that SseA occupies a portion of the coiled-coil. SseA occupancy of this motif is envisioned to be sufficient to prevent premature SseB self-association inside bacteria. Domain mapping on the chaperone was also performed. A deletion of the SseA N-terminus, or site-directed mutations within this region, allowed stabilization of SseB, but its export was disrupted. Therefore, the N-terminus of SseA provides a function that is essential for SseB export, but dispensable for partner binding and stabilization.

Amino Acid Sequence↗

PubMed1991

Differential effect of aging on B-cell immune responses to cholera toxin in the inductive and effector sites of the mucosal immune system.

The age-associated primary immune response of B cells from the Peyer's patches (PP), the lamina propria (LP), the mesenteric lymph nodes (MLN), and the spleen of mice following oral immunization with cholera toxin (CTx) was investigated. The induction of immune responses was assessed in 4-, 11-, and 24-month-old, individual C57BL/6J male mice by determining the number and isotype of anti-CTx ELISPOT-forming cells (SFC) in the PP, LPL, MLN, and spleen and the titer and isotype of serum anti-CTx antibody. The data indicate a significant age-associated decline in immunoglobulin G (IgG) and IgA anti-CTx SFC in the LP B cells but only in IgA anti-CTx SFC in the PP. No decline was seen in the anti-CTx SFC response in the MLN and spleen. Peroral immunization of mice with CTx resulted in a serum anti-CTx antibody response which was predominantly of the IgG class in all three age groups of mice tested. There was no age-associated decline in anti-CTx IgM, IgG, or IgA titers in serum. Isoelectric focusing and affinity immunoblotting revealed several distinct new antibody clonotypes in the immune serum of old mice following oral immunization with CTx. The results indicate a loss of immune responsiveness to CTx following oral immunization in senescent PP and LP B cells. The MLN and spleen B-cell responses were found to be refractory to the loss of immune function with aging. These findings suggest a differential effect of aging in the inductive and effector sites of the mucosal immune system, and the loss of antigen-specific IgA responses at mucosal sites may have adverse effects on the host's defense against potential pathogens.

Administration, Oral↗

PubMed2006

The Helicobacter pylori cag pathogenicity island protein CagN is a bacterial membrane-associated protein that is processed at its C terminus.

Helicobacter pylori infects nearly half the world's population and is associated with a spectrum of gastric maladies. Infections with cytotoxin-associated gene pathogenicity island (cag PAI)-containing strains are associated with an increased risk for gastric cancer. The cag PAI contains genes encoding a type IV secretion system (T4SS) and a delivered effector, CagA, that becomes tyrosine phosphorylated upon delivery into host cells and initiates changes in cell signaling. Although some cag PAI genes have been shown to be required for CagA delivery, a subset of which are homologues of T4SS genes from Agrobacterium tumefaciens, the majority have no known function or homologues. We have performed a detailed investigation of one such cag PAI protein, CagN, which is encoded by the gene HP0538. Our results show that CagN is not delivered into host cells and instead is associated with the bacterial membrane. We demonstrate that CagN is cleaved at its C terminus by a mechanism that is independent of other cag PAI proteins. Finally, we show that a delta cagN mutant is not impaired in its ability to deliver CagA to gastric epithelial cells and initiate cell elongation.

Antigens, Bacterial↗

PubMed1996

The role of nitric oxide in experimental glomerulonephritis.

In recent years, nitric oxide (NO) has been identified as an effector molecule with multiple biological functions. NO production is physiologically involved in the regulation of vascular tone, platelet aggregation and hormone release, in neurotransmission, and in immune defense against several pathogens. However, uncontrolled up-regulation of NO release by cytokine-inducible NO synthases (iNOSs) may cause tissue damage in immune-mediated diseases. In experimental glomerulonephritis, there is now good evidence that glomerular induction of NO synthesis mediates glomerular cell injury. In contrast, an intact constitutive NO release within the glomerular vasculature may be protective by decreasing glomerular capillary pressure. This review discusses the pathophysiological role of NO in glomerulonephritis based on experimental data and provides a perspective for potential anti-inflammatory treatment approaches selectively targeting iNOS overexpression.

Animals↗

PubMed2001

Regulation of both gene expression and protein stability provides genetically assisted target evaluation (GATE) for microbial target validation.

The attempt to develop novel antibiotics, active against organisms resistant to current therapies, has led researchers to seek and explore new drug targets. The rapid sequencing and analysis of entire microbial genomes has identified large numbers of genes that may be sufficiently different from their human counterparts to be exploited as targets for antimicrobial treatment. As a first step, the importance of the various putative targets for microbial growth and survival must be assessed. Emerging validation technologies are becoming increasingly sophisticated and, in certain cases, allow prioritisation of the best targets. In this paper, genetically assisted target evaluation (GATE) is introduced as a versatile target validation technology. GATE concomitantly manipulates both synthesis and stability of the targeted protein using copper ions as an effector. This technology allows rapid quantitation of the lethal consequences of inactivation of targeted gene products in Saccharomyces cerevisiae. Additional tools can then be applied to extend these results into pathogenic organisms, such as Candida albicans.

Animals↗

PubMed2004

Listeria monocytogenes as a vaccine vector: virulence attenuation or existing antivector immunity does not diminish therapeutic efficacy.

The bacterium L. monocytogenes is a proposed vaccine carrier based upon the observation that this pathogen replicates within the intracytoplasmic environment facilitating delivery of Ag to the endogenous Ag processing and presentation pathway with subsequent stimulation of peptide specific MHC class I-restricted CD8(+) effector cells. In this report, we evaluate virulence-attenuated strains of Listeria monocytogenes as vaccine vectors and examine whether existing antivector (antilisterial) immunity limits or alters its efficacy as a therapeutic cancer vaccine. Following immunization with virulence-attenuated mutants, we found that the effectiveness of L. monocytogenes as a recombinant cancer vaccine remains intact. In addition, we found that antibiotic treatment initiated 24 or 36 h following therapeutic immunization with recombinant L. monocytogenes allows full development of the antitumor response. We also demonstrate that the vaccine vector potential of L. monocytogenes is not limited in animals with existing antilisterial immunity. For these latter studies, mice previously immunized with wild-type L. monocytogenes were infused with melanoma cells and then 5 days later challenged with recombinant tumor Ag expressing L. monocytogenes. Collectively, these results add additional support for the use of L. monocytogenes as a vaccine vector and underscore its potential to be used repeatedly for stimulation of recall responses concomitant with primary cell-mediated responses to newly delivered heterologous tumor-associated epitopes.

Animals↗

PubMed2003

Vaccination with dendritic cells pulsed with peptides of myelin basic protein promotes functional recovery from spinal cord injury.

Injury-induced self-destructive processes cause significant functional loss after incomplete spinal cord injury (SCI). Cellular elements of both the innate (macrophage) and the adaptive (T-cell) immune response can, if properly activated and controlled, promote post-traumatic regrowth and protection after SCI. Dendritic cells (DCs) trigger activation of effector and regulatory T-cells, providing a link between the functions of the innate and the adaptive immune systems. They also initiate and control the body's response to pathogenic agents and regulate immune responses to both foreign and self-antigens. Here we show that post-injury injection of bone marrow-derived DCs pulsed with encephalitogenic or nonencephalitogenic peptides derived from myelin basic protein, when administered (either systemically or locally by injection into the lesion site) up to 12 d after the injury, led to significant and pronounced recovery from severe incomplete SCI. No significant protection was seen in DC recipients deprived of mature T-cells. Flow cytometry, RT-PCR, and proliferation assays indicated that the DCs prepared and used here were mature and immunogenic. Taken together, the results suggest that the DC-mediated neuroprotection was achieved via the induction of a systemic T-cell-dependent immune response. Better preservation of neural tissue and diminished formation of cysts and scar tissue accompanied the improved functional recovery in DC-treated rats. The use of antigen-specific DCs may represent an effective way to obtain, via transient induction of an autoimmune response, the maximal benefit of immune-mediated repair and maintenance as well as protection against self-destructive compounds.

Animals↗

PubMed2005

[Functions of microglia in immune mechanisms in the central nervous system].

Microglia are only one type of professional immune cells in the central nervous system, functioning as scavenger cells that remove pathogens, and as antigen presenting cells that present brain-specific antigens to invading T cells. They also play a critical role in the pathophysiology of various CNS disorders as effector cells to destroy neural cells by secreting inflammatory cytokines, radicals, and glutamate. At the same time, they can protect neural functions by producing neurotrophic factors. Thus, to study the mechanisms for regulation of microglial functions may be useful for understanding the etiology and future therapeutic strategy for intractable neurological disorders.

Animals↗

PubMedDate not supplied

[Inhibition of expontaneous cytotoxicity and antibody dependency by rheumatoid synovial fluid].

A number of authors have pointed out a diminution of ADCC (Antibody dependent cellular cytotoxicity) in lymphocytes from peripheral blood of patients with rheumatoid arthritis (RA). It has also been found that the addition of rheumatoid serum inhibits ADCC and also spontaneous cellular cytotoxicity (SCC). This effect could be the result of blocking of effector cell receptors for the Fc fragment of IgG by anti-immunoglobulins and/or immune complexes, present in great quantities in rheumatoid serum. We investigated the effect of synovial fluid on the ADCC and SCC shown by purified suspensions of lymphocytes from healthy donors and RA patients towards chicken erythrocytes tagged with 51 Cr. The samples of synovial fluid from patients with RA or arthrosis did not influence per se the spontaneous release of 51 Cr, once their complement had been removed. Seven-eight of the rheumatoid synovial fluid (RSF) produced a significant decline (p less than 0.01) of SCC. Lymphocytes from the peripheral blood of RA patients showed a greater decline in SCC after the addition of RSF than those from healthy subjects (p less than 0.02). In 14/16 RSF and 5/7 samples of arthrosis synovial fluid (ASF) the ability to diminish ADCC significantly (P less than 0.01) was shown. RSF maintained this inhibitory effect in 1:40 and 1:80 dilutions, whereas in these conditions ASF had no effect on ADCC. RSF and ASF, before their complement was removed, showed an opposite effect, provoking an increase in cytotoxic activity, both SCC and ADCC, though in different proportions. These experiments show that RSF, like rheumatoid serum, inhibits ADCC and SCC, possibly by the same mechanism which blocks the Fc receptors by means of immune complexes, and coincides in its general lines with the recent findings of Díaz Jouanen et al. The pathogenetic implications of this phenomenon are difficult to clarify at present. Its occurrence in vivo would represent the establishment of a local block of cytotoxic effector cells (protector effect), which, on the other hand, would no longer be able to exercise their destructive action against cells responsible for the initiation and/or maintenance of articular damage (pathogenic effect). The non-participation of T cells, in these types of cytotoxicity, previously shown by other authors, accentuates the importance of thymus-independent regulatory systems in the mechanisms which maintain articular damage in RA.

Antibody-Dependent Cell Cytotoxicity↗

PubMed1996

B-cell activation in vitro by helper T cells specific to region alpha 146-162 of Torpedo californica nicotinic acetylcholine receptor.

We have previously mapped the T and B cell epitopes on the alpha-subunit of acetylcholine receptor (AChR) in human myasthenia gravis (MG) and in experimental autoimmune MG-susceptible (C57BL/6 (B6)) and nonsusceptible mouse strains. In addition to regions recognized by both T and B cells, the AChR alpha-subunit has regions that are recognized solely by T cells. An exclusive T cell epitope within residues alpha 146-162 of Torpedo californica (t), tAChR, plays an important role in experimental autoimmune MG pathogenesis in B6 mice. To study its function, we established, from tAChR-primed B6 mice, two t alpha 146-162-specific T cell lines (P14Th) which comprised Th2-type cells because they secreted IL-4 but not IL-2. P14Th did not recognize the corresponding region on mouse (m) AChR (m alpha 146-162). They caused in vitro differentiation of tAChR-primed B cells into plasma cells that secreted anti-AChR Abs directed, in decreasing order, against the following tAChR alpha regions: t alpha 122-138 > t alpha 134-150 > t alpha 45-60 > t alpha 170-186 > t alpha 56-71. Little or no Ab response could be detected against peptides t alpha 182-198 or t alpha 146-162 itself. The major enhancement was in the Abs against region t alpha 122-150 (spanning the t alpha 122-138/t alpha 134-150 overlap) that is involved in ACh binding. These Abs cross-reacted completely with m alpha 122-150, the corresponding region on mAChR. Therefore, t alpha 146-162-specific T cells, although unable to recognize m alpha 146-162, are nevertheless pathogenic because they help B cells responding to a tAChR region that is conserved in mAChR and involved in ACh binding. These Abs cross-react with the corresponding effector-binding region of mAChR, thereby disrupting the normal physiologic function of the mouse receptor.

Amino Acid Sequence↗

PubMed1999

Defects of T-cell effector function and post-thymic maturation in X-linked hyper-IgM syndrome.

X-linked hyper-IgM syndrome (XHIM) results from mutations in the gene encoding for CD40 ligand (CD154). Patients with the syndrome suffer from infections with opportunistic pathogens such as Cryptosporidium and Pneumocystis carinii. In this study, we demonstrate that activated T cells from patients with XHIM produce markedly reduced levels of IFN-gamma, fail to induce antigen-presenting cells to synthesize IL-12, and induce greatly reduced levels of TNF-alpha. In addition, we show that the patients' circulating T lymphocytes of both the CD4(+) and CD8(+) subsets contain a markedly reduced antigen-primed population, as determined by CD45RO expression. Finally, we demonstrate that the defects in antigen priming are likely due to the lack of CD154 expression and insufficient costimulation of T cells by CD80/CD86 interactions. Taken together, this study offers a basis for the increased susceptibility of patients with XHIM to certain opportunistic infections.

Adolescent↗