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PubMed2005

Type III secretion system cluster 3 is required for maximal virulence of Burkholderia pseudomallei in a hamster infection model.

Burkholderia pseudomallei, the etiological agent of melioidosis, is an animal pathogen capable of inducing a highly fatal septicemia. B. pseudomallei possesses three type III secretion system (TTSS) clusters, two of which (TTSS1 and TTSS2) are homologous to the TTSS of the plant pathogen Ralstonia solanacearum, and one (TTSS3) is homologous to the Salmonella SPI-1 mammalian pathogenicity island. We have demonstrated that TTSS3 is required for the full virulence of B. pseudomallei in a hamster model of infection. We have also examined the virulence of B. pseudomallei mutants deficient in several putative TTSS3 effector molecules, and found no significant attenuation of B. pseudomallei virulence in the hamster model.

Animals↗

PubMed1984

Cell-mediated damage to helminths.

Although it is difficult to draw any sweeping conclusions that would be applicable to all helminth infections, the main features that are emphasized in this review may be summarized briefly. Pathogenic helminths, although extremely diverse in structure and behaviour, have one common feature, namely that they present to the host's defenses large, non-phagocytosable surfaces. Because of this, they are susceptible to a range of effector mechanisms differing either quantitatively or qualitatively from those that are active against other parasites or against normal or abnormal host cells. As an extreme example, the various types of cytotoxic lymphocyte, with one interesting exception, are inactive against helminths. Instead, helminth infections are characterized by high IgE responses and increased numbers of circulating eosinophils. Such eosinophils are activated, and show a marked capacity to kill a variety of target helminths in vitro. Further activation may occur in response to mast cell mediators released as a result of IgE-dependent degranulation; and IgE, as well as IgG and complement, can mediate eosinophil attachment and killing. It may therefore be suggested that the eosinophil/IgE/mast cell axis represents a powerful host defense against helminth infections. IgE can also mediate macrophage-dependent killing of several helminths, a process which involves a functional change in the macrophage, resembling activation. Although eosinophil-mediated and IgE-dependent macrophage-mediated effects are particularly potent, other effector cells are not excluded: in certain circumstances, neutrophils and conventionally activated macrophages may be equally or more effective. Neutrophils appear to act solely by oxidative killing mechanisms, whereas degranulation and the release of toxic granule contents is equally or more important in eosinophil-mediated damage. Different stages of different helminths vary in their degree of susceptibility to different mechanisms. Eosinophils appear to be somewhat less active than neutrophils against ensheathed nematodes, whereas trematodes and exsheathed nematodes are highly susceptible to eosinophil attack. In many experimental helminth infections, studies in vivo suggest a role for antibody-dependent cell-mediated immune effector mechanisms. The identity of the effector cell is difficult to establish because of a lack of techniques for specific manipulation of individual cell types, but histological studies frequently point to a strong eosinophil or macrophage involvement. The development and analysis of in vitro assays allows the study of immune effector mechanisms in man.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2003

The ocular humoral immune response in health and disease.

This review focuses on several aspects of humoral immunologic defence of the ocular surface and intraocular compartment. Secretory IgA (sIgA) is a major component of lacrimal fluid and contributes to the first line of defence against infection of the ocular surface. Recent findings show that part of the lacrimal gland (LG) IgA repertoire consists of so-called natural IgA antibodies. How B cells responsible for these natural IgA antibodies are distributed to effector mucosal sites like the LG is not known. Extensive data are now available on the regionalization of mucosal IgA responses in murine gut, involving peritoneal B cells, the prototypic natural antibody producing cells. By comparing elaborate experiments done in mice with the much less extensive data on the LG, it becomes clear that this gland is a unique, but poorly investigated effector organ of the mucosal immune system. In addition to the humoral immune response at the surface of the eye, the production of antibodies within the ocular compartment also has several fascinating features. The detection of pathogen-specific antibodies in intraocular fluid (IOF) of uveitis patients is accepted as a diagnostic tool, but the specificity of these intraocular antibodies was not investigated in much detail. Recent data however, demonstrate that even antibodies recognizing the same antigen in both serum and IOF still differ in the epitopes they recognize. This reveals that the intraocular compartment largely determines its own antibody profile in the defence against intra-ocular pathogens. Several models as to how an exclusive intra-ocular B cell repertoire may be generated are presented.

Animals↗

PubMed2005

The yin and yang of type I interferon activity in bacterial infection.

Interferons (IFNs) are cytokines that are important for immune responses, particularly to intracellular pathogens. They are divided into two structurally and functionally distinct types that interact with different cell-surface receptors. Classically, type I IFNs are potent antiviral immunoregulators, whereas the type II IFN enhances antibacterial immunity. However, as outlined here, type I IFNs are also produced in response to infection with other pathogens, and an increasing body of work shows that type I IFNs have an important role in the host response to bacterial infection. Strikingly, their activity can be either favourable or detrimental, and can influence various immune effector mechanisms.

Animals↗

PubMed2006

Molecular model of a type III secretion system needle: Implications for host-cell sensing.

Type III secretion systems are essential virulence determinants for many Gram-negative bacterial pathogens. The type III secretion system consists of cytoplasmic, transmembrane, and extracellular domains. The extracellular domain is a hollow needle protruding above the bacterial surface and is held within a basal body that traverses both bacterial membranes. Effector proteins are translocated, via this external needle, directly into host cells, where they subvert normal cell functions to aid infection. Physical contact with host cells initiates secretion and leads to formation of a pore, thought to be contiguous with the needle channel, in the host-cell membrane. Here, we report the crystal structure of the Shigella flexneri needle subunit MxiH and a complete model for the needle assembly built into our three-dimensional EM reconstruction. The model, combined with mutagenesis data, reveals that signaling of host-cell contact is relayed through the needle via intersubunit contacts and suggests a mode of binding for a tip complex.

Amino Acid Sequence↗

PubMed2000

Trivalent ions activate abscisic acid-inducible promoters through an ABI1-dependent pathway in rice protoplasts.

The plant hormone abscisic acid (ABA) mediates many vital processes in plant growth and development, including seed dormancy, cell division, water use efficiency, and adaptation to drought, salinity, chilling, pathogen attack, and UV light. Our understanding of ABA signal transduction is fragmentary and would benefit from specific and facile probes of the process. Protoplasts from rice (Oryza sativa L. cv IR54) embryonic suspension cultures cotransformed with effector plasmids encoding the maize (Zea mays) VIVIPAROUS1 cDNA and/or the Arabidopsis dominant negative mutant (abi1-1) ABA-insensitive cDNA demonstrated genetic interactions of VIVIPAROUS1 and abi1-1 in transactivation of the ABA-inducible HVA1 promoter from barley (Hordeum vulgare), suggesting the mechanisms of these effectors are conserved among monocots and dicots. Trivalent ions have been shown to act as an effector of gene expression in plants and animals, although the mechanism of action is unknown. We show in two complementary transient ABA-inducible gene expression assays (beta-glucuronidase and luciferase enzymatic activities and quantitative flow cytometry of green fluorescent protein) that trivalent ions specifically interact with an ABI1-dependent ABA-signaling pathway leading to gene expression. Trivalent ions mimic ABA effects on gene expression and may be a useful tool to study ABA signaling.

Abscisic Acid↗

PubMed2006

Not-so-great expectations: re-assessing the essence of T-cell memory.

We are often taught that secondary, or memory, responses by lymphocytes are more vigorous than primary responses. An expectation commonly associated with this notion is that the initial encounter with a pathogen should result in immunity to re-infection. Although this outcome is sometimes the case, it is not universally true. In this review, we propose a unified model of T-cell memory to explain the apparent successes and failures of eliciting vaccine-like protection from prior encounters with pathogens. We speculate that memory T cells arise as an invariant consequence of clonal selection during an immune response. The quality of memory T cells, however, seems to vary in the degree to which they have acquired effector characteristics and, thus, their ability to confer immunity to re-infection. Although not all memory T cells possess the embellished attributes of fully developed effector cells, they all seem to share the rudimentary quality of preserving an antigen specificity that has proven itself useful. We suggest that the ability to maintain the integrity of the T-cell repertoire, more than establishing immunity to re-infection, may represent the fundamental form of memory for the adaptive immune system.

Animals↗

PubMed2004

Abnormal interleukin-7 function in common variable immunodeficiency.

Common variable immunodeficiency (CVID) is characterized by low levels of circulating immunoglobulins, leading to frequent infections, particularly of the respiratory tract. Frequently, T-cell abnormalities are observed. Interleukin-7 (IL-7) is involved in the homeostasis of lymphocytes, and may be elevated in lymphopenia. Mutations of genes related to IL-7 may lead to severe immunodeficiency disorders. We report elevated plasma levels of circulating IL-7 in a subgroup of CVID. These patients have increased numbers of circulating CD8+ T cells with decreased apoptosis and a predominance of CC chemokine receptor 7- (CCR7-) effector-memory T cells. Moreover, in some of these patients there is impaired response to IL-7 as assessed by in vitro proliferation and secretion of interferon gamma and transforming growth factor beta. These findings suggest novel pathogenic mechanisms and specific targets for further research in CVID.

Adult↗

PubMed2004

Controlling the Toll road to dendritic cell polarization.

The activation of dendritic cells (DC) via Toll-like receptors (TLRs) plays a decisive role in shaping the outcome of primary immune responses. Following TLR engagement by microbial products, DC migrate from peripheral tissues to lymphoid organs and up-regulate major histocompatibility complex and costimulatory molecules, acquiring the unique capacity to prime pathogen-specific, naïve T cells. In addition, DC determine the character of the ensuing immune response by secreting cytokines that drive the development of T cells into T helper cell type 1 (Th1), Th2, or T regulatory effector cells. Three major factors influence the pattern of cytokines released by DC and accordingly, the Th balance: the lineage to which DC belong; the maturation stimulus; and inflammatory mediators present at the site of infection. A major focus of this review is the capacity of DC to integrate these factors and elicit distinct classes of immune responses.

Animals↗

PubMed2003

The pathogenesis of CIDP: rationale for treatment with immunomodulatory agents.

Current knowledge about the pathogenic mechanisms involved in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) supports an autoimmune etiology. Some of the cell and humorally mediated immune responses that contribute to the development of CIDP resemble those implicated in multiple sclerosis (MS). The effector role of circulating antibodies has recently been revisited. In addition, similar to the situation in MS, histopathologic studies support the heterogeneity of disease mechanisms in CIDP, with variants showing axon damage. In addition to intravenous immunoglobulin (IVIg), prednisone, and plasma exchange, immunomodulatory drugs also were used to treat CIDP, although no definitive trial data are available. One class of immunomodulators, interferon beta formulations, has proven efficacy in the treatment of MS, and because of clinical similarities between the two diseases it is attractive to investigate whether some agents that are effective in the treatment of MS would also be effective in CIDP. Preliminary studies have evaluated the effects of interferon beta formulations in the treatment of CIDP, one of which has shown promising results and warrants further investigation.

Adjuvants, Immunologic↗

PubMed2006

Calpain-regulated p35/cdk5 plays a central role in dopaminergic neuron death through modulation of the transcription factor myocyte enhancer factor 2.

The mechanisms underlying dopamine neuron loss in Parkinson's disease (PD) are not clearly defined. Here, we delineate a pathway by which dopaminergic loss induced by 1-methyl-4-phenyl 1,2,3,6 tetrahydropyridine (MPTP) is controlled in vivo. We reported previously that calpains play a central required role in dopamine loss after MPTP treatment. Here, we provide evidence that the downstream effector pathway of calpains is through cyclin-dependent kinase 5 (cdk5)-mediated modulation of the transcription factor myocyte enhancer factor 2 (MEF2). We show that MPTP-induced conversion of the cdk5 activator p35 to a pathogenic p25 form is dependent on calpain activity in vivo. In addition, p35 deficiency attenuates MPTP-induced dopamine neuron loss and behavioral outcome. Moreover, MEF2 is phosphorylated on Ser444, an inactivating site, after MPTP treatment. This phosphorylation is dependent on both calpain and p35 activity, consistent with the model that calpain-mediated activation of cdk5 results in phosphorylation of MEF2 in vivo. Finally, we provide evidence that MEF2 is critical for dopaminergic loss because "cdk5 phosphorylation site mutant" of MEF2D provides neuroprotection in an MPTP mouse model of PD. Together, these data indicate that calpain-p35-p25/cdk5-mediated inactivation of MEF2 plays a critical role in dopaminergic loss in vivo.

Animals↗

PubMed2005

Osteopontin is not required for the development of Th1 responses and viral immunity.

Osteopontin (OPN) has been defined as a key cytokine promoting the release of IL-12 and hence inducing the development of protective cell-mediated immunity to viruses and intracellular pathogens. To further characterize the role of OPN in antiviral immunity, OPN-deficient (OPN-/-) mice were analyzed after infection with influenza virus and vaccinia virus. Surprisingly, we found that viral clearance, lung inflammation, and recruitment of effector T cells to the lung were unaffected in OPN-/- mice after influenza infection. Furthermore, effector status of T cells was normal as demonstrated by normal IFN-gamma production and CTL lytic activity. Moreover, activation and Th1 differentiation of naive TCR transgenic CD4+ T cells by dendritic cells and cognate Ag was normal in the absence of OPN in vitro. Contrary to a previous report, we found that OPN-/- mice mounted a normal immune response to Listeria monocytogenes. In conclusion, OPN is dispensable for antiviral immune responses against influenza virus and vaccinia virus.

Animals↗

PubMed2006

High mobility group B1 protein suppresses the human plasmacytoid dendritic cell response to TLR9 agonists.

Plasmacytoid dendritic cells (PDC) are innate immune effector cells that are recruited to sites of chronic inflammation, where they modify the quality and nature of the adaptive immune response. PDCs modulate adaptive immunity in response to signals delivered within the local inflammatory milieu by pathogen- or damage-associated molecular pattern, molecules, and activated immune cells (including NK, T, and myeloid dendritic cells). High mobility group B1 (HMGB1) is a recently identified damage-associated molecular pattern that is released during necrotic cell death and also secreted from activated macrophages, NK cells, and mature myeloid dendritic cells. We have investigated the effect of HMGB1 on the function of PDCs. In this study, we demonstrate that HMGB1 suppresses PDC cytokine secretion and maturation in response to TLR9 agonists including the hypomethylated oligodeoxynucleotide CpG- and DNA-containing viruses. HMGB1-inhibited secretion of several proinflammatory cytokines including IFN-alpha, IL-6, TNF-alpha, inducible protein-10, and IL-12. In addition, HMGB1 prevented the CpG induced up-regulation of costimulatory molecules on the surface of PDC and potently suppressed their ability to drive generation of IFN-gamma-secreting T cells. Our observations suggest that HMGB1 may play a critical role in regulating the immune response during chronic inflammation and tissue damage through modulation of PDC function.

Cell Proliferation↗

PubMed1993

Purification and characterization of chimeric human IgA1 and IgA2 expressed in COS and Chinese hamster ovary cells.

Ag-specific chimeric human IgA molecules, of the two human subclasses, IgA1 and IgA2, have been expressed in two mammalian cell systems. Analysis of the secreted IgA molecules, purified in milligram quantities from stable Chinese hamster ovary transfectants by Ag affinity chromatography, has allowed a direct comparison of the biologic properties of the two subclasses. HPLC gel filtration analysis revealed that in both subclasses, the IgA molecules associate predominantly into dimers. The monomer units are presumed to interact noncovalently, inasmuch as no dimers are evident when the antibodies are subjected to SDS-PAGE. The recombinant antibodies are glycosylated, inasmuch as a lectin blotting procedure revealed that the H chains of both subclasses are recognized by Con A. When subjected to digestion by preparations of IgA1-specific proteases secreted by two pathogenic streptococcal strains, Streptococcus sanguis and Streptococcus oralis, the recombinant IgA molecules behave just as their natural equivalents. Thus, only the chimeric IgA1 molecule is cleaved, with the IgA2 remaining intact. In terms of interaction with natural effector molecules, both recombinant IgA isotypes were shown to interact with Fc alpha receptors on calcitriol-stimulated HL-60 cells with similar affinity, but neither antibody was found to interact with human C1q. The expression system described readily permits manipulation of the human IgA genes, which should lead to a fuller molecular understanding of how this important antibody mediates its function.

Animals↗

PubMed1998

Role of cytokines in pathogenesis of Helicobacter pylori-induced mucosal damage.

In Helicobacter pylori infection both bacterial and host factors contribute to gastroduodenal mucosal damage. Indirect damage will result from the persistent innate and specific inflammatory response induced by bacterial products and the alterations in gastric physiology associated with infection. Cytokines play a critical role in the initiation and modulation of gastrointestinal inflammation. The gastric epithelium, which secretes chemokines in response to H. pylori, has a role in initiating acute inflammation. Bacterial induction of epithelial chemokines such as IL-8 involves protein tyrosine phosphorylation and NF-kappaB activation. Multiple genes in the cag pathogenicity island are essential for induction of epithelial chemokines. In vivo infection with cag-positive strains is associated with increased mucosal chemokines and inflammatory responses. Th1 cell-mediated responses characterized by interferon-gamma-secreting effector cells are also associated with increased mucosal inflammation. Variations in the magnitude and characteristics of the host cytokine responses induced by H. pylori are considered important factors determining the degree of chronic inflammation.

Animals↗

PubMed2007

A recombinant non-pathogenic Leishmania vaccine expressing human immunodeficiency virus 1 (HIV-1) Gag elicits cell-mediated immunity in mice and decreases HIV-1 replication in human tonsillar tissue following exposure to HIV-1 infection.

Live-vector human immunodeficiency virus (HIV) vaccines are an integral part of a number of HIV vaccine regimens currently under evaluation that have yielded promising results in pre-clinical testing. In this report, a non-pathogenic protozoan parasitic vector, Leishmania tarentolae, which shares common target cells with HIV-1, was used to express full-length HIV-1 Gag protein. Immunization of BALB/c mice with recombinant L. tarentolae led to the expansion of HIV-1 Gag-specific T cells and stimulated CD8(+) T cells to produce gamma interferon in response to specific viral Gag epitopes. A booster immunization with recombinant L. tarentolae elicited effector memory HIV-1 Gag-specific CD4(+) T lymphocytes and increased antibody titres against HIV-1 Gag. Most importantly, immunization of human tonsillar tissue cultured ex vivo with Gag-expressing L. tarentolae vaccine vector elicited a 75% decrease in virus replication following exposure of the immunized tonsils to HIV-1 infection. These results demonstrated that recombinant L. tarentolae is capable of eliciting effective immune responses in mice and human systems, respectively, and suggest that this novel non-pathogenic recombinant vaccine vector shows excellent promise as a vaccination strategy against HIV-1.

AIDS Vaccines↗

PubMed1996

The relevance of opioids and opioid receptors on immunocompetence and immune homeostasis.

Since the previous review on the role of opioids in the immune system, numerous investigative teams have contributed to the growing pool of information illustrating the tangible relationship between opioids and immune function, particularly as this association pertains to bacterial and viral pathogens. In addition, the recent cloning of both neural- and immune-derived opioid receptors will ultimately facilitate the identification of molecular events that are responsible for the immunomodulatory effects that are mediated by receptor ligation. Specifically, the administration of opioids in vivo can potentially affect the immune system either through direct interaction with receptors on the effector cells or indirectly, through the ligation of receptors found within the central nervous system. This indirect routing is hypothesized to involve secondary pathways including the hypothalamic pituitary adrenal (HPA) axis and the sympathetic nervous system ultimately resulting in immunomodulation. Consequently, a portion of this review addresses the recent data on leukocyte-derived opioid receptors and the potential immunoregulatory role relative to opiold receptors found within the central nervous system. In addition, recent observations on the effects of opioids and immunocompetence is reviewed from both a molecular and cellular perspective. Finally, the consequence of opioid exposure on the competence of the host immune system to microbial pathogens is summarized.

Amino Acid Sequence↗

PubMed2003

Src in human carcinogenesis.

The signaling machinery in cells is a complex, multi-factorial network of cross-talking proteins that enables dynamic communication between upstream causal factors and downstream effectors. Non-receptor tyrosine kinases, including Src, are the intermediates of information transfer, controlling pathways as diverse as cell growth, migration, death, and genome maintenance. When expressed as viral genes these proteins are potent carcinogens, yet analogous genetic alterations are rarely observed in human tumors. In seeking to characterize the role of the non-receptor tyrosine kinase Src in neoplasia, arguments can be made that the consequences of mutation, or perturbations in the activity or expression of this protein is a determinative factor in clinical prognosis and pathogenicity. In a variety of tumor types including those derived from the colon and breast, the Src non-receptor tyrosine kinase is either overexpressed or constitutively active in a large percentage of the tumors. Increased expression or activity of Src correlates with the stage and metastatic potential of some neoplasia.

Animals↗