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PubMed1985

Bronchoalveolar T lymphocytes and pulmonary sarcoidosis.

In recent years, our understanding of the pathogenesis of sarcoidosis has markedly changed. Originally, it was felt that sarcoidosis was a disease that was caused by a state of anergy. More recent studies suggest that sarcoidosis is not a disease of anergy but is mediated by a classic, heightened cellular immune process. It is hoped that additional studies utilizing inflammatory and immune effector cells obtained from sites of disease will further elucidate the pathogenic mechanisms leading to granuloma formation in patients with sarcoidosis.

Antibody Formation↗

PubMed2004

The scorpine family of defensins: gene structure, alternative polyadenylation and fold recognition.

Small cationic antimicrobial peptides (SCAMPs) as effectors of animal innate immunity provide the first defense against infectious pathogens. This class of molecules exists widely in invertebrate hemolymph and vertebrate skin secretion, but animal venoms are emerging as a new rich resource. Scorpine is a unique scorpion venom defensin peptide that has an extended amino-terminal sequence similar to cecropins. From the African scorpion Opistophthalmus carinatus venom gland, we isolated and identified several cDNAs encoding four new homologs of scorpine (named opiscorpines 1-4). Importantly, we show for the first time the existence of multiple opiscorpine mRNAs with variable 3' untranslated regions (UTRs) in the venom gland, which may be generated by alternative usage of polyadenylation signals. The complete opiscorpine gene structure including its promoter region is determined by genomic DNA amplification. Two large introns were found to be located within the 5' UTR and at the boundary of the mature peptide-coding region. Such a gene structure is distinct, when compared with other scorpion venom peptide genes. However, a comparative promoter analysis revealed that both opiscorpine and scorpion venom neurotoxins share a similar promoter organization. Sequence analysis and structural modeling allow us to group the scorpines and scorpion long-chain K-channel toxins together into one family that shares a similar fold with two distinct domains. The N-terminal cecropin-like domain displaying a clear antimicrobial activity implies that the scorpine family represents a group of real naturally occurring hybrids. Based on the phylogenetic analysis, a possible cooperative interaction between the N and C domains is elucidated, which provides an evolutionary basis for the design of a new class of anti-infectious drugs.

Amino Acid Sequence↗

PubMed1994

Manipulating blood T cells and B cells from squirrel monkeys: some technical considerations.

The squirrel monkey Saimiri sciureus is an experimental host for a range of human pathogens, and for the assessment of vaccine candidate antigens and vaccine strategies. This experimental host is thus particularly suitable for the follow-up of humoral responses. To understand some of the mechanisms that underlie the defense against experimental pathogens, there is a need of basic knowledge on cellular immune effectors also. The authors report here their experience in characterizing squirrel monkey blood T and B lymphocytes, and in studying in vitro induced activation and proliferation of T and B cells. Particular emphasis is given to the in vitro differentiation of squirrel monkey B cells into immunoglobulin secreting cells, with respect to Plasmodium falciparum antigens.

Animals↗

PubMed1995

IgG asymmetric anti-ovalbumin antibodies synthesized by virgin and pregnant rats.

A study on the synthesis of asymmetrical IgG molecules 'with no specific activity' and with anti-ovalbumin activity was carried out both in virgin rats and in rats inoculated with ovalbumin and made pregnant by syngeneic and allogeneic males. Before pregnancy, female rats synthesize about 23% of asymmetrical IgG molecules, when the level of these molecules is assessed in total IgG, in anti-ovalbumin IgG and in the supernatant from the adsorption of anti-ovalbumin antibodies. On the other hand, anti-ovalbumin antibodies isolated are predominantly of the symmetrical IgG type; they are also precipitants and effectors of the biological mechanisms that the host operates to preserve pathogenic antigens (bacteria, parasites). In rats pregnant by syngeneic and allogeneic males, the ratio asymmetric/symmetric IgG molecules increases, and the anti-ovalbumin antibodies are mainly of the asymmetrical IgG type, which aid antigen-blocking. Similar results are found in virgin rats, immunized with ovalbumin and intraperitoneally transferred simultaneously with supernatants of placental cultures. These results suggest that, during pregnancy, there is an increase of the IgG asymmetric/symmetric molecule ratio, produced by placental factors, whatever the immunogen specificity may be. Speculations about this fact are presented.

Animals↗

PubMed2006

Pathogens reWritE Rho's rules.

Many bacterial pathogens use a specialized "type III" secretion system to deliver virulence effector proteins into host mammalian cells. In this issue of Cell, Alto et al. (2006) describe a new family of effectors that share a WxxxE sequence motif. These effectors directly stimulate host signaling pathways by mimicking activated Ras-like cellular GTPases.

Amino Acid Motifs↗

PubMed2003

Genomic approaches in Xanthomonas campestris pv. vesicatoria allow fishing for virulence genes.

Xanthomonas campestris pv. vesicatoria is an economically important pathogen of pepper and tomato and has been established as a model organism to study bacterial infection strategies. In the last two decades, intensive genetic and molecular analyses led to the isolation of many genes that play a role in the intimate molecular relationship with the host plant. Essential for pathogenicity is a type III protein secretion system, which delivers bacterial effector proteins into the host cell. Currently, the genome of X. campestris pv. vesicatoria is being sequenced. The availability of genomic sequence information will pave the way for the identification of new bacterial virulence factors by bioinformatic approaches. In this article, we will present preliminary data from the genomic sequence analysis and describe recent and novel studies to identify bacterial type III effector genes.

Chromosome Mapping↗

PubMed2001

Calcitermin, a novel antimicrobial peptide isolated from human airway secretions.

The human airways are protected from pathogenic colonization by a blanket of fluid impregnated with innate antimicrobial effector molecules. Among several previously uncharacterized components, we isolated a peptide that had activity primarily targeting Gram-negative bacteria. We named the peptide 'calcitermin' since its amino acid sequence and mass were equivalent to the 15 C-terminal residues of the S100 protein, calgranulin C. The antimicrobial activity of calcitermin was enhanced in acidic buffers (pH 5.4) and in the presence of micromolar concentrations of ZnCl(2). Analysis revealed a putative zinc-binding consensus sequence as well as an alpha-helical conformation in structure-promoting solvents.

Amino Acid Sequence↗

PubMed2004

Membrane lipid composition protects Entamoeba histolytica from self-destruction by its pore-forming toxins.

The protozoan parasite and human pathogen Entamoeba histolytica is protected against killing by its own lytic effector proteins. Amoebae withstand doses of amoebapores, their pore-forming polypeptides, that readily kill human Jurkat T cells. Moreover, the polypeptides do not bind to the amoebic surface membrane as evidenced by using fluorescently labelled amoebapores and confocal laser microscopy. Experiments employing liposomes as a minimalistic membrane system and the major isoform amoebapore A revealed that the lipid composition of amoebic membranes prevents binding of the cytolytic molecule and that both the phospholipid ingredients and the high content of cholesterol contributes to the protection of the toxin-producing cell.

Adenosine Triphosphate↗

PubMed2000

Modulating chemokines: more lessons from viruses.

Chemokines are crucial effector molecules involved in orchestrating the host inflammatory response against invading pathogens. Viruses have devised several strategies for exploiting or neutralizing chemokines or their receptors to further their own propagation or elude host defenses. Insight into strategies used by viruses to modulate chemokines might help generate novel approaches for treating viral diseases and chemokine-mediated inflammatory disorders.

Animals↗

PubMed1998

Peptides bound to major histocompatibility complex molecules.

Peptides are the means by which immune effector T cells recognize and defend against the foreign proteins of pathogens. T cell recognition of these molecules, however, is strictly dependent on peptide binding to the receptor-like molecules of the major histocompatibility complex (MHC) locus. The basic unit of recognition is a trimolecular complex consisting of the T cell antigen receptor, the MHC molecule, and the MHC-bound peptide ligand. The multistep process that culminates in MHC presentation of peptides to T cells begins in the last phases of protein catabolism. While the individual roles of many key molecules involved in peptide presentation have recently been defined, there still remain many questions regarding processing of proteins into MHC-bound peptides. This review summarizes the recent developments in peptide antigen processing for MHC molecules, with focus on how proteins are believed to be sampled and selected for degradation into peptides.

Animals↗

PubMed2000

Macrophage lectins in host defence.

Macrophage lectins contribute to host defence by a variety of mechanisms. The best characterised, mannose receptor (MR) and complement receptor three (CR3), are both able to mediate phagocytosis of pathogenic microbes and induce intracellular killing mechanisms. The regulation of the effector functions induced via MR is complex, and may involve both host and microbial factors. Therefore, MR is likely to play a dynamic role in the response to infection; it may act as a classical pattern recognition receptor in phagocytosis, whereas other poorly characterised factors may make a more decisive contribution to its function in physiologic settings. In contrast, the lectin site of CR3 appears to lack host-derived ligands and may be a true pattern recognition receptor. Further studies are required to evaluate the roles of other macrophage lectins in recognition of and responses to microbes.

Animals↗

PubMed2000

Effector proteins of phytopathogenic bacteria: bifunctional signals in virulence and host recognition.

Phytopathogenic bacteria deliver effectors of disease into plant hosts via a Type III secretion system. These Type III effectors have genetically determined roles in virulence. They also are among the components recognized by the putative receptors of the plant innate immune system. Recent breakthroughs include localization of some of these Type III effectors to specific host cell compartments, and the first dissection of pathogenicity islands that carry them.

Bacteria↗

PubMed2002

Solution structure and phosphopeptide binding to the N-terminal domain of Yersinia YopH: comparison with a crystal structure.

Virulence of pathogenic bacteria of the genus Yersinia requires the injection of six effector proteins into the cytoplasm of host cells. The amino-terminal domain of one of these effectors, the tyrosine phosphatase YopH, is essential for translocation of YopH, as well as for targeting it to phosphotyrosine-containing substrates of the type pYxxP. We report the high-resolution solution structure of the N-terminal domain (residues 1-129) from the Yersinia pseudotuberculosis YopH (YopH-NT) in complex with N-acetyl-DEpYDDPF-NH(2), a peptide derived from an in vivo protein substrate. In contrast to the domain-swapped dimer observed in a crystal structure of the same protein (Smith, C. L., Khandelwal, P., Keliikuli, K., Zuiderweg, E. R. P., and Saper, M. A. (2001) Mol. Microbiol. 42, 967-979), YopH-NT is monomeric in solution. The peptide binding site is located on a beta-hairpin that becomes the crossover point in the dimer structure. The binding site has several characteristics that are reminiscent of SH2 domains, which also bind to pYxxP sequences.

Amino Acid Sequence↗

PubMed2001

Maintenance of an unfolded polypeptide by a cognate chaperone in bacterial type III secretion.

Many bacterial pathogens use a type III protein secretion system to deliver virulence effector proteins directly into the host cell cytosol, where they modulate cellular processes. A requirement for the effective translocation of several such effector proteins is the binding of specific cytosolic chaperones, which typically interact with discrete domains in the virulence factors. We report here the crystal structure at 1.9 A resolution of the chaperone-binding domain of the Salmonella effector protein SptP with its cognate chaperone SicP. The structure reveals that this domain is maintained in an extended, unfolded conformation that is wound around three successive chaperone molecules. Short segments from two different SptP molecules are juxtaposed by the chaperones, where they dimerize across a hydrophobic interface. These results imply that the chaperones associated with the type III secretion system maintain their substrates in a secretion-competent state that is capable of engaging the secretion machinery to travel through the type III apparatus in an unfolded or partially folded manner.

Bacterial Proteins↗

PubMed2001

Structural and biochemical characterization of the type III secretion chaperones CesT and SigE.

Several Gram-negative bacterial pathogens have evolved a type III secretion system to deliver virulence effector proteins directly into eukaryotic cells, a process essential for disease. This specialized secretion process requires customized chaperones specific for particular effector proteins. The crystal structures of the enterohemorrhagic Escherichia coli O157:H7 Tir-specific chaperone CesT and the Salmonella enterica SigD-specific chaperone SigE reveal a common overall fold and formation of homodimers. Site-directed mutagenesis suggests that variable, delocalized hydrophobic surfaces observed on the chaperone homodimers are responsible for specific binding to a particular effector protein. Isothermal titration calorimetry studies of Tir-CesT and enzymatic activity profiles of SigD-SigE indicate that the effector proteins are not globally unfolded in the presence of their cognate chaperones.

Amino Acid Sequence↗

PubMed2007

Cr(VI)-stimulated STAT3 tyrosine phosphorylation and nuclear translocation in human airway epithelial cells requires Lck.

Chronic inhalation of low amounts of Cr(VI) promotes pulmonary diseases and cancers through poorly defined mechanisms. SFKs (Src family kinases) in pulmonary airway cells may mediate Cr(VI) signalling for lung injury, although the downstream effectors of Cr(VI)-stimulated SFKs and how they relate to pathogenic gene induction are unknown. Therefore SFK-dependent activation of transcription factors by non-cytotoxic exposure of human bronchial epithelial cells to Cr(VI) was determined. Protein-DNA binding arrays demonstrated that exposing BEAS 2B cells to 5 microM Cr(VI) for 4 and 24 h resulted in increased protein binding to 25 and 43 cis-elements respectively, while binding to 12 and 16 cis-elements decreased. Of note, Cr(VI) increased protein binding to several STAT (signal transducer and activator of transcription) cis-elements. Cr(VI) stimulated acute tyrosine phosphorylation and nuclear translocation of STAT1 over a 4 h period and a prolonged activation of STAT3 that reached a peak between 48 and 72 h. This prolonged activation was observed for both STAT3alpha and STAT3beta. Immunofluorescent confocal microscopy confirmed that Cr(VI) increased nuclear localization of phosphorylated STAT3 for more than 72 h in both primary and BEAS 2B human airway cells. Cr(VI) induced transactivation of both a STAT3-driven luciferase reporter construct and the endogenous inflammatory gene IL-6 (interleukin-6). Inhibition with siRNA (small interfering RNA) targeting the SFK Lck, but not dominant-negative JAK (Janus kinase), prevented Cr(VI)-stimulated phosphorylation of both STAT3 isoforms and induction of IL-6. The results suggest that Cr(VI) activates epithelial cell Lck to signal for prolonged STAT3 activation and transactivation of IL-6, an important immunomodulator of lung disease progression.

Active Transport, Cell Nucleus↗

PubMed1999

Structured reactions of serum IgM repertoires to immunization are dependent on major histocompatibility complex genes.

In normal animals, responses to immunization include alterations in the serum IgM antibody repertoire, as scored on autologous tissue antigens with no respect for the immunizing antigen. These immunogen-nonspecific antibody reactions were found previously to display specific structures dependent on strain and immunization protocols. Using major histocompatability complex (MHC)-congenic Lewis rats, we show that such IgM repertoire reactions are under the control of MHC-linked genes, including a class I locus. This strongly suggests the involvement of T cells restricted by both class I and class II MHC, in regulating serum IgM repertoires. Immunogen-nonspecific repertoire reactions to immunization may, therefore, represent degenerate, but prototypical, reactions or regulatory mechanisms embodying the natural repertoires of T- and B cells connected to autoantigens. Natural (auto)immunity could so serve to regulate the effector class of adaptive immune responses, particularly in order to avoid pathogenic autoreactivity following specific immunization with self-cross-reacting antigens. Appropriate analysis of nonspecific repertoire reactions could therefore contribute to the understanding of general structures of immune regulation and natural tolerance.

Animals↗

PubMed2003

Chronic beryllium disease: immune-mediated destruction with implications for organ-specific autoimmunity.

Chronic beryllium disease (CBD) is caused by exposure to beryllium in the workplace and is characterized by an accumulation of beryllium-specific CD4+ T cells with granulomatous inflammation in the lung. Owing to its unique physical properties, beryllium is used in a variety of high-technology industries, and CBD continues to be an important public health concern. CBD develops in up to 16% of exposed workers, depending on genetic susceptibility and the nature of the exposure. Increased susceptibility has been associated with particular HLA-DP alleles, especially those possessing negatively charged residues at certain positions of the peptide-binding pocket. The mechanism for this disease association lies in the ability of certain HLA-DP molecules, with associated peptides, to bind and present beryllium to pathogenic CD4+ T cells. In patients with CBD, large numbers of effector memory CD4+ T cells are compartmentalized to the lung, and these cells are poised to release T helper 1-type cytokines upon beryllium recognition. In the same patients, however, beryllium-specific T cells are barely detectable in the circulation. As opposed to those present in blood, beryllium-specific cells in the lung no longer require the engagement of CD28 for optimal T-cell activation and in fact frequently lose the expression of CD28. These findings in CBD have important implications for studies in autoimmune diseases, including those in which the antigen is unknown and the target organ is inaccessible.

Autoimmune Diseases↗