Role of LMP1 in immune control of EBV infection

The Epstein-Barr virus (EBV) encoded latent membrane protein (LMP1) plays a crucial role in the long-term persistence of this virus within the cells of the immune system. Not only is this protein critical for the transformation of resting B cells by EBV, it also displays pleiotropic effects on various cellular proteins expressed in the host cell. These include up-regulation of expression of B cell activation antigens, adhesion molecules and various components of the antigen processing pathway. Here we discuss how LMP1 acts like an expression 'switch' which, depending on the stage of EBV infection, manoeuvres various pathways that either modulate the immune system towards or against its survival.

Clinically significant drug interactions with agents specific for migraine attacks

The drugs which provide specific relief from migraine attacks, the ergopeptides (ergotamine and dihydroergotamine) and the various 'triptans' (notably sumatriptan), are often prescribed for persons already taking various migraine preventative agents, and sometimes drugs for other indications. As a result, migraine-specific drugs may become involved in drug-drug interactions. The migraine-specific drugs all act as agonists at certain subclasses of serotonin (5-hydroxytryptamine; 5-MT) receptor, particularly those of the 5-HT1D subtype, and produce vasoconstriction through these receptor-mediated mechanisms. The oral bioavailabilities of these drugs, particularly those of the ergopeptides, are often incomplete, due to extensive presystemic metabolism. As a result, if migraine-specific agents are coadministered with drugs with vasoconstrictive properties, or with drugs which inhibit the metabolism of the migraine-specific agents, there is a risk of interactions occurring which produce manifestations of excessive vasoconstriction. This can also occur through pharmacodynamic mechanisms, as when ergopeptides or triptans are coadministered with methysergide or propranolol (although a pharmacokinetic element may apply in relation to the latter interaction), or if one migraine-specific agent is used shortly after another. When egopeptide metabolism is inhibited by the presence of macrolide antibacterials, particularly troleandomycin and erythromycin, the resultant interaction can produce ergotism, sometimes leading to gangrene. Similar pharmacokinetic mechanisms, with their vasoconstrictive consequences, probably apply to combination of the ergopeptides with HIV protease inhibitors (indinavir and ritonavir), heparin, cyclosporin or tacrolimus. Inhibition of triptan metabolism by monoamine oxidase A inhibitors, e.g. moclobemide, may raise circulating triptan concentrations, although this does not yet seem to have led to reported clinical problems. Caffeine may cause increased plasma ergotamine concentrations through an as yet inadequately defined pharmacokinetic interaction. However, a direct antimigraine effect of caffeine may contribute to the claimed increased efficacy of ergotamine-caffeine combinations in relieving migraine attacks. Serotonin syndromes have been reported as probable pharmacodynamic consequences of the use of ergots or triptans in persons taking serotonin reuptake inhibitors. There have been two reports of involuntary movement disorders when sumatriptan has been used by patients already taking loxapine. Nearly all the clinically important interactions between the ergopeptide antimigraine agents and currently marketed drugs are likely to have already come to notice. In contrast, new interactions involving the triptans are likely to be recognised as additional members of this family of drugs, with their different patterns of metabolism and pharmacokinetics, are marketed.

Immune-derived opioids and peripheral antinociception

1. Recent findings have suggested a significant involvement of the immune system in the control of pain. Immune cells contain opioid peptides that are released within inflamed tissue and act at opioid receptors on peripheral sensory nerve endings. It is also apparent that different types of lymphocytes contain P-endorphin, memory T cells containing more beta -endorphin than naive cells. 2. These findings highlight an integral link between immune cell migration and inflammatory pain, The present review highlights immune system involvement in the site-directed control of inflammatory pain. 3. Full-length mRNA transcripts for opioid precursor proteins are expressed in immune cells. Increased expression of pro-opiomelanocortin mRNA and beta -endorphin has been demonstrated in stimulated lymphocytes and lymphocytes from animals with inflammation. 4. Cytokines and corticotropin-releasing factor (CRF) release opioids from immune cells, Potent peripheral analgesia due to direct injection of CRF can be blocked by antagonists to CRF, antibodies to opioid peptides, antisense to CRF and opioid receptor-specific antagonists. The release of opioid peptides from lymphocytes is calcium dependent and opioid receptor specific. Furthermore, endogenous sources of opioid peptides produce potent analgesia when implanted into the spinal cord. 5. Activated immune cells migrate directly to inflamed tissue using cell adhesion molecules to adhere to the epithelial surface of the vasculature in inflamed tissue. Lymphocytes that have been activated can express opioid peptides, Memory type T cells that contain opioid peptides are present within inflamed tissue; naive cells are not present in inflamed tissue and do not contain opioid peptides, Inhibiting the migration of memory type T cells into inflamed tissue by blocking selectins results in reduced numbers of beta -endorphin containing cells, a reduced quantity of beta -endorphin in inflamed paws and reduced stress- and CRF-induced peripheral analgesia. 6. Immunosuppression is associated with increased pain in patients. Moreover, immunosuppression results in decreased lymphocyte numbers as well as decreased analgesia in animal models.

A twin study of the etiology of prolonged fatigue and immune activation

Risk factors to prolonged fatigue syndromes (PFS) are controversial. Pre-morbid and/or current psychiatric disturbance, and/or disturbed cell-mediated immunity (CMI), have been proposed as etiologic factors. Self-report measures of fatigue and psychologic distress and three in vitro measures of CMI were collected from 124 twin pairs. Crosstwincrosstrait correlations were estimated for the complete monozygotic (MZ; 79 pairs) and dizygotic (DZ; 45 pairs) twin groups. Multivariate genetic and environmental models were fitted to explore the patterns of covariation between etiologic factors. For fatigue, the MZ correlation was more than double the DZ correlation (0.49 versus 0.16) indicating strong genetic control of familial aggregation. By contrast, for in vitro immune activation measures MZ and DZ correlations were similar (0.49–0.69 versus 0.42–0.53) indicating the etiologic role of shared environments. As small univariate associations were noted between prolonged fatigue and the in vitro immune measures (r = −0.07 to −0.12), multivariate models were fitted. Relevant etiologic factors included: a common genetic factor accounting for 48% of the variance in fatigue which also accounted for 4%, 6% and 8% reductions in immune activation; specific genetic factors for each of the in vitro immune measures; a shared environment factor influencing the three immune activation measures; and, most interestingly, unique environmental influences which increased fatigue but also increased markers of immune activation. PFS that are associated with in vitro measures of immune activation are most likely to be the consequence of current environmental rather than genetic factors. Such environmental factors could include physical agents such as infection and/or psychologic stress.

The effects of interleukin-10 depletion in vivo on the immune response to Porphyromonas gingivalis in a murine model

Background: The immune response to Porphyromonas gingivalis in the mouse abscess model is known to be dependent upon CD4 T-cell activation and the regulatory role of cytokines. The role of interleukin-10 (IL-10) in this mouse model was examined in vivo. Methods: One-week-old, female BALB/c mice were divided into 4 groups. Groups 1 and 2 were given intraperitoneal (ip) injections of phosphate buffered saline (PBS) weekly for 5 weeks. Group 3 was given an ip injection of rat immunoglobulin. Group 4 was injected with rat anti-IL-10 antibodies. At week 6, group 1 was sham-immunized with PBS, and groups 2, 3, and 4 were injected with P gingivalis lipopolysaccharide (Pg-LPS) weekly for 2 weeks. One week after the final immunization, delayed-type hypersensitivity (DTH) was assessed by footpad swelling to Pg-LPS. The level of serum antibodies to Pg-LPS and IFN-gamma (IFN-gamma) was determined by enzyme-linked immunosorbent assay. Dorsal abscess formation induced by the injection of viable P gingivalis was examined daily for 30 days. Results: The footpad swelling of the anti-IL-10-treated group (group 4) was significantly higher than that of groups 1 to 3. Similarly, the serum IFN-gamma level in group 4 was much higher than that of the other experimental groups. There was no significant difference in serum IgG antibodies to Pg-LPS in any of the experimental groups. However, the level of IgM antibodies in group 4 mice was significantly lower than that in groups 2 and 3. In addition, serum IgG1 was suppressed in group 4 mice, while IgG2a antibodies were raised. However, there was no difference observed between the levels of IgG2b and IgG3 antibodies in any group of mice. The lesions in sham-immunized mice (group 1) persisted for 30 days, and those in group 2 and 3 were undetected by day 18 and 20, respectively. In sharp contrast, lesions in group 4 had healed completely by day 13. Conclusions: This study has shown that IL-10 depletion in vivo in P gingivalis LPS-induced immune response in mice led to an elevated DTH response, an increase in serum IFN-gamma levels, and raised levels of IgG and IgG2a antibodies. Treatment with anti-IL-10 antibodies resulted in suppressed IgG I and IgM responses and a more rapid healing of abscesses than in non-IL-10-depleted mice. These results suggest that IL-10 depletion in Pg-LPS-induced immune response in mice may lead to a Th1-like immune response and provide strong protection against a subsequent challenge with live P gingivalis in an abscess model.

Genotype-by-management interactions for grain yield and grain protein concentration of wheat

The magnitude of genotype-by-management (G x M) interactions for grain yield and grain protein concentration was examined in a multi-environment trial (MET) involving a diverse set of 272 advanced breeding lines from the Queensland wheat breeding program. The MET was structured as a series of management-regimes imposed at 3 sites for 2 years. The management-regimes were generated at each site-year as separate trials in which planting time, N fertiliser application rate, cropping history, and irrigation were manipulated. irrigation was used to simulate different rainfall regimes. From the combined analysis of variance, the G x M interaction variance components were found to be the largest source of G x E interaction variation for both grain yield (0.117 +/- 0.005 t(2) ha(-2); 49% of total G x E 0.238 +/- 0.028 t(2) ha(-2)) and grain protein concentration (0.445 +/- 0.020%(2); 82% of total G x E 0.546 +/- 0.057%(2)), and in both cases this source of variation was larger than the genotypic variance component (grain yield 0.068 +/- 0.014 t(2) ha(-2) and grain protein 0.203 +/- 0.026%(2)). The genotypic correlation between the traits varied considerably with management-regime, ranging from -0.98 to -0.31, with an estimate of 0.0 for one trial. Pattern analysis identified advanced breeding lines with improved grain yield and grain protein concentration relative to the cultivars Hartog, Sunco and Meteor. It is likely that a large component of the previously documented G x E interactions for grain yield of wheat in the northern grains region are in part a result of G x M interactions. The implications of the strong influence of G x M interactions for the conduct of wheat breeding METs in the northern region are discussed. (C) 2001 Elsevier Science B.V. All rights reserved.

Microbial interactions with tannins: Nutritional consequences for ruminants

Polyphenolics are widely distributed in the plant kingdom and are often present in the diet of herbivores. The two major groups of plant polyphenolic compounds other than lignin are condensed and hydrolysable tannins. These compounds can have toxic and/or antinutritional effects on the animal. It is well established that tannins complex with dietary proteins can reduce nitrogen supply to the animal, but the ability of gastrointestinal microorganisms to metabolise these compounds and their effects on microbial populations have received little attention. In this paper, we review recent literature on the topic as well as present research from our laboratories on the effect of condensed tannins on rumen microbial ecology and rumen metabolism. Interactions of tannins with dietary components and endogenous protein in the rumen and post-ruminally, and their impact on the nutrition of the animal are considered. (C) 2001 Elsevier Science B.V. All rights reserved.

Immune responses to ISCOM (R) formulations in animal and primate models

ISCOMs(R) are typically 40 nm cage-like structures comprising antigen, saponin, cholesterol and phospholipid. ISCOMs(R) have been shown to induce antibody responses and activate T helper cells and cyrolytic T lymphocytes in a number of animal species, including non-human primates. Recent clinical studies have demonstrated that ISCOMs(R) are also able to induce antibody and cellular immune responses in humans. This review describes the current understanding of the ability of ISCOMs(R) to induce immune responses and the mechanisms underlying this property. Recent progress in the characterisation and manufacture of ISCOMs(R) will also be discussed. (C) 2001 Elsevier Science Ltd. All rights reserved.

Immune responses in hookworm infections

Hookworms infect perhaps one-fifth of the entire human population, yet little is known about their interaction with our immune system. The two major species are Necator americanus, which is adapted to tropical conditions, and Ancylostoma duodenale, which predominates in more temperate zones. While having many common features, they also differ in several key aspects of their biology. Host immune responses are triggered by larval invasion of the skin, larval migration through the circulation and lungs, and worm establishment in the intestine, where adult worms feed on blood and mucosa while injecting various molecules that facilitate feeding and modulate host protective responses. Despite repeated exposure, protective immunity does not seem to develop in humans, so that infections occur in all age groups (depending on exposure patterns) and tend to be prolonged. Responses to both larval and adult worms have a characteristic T-helper type 2 profile, with activated mast cells in the gut mucosa, elevated levels of circulating immunoglobulin E, and eosinoophilia in the peripheral blood and local tissues, features also characteristic of type I hypersensitivity reactions. The longevity of adult hookworms is determined probably more by parasite genetics than by host immunity. However, many of the proteins released by the parasites seem to have immunomodulatory activity, presumably for self-protection. Advances in molecular biotechnology enable the identification and characterization of increasing numbers of these parasite molecules and should enhance our detailed understanding of the protective and pathogenetic mechanisms in hookworm infections.

Evaluation of synergistic interactions between the Colorado potato beetle (Coleoptera : Chrysomelidae) pathogen Beauveria bassiana and the insecticides, imidacloprid, and cyromazine

Laboratory studies investigated the interaction between the fungal entomopathogen Beauveria bassiana (Balsamo) Vuillemin and sublethal doses of the insecticides imidacloprid and cyromazine when applied to larvae of the Colorado potato beetle, Leptinotarsa decemlinenta (Say). When second instars were fed potato leaf discs treated with sublethal doses of imidacloprid and a range of doses of B. bassiana, a synergistic action was demonstrated. Similar results were observed when larvae were sprayed directly with B. bassiana conidia and immediately fed leaf discs treated with imidacloprid. No synergistic interaction was detected when larvae were fed leaf discs treated with sublethal doses of imidacloprid 24 h after application of R. bassiana conidia to larvae. However, a synergistic interaction was detected when larvae were fed leaf discs treated with imidacloprid and sprayed with B, bassiana conidia 24 h later. Although sublethal doses of both imidacloprid and the triazine insect growth regulator (IGR) cyromazine prolonged the duration of the second instar, only imidacloprid interacted with B. bassiana to produce a synergistic response in larval mortality. In leaf consumption studies, the highest dose of B, bassiana tested promoted feeding in inoculated second instars. Feeding was inhibited when larvae were fed foliage treated with sublethal doses of imidacloprid and significantly reduced when fed foliage treated with a sublethal dose of cyromazine. Starvation of larvae for 24 h immediately after B. bassiana treatment produced a similar result to the combined treatment of B. bassiana and imidacloprid and increased the level of mycosis when compared with B. bassiana controls. Imidacloprid treatment affected neither the rate of germination of B. bassiana conidia on the insect cuticle nor the rate at which conidia were removed from the integument after application. The statistical analysis used to detect synergism and the possible role of starvation-induced stress factors underlying the observed synergistic interactions are discussed.

The gene encoding the immunoregulatory signaling molecule CMRF-35A localized to human chromosome 17 in close proximity to other members of the CMRF-35 family

The immunoregulatory signaling (IRS) family includes several molecules, which play major roles in the regulation of the immune response. The CMRF-35A and CMRF-35H molecules are two new members of the IRS family of molecules, that are found on a wide variety of haemopoietic lineages. The extracellular functional interactions of these molecules is presently unknown, although CMRF-35H on initiate an inhibitory signal and is internalized when cross-linked. In this paper, we described the gene structure for the CMRF-35A gene and its localization to human chromosome 17. The gene consists of four exons spanning approximately 4.5 kb. Exon 1 encodes the 5' untranslated region and leader sequence, exon 2 encodes the immunoglobulin (Ig)-like domain, exon 3 encodes the membrane proximal region and exon 4 encodes the transmembrane region, the cytoplasmic tail and the 3' untranslated region. A region in the 5' flanking sequence of the CMRF-35A gene, that promoted expression of a reporter gene was identified. The genes for the CMRF-35A and CMRF-35H molecules are closely linked on chromosome 17. Similarity between the Ig-like exons and the preceding intron of the two genes suggests exon duplication was involved in their evolution. We also identified a further member of the CMRF-35 family, the CMRF-35J pseudogene. This gene appears to have arisen by gene duplication of the CMRF-35A gene. These three loci-the CMRF-35A, CMRF-35J and CMRF-35H genes-form a new complex of IRS genes on chromosome 17.