Autoimmunity and inflammation due to a gain-of-function mutation in phospholipase C gamma 2 that specifically increases external Ca2+ entry

The identification of specific genetic loci that contribute to inflammatory and autoimmune diseases has proved difficult due to the contribution of multiple interacting genes, the inherent genetic heterogeneity present in human populations, and a lack of new mouse mutants. By using N-ethyl-N-nitrosourea (ENU) mutagenesis to discover new immune regulators, we identified a point mutation in the murine phospholipase Cg2 (Plcg2) gene that leads to severe spontaneous inflammation and autoimmunity. The disease is composed of an autoimmune component mediated by autoantibody immune complexes and B and T cell independent inflammation. The underlying mechanism is a gain-of-function mutation in Plcg2, which leads to hyperreactive external calcium entry in B cells and expansion of innate inflammatory cells. This mutant identifies Plcg2 as a key regulator in an autoimmune and inflammatory disease mediated by B cells and non-B, non-T haematopoietic cells and emphasizes that by distinct genetic modulation, a single point mutation can lead to a complex immunological phenotype.     

Maternal pituitary-adrenal responsiveness as a function of differential treatment of rat pups

The effects of litter separation and pup treatment on the maternal pituitary-adrenal system were investigated in 3 experiments. Lactating females did not show a pituitary-adrenal response to separation from their pups. However, the lactating females showed an increase in plasma corticosterone when their pups had been briefly removed and then returned. If, in addition, the pups were subjected to a noxious stimulus (electric shock) during the 2-min separation, mothers showed a further increase in corticosterone. When pups were returned after 3 hr of separation, mothers again showed a differential pattern of corticoid responsiveness. The magnitude of the mother's pituitary adrenocortical response depended upon the intensity of treatment given to the pups. These data lend physiological support to behavioral studies which have shown that maternal behavior is differentially influenced by pup-produced stimuli.     

The effects of school-based intervention programs on aggressive behavior: a meta-analysis

Research on the effectiveness of school-based programs for preventing or reducing aggressive behavior was synthesized with a meta-analysis. Changes in aggressive behavior between pretest and posttest were analyzed for developmental patterns and characteristics associated with differential effects. Control groups showed little change in aggressive behavior, but there were significant reductions among intervention groups. Most studies were conducted on demonstration programs; the few studies of routine practice programs showed much smaller effects. Among demonstration programs, positive outcomes were associated with a variety of study, subject, and intervention characteristics. Most notably, higher risk youth showed greater reductions in aggressive behavior, poorly implemented programs produced smaller effects, and different types of programs were generally similar in their effectiveness, other things equal.     

Null mutation in human ciliary neurotrophic factor gene confers higher body mass index in males

Ciliary neurotrophic factor (CNTF) administration reduces weight in leptin-resistant mice via the signalling pathway normally activated by leptin. A G>A null mutation in the CNTF gene results in complete absence of protein. We hypothesised that absence of CNTF could lead to diminished initiation of anorectic pathways, with consequent increase in body mass. In 575 Caucasian men aged 59-73 years, the A/A genotype (frequency 1.9%) was associated with a 10 kg increase in weight (P=0.03, 2 df) and 3 kg/m(2) greater BMI (P=0.02, 2 df). There was no effect in women. The CNTF G>A null mutation therefore confers a moderate effect on obesity in males of A/A genotype, who represent 1% of the general population.     

Neural precursor proliferation and newborn cell survival in the adult rat dentate gyrus are affected by vitamin E deficiency

The adult hippocampal neurogenesis is affected by vitamin E deficiency. In the present investigation we examined if neural precursor proliferation, newborn cell survival or both are altered by vitamin E deficiency. 5-Bromo-2'-deoxyuridine (BrdU) was employed as a marker of proliferating cells. BrdU-labelled cells were revealed 1 and 30 days after BrdU administration in order to evaluate proliferation and newborn cell survival, respectively. Cell proliferation decreased in controls from juvenile to adult age, and the decrease was lesser in vitamin E deficiency. Thus we found a higher number of proliferating cells in vitamin E-deficient rats than in age-matched controls at 5 months of age. Comparing the number of BrdU-positive cells between 1 and 30 days after the last BrdU injection revealed a remarkable decrease in all groups; this is the greatest in vitamin E-deficient rats and the lowest in control rats. Consistently cell death in the dentate gyrus, assessed by TUNEL technique, was found to decrease from 1 to 5 months of age, but at 5 months it was significantly higher in vitamin E-deficient rats than in age-matched controls. These data show that vitamin E deficiency enhances neural precursor proliferation and cell death during adult neurogenesis.     

Multilocus haplotype analyses reveal association between 5 novel IL-15 polymorphisms and asthma

BACKGROUND: IL-15 is a T(H)1-related cytokine that is involved in the inflammatory response in various infectious and autoimmune diseases. IL-15 has recently been shown to be upregulated in T-cell-mediated inflammatory disorders. The observations suggest a potential role for this cytokine in a variety of pathologic conditions, including T(H)1-mediated and T(H)2-mediated inflammatory diseases. OBJECTIVE: In this study, we searched for single nucleotide polymorphisms in the whole IL-15 gene and investigated their association with inflammatory and/or atopic phenotypes. METHODS: The screening for single nucleotide polymorphisms was performed by single-strand conformation polymorphism analysis. Genotyping of the identified polymorphisms was performed by restriction fragment length polymorphism. Genotypic association analysis used the Armitage trend test. Haplotype frequency estimation and subsequent testing for differences between cases and controls were performed by using the programs FASTEHPLUS and FAMHAP. RESULTS: We identified 5 novel noncoding nucleotide sequence variants, all of which were typed in our asthmatic, our atopic, and our control population. According to the Armitage trend test, none of the 5 polymorphisms is associated with the phenotype bronchial asthma or atopy. However, multilocus haplotype analysis based on simulations to find out whether the haplotype frequencies differed between cases and controls by using the program FAMHAP yielded a P value of 6.1 x 10(-5) in the asthmatic versus the control population, which is highly significant. Furthermore, we obtained a nominally significant result of P=.0232 for the atopic versus the control population by using FAMHAP. CONCLUSION: These results strongly underscore previous findings that suggest a potential role of this cytokine in allergic diseases.     

Active and inactive influenza virus induction of tumor necrosis factor-alpha and nitric oxide in J774.1 murine macrophages: modulation by interferon-gamma and failure to induce apoptosis

Infection of J774.1 murine macrophages by influenza A virus (IAV) induces two major responses, production of host defense molecules and death by apoptosis. We investigated whether induction of two cytotoxic compounds, tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO), directly caused IAV-induced apoptosis, and whether induction could be modulated by interferon-gamma (IFN-gamma) or the replication competence of the virus. Live IAV potently induced production of both TNF-alpha and NO, but UV inactivated virus was a poor inducer of both molecules. When cells were pre-treated with IFN-gamma, inactive IAV became as effective an inducer of NO, but not TNF-alpha, as live IAV. Amantadine, which antagonizes viral entry and replication, partly inhibited TNF-alpha and NO production in unprimed cells, but did not inhibit NO in IFN-gamma primed cells. IAV-induced cytotoxicity was not due to the induction of TNF-alpha or NO. Cells were insensitive to either TNF-alpha-containing supernatants or to recombinant TNF-alpha. Anti-TNF-alpha antibody did not protect cells from IAV-induced cell death, and anti-oxidants that inhibited TNF-alpha production also failed to increase cell survival. Inhibitors of NO production did not protect from IAV-induced cell death, either alone or in combination with superoxide dismutase (SOD). We conclude that, even though IAV was a potent inducer of TNF-alpha and NO in macrophages, IAV-induced apoptosis was not mediated directly by them. Importantly, viral replication was not required for the induction of TNF-alpha or NO, and the action of inactive IAV could be potentiated by IFN-gamma.     

Assessment of HIV-1 entry inhibitors by MLV/HIV-1 pseudotyped vectors

Background  

Murine leukemia virus (MLV) vector particles can be pseudotyped with a truncated variant of the human immunodeficiency virus type 1 (HIV-1) envelope protein (Env) and selectively target gene transfer to human cells expressing both CD4 and an appropriate co-receptor. Vector transduction mimics the HIV-1 entry process and is therefore a safe tool to study HIV-1 entry.