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1.  Antiinflammatory and Immunomodulating Properties of Fungal Metabolites 
Mediators of Inflammation  2005;2005(2):63-80.
We discuss current information on the ability of extracts and isolated metabolites from mushrooms to modulate immune responses. This can result in a more enhanced innate and acquired disease resistance. The major immunomodulating effects of these active substances derived from mushrooms include mitogenicity and activation of immune effector cells, such as lymphocytes, macrophages, and natural killer cells, resulting in the production of cytokines, including interleukins (ILs), tumor necrosis factor alpha (TNF)-α, and interferon gamma (INF)-γ. In particular, the ability of selective mushroom extracts to modulate the differentiation capacity of CD4+ T cells to mature into TH1 and/or TH2 subsets will be discussed. As a consequence these extracts will have profound effects in particular diseases, like chronic autoimmune TH1-mediated or allergic TH2-mediated diseases. Immunosuppressive effects by mushroom components have also been observed. The therapeutic effects of mushrooms, such as anticancer activity, suppression of autoimmune diseases, and allergy have been associated with their immunomodulating effects. However, further studies are needed to determine the molecular mechanisms of the immunomodulating effects of mushrooms metabolites both individually and in complex mixtures, for example, extracts.
doi:10.1155/MI.2005.63
PMCID: PMC1160565  PMID: 16030389
2.  Genetic and Phenotypic Selection Affect Natural (Auto-) Antibody Reactivity of Chickens 
PLoS ONE  2013;8(9):e72276.
Specificity, antibody isotype distribution and levels of natural antibodies (NAb) may be potential informative parameters for immune mediated natural disease resistance, immune modulation, and maintenance of physiological homeostasis. A large proportion of mammalian NAb have affinity for or are directed against self-antigens; so called natural auto antibodies (N(A)Ab). In the present study we showed the presence and typed levels and isotypes (total immunoglobulins, IgG and IgM) of N(A)Ab in plasma binding the ‘auto-antigen’ complex chicken liver cell lysate (CLL) of one-year old chickens from different genotype and phenotype backgrounds by ELISA and quantitative Western blotting. Higher levels of N(A)Ab binding CLL were found in plasma from chickens genetically selected for high specific antibody responses. In all birds, extensive staining patterns of plasma antibodies binding CLL were found for all isotypes, with IgG binding the highest number of CLL antigens and also showing the highest variation in staining patterns between individuals. Patterns of IgM antibodies binding CLL appeared to be more similar in all lines. Significant differences of binding patterns of N(A)Ab (antigen fragments of CLL and staining intensity) were detected between the different chicken lines, and lines could be clustered on the basis of their auto-antibody profile. In addition, also individual differences within lines were found. The present results indicate that analysis of the levels and the N(A)Ab repertoire of poultry like in mammals could provide a new way of distinguishing differences of immune competence and immune maturation between individuals, and could provide tools to select birds for health traits, or optimize hygiene and husbandry procedures.
doi:10.1371/journal.pone.0072276
PMCID: PMC3770630  PMID: 24039748
3.  Citrus/Cydonia Compositum Subcutaneous Injections versus Nasal Spray for Seasonal Allergic Rhinitis: A Randomized Controlled Trial on Efficacy and Safety 
ISRN Allergy  2011;2011:836051.
Background. Clinical experiences in vitro and clinical studies have demonstrated the curative potency and safety of Citrus/Cydonia compositum in seasonal allergic rhinitis treatment. Objectives. To compare the efficacy and safety of two routes of administration (nasal spray versus subcutaneous injections). Methodology: Design. a national, randomised, comparative clinical trial with two parallel groups. Participants. 23 patients fulfilled the study requirements. Intervention. after a one- or two-week wash-out period, 23 patients were randomized, to a 6-week treatment period. Outcomes. immunological and symptom severity changes and safety. Immunologic outcome assessments were blinded to group assignment. 23 patients were randomized and from 22/23 patients (11 in each group) blood samples were analyzed before and after treatment. Conclusion. Both routes of administration demonstrate immunological and clinical effects, with larger inflammatory and innate immunological effects of the nasal spray route and larger allergen-specific clinical effects of the subcutaneous route, and are safe.
doi:10.5402/2011/836051
PMCID: PMC3658594  PMID: 23724234
4.  Protection against Diarrhea Associated with Giardia intestinalis Is Lost with Multi-Nutrient Supplementation: A Study in Tanzanian Children 
Background
Asymptomatic carriage of Giardia intestinalis is highly prevalent among children in developing countries, and evidence regarding its role as a diarrhea-causing agent in these settings is controversial. Impaired linear growth and cognition have been associated with giardiasis, presumably mediated by malabsorption of nutrients. In a prospective cohort study, we aim to compare diarrhea rates in pre-school children with and without Giardia infection. Because the study was conducted in the context of an intervention trial assessing the effects of multi-nutrients on morbidity, we also assessed how supplementation influenced the relationship between Giardia and diarrhoea rates, and to what extent Giardia modifies the intervention effect on nutritional status.
Methods and Findings
Data were collected in the context of a randomized placebo-controlled efficacy trial with 2×2 factorial design assessing the effects of zinc and/or multi-micronutrients on morbidity (n = 612; height-for-age z-score <−1.5 SD). Outcomes measures were episodes of diarrhea (any reported, or with ≥3 stools in the last 24 h) and fever without localizing signs, as detected with health-facility based surveillance. Giardia was detected in stool by enzyme-linked immunosorbent assay. Among children who did not receive multi-nutrients, asymptomatic Giardia infection at baseline was associated with a substantial reduction in the rate of diarrhea (HR 0.32; 0.15–0.66) and fever without localizing signs (HR 0.56; 0.36–0.87), whereas no such effect was observed among children who received multi-nutrients (p-values for interaction 0.03 for both outcomes). This interaction was independent of age, HAZ-scores and distance to the research dispensary. There was no evidence that Giardia modified the intervention effect on nutritional status.
Conclusion
Although causality of the Giardia-associated reduction in morbidity cannot be established, multi-nutrient supplementation results in a loss of this protection and thus seems to influence the proliferation or virulence of Giardia or associated intestinal pathogens.
Author Summary
Giardia intestinalis is a well-known cause of diarrhea in industrialized countries. In children in developing countries, asymptomatic infections are common and their role as cause of diarrhea has been questioned. In a cohort of rural Tanzanian pre-school children, we assessed the association between the presence of Giardia at baseline and subsequent diarrhea risk. The study was conducted in the context of a randomised trial assessing the effect of supplementation with zinc and other micro-nutrients on malaria, and half of the children daily received a multi-nutrient supplement. Surprisingly, we found that the presence of Giardia at baseline was associated with a substantial reduction in diarrhea risk. Multivariate statistical analysis showed that this protection could not be explained by differences in age or walking distance to the dispensary between children with and without Giardia. Because we cannot exclude that children differed in other (unmeasured) characteristics, we cannot draw firm conclusions about the causality of the observed association, but our findings support the view that the parasite is not an important cause of diarrhea in highly endemic settings. Striking was that the Giardia-associated protection was lost when children received multi-nutrients. Our data do not provide information about the mechanisms involved, but suggest that multi-nutrients may influence the compositionor pathogenicity of intestinal biota.
doi:10.1371/journal.pntd.0001158
PMCID: PMC3110167  PMID: 21666789
5.  Modulation of Human Immune Responses by Bovine Interleukin-10 
PLoS ONE  2011;6(3):e18188.
Cytokines can be functionally active across species barriers. Bovine IL-10 has an amino acid sequence identity with human IL-10 of 76.8%. Therefore, the aim of this study was to evaluate whether bovine IL-10 has immunomodulatory activities on human monocytes and dendritic cells. Peripheral blood monocytes were isolated from healthy donors, and used directly or allowed to differentiate to dendritic cells under the influence of IL-4 and GM-CSF. Recombinant bovine IL-10 inhibited TLR induced activation of monocytes, and dose-dependently inhibited LPS-induced activation of monocyte-derived DCs comparable to human IL-10. By using blocking antibodies to either bovine IL-10 or the human IL-10 receptor it was demonstrated that inhibition of monocyte activation by bovine IL-10 was dependent on binding of bovine IL-10 to the human IL-10R. These data demonstrate that bovine IL-10 potently inhibits the activation of human myeloid cells in response to TLR activation. Bovine IL-10 present in dairy products may thus potentially contribute to the prevention of necrotizing enterocolitis and allergy, enhance mucosal tolerance induction and decrease intestinal inflammation and may therefore be applicable in infant foods and in immunomodulatory diets.
doi:10.1371/journal.pone.0018188
PMCID: PMC3064667  PMID: 21464967
6.  Trypanosomiasis-Induced Th17-Like Immune Responses in Carp 
PLoS ONE  2010;5(9):e13012.
Background
In mammalian vertebrates, the cytokine interleukin (IL)-12 consists of a heterodimer between p35 and p40 subunits whereas interleukin-23 is formed by a heterodimer between p19 and p40 subunits. During an immune response, the balance between IL-12 and IL-23 can depend on the nature of the pathogen associated molecular pattern (PAMP) recognized by, for example TLR2, leading to a preferential production of IL-23. IL-23 production promotes a Th17-mediated immune response characterized by the production of IL-17A/F and several chemokines, important for neutrophil recruitment and activation. For the cold blooded vertebrate common carp, only the IL-12 subunits have been described so far.
Methodology/Principal Findings
Common carp is the natural host of two protozoan parasites: Trypanoplasma borreli and Trypanosoma carassii. We found that these parasites negatively affect p35 and p40a gene expression in carp. Transfection studies of HEK293 and carp macrophages show that T. carassii-derived PAMPs are agonists of carp TLR2, promoting p19 and p40c gene expression. The two protozoan parasites induce different immune responses as assessed by gene expression and histological studies. During T. carassii infections, in particular, we observed a propensity to induce p19 and p40c gene expression, suggestive of the formation of IL-23. Infections with T. borreli and T. carassii lead to an increase of IFN-γ2 gene expression whereas IL-17A/F2 gene expression was only observed during T. carasssii infections. The moderate increase in the number of splenic macrophages during T. borreli infection contrasts the marked increase in the number of splenic neutrophilic granulocytes during T. carassii infection, along with an increased gene expression of metalloproteinase-9 and chemokines.
Conclusion/Significance
This is the first study that provides evidence for a Th17-like immune response in fish in response to infection with a protozoan parasite.
doi:10.1371/journal.pone.0013012
PMCID: PMC2946394  PMID: 20885956
7.  Multidose Streptozotocin Induction of Diabetes in BALB/c Mice Induces a Dominant Oxidative Macrophage and a Conversion of TH1 to TH2 Phenotypes During Disease Progression 
Mediators of Inflammation  2005;2005(4):202-209.
Macrophages (Mp) are implicated in both early and late phases in type 1 diabetes development. Recent study has suggested that a balance between reductive Mp (RMp) and oxidative Mp (OMp) is possible to regulate TH1/TH2 balance. The aim of this study is to investigate the redox status of peritoneal Mp and its cytokine profile during the development of autoimmune diabetes induced by multiple low-dose streptozotocin in BALB/c mice. Meanwhile, the polarization of TH1/TH2 of splenocytes or thymocytes was also examined. We found that peritoneal Mp appeared as an “incomplete” OMp phenotype with decreased icGSH along with disease progression. The OMp showed reduced TNF-α, IL-12, and NO production as well as defective phagocytosis activity compared to nondiabetic controls; however, there was no significant difference with IL-6 production. On the other hand, the levels of IFN-γ or IL-4 of splenocytes in diabetic mice were significantly higher compared to the control mice. The ratio of IFN-γ to IL-4 was also higher at the early stage of diabetes and then declined several weeks later after the occurrence of diabetes, suggesting a pathogenetic TH1 phenotype from the beginning gradually to a tendency of TH2 during the development of diabetes. Our results implied that likely OMp may be relevant in the development of type 1 diabetes; however, it is not likely the only factor regulating the TH1H/TH2 balance in MLD-STZ-induced diabetic mice.
doi:10.1155/MI.2005.202
PMCID: PMC1526479  PMID: 16192669
8.  T helper cell polarisation as a measure of the maturation of the immune response. 
Mediators of Inflammation  2003;12(5):285-292.
BACKGROUND: T helper cell polarisation is important under chronic immune stimulatory conditions and drives the type of the evolving immune response. Mice treated with superantigens in vivo display strong effects on Th subset differentiation. The aim of the study was to detect the intrinsic capacity of T cells to polarise under various ex vivo conditions. METHODS: Purified CD4+ T cells obtained from super-antigen-treated mice were cultured under Th polarising conditions in vitro. By combining intracellular cytokine staining and subsequent flow cytometric analysis with quantitative cytokine measurements in culture supernatants by enzyme-linked immunosorbent assay (ELISA), the differential Th polarising capacity of the treatment can be detected in a qualitative and quantitative manner. RESULTS AND CONCLUSIONS: BALB/c mice were shown to be biased to develop strong Th2 polarised immune responses using Th0 stimulation of purified CD4+ T cells from phosphate-buffered saline-treated mice. Nevertheless, our analysis methodology convincingly showed that even in these mice, Toxic Shock Syndrome Toxin-1 treatment in vivo resulted in a significantly stronger Th1 polarising effect than control treatment. Our results indicate that populations of Th cells can be assessed individually for their differential Th1 or Th2 maturation capacity in vivo by analysing robust in vitro polarisation cultures combined with intracellular cytokine staining and ELISA.
PMCID: PMC1781629  PMID: 14760935
9.  Involvement of T Cells in Enhanced Resistance to Klebsiella pneumoniae Septicemia in Mice Treated with Liposome-Encapsulated Muramyl Tripeptide Phosphatidylethanolamine or Gamma Interferon 
Infection and Immunity  1998;66(5):1962-1967.
We have previously shown that prophylactic administration of the liposome-encapsulated immunomodulating agents muramyl tripeptide phosphatidylethanolamine (MTPPE) and gamma interferon (IFN-γ) results in strongly increased survival of mice from a normally lethal septicemia with Klebsiella pneumoniae. It was anticipated that the treatment acts on macrophages and nonspecifically augments host resistance to various infections. In the present study, we provide evidence for a key role for T cells in host defense potentiation by the liposomal immunomodulators toward K. pneumoniae septicemia. It is shown that both CD4 and CD8 cells are important in immunomodulation, most likely due to production of IFN-γ. Depletion of circulating IFN-γ resulted in strong reduction of the antimicrobial host defense activation. Administration of interleukin-10 resulted in decreased antimicrobial host defense activation by liposomal immunomodulators. Moreover, administration of liposomal immunomodulators was shown to induce predominantly T-helper type 1 (Th1) cell populations in the spleen. These findings indicate that immunomodulation with liposomal MTPPE and IFN-γ favors Th1 and NK cell activation.
PMCID: PMC108150  PMID: 9573076
10.  Book Review 
Mediators of Inflammation  1996;5(3):235-236.
doi:10.1155/S0962935196000348
PMCID: PMC2365788  PMID: 18475723
11.  Cytokines in Clinical and Experimental Transplantation 
Mediators of Inflammation  1994;3(6):403-410.
Allograft rejection is a complex process, which requires interactions between different cell types and a variety of soluble factors, such as cytokines. In this review we discuss the role of cytokines in the induction and effector phases of the rejection process and in the induction and maintenance of allospecific graft tolerance. Furthermore, we discuss the feasibility of clinical graft function monitoring by measuring cytokines and the possibilities for intervention in the cytokine network in order to inhibit graft rejection and eventually obtain graft acceptance.
doi:10.1155/S0962935194000566
PMCID: PMC2365586  PMID: 18475587
12.  Effect of Preventive Supplementation with Zinc and Other Micronutrients on Non-Malarial Morbidity in Tanzanian Pre-School Children: A Randomized Trial 
PLoS ONE  2012;7(8):e41630.
Background
The efficacy of preventive zinc supplementation against diarrhea and respiratory illness may depend on simultaneous supplementation with other micronutrients. We aimed to assess the effect of supplementation with zinc and multiple micronutrients on diarrhea and other causes of non-malarial morbidity.
Methods and Findings
Rural Tanzanian children (n = 612) aged 6–60 months and with height-for-age z-score < –1.5 SD were randomized to daily supplementation with zinc (10 mg) alone, multi-nutrients without zinc, multi-nutrients with zinc, or placebo. Children were followed for an average of 45 weeks. During follow-up, we recorded morbidity episodes. We found no evidence that concurrent supplementation with multi-nutrients influenced the magnitude of the effect of zinc on rates of diarrhea, respiratory illness, fever without localizing signs, or other illness (guardian-reported illness with symptoms involving skin, ears, eyes and abscesses, but excluding trauma or burns). Zinc supplementation reduced the hazard rate of diarrhea by 24% (4%–40%). By contrast, multi-nutrients seemed to increase this rate (HR; 95% CI: 1.19; 0.94–1.50), particularly in children with asymptomatic Giardia infection at baseline (2.03; 1.24–3.32). Zinc also protected against episodes of fever without localizing signs (0.75; 0.57–0.96), but we found no evidence that it reduced the overall number of clinic visits.
Conclusions
We found no evidence that the efficacy of zinc supplements in reducing diarrhea rates is enhanced by concurrent supplementation with other micronutrients. By reducing rates of fever without localizing signs, supplementation with zinc may reduce inappropriate drug use with anti-malarial medications and antibiotics.
Trial Registration
ClinicalTrials.gov NCT00623857
doi:10.1371/journal.pone.0041630
PMCID: PMC3411720  PMID: 22870238
13.  Effect of Supplementation with Zinc and Other Micronutrients on Malaria in Tanzanian Children: A Randomised Trial 
PLoS Medicine  2011;8(11):e1001125.
Hans Verhoef and colleagues report findings from a randomized trial conducted among Tanzanian children at high risk for malaria. Children in the trial received either daily oral supplementation with either zinc alone, multi-nutrients without zinc, multi-nutrients with zinc, or placebo. The investigators did not find evidence from this study that zinc or multi-nutrients protected against malaria episodes.
Background
It is uncertain to what extent oral supplementation with zinc can reduce episodes of malaria in endemic areas. Protection may depend on other nutrients. We measured the effect of supplementation with zinc and other nutrients on malaria rates.
Methods and Findings
In a 2×2 factorial trial, 612 rural Tanzanian children aged 6–60 months in an area with intense malaria transmission and with height-for-age z-score≤−1.5 SD were randomized to receive daily oral supplementation with either zinc alone (10 mg), multi-nutrients without zinc, multi-nutrients with zinc, or placebo. Intervention group was indicated by colour code, but neither participants, researchers, nor field staff knew who received what intervention. Those with Plasmodium infection at baseline were treated with artemether-lumefantrine. The primary outcome, an episode of malaria, was assessed among children reported sick at a primary care clinic, and pre-defined as current Plasmodium infection with an inflammatory response, shown by axillary temperature ≥37.5°C or whole blood C-reactive protein concentration ≥8 mg/L. Nutritional indicators were assessed at baseline and at 251 days (median; 95% reference range: 191–296 days). In the primary intention-to-treat analysis, we adjusted for pre-specified baseline factors, using Cox regression models that accounted for multiple episodes per child. 592 children completed the study. The primary analysis included 1,572 malaria episodes during 526 child-years of observation (median follow-up: 331 days). Malaria incidence in groups receiving zinc, multi-nutrients without zinc, multi-nutrients with zinc and placebo was 2.89/child-year, 2.95/child-year, 3.26/child-year, and 2.87/child-year, respectively. There was no evidence that multi-nutrients influenced the effect of zinc (or vice versa). Neither zinc nor multi-nutrients influenced malaria rates (marginal analysis; adjusted HR, 95% CI: 1.04, 0.93–1.18 and 1.10, 0.97–1.24 respectively). The prevalence of zinc deficiency (plasma zinc concentration <9.9 µmol/L) was high at baseline (67% overall; 60% in those without inflammation) and strongly reduced by zinc supplementation.
Conclusions
We found no evidence from this trial that zinc supplementation protected against malaria.
Trial Registration
ClinicalTrials.gov NCT00623857
Please see later in the article for the Editors' Summary.
Editors' Summary
Background
Malaria is a serious global public-health problem. Half of the world's population is at risk of this parasitic disease, which kills a million people (mainly children living in sub-Saharan Africa) every year. Malaria is transmitted to people through the bites of infected night-flying mosquitoes. Soon after entering the human body, the parasite begins to replicate in red blood cells, bursting out every 2–3 days and infecting more red blood cells. The presence of the parasite in the blood stream (parasitemia) causes malaria's characteristic recurring fever and can cause life-threatening organ damage and anemia (insufficient quantity of red blood cells). Malaria transmission can be reduced by using insecticide sprays to control the mosquitoes that spread the parasite and by avoiding mosquito bites by sleeping under insecticide-treated bed nets. Effective treatment with antimalarial drugs can also reduce malaria transmission.
Why Was This Study Done?
One reason why malaria kills so many children in Africa is poverty. Many children in Africa are malnourished, and malnutrition—in particular, insufficient micronutrients in the diet—impairs the immune system, which increases the frequency and severity of many childhood diseases. Micronutrients are vitamins and minerals that everyone needs in small quantities for good health. Zinc is one of the micronutrients that helps to maintain a healthy immune system, but zinc deficiency is very common among African children. Zinc supplementation has been shown to reduce the burden of diarrhea in developing countries, so might it also reduce the burden of malaria? Unfortunately, the existing evidence is confusing—some trials show that zinc supplementation protects against malaria but others show no evidence of protection. One possibility for these conflicting results could be that zinc supplementation alone is not sufficient—supplementation with other micronutrients might be needed for zinc to have an effect. In this randomized trial (a study that compares the effects of different interventions in groups that initially are similar in all characteristics except for intervention), the researchers investigate the effect of supplementation with zinc alone and in combination with other micronutrients on the rate of uncomplicated (mild) malaria among children living in Tanzania.
What Did the Researchers Do and Find?
The researchers enrolled 612 children aged 6–60 months who were living in a rural area of Tanzania with intense malaria transmission and randomly assigned them to receive daily oral supplements containing zinc alone, multi-nutrients (including iron) without zinc, multi-nutrients with zinc, or a placebo (no micronutrients). Nutritional indicators (including zinc concentrations in blood plasma) were assessed at baseline and 6–10 months after starting the intervention. During the study period, there were 1,572 malaria episodes. The incidence of malaria in all four intervention groups was very similar (about three episodes per child-year), and there was no evidence that multi-nutrients influenced the effect of zinc (or vice versa). Moreover, none of the supplements had any effect on malaria rates when compared to the placebo, even though the occurrence of zinc deficiency was strongly reduced by zinc supplementation. In a secondary analysis in which they analyzed their data by iron status at baseline, the researchers found that multi-nutrient supplementation increased the overall number of malaria episodes in children with iron deficiency by 41%, whereas multi-nutrient supplementation had no effect on the number of malaria episodes among children who were iron-replete at baseline.
What Do These Findings Mean?
In this study, the researchers found no evidence that zinc supplementation protected against malaria among young children living in Tanzania when given alone or in combination with other multi-nutrients. However, the researchers did find some evidence that multi-nutrient supplementation may increase the risk of malaria in children with iron deficiency. Because this finding came out of a secondary analysis of the data, it needs to be confirmed in a trial specifically designed to assess the effect of multi-nutrient supplements on malaria risk in iron-deficient children. Nevertheless, it is a potentially worrying result because, on the basis of evidence from a single study, the World Health Organization currently recommends that regular iron supplements be given to iron-deficient children in settings where there is adequate access to anti-malarial treatment. This recommendation should be reconsidered, suggest the researchers, and the safety of multi-nutrient mixes that contain iron and that are dispensed in countries affected by malaria should also be carefully evaluated.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001125.
Information is available from the World Health Organization on malaria (in several languages), on micronutrients, and on zinc deficiency; the 2010 World Malaria Report provides details of the current global malaria situation
The US Centers for Disease Control and Prevention provide information on malaria (in English and Spanish), including a selection of personal stories about malaria
Information is available from the Roll Back Malaria Partnership on the global control of malaria and on malaria in Africa
The Malaria Centre at the UK London School of Hygiene & Tropical Medicine develops tools, techniques, and knowledge about malaria, and has a strong emphasis on teaching, training, and translating research outcomes into practice
The Micronutrient Initiative, the Global Alliance for Improved Nutrition, and the Flour Fortification Initiative are not-for-profit organizations dedicated to ensuring that people in developing countries get the minerals and vitamins they need to survive and thrive
The International Zinc Nutrition Consultative Group (iZiNCG) is a non-profit organization that aims to promote and assist efforts to reduce zinc deficiency worldwide, through advocacy efforts, education, and technical assistance
MedlinePlus provides links to additional information on malaria (in English and Spanish)
doi:10.1371/journal.pmed.1001125
PMCID: PMC3222646  PMID: 22131908
14.  Effect of Heating and Glycation on the Allergenicity of 2S Albumins (Ara h 2/6) from Peanut 
PLoS ONE  2011;6(8):e23998.
Background
Peanut allergy is one of the most common and severe food allergies, and processing is known to influence the allergenicity of peanut proteins. We aimed to establish the effect of heating and glycation on the IgE-binding properties and biological activity of 2S albumins (Ara h 2/6) from peanut.
Methodology/Principal Findings
Native Ara h 2/6 was purified from raw peanuts and heated in solution (15 min, 110°C) in the presence or absence of glucose. Ara h 2 and 6 were also purified from roasted peanut. Using PBMC and sera from peanut-allergic patients, the cellular proliferative potency and IgE reactivity (reverse EAST inhibition) and functionality (basophil degranulation capacity) of allergens were assessed. Heating Ara h 2/6 at 110°C resulted in extensive denaturation, hydrolysis and aggregation of the protein, whilst Ara h 2 and 6 isolated from roasted peanut retained its native conformation. Allergen stimulation of PBMC induced proliferation and Th2 cytokine secretion which was unaffected by thermal processing. Conversely, IgE reactivity and functionality of Ara h 2/6 was decreased by heating. Whilst heating-glycation further reduced the IgE binding capacity of the proteins, it moderated their loss of histamine releasing capacity. Ara h 2 and 6 purified from roasted peanut demonstrated the same IgE reactivity as unheated, native Ara h 2/6.
Conclusions/Significance
Although no effect of processing on T-cell reactivity was observed, heat induced denaturation reduced the IgE reactivity and subsequent functionality of Ara h 2/6. Conversely, Ara h 2 and 6 purified from roasted peanut retained the structure and IgE reactivity/functionality of the native protein which may explain the allergenic potency of this protein. Through detailed molecular study and allergenicity assessment approaches, this work then gives new insights into the effect of thermal processing on structure/allergenicity of peanut proteins.
doi:10.1371/journal.pone.0023998
PMCID: PMC3162016  PMID: 21901150
15.  A Novel Soluble Immune-Type Receptor (SITR) in Teleost Fish: Carp SITR Is Involved in the Nitric Oxide-Mediated Response to a Protozoan Parasite 
PLoS ONE  2011;6(1):e15986.
Background
The innate immune system relies upon a wide range of germ-line encoded receptors including a large number of immunoglobulin superfamily (IgSF) receptors. Different Ig-like immune receptor families have been reported in mammals, birds, amphibians and fish. Most innate immune receptors of the IgSF are type I transmembrane proteins containing one or more extracellular Ig-like domains and their regulation of effector functions is mediated intracellularly by distinct stimulatory or inhibitory pathways.
Methodology/Principal Findings
Carp SITR was found in a substracted cDNA repertoire from carp macrophages, enriched for genes up-regulated in response to the protozoan parasite Trypanoplasma borreli. Carp SITR is a type I protein with two extracellular Ig domains in a unique organisation of a N-proximal V/C2 (or I-) type and a C-proximal V-type Ig domain, devoid of a transmembrane domain or any intracytoplasmic signalling motif. The carp SITR C-proximal V-type Ig domain, in particular, has a close sequence similarity and conserved structural characteristics to the mammalian CD300 molecules. By generating an anti-SITR antibody we could show that SITR protein expression was restricted to cells of the myeloid lineage. Carp SITR is abundantly expressed in macrophages and is secreted upon in vitro stimulation with the protozoan parasite T. borreli. Secretion of SITR protein during in vivo T. borreli infection suggests a role for this IgSF receptor in the host response to this protozoan parasite. Overexpression of carp SITR in mouse macrophages and knock-down of SITR protein expression in carp macrophages, using morpholino antisense technology, provided evidence for the involvement of carp SITR in the parasite-induced NO production.
Conclusion/Significance
We report the structural and functional characterization of a novel soluble immune-type receptor (SITR) in a teleost fish and propose a role for carp SITR in the NO-mediated response to a protozoan parasite.
doi:10.1371/journal.pone.0015986
PMCID: PMC3031540  PMID: 21305002

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