Lipophilic Allergens, Different Modes of Allergen-Lipid Interaction and Their Impact on Asthma and Allergy

Molecular allergology research has provided valuable information on the structure and function of single allergenic molecules. There are several allergens in food and inhalant allergen sources that are able to interact with lipid ligands via different structural features: hydrophobic pockets, hydrophobic cavities, or specialized domains. For only a few of these allergens information on their associated ligands is already available. Several of the allergens are clinically relevant, so that it is highly probable that the individual structural features with which they interact with lipids have a direct effect on their allergenic potential, and thus on allergy development. There is some evidence for a protective effect of lipids delaying the enzymatic digestion of the peanut (Arachis hypogaea) allergen Ara h 8 (hydrophobic pocket), probably allowing this molecule to get to the intestinal immune system intact (sensitization). Oleosins from different food allergen sources are part of lipid storage organelles and potential marker allergens for the severity of the allergic reaction. House dust mite (HDM), is more often associated with allergic asthma than other sources of inhalant allergens. In particular, lipid-associated allergens from Dermatophagoides pteronyssinus which are Der p 2, Der p 5, Der p 7, Der p 13, Der p 14, and Der p 21 have been reported to be associated with severe allergic reactions and respiratory symptoms such as asthma. The exact mechanism of interaction of these allergens with lipids still has to be elucidated. Apart from single allergens glycolipids have been shown to directly induce allergic inflammation. Several—in parts conflicting—data exist on the lipid (and allergen) and toll-like receptor interactions. For only few single allergens mechanistic studies were performed on their interaction with the air-liquid interface of the lungs, in particular with the surfactant components SP-A and SP-D. The increasing knowledge on protein-lipid-interaction for lipophilic and hydrophobic food and inhalant allergens on the basis of their particular structure, of their capacity to be integral part of membranes (like the oleosins), and their ability to interact with membranes, surfactant components, and transport lipids (like the lipid transfer proteins) are essential to eventually clarify allergy and asthma development

Lipid Mediators From Timothy Grass Pollen Contribute to the Effector Phase of Allergy and Prime Dendritic Cells for Glycolipid Presentation

Plant pollen are an important source of antigens that evoke allergic responses. Protein antigens have been the focus of studies aiming to elucidate the mechanisms responsible for allergic reactions to pollen. However, proteins are not the sole active agent present in pollen. It is known that pollen grains contain lipids essential for its reproduction and bioactive lipid mediators. These small molecular compounds are co-delivered with the allergens and hence have the potential to modulate the immune response of subjects by activating their innate immune cells. Previous reports showed that pollen associated lipid mediators exhibited neutrophil- and eosinophil-chemotactic activity and induced polarization of dendritic cells (DCs) toward a Th2-inducing phenotype. In our study we performed chemical analyses of the pollen associated lipids, that are rapidly released upon hydration. As main components we have identified different types of phytoprostanes (PhytoPs), and for the first time phytofurans (PhytoFs), with predominating 16-F1t-PhytoPs (PPF1-I), 9-F1t-PhytoPs (PPF1-II), 16-E1t-PhytoPs (PPE1-I) and 9-D1t-PhytoPs (PPE1-II), and 16(RS)-9-epi-ST-Δ14-10-PhytoFs. Interestingly 16-E1t-PhytoP and 9-D1t-PhytoPs were found to be bound to glycerol. Lipid-containing samples (aqueous pollen extract, APE) induced murine mast cell chemotaxis and IL-6 release, and enhanced their IgE-dependent degranulation, demonstrating a role for these lipids in the immediate effector phase of allergic inflammation. Noteworthy, mast cell degranulation seems to be dependent on glycerol-bound, but not free phytoprostanes. On murine dendritic cells, APE selectively induced the upregulation of CD1d, likely preparing lipid-antigen presentation to iNKT cells. Our report contributes to the understanding of the activity of lipid mediators in the immediate effector phase of allergic reactions but identifies a yet undescribed pathway for the recognition of pollen-derived glycolipids by iNKT cells

Natural Killer T Cells Activated by a Lipopeptidophosphoglycan from Entamoeba histolytica Are Critically Important To Control Amebic Liver Abscess

The innate immune response is supposed to play an essential role in the control of amebic liver abscess (ALA), a severe form of invasive amoebiasis due to infection with the protozoan parasite Entamoeba histolytica. In a mouse model for the disease, we previously demonstrated that Jα18-/- mice, lacking invariant natural killer T (iNKT) cells, suffer from more severe abscess development. Here we show that the specific activation of iNKT cells using α-galactosylceramide (α-GalCer) induces a significant reduction in the sizes of ALA lesions, whereas CD1d−/− mice develop more severe abscesses. We identified a lipopeptidophosphoglycan from E. histolytica membranes (EhLPPG) as a possible natural NKT cell ligand and show that the purified phosphoinositol (PI) moiety of this molecule induces protective IFN-γ but not IL-4 production in NKT cells. The main component of EhLPPG responsible for NKT cell activation is a diacylated PI, (1-O-[(28∶0)-lyso-glycero-3-phosphatidyl-]2-O-(C16:0)-Ins). IFN-γ production by NKT cells requires the presence of CD1d and simultaneously TLR receptor signalling through MyD88 and secretion of IL-12. Similar to α-GalCer application, EhLPPG treatment significantly reduces the severity of ALA in ameba-infected mice. Our results suggest that EhLPPG is an amebic molecule that is important for the limitation of ALA development and may explain why the majority of E. histolytica-infected individuals do not develop amebic liver abscess

Influence of clinical and neurocognitive factors in psychosocial functioning after a first episode non-affective psychosis: differences between males and females

BackgroundDeficits in psychosocial functioning are present in the early stages of psychosis. Several factors, such as premorbid adjustment, neurocognitive performance, and cognitive reserve (CR), potentially influence functionality. Sex differences are observed in individuals with psychosis in multiple domains. Nonetheless, few studies have explored the predictive factors of poor functioning according to sex in first-episode psychosis (FEP). This study aimed to explore sex differences, examine changes, and identify predictors of functioning according to sex after onset.Materials and methodsThe initial sample comprised 588 individuals. However, only adults with non-affective FEP (n = 247, 161 males and 86 females) and healthy controls (n = 224, 142 males and 82 females) were included. A comprehensive assessment including functional, neuropsychological, and clinical scales was performed at baseline and at 2-year follow-up. A linear regression model was used to determine the predictors of functioning at 2-year follow-up.ResultsFEP improved their functionality at follow-up (67.4% of both males and females). In males, longer duration of untreated psychosis (β = 0.328, p = 0.003) and worse premorbid adjustment (β = 0.256, p = 0.023) were associated with impaired functioning at 2-year follow-up, while in females processing speed (β = 0.403, p = 0.003), executive function (β = 0.299, p = 0.020) and CR (β = −0.307, p = 0.012) were significantly associated with functioning.ConclusionOur data indicate that predictors of functioning at 2-year follow-up in the FEP group differ according to sex. Therefore, treatment and preventative efforts may be adjusted taking sex into account. Males may benefit from functional remediation at early stages. Conversely, in females, early interventions centered on CR enhancement and cognitive rehabilitation may be recommended

Testosterone modulates murine NKT cell specific IFNγ production.

<p>A) Liver lymphocytes from placebo or testosterone treated naïve female mice were gradient purified, T cells were isolated by magnetic cell sorting and co-cultured for 48 h with αGalCer (2 µg/ml) or EhLPPG (4 µg/ml) pre-pulsed APCs. Medium control comprises NKT cells co-cultured with naive APC’s. IFN<b>γ</b> in the supernatant was quantified using ELISA. B) Liver lymphocytes were isolated from naïve male or orchiectomized male mice and co-cultured with pre-pulsed APCs as described above. IFN<b>γ</b> production was quantified using ELISA. C/D) Identical experiments as performed in A and B but cells were isolated from the livers of ameba-infected female and male mice- Three independent experiments were performed (data express mean +/− SD, statistics: student`s t test).</p

Influence of testosterone on the development of ALA.

<p>A) Time schedule of gonadectomy, testosterone substitution and intrahepatic infection with <i>E. histolytica</i> trophozoites. B) Serum testosterone levels in placebo treated naïve female mice, testosterone substituted female mice and male mice measured by ELISA (ng/ml). C) Size of ALA in testosterone treated, ovariectomized (ovx) or naïve female mice. Score values indicative for the size of ALA determined on day 7 post intrahepatic infection with 1×10⁵ virulent <i>E. histolytica</i> trophozoites of naïve female mice treated either with testosterone or placebo are shown (score 0: no abscess; score 1: abscess <1 mm; score 2∶1 to 5 mm; score 3: >5 mm). D) Re-isolation rate of <i>E. histolytica</i> trophozoites from abscessed liver tissue of ovariectomized (ovx) and naïve female mice treated either with testosterone or placebo. Results were obtained from at least 3 independent trials each comprising of 7 animals (statistics: Mann Whitney U test).</p

Characterization of the IFNγ producing gender specific murine NKT cell subpopulation.

<p>NKT cell subsets (PE- αGalCer -CD1d tetramer/CD4⁺) from female and male mice. IFN<b>γ</b> was determined following 48 h of co-cultivation with pre-pulsed APCs as described above (2 independent experiments were performed, a summary of data is expressed as mean +/− SD, statistics: student t test).</p

Characterization of NKT cells frequencies and NKT cell specific IFNγ production in female and male mice.

<p>A) NKT cell frequencies in the liver of female and male mice at different ages are shown. NKT cell numbers were determined as percentage of αGalCer -CD1d tetramer positive cells to CD3⁺ T cells. B) IFN<b>γ</b> production of NKT cells sorted (αGalCer -CD1d tetramer) from the liver of female or male mice after 48 h of co-incubation with αGalCer (4 µg/ml) or EhLLPG (8 µg/ml) pre-pulsed APCs. Medium control includes NKT cells co-cultured with naive APC’s. IFN<b>γ</b> production was quantified by ELISA (5 independent experiments were performed, a summary of data is expressed as mean +/− SD, statistics: student t test). C) IFN<b>γ</b> production of male or female NKT cells upon stimulation with αGalCer pre-pulsed male or female APCs.</p

Influence of gonadectomy on the size of ALA in the mouse model for the disease.

<p>Eight weeks old male and female mice were gonadectomized and intrahepatically challenged with 1×10⁵<i>E. histolytica</i> trophozoites seven weeks after castration. The animals were sacrificed 7 days post infection, the sizes of abscesses were determined and transformed into score values (score 0: no abscess; score 1: abscess <1 mm; score 2∶1 to 5 mm; score 3: >5 mm) (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0055694#pone-0055694-g001" target="_blank">Fig. 1A</a>) or the re-isolation rate of live <i>E. histolytica</i> trophozoites from abscessed liver tissue was determined (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0055694#pone-0055694-g001" target="_blank">Fig. 1B</a>). Results were obtained from 3 independent trials each comprising 7 animals (statistics: Mann Whitney U test).</p