Surface sialic acids taken from the host allow trypanosome survival in tsetse fly vectors

The African trypanosome Trypanosoma brucei, which causes sleeping sickness in humans and Nagana disease in livestock, is spread via blood-sucking Tsetse flies. In the fly's intestine, the trypanosomes survive digestive and trypanocidal environments, proliferate, and translocate into the salivary gland, where they become infectious to the next mammalian host. Here, we show that for successful survival in Tsetse flies, the trypanosomes use trans-sialidase to transfer sialic acids that they cannot synthesize from host's glycoconjugates to the glycosylphosphatidylinositols (GPIs), which are abundantly expressed on their surface. Trypanosomes lacking sialic acids due to a defective generation of GPI-anchored trans-sialidase could not survive in the intestine, but regained the ability to survive when sialylated by means of soluble trans-sialidase. Thus, surface sialic acids appear to protect the parasites from the digestive and trypanocidal environments in the midgut of Tsetse flies.     

Accuracy of automatic tube compensation in new-generation mechanical ventilators

OBJECTIVE: To compare performance of flow-adapted compensation of endotracheal tube resistance (automatic tube compensation, ATC) between the original ATC system and ATC systems incorporated in commercially available ventilators. DESIGN: Bench study. SETTING: University research laboratory. SUBJECTS: The original ATC system, Dr?ger Evita 2 prototype, Dr?ger Evita 4, Puritan-Bennett 840. INTERVENTIONS: The four ventilators under investigation were alternatively connected via different sized endotracheal tubes and an artificial trachea to an active lung model. Test conditions consisted of two ventilatory modes (ATC vs. continuous positive airway pressure), three different sized endotracheal tubes (inner diameter 7.0, 8.0, and 9.0 mm), two ventilatory rates (15/min and 30/min), and four levels of positive end-expiratory pressure (0, 5, 10, and 15 cm H2O). MEASUREMENTS AND MAIN RESULTS: Performance of tube compensation was assessed by the amount of tube-related (additional) work of breathing (WOBadd), which was calculated on the basis of pressure gradient across the endotracheal tube. Compared with continuous positive airway pressure, ATC reduced inspiratory WOBadd by 58%, 68%, 50%, and 97% when using the Evita 4, the Evita 2 prototype, the Puritan-Bennett 840, and the original ATC system, respectively. Depending on endotracheal tube diameter and ventilatory pattern, inspiratory WOBadd was 0.12-5.2 J/L with the original ATC system, 1.5-28.9 J/L with the Puritan-Bennett 840, 10.4-21.0 J/L with the Evita 2 prototype, and 10.1-36.1 J/L with the Evita 4 (difference between each ventilator at identical test situations, p <.025). Expiratory WOBadd was reduced by 5%, 26%, 1%, and 70% with the Evita 4, the Evita 2 prototype, the Puritan-Bennett 840, and the original ATC system, respectively. The expiratory WOBadd caused by an endotracheal tube of 7.0 mm inner diameter was 5.5-42.2 J/L at a low ventilatory rate and 19.6-82.3 J/L at a high ventilatory rate. It was lowest with the original ATC system and highest with the Evita 4 ventilator (p <.025). CONCLUSIONS: Flow-adapted tube compensation by the original ATC system significantly reduced tube-related inspiratory and expiratory work of breathing. The commercially available ATC modes investigated here may be adequate for inspiratory but probably not for expiratory tube compensation.     

IgE-binding epitopes: a reappraisal

Here, we discuss various questions related to IgE epitopes: What are the technical possibilities and pitfalls, what is currently known, how can we put this information into hypothetical frameworks and the unavoidable question: how useful is this information for patient care or allergenicity prediction? We discuss the information obtained by (i) 3D structures of allergen-antibody complexes; (ii) analysis of allergen analogues; (iii) mimics without obvious structural similarity; (iv) mAbs competing with IgE; (v) repertoire analysis of cloned IgEs, and other developments. Based on limited data, four suggestions are presented in the literature: (i) IgE might be more cross-reactive than IgG; (ii) IgE might be more often directed to immunologically 'uninviting' surfaces; (iii) IgE epitopes may tend to cluster and (iv) IgE paratopes might have a higher intrinsic flexibility. While these are not proven facts, they still can generate hypotheses for future research. The hypothesis is put forward that the IgE repertoire of switched B-cells is less influenced by positive selection, because positive selection might not be able to rescue IgE-switched B cells. While this might be of interest for the discussion about mechanisms leading to allergen-sensitization, we need to be modest in answering the 'clinical relevance' question. Current evidence indicates the IgE-epitope repertoire is too big to make specific IgE epitopes a realistic target for diagnosis, treatment or allergenicity prediction. In-depth analysis of a few selected IgE epitope-peptides or mimitopes derived from allergen-sequences and from random peptide libraries, respectively, might well prove rewarding in relation to diagnosis and prognosis of allergy, particularly food allergy.     

Interleukins, from 1 to 37, and interferon-γ: receptors, functions, and roles in diseases

Advancing our understanding of mechanisms of immune regulation in allergy, asthma, autoimmune diseases, tumor development, organ transplantation, and chronic infections could lead to effective and targeted therapies. Subsets of immune and inflammatory cells interact via ILs and IFNs; reciprocal regulation and counter balance among T(h) and regulatory T cells, as well as subsets of B cells, offer opportunities for immune interventions. Here, we review current knowledge about ILs 1 to 37 and IFN-γ. Our understanding of the effects of ILs has greatly increased since the discoveries of monocyte IL (called IL-1) and lymphocyte IL (called IL-2); more than 40 cytokines are now designated as ILs. Studies of transgenic or knockout mice with altered expression of these cytokines or their receptors and analyses of mutations and polymorphisms in human genes that encode these products have provided important information about IL and IFN functions. We discuss their signaling pathways, cellular sources, targets, roles in immune regulation and cellular networks, roles in allergy and asthma, and roles in defense against infections.     

A model for the involvement of neural cell adhesion molecules in stress-related mood disorders

Critical interactions between genetic and environmental factors -- among which stress is one of the most potent non-genomic factors -- are involved in the development of mood disorders. Intensive work during the past decade has led to the proposal of the network hypothesis of depression [Castren E: Nat Rev Neurosci 2005;6:241-246]. In contrast to the earlier chemical hypothesis of depression that emphasized neurochemical imbalance as the cause of depression, the network hypothesis proposes that problems in information processing within relevant neural networks might underlie mood disorders. Clinical and preclinical evidence supporting this hypothesis are mainly based on observations from depressed patients and animal stress models indicating atrophy (with basic research pointing at structural remodeling and decreased neurogenesis as underlying mechanisms) and malfunctioning of the hippocampus and prefrontal cortex, as well as the ability of antidepressant treatments to have the opposite effects. A great research effort is devoted to identify the molecular mechanisms that are responsible for the network effects of depression and antidepressant actions, with a great deal of evidence pointing at a key role of neurotrophins (notably the brain-derived neurotrophic factor) and other growth factors. In this review, we present evidence that implicates alterations in the levels of the neural cell adhesion molecules of the immunoglobulin superfamily, NCAM and L1, among the mechanisms contributing to stress-related mood disorders and, potentially, in antidepressant action.     

Role of CD11b+ Macrophages in Intraperitoneal Lipopolysaccharide-Induced Aberrant Lymphangiogenesis and Lymphatic Function in the Diaphragm

Lymphatic vessels in the diaphragm are essential for draining peritoneal fluid, but little is known about their pathological changes during inflammation. Here we characterized diaphragmatic lymphatic vessels in a peritonitis model generated by daily i.p. administration of lipopolysaccharide (LPS) in mice. Intraperitoneal LPS increased lymphatic density, branching, sprouts, connections, and network formation in the diaphragm in time- and dose-dependent manners. These changes were reversible on discontinuation of LPS administration. The LPS-induced lymphatic density and remodeling occur mainly through proliferation of lymphatic endothelial cells. CD11b⁺ macrophages were massively accumulated and closely associated with the lymphatic vessels changed by i.p. LPS. Both RT-PCR assays and experiments with vascular endothelial growth factor-C/D blockade and macrophage-depletion indicated that the CD11b⁺ macrophage-derived lymphangiogenic factors vascular endothelial growth factor-C/D could be major mediators of LPS-induced lymphangiogenesis and lymphatic remodeling through paracrine activity. Functional assays with India ink and fluorescein isothiocyanate-microspheres indicated that impaired peritoneal fluid drainage in diaphragm of LPS-induced peritonitis mice was due to inflammatory fibrosis and massive attachment of CD11b⁺ macrophages on the peritoneal side of the diaphragmatic lymphatic vessels. These findings reveal that CD11b⁺ macrophages play an important role in i.p. LPS-induced aberrant lymphangiogenesis and lymphatic dysfunction in the diaphragm.The peritoneum provides the lining of the peritoneal cavity and is the most extensive serous membrane in the body.¹ The peritoneal membrane is formed by a single layer of mesothelial cells. Beneath the mesothelial cells, there is a very thin and discontinuous layer of connective tissue and a layer of fenestrated lymphatic vessels.² These three layers not only function as an absorptive surface for peritoneal fluid but also remove pathogens and prevent cells from leaking through damage in the gastrointestinal tract or ascending through the female genital tract.^3,4 The peritoneum also plays crucial roles in the local defensive response against bacterial invasion with appropriate activation of resident immune cells and the recruitment of circulating immune cells.^5,6Lymphatic vessels have distinctive morphologies and functions in different tissues and organs.^7,8 Lymphatic vessels play an essential role in the maintenance of tissue fluid homeostasis through regulated uptake of protein-rich interstitial fluid into draining lymphatic vessels and transport of the drained lymphatic fluid into the blood vasculature via collecting lymphatic vessels.⁹ In addition, lymphatic vessels have roles in lipid absorption, antigen presentation, tumor metastasis, and wound healing.^{10,11,12,13,14,15,16} Lymphatic vessels beneath the peritoneum, particularly lymphatic vessels on the peritoneal side of the muscular region of diaphragm, provide the central route for draining peritoneal fluid.^2,17,18Lymphatic vessels on the peritoneal side of the diaphragm are largely attenuated but well designed for fluid absorption with extremely flattened and broad lumina (also called lacunae), which are connected with openings between mesothelial cells covering the peritoneal surface.^2,19 In comparison, lymphatic vessels on the pleural side of diaphragm are tubular, like other lymphatic vessels.^20,21 There are seven to nine parallel lymphatic strips on each hemisphere (sterno-costal muscular region) of the peritoneal side of diaphragm, and these lymphatic vessels are directly connected to the tubular lymphatic vessels on the pleural side by transmural lymphatic branches.^20,21,22 Therefore, the peritoneal fluid absorbed by lymphatic lacunae is directly transported into the lymphatic vessels on the pleural side. In contrast, there are few lymphatic vessels in the central tendon region of the diaphragm. However, little is known about relationship between the structural and functional changes of diaphragmatic lymphatic vessels and peritoneal illnesses.Our understanding of the molecular and cellular regulation of new lymphatic vessel formation, “lymphangiogenesis,” has greatly advanced in recent years.¹⁰ Among lymphangiogenic growth factors, the roles of vascular endothelial growth factor (VEGF)-C and VEGF-D (VEGF-C/D) and their lymphatic vessel-specific receptor VEGF receptor-3 (VEGFR-3) are specific and essential in lymphangiogenesis.¹⁰ In addition, VEGF-A and its receptors play additional roles in lymphangiogenesis in certain pathological conditions.^10,11 Moreover, proinflammatory cytokine-induced activation of macrophages is closely involved in pathological lymphangiogenesis in tracheal mucosa and cornea by reciprocal interactions with the VEGF-C/D-VEGFR-3 system.^12,13,14,15 However, the relationship between proinflammatory cytokine-induced activation of macrophages and pathological changes of diaphragmatic lymphatic vessels during peritonitis is unknown.In this study, we investigated how acute inflammatory peritonitis affects the diaphragmatic lymphatic vessels structurally and functionally and what roles are played by activated macrophages in this situation. To generate a peritonitis model, we administered lipopolysaccharide (LPS; endotoxin) directly into the peritoneal cavity of mouse. LPS is a well-known cell wall component of most Gram-negative bacteria and acts as a potent initiator of inflammation.^23,24 Interestingly, mice with LPS-induced peritonitis displayed aberrant lymphangiogenesis, lymphatic remodeling, and lymphatic dysfunction in the diaphragm. We have defined the underlying mechanisms and the responsible molecules by using specific blocking agents to reveal the roles of critical effector cells and molecules. Our results show that CD11b⁺ macrophages have an important role in LPS-induced aberrant lymphangiogenesis and lymphatic dysfunction in the diaphragm.