Allergic diseases mediated by T helper type (Th) 2 cell immune responses are rising dramatically in most developed countries. Exaggerated Th2 cell reactivity could result, for example, from ...diminished exposure to Th1 cell-inducing microbial infections. Epidemiological studies, however, indicate that Th2 cell-stimulating helminth parasites may also counteract allergies, possibly by generating regulatory T cells which suppress both Th1 and Th2 arms of immunity. We therefore tested the ability of the Th2 cell-inducing gastrointestinal nematode Heligmosomoides polygyrus to influence experimentally induced airway allergy to ovalbumin and the house dust mite allergen Der p 1. Inflammatory cell infiltrates in the lung were suppressed in infected mice compared with uninfected controls. Suppression was reversed in mice treated with antibodies to CD25. Most notably, suppression was transferable with mesenteric lymph node cells (MLNC) from infected animals to uninfected sensitized mice, demonstrating that the effector phase was targeted. MLNC from infected animals contained elevated numbers of CD4(+)CD25(+)Foxp3(+) T cells, higher TGF-beta expression, and produced strong interleukin (IL)-10 responses to parasite antigen. However, MLNC from IL-10-deficient animals transferred suppression to sensitized hosts, indicating that IL-10 is not the primary modulator of the allergic response. Suppression was associated with CD4(+) T cells from MLNC, with the CD4(+)CD25(+) marker defining the most active population. These data support the contention that helminth infections elicit a regulatory T cell population able to down-regulate allergen induced lung pathology in vivo.
AU-rich elements (AREs) located in the 3′untranslated region target the mRNAs encoding many protooncoproteins, cytokines, and lymphokines for rapid degradation. HuR, a ubiquitously expressed member ...of the embryonic lethal abnormal vision (ELAV) family of RNA-binding proteins, binds ARE sequences and selectively stabilizes ARE-containing reporter mRNAs when overexpressed in transiently transfected cells. HuR appears predominantly nucleoplasmic but has been shown to shuttle between the nucleus and cytoplasm via a novel shuttling sequence HNS. We report generation of a mouse monoclonal antibody 3A2 that both immunoblots and immunoprecipitates HuR protein; it recognizes an epitope located in the first of HuR's three RNA recognition motifs. This antibody was used to probe HuR interactions with mRNA before and after heat shock, a condition that has been reported to stabilize ARE-containing mRNAs. At 37 degrees C, approximately one-third of the cytoplasmic HuR appears polysome associated, and in vivo UV crosslinking reveals that HuR interactions with poly(A)+RNA are predominantly cytoplasmic rather than nuclear. This comprises evidence that HuR directly interacts with mRNA in vivo. After heat shock, 12-15% of HuR accumulates in discrete foci in the cytoplasm, but surprisingly the majority of HuR crosslinks instead to nuclear poly(A)+RNA, whose levels are dramatically increased in the stressed cells. This behavior of HuR differs from that of another ARE-binding protein, hnRNP D, which has been implicated as an effector of mRNA decay rather than mRNA stabilization and of the general pre-RNA-binding protein hnRNP A1. We interpret these differences to mean that the temporal association of HuR with ARE-containing mRNAs is different from that of these other two proteins.
Parasitic infections are a major theme in the "hygiene hypothesis", as allergies and autoimmune diseases are less prevalent in countries with higher burdens of helminths and other parasitic ...organisms. Helminths"-the grouping of multicellular worm parasites including nematodes, cestodes and trematodes-tend to establish long-lived, chronic infections indicating successful down-modulation of the host immune system. In this review, we describe the intricate immunology of host-helminth interactions and how parasites manipulate immune responses to enhance their survival. In so doing, they often minimise immunopathology and, it is suggested, reduce host susceptibility to, and severity of allergic and autoimmune diseases. Studies on helminth-infected communities and individuals support the hypothesis that an immuno-regulatory network promoted by parasites extends its influence to limiting allergies. Experimental models are now probing more deeply into the area of immune modulation by helminths, and we discuss the likely mechanisms by which helminths could be establishing a strongly regulatory environment. Understanding and harnessing the modulatory capacity of helminths may uncover novel therapeutic interventions, mimicking and exploiting their evolution for our benefit. Parasitic infections are a major theme in the "hygiene hypothesis", as allergies and autoimmune diseases are less prevalent in countries with higher burdens of helminths and other parasitic organisms. Helminths"-the grouping of multicellular worm parasites including nematodes, cestodes and trematodes-tend to establish long-lived, chronic infections indicating successful down-modulation of the host immune system. In this review, we describe the intricate immunology of host-helminth interactions and how parasites manipulate immune responses to enhance their survival. In so doing, they often minimise immunopathology and, it is suggested, reduce host susceptibility to, and severity of allergic and autoimmune diseases. Studies on helminth-infected communities and individuals support the hypothesis that an immuno-regulatory network promoted by parasites extends its influence to limiting allergies. Experimental models are now probing more deeply into the area of immune modulation by helminths, and we discuss the likely mechanisms by which helminths could be establishing a strongly regulatory environment. Understanding and harnessing the modulatory capacity of helminths may uncover novel therapeutic interventions, mimicking and exploiting their evolution for our benefit.
There is increasing interest in helminth parasite modulation of the immune system, both from the fundamental perspective of the “arms race” between host and parasite, and equally importantly, to ...understand if parasites offer new pathways to abate and control untoward immune responses in humans. This article reviews the epidemiological and experimental evidence for parasite down‐regulation of host immunity and immunopathology, in allergy and other immune disorders, and recent progress towards defining the mechanisms and molecular mediators which parasites exploit in order to modulate their host. Among these are novel products that interfere with epithelial cell alarmins, dendritic cell activation, macrophage function and T‐cell responsiveness through the promotion of an immunoregulatory environment. These modulatory effects assist parasites to establish and survive, while dampening immune reactivity to allergens, autoantigens and microbiome determinants.
Helminth parasite infections are associated with a battery of immunomodulatory mechanisms that affect all facets of the host immune response to ensure their persistence within the host. This ...broad-spectrum modulation of host immunity has intended and unintended consequences, both advantageous and disadvantageous. Thus the host can benefit from suppression of collateral damage during parasite infection and from reduced allergic, autoimmune, and inflammatory reactions. However, helminth infection can also be detrimental in reducing vaccine responses, increasing susceptibility to coinfection and potentially reducing tumor immunosurveillance. In this review we will summarize the panoply of immunomodulatory mechanisms used by helminths, their potential utility in human disease, and prospective areas of future research.
The profile of global health today presents a striking reciprocal distribution between parasitic diseases in many of the world's lower-income countries, and ever-increasing levels of inflammatory ...disorders such as allergy, autoimmunity and inflammatory bowel diseases in the more affluent societies. Attention is particularly focused on helminth worm parasites, which are associated with protection from allergy and inflammation in both epidemiologic and laboratory settings. One mechanistic explanation of this is that helminths drive the regulatory arm of the immune system, abrogating the ability of the host to expel the parasites, while also dampening reactivity to many bystander specificities. Interest has therefore heightened into whether helminth parasites, or their products, hold therapeutic potential for immunologic disorders of the developed world. In this narrative review, progress across a range of trials is discussed, together with prospects for isolating individual molecular mediators from helminths that may offer defined new therapies for inflammatory conditions.
The iron-nickel contact surfaces of reed switches after ion-induced modification have been studied using methods of Auger-electron spectroscopy, X-ray photoelectron spectroscopy, atomic force ...microscopy, and optical microscopy. It was demonstrated that the corrosion stability and erosion resistance of the modified contacts is associated with the features of surface topography as well as with a formation of nitride layers. Experimental grounds for a production possibility of reed switches with the modified contact surface instead of electroplating based on the precious metals are given.
Helminths are extraordinarily successful parasites due to their ability to modulate the host immune response. They have evolved a spectrum of immunomodulatory molecules that are now beginning to be ...defined, heralding a molecular revolution in parasite immunology. These discoveries have the potential both to transform our understanding of parasite adaptation to the host and to develop possible therapies for immune-mediated disease. In this review we will summarize the current state of the art in parasite immunomodulation and discuss perspectives on future areas for research and discovery.
Parasitic helminths modulate the immune system, preventing immune-mediated ejection and suppressing immune-mediated diseases. In this review, Maizels and colleagues describe the secreted molecules by which parasites achieve this and the methods by which these molecules have evolved.
Helminth parasitic infections are a major global health and social burden. The host defence against helminths such as Nippostrongylus brasiliensis is orchestrated by type 2 cell-mediated immunity. ...Induction of type 2 cytokines, including interleukins (IL) IL-4 and IL-13, induce goblet cell hyperplasia with mucus production, ultimately resulting in worm expulsion. However, the mechanisms underlying the initiation of type 2 responses remain incompletely understood. Here we show that tuft cells, a rare epithelial cell type in the steady-state intestinal epithelium, are responsible for initiating type 2 responses to parasites by a cytokine-mediated cellular relay. Tuft cells have a Th2-related gene expression signature and we demonstrate that they undergo a rapid and extensive IL-4Rα-dependent amplification following infection with helminth parasites, owing to direct differentiation of epithelial crypt progenitor cells. We find that the Pou2f3 gene is essential for tuft cell specification. Pou2f3(-/-) mice lack intestinal tuft cells and have defective mucosal type 2 responses to helminth infection; goblet cell hyperplasia is abrogated and worm expulsion is compromised. Notably, IL-4Rα signalling is sufficient to induce expansion of the tuft cell lineage, and ectopic stimulation of this signalling cascade obviates the need for tuft cells in the epithelial cell remodelling of the intestine. Moreover, tuft cells secrete IL-25, thereby regulating type 2 immune responses. Our data reveal a novel function of intestinal epithelial tuft cells and demonstrate a cellular relay required for initiating mucosal type 2 immunity to helminth infection.
The cycle of activities of the creation of principally new generation of reed switches with nanostructured contact surfaces was implemented. Experimental justification of the opportunity of reed ...switches creation with modified contact surface was given (instead of precious metals-based galvanic coating). Principally new technological process of modification of magnetically operated contacts contacting surfaces was developed, based on the usage of the ion-plasma methods of nanolayers and nanostructures forming having specified contact features.
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