IL-6 controls susceptibility to helminth infection by impeding Th2 responsiveness and altering the Treg phenotype in vivo

IL-6 plays a pivotal role in favoring T-cell commitment toward a Th17 cell rather than Treg-cell phenotype, as established through in vitro model systems. We predicted that in the absence of IL-6, mice infected with the gastrointestinal helminth Heligmosomoides polygyrus would show reduced Th17-cell responses, but also enhanced Treg-cell activity and consequently greater susceptibility. Surprisingly, worm expulsion was markedly potentiated in IL-6-deficient mice, with significantly stronger adaptive Th2 responses in both IL-6−/− mice and BALB/c recipients of neutralizing anti-IL-6 monoclonal Ab. Although IL-6-deficient mice showed lower steady-state Th17-cell levels, IL-6-independent Th17-cell responses occurred during in vivo infection. We excluded the Th17 response as a factor in protection, as Ab neutralization did not modify immunity to H. polygyrus infection in BALB/c mice. Resistance did correlate with significant changes to the associated Treg-cell phenotype however, as IL-6-deficient mice displayed reduced expression of Foxp3, Helios, and GATA-3, and enhanced production of cytokines within the Treg-cell population. Administration of an anti-IL-2:IL-2 complex boosted Treg-cell proportions in vivo, reduced adaptive Th2 responses to WT levels, and fully restored susceptibility to H. polygyrus in IL-6-deficient mice. Thus, in vivo, IL-6 limits the Th2 response, modifies the Treg-cell phenotype, and promotes host susceptibility following helminth infection

Suppression of allergic airway inflammation by helminth-induced regulatory T cells

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-β 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

In vivo nematicidal potential of camel milk on Heligmosomoides polygyrus gastro-intestinal nematode of rodents

Following our previous fi ndings on the in vitro anthelmintic effect of camel milk on Haemonchus contortus, the current study aimed at investigating its in vivo effect. Investigations were carried out using mice infected with Heligmosomoides polygyrus which is a parasite commonly used to test the effi cacy of anthelmintics. Thirty six Swiss white mice of both sexes aged 5 – 6 weeks old, and weighing between 20 and 25 g were orally infected with 0.5 ml dose of 100, 1-week-old H. polygyrus infective larvae (L3 ). After the pre-patent period, infected animals were randomly divided into 6 groups of 6 animals each. The nematicidal effi cacy of camel milk was monitored through faecal egg count reduction (FECR) and total worm count reduction (TWCR). Four doses (8.25; 16.5; 33.0; 66.0 ml/kg body weight (bw)) for fresh camel milk and 22 mg/kg bw for albendazole were studied using a bioassay. Albendazole and 4 % dimethylsulfoxide were included in the protocol as reference drug and placebo, respectively. For all tested doses except 8.25 ml/kg bw, camel milk was effective in vivo against H. polygyrus reducing both faecal egg count and worm count (p < 0.05). The dose 66 ml/kg bw showed the highest nematicidal activity causing a 76.75 % FECR and a 69.62 % TWCR 7 day after initiating the treatment. These results support the possible use of camel milk in the control of gastro-intestinal helminthiasis

Innate lymphoid cells in helminth infections—obligatory or accessory?

ILCs burst onto the immunological scene with their roles in bacterial and helminth infections. As their influence has emerged, it has become clear that they play a fundamental role in regulating intestinal homeostasis and the immune response during inflammation. A subset of ILCs, ILC2s, has become the focus of attention for many helminth biologists - stepping into the limelight as both an initiator and amplifier of the elusive type-2 response. In many of the early reports, conclusions as to their function were based on experiments using unadapted parasites or immune-compromised hosts. In this review we re-examine the generation and function of type-2 ILCs in helminth infection and the extent to which their roles may be essential or redundant, in both primary and challenge infections. ILC2s will be discussed in terms of a broader innate network, which when in dialogue with adaptive immunity, allows the generation of the anti-parasite response. Finally, we will review how our understanding of how helminths manipulate ILC2 populations to benefit their survival, as well as dampen systemic inflammation in the host, can be used to improve strategies to control disease

Innate type 2 immunity in helminth infection is induced redundantly and acts autonomously following CD11c+ cell depletion

Infection with gastrointestinal helminths generates a dominant type 2 response among both adaptive (Th2) and innate (macrophage, eosinophil, and innate lymphoid) immune cell types. Two additional innate cell types, CD11chigh dendritic cells (DCs) and basophils, have been implicated in the genesis of type 2 immunity. Investigating the type 2 response to intestinal nematode parasites, including Heligmosomoides polygyrus and Nippostrongylus brasiliensis, we first confirmed the requirement for DCs in stimulating Th2 adaptive immunity against these helminths through depletion of CD11chigh cells by administration of diphtheria toxin to CD11c.DOG mice. In contrast, responsiveness was intact in mice depleted of basophils by antibody treatment. Th2 responses can be induced by adoptive transfer of DCs, but not basophils, exposed to soluble excretory-secretory products from these helminths. However, innate type 2 responses arose equally strongly in the presence or absence of CD11chigh cells or basophils; thus, in CD11c.DOG mice, the alternative activation of macrophages, as measured by expression of arginase-1, RELM-α, and Ym-1 (Chi3L3) in the intestine following H. polygyrus infection or in the lung following N. brasiliensis infection, was unaltered by depletion of CD11c-expressing DCs and alveolar macrophages or by antibody-mediated basophil depletion. Similarly, goblet cell-associated RELM-β in lung and intestinal tissues, lung eosinophilia, and expansion of innate lymphoid (“nuocyte”) populations all proceeded irrespective of depletion of CD11chigh cells or basophils. Thus, while CD11chigh DCs initiate helminth-specific adaptive immunity, innate type 2 cells are able to mount an autonomous response to the challenge of parasite infection

ICOS controls Foxp3+ regulatory T-cell expansion, maintenance, and IL-10 production during helminth infection

Foxp3(+) regulatory T (Treg) cells are key immune regulators during helminth infections, and identifying the mechanisms governing their induction is of principal importance for the design of treatments for helminth infections, allergies and autoimmunity. Little is yet known regarding the co-stimulatory environment that favours the development of Foxp3(+) Treg-cell responses during helminth infections. As recent evidence implicates the co-stimulatory receptor ICOS in defining Foxp3(+) Treg-cell functions, we investigated the role of ICOS in helminth-induced Foxp3(+) Treg-cell responses. Infection of ICOS(−/−) mice with Heligmosomoides polygyrus or Schistosoma mansoni led to a reduced expansion and maintenance of Foxp3(+) Treg cells. Moreover, during H. polygyrus infection, ICOS deficiency resulted in increased Foxp3(+) Treg-cell apoptosis, a Foxp3(+) Treg-cell specific impairment in IL-10 production, and a failure to mount putatively adaptive Helios(−)Foxp3(+) Treg-cell responses within the intestinal lamina propria. Impaired lamina propria Foxp3(+) Treg-cell responses were associated with increased production of IL-4 and IL-13 by CD4(+) T cells, demonstrating that ICOS dominantly downregulates Type 2 responses at the infection site, sharply contrasting with its Type 2-promoting effects within lymphoid tissue. Thus, ICOS regulates Type 2 immunity in a tissue-specific manner, and plays a key role in driving Foxp3(+) Treg-cell expansion and function during helminth infections

Stellar coronal astronomy - a review

Coronal astronomy is by now a fairly mature discipline, with a quarter century having gone by since the detection of the first stellar X-ray coronal source (Capella), and having benefitted from a series of major orbiting observing facilities. Several observational characteristics of coronal X-ray and EUV emission have been solidly established through extensive observations, and are by now common, almost text-book, knowledge. At the same time the implications of coronal astronomy for broader astrophysical questions (e.g. Galactic structure, stellar formation, stellar structure, etc.) have become appreciated. The interpretation of stellar coronal properties is however still often open to debate, and will need qualitatively new observational data to book further progress. In the present review we try to recapitulate our view on the status of the field at the beginning of a new era, in which the high sensitivity and the high spectral resolution provided by Chandra and XMM-Newton will address new questions which were not accessible before.Comment: Space Science Reviews, in press, 132 pages (full paper available at ftp://astro.esa.int/pub/ffavata/Papers/ssr-preprint.pdf

Regulation of pathogenesis and immunity in helminth infections

Helminths are multicellular eukaryotic parasites that infect over one quarter of the world’s population. Through coevolution with the human immune system, these organisms have learned to exploit immunoregulatory pathways, resulting in asymptomatic tolerance of infections in many individuals. When infections and the resulting immune responses become dysregulated, however, acute and chronic pathologies often develop. A recent international meeting focused on how these parasites modulate host immunity and how control of parasitic and immunopathological disease might be achieved

Innate Lymphoid Cells in Helminth Infections—Obligatory or Accessory?

ILCs burst onto the immunological scene with their involvement in bacterial and helminth infections. As their influence has emerged, it has become clear that they play a fundamental role in regulating barrier tissue homeostasis and the immune response during inflammation. A subset of ILCs, ILC2s, has become the focus of attention for many helminth biologists—stepping into the limelight as both the elusive initiator and amplifier of the type-2 response. In many of the early reports, conclusions as to their function were based on experiments using unadapted parasites or immune-compromised hosts. In this review we re-examine the generation and function of type-2 ILCs in helminth infection and the extent to which their roles may be essential or redundant, in both primary and challenge infections. ILC2s will be discussed in terms of a broader innate network, which when in dialogue with adaptive immunity, allows the generation of the anti-parasite response. Finally, we will review how helminths manipulate ILC2 populations to benefit their survival, as well as dampen systemic inflammation in the host, and how this understanding may be used to improve strategies to control disease