60 research outputs found
Blockade of IL-33 release and suppression of type 2 innate lymphoid cell responses by helminth secreted products in airway allergy
Helminth parasites such as the nematode Heligmosomoides polygyrus strongly inhibit T helper type 2 (Th2) allergy, as well as colitis and autoimmunity. Here, we show that the soluble excretory/secretory products of H. polygyrus (HES) potently suppress inflammation induced by allergens from the common fungus Alternaria alternata. Alternaria extract, when administered to mice intranasally with ovalbumin (OVA) protein, induces a rapid (1â48 h) innate response while also priming an OVA-specific Th2 response that can be evoked 14 days later by intranasal administration of OVA alone. In this model, HES coadministration with Alternaria/OVA suppressed early IL-33 release, innate lymphoid cell (ILC) production of IL-4, IL-5, and IL-13, and localized eosinophilia. Upon OVA challenge, type 2 ILC (ILC2)/Th2 cytokine production and eosinophilia were diminished in HES-treated mice. HES administration 6 h before Alternaria blocked the allergic response, and its suppressive activity was abolished by heat treatment. Administration of recombinant IL-33 at sensitization with Alternaria/OVA/HES abrogated HES suppression of OVA-specific responses at challenge, indicating that suppression of early Alternaria-induced IL-33 release could be central to the anti-allergic effects of HES. Thus, this helminth parasite targets IL-33 production as part of its armory of suppressive effects, forestalling the development of the type 2 immune response to infection and allergic sensitization
IL-1ÎČ Suppresses Innate IL-25 and IL-33 Production and Maintains Helminth Chronicity.
Approximately 2 billion people currently suffer from intestinal helminth infections, which are typically chronic in nature and result in growth retardation, vitamin A deficiency, anemia and poor cognitive function. Such chronicity results from co-evolution between helminths and their mammalian hosts; however, the molecular mechanisms by which these organisms avert immune rejection are not clear. We have found that the natural murine helminth, Heligmosomoides polygyrus bakeri (Hp) elicits the secretion of IL-1ÎČ in vivo and in vitro and that this cytokine is critical for shaping a mucosal environment suited to helminth chronicity. Indeed in mice deficient for IL-1ÎČ (IL-1ÎČ(-/-)), or treated with the soluble IL-1ÎČR antagonist, Anakinra, helminth infection results in enhanced type 2 immunity and accelerated parasite expulsion. IL-1ÎČ acts to decrease production of IL-25 and IL-33 at early time points following infection and parasite rejection was determined to require IL-25. Taken together, these data indicate that Hp promotes the release of host-derived IL-1ÎČ that suppresses the release of innate cytokines, resulting in suboptimal type 2 immunity and allowing pathogen chronicity
A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)
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Observation of Two New Excited Îb0 States Decaying to Îb0 K-Ï+
Two narrow resonant states are observed in the Îb0K-Ï+ mass spectrum using a data sample of proton-proton collisions at a center-of-mass energy of 13 TeV, collected by the LHCb experiment and corresponding to an integrated luminosity of 6 fb-1. The minimal quark content of the Îb0K-Ï+ system indicates that these are excited Îb0 baryons. The masses of the Îb(6327)0 and Îb(6333)0 states are m[Îb(6327)0]=6327.28-0.21+0.23±0.12±0.24 and m[Îb(6333)0]=6332.69-0.18+0.17±0.03±0.22 MeV, respectively, with a mass splitting of Îm=5.41-0.27+0.26±0.12 MeV, where the uncertainties are statistical, systematic, and due to the Îb0 mass measurement. The measured natural widths of these states are consistent with zero, with upper limits of Î[Îb(6327)0]<2.20(2.56) and Î[Îb(6333)0]<1.60(1.92) MeV at a 90% (95%) credibility level. The significance of the two-peak hypothesis is larger than nine (five) Gaussian standard deviations compared to the no-peak (one-peak) hypothesis. The masses, widths, and resonant structure of the new states are in good agreement with the expectations for a doublet of 1D Îb0 resonances
Secretion of Protective Antigens by Tissue-Stage Nematode Larvae Revealed by Proteomic Analysis and Vaccination-Induced Sterile Immunity
Gastrointestinal nematode parasites infect over 1 billion humans, with little evidence for generation of sterilising immunity. These helminths are highly adapted to their mammalian host, following a developmental program through successive niches, while effectively down-modulating host immune responsiveness. Larvae of Heligmosomoides polygyrus, for example, encyst in the intestinal submucosa, before emerging as adult worms into the duodenal lumen. Adults release immunomodulatory excretory-secretory (ES) products, but mice immunised with adult H. polygyrus ES become fully immune to challenge infection. ES products of the intestinal wall 4th stage (L4) larvae are similarly important in host-parasite interactions, as they readily generate sterile immunity against infection, while released material from the egg stage is ineffective. Proteomic analyses of L4 ES identifies protective antigen targets as well as potential tissue-phase immunomodulatory molecules, using as comparators the adult ES proteome and a profile of H. polygyrus egg-released material. While 135 proteins are shared between L4 and adult ES, 72 are L4 ES-specific; L4-specific proteins correspond to those whose transcription is restricted to larval stages, while shared proteins are generally transcribed by all life cycle forms. Two protein families are more heavily represented in the L4 secretome, the Sushi domain, associated with complement regulation, and the ShK/SXC domain related to a toxin interfering with T cell signalling. Both adult and L4 ES contain extensive but distinct arrays of Venom allergen/Ancylostoma secreted protein-Like (VAL) members, with acetylcholinesterases (ACEs) and apyrase APY-3 particularly abundant in L4 ES. Serum antibodies from mice vaccinated with L4 and adult ES react strongly to the VAL-1 protein and to ACE-1, indicating that these two antigens represent major vaccine targets for this intestinal nematode. We have thus defined an extensive and novel repertoire of H. polygyrus proteins closely implicated in immune modulation and protective immunity
Measurement of antiproton production from antihyperon decays in p He collisions at âsNN = 110 GeV
The interpretation of cosmic antiproton flux measurements from space-borne experiments is currently limited by the knowledge of the antiproton production cross-section in collisions between primary cosmic rays and the interstellar medium. Using collisions of protons with an energy of 6.5TeV incident on helium nuclei at rest in the proximity of the interaction region of the LHCb experiment, the ratio of antiprotons originating from antihyperon decays to prompt production is measured for antiproton momenta between 12 and 110GeV. The dominant antihyperon contribution, namely ÎÂŻâpÂŻÏ+ decays from promptly produced ÎÂŻ particles, is also exclusively measured. The results complement the measurement of prompt antiproton production obtained from the same data sample. At the energy scale of this measurement, the antihyperon contributions to antiproton production are observed to be significantly larger than predictions of commonly used hadronic production models
Direct CP violation in charmless three-body decays of B± mesons
Measurements of
C
P
asymmetries in charmless three-body decays of
B
±
mesons are reported using proton-proton collision data collected by the LHCb detector, corresponding to an integrated luminosity of
5.9
â
â
fb
â
1
. The previously observed
C
P
asymmetry in
B
±
â
Ï
±
K
+
K
â
decays is confirmed, and
C
P
asymmetries are observed with a significance of more than five standard deviations in the
B
±
â
Ï
±
Ï
+
Ï
â
and
B
±
â
K
±
K
+
K
â
decays, while the
C
P
asymmetry of
B
±
â
K
±
Ï
+
Ï
â
decays is confirmed to be compatible with zero. The distributions of these asymmetries are also studied as a function of the three-body phase space and suggest contributions from rescattering and resonance interference processes. An indication of the presence of the decays
B
±
â
Ï
±
Ï
c
0
(
1
P
)
in both
B
±
â
Ï
±
Ï
+
Ï
â
and
B
±
â
Ï
±
K
+
K
â
decays is observed, as is
C
P
violation involving these amplitudes
Measurement of J/Ï -pair production in pp collisions at âs = 13 TeV and study of gluon transverse-momentum dependent PDFs
The production cross-section of J/Ï pairs in proton-proton collisions at a centre-of-mass energy of âs = 13 TeV is measured using a data sample corresponding to an integrated luminosity of 4.2 fbâ1 collected by the LHCb experiment. The measurement is performed with both J/Ï mesons in the transverse momentum range 0 < pT< 14 GeV/c and rapidity range 2.0 < y < 4.5. The cross-section of this process is measured to be 16.36 ± 0.28 (stat) ± 0.88 (syst) nb. The contributions from single-parton scattering and double-parton scattering are separated based on the dependence of the cross-section on the absolute rapidity difference ây between the two J/Ï mesons. The effective cross-section of double-parton scattering is measured to be Ïeff = 13.1 ± 1.8 (stat) ± 2.3 (syst) mb. The distribution of the azimuthal angle ÏCS of one of the J/Ï mesons in the Collins-Soper frame and the pT-spectrum of the J/Ï pairs are also measured for the study of the gluon transverse-momentum dependent distributions inside protons. The extracted values of âšcos 2ÏCSâ© and âšcos 4ÏCSâ© are consistent with zero, but the presence of azimuthal asymmetry at a few percent level is allowed
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