IL-22 mediates goblet cell hyperplasia and worm expulsion in intestinal helminth infection.

Type 2 immune responses are essential in protection against intestinal helminth infections. In this study we show that IL-22, a cytokine important in defence against bacterial infections in the intestinal tract, is also a critical mediator of anti-helminth immunity. After infection with Nippostrongylus brasiliensis, a rodent hookworm, IL-22-deficient mice showed impaired worm expulsion despite normal levels of type 2 cytokine production. The impaired worm expulsion correlated with reduced goblet cell hyperplasia and reduced expression of goblet cell markers. We further confirmed our findings in a second nematode model, the murine whipworm Trichuris muris. T.muris infected IL-22-deficient mice had a similar phenotype to that seen in N.brasiliensis infection, with impaired worm expulsion and reduced goblet cell hyperplasia. Ex vivo and in vitro analysis demonstrated that IL-22 is able to directly induce the expression of several goblet cell markers, including mucins. Taken together, our findings reveal that IL-22 plays an important role in goblet cell activation, and thus, a key role in anti-helminth immunity

ERS International Congress 2022: highlights from the Respiratory Clinical Care and Physiology Assembly

It is a challenge to keep abreast of all the clinical and scientific advances in the field of respiratory medicine. This article contains an overview of the laboratory-based science, clinical trials and qualitative research that were presented during the 2022 European Respiratory Society International Congress within the sessions from the five groups of Assembly 1 (Respiratory Clinical Care and Physiology). Selected presentations are summarised from a wide range of topics: clinical problems, rehabilitation and chronic care, general practice and primary care, mobile/electronic health (m-health/e-health), clinical respiratory physiology, exercise and functional imaging

Crustal structure across the Grand Banks–Newfoundland Basin Continental Margin – II. Results from a seismic reflection profile

Author Posting. © Blackwell, 2006. This is the author's version of the work. It is posted here by permission of Blackwell for personal use, not for redistribution. The definitive version was published in Geophysical Journal International 167 (2006): 157-170, doi:10.1111/j.1365-246X.2006.02989.x.New multi-channel seismic (MCS) reflection data were collected over a 565km transect covering the non-volcanic rifted margin of the central eastern Grand Banks and the Newfoundland Basin in the northwestern Atlantic. Three major crustal zones are interpreted from west to east over the seaward 350-km of the profile: (1) continental crust; (2) transitional basement; (3) oceanic crust. Continental crust thins over a wide zone (~160 km) by forming a large rift basin (Carson Basin) and seaward fault block, together with a series of smaller fault blocks eastward beneath the Salar and Newfoundland basins. Analysis of selected previous reflection profiles (Lithoprobe 85-4, 85-2 and Conrad NB-1) indicates that prominent landward-dipping reflections observed under the continental slope are a regional phenomenon. They define the landward edge of a deep serpentinized mantle layer, which underlies both extended continental crust and transitional basement. The 80-km-wide transitional basement is defined landward by a basement high that may consist of serpentinized peridotite and seaward by a pair of basement highs of unknown crustal origin. Flat and unreflective transitional basement most likely is exhumed, serpentinized mantle, although our results do not exclude the possibility of anomalously thinned oceanic crust. A Moho reflection below interpreted oceanic crust is first observed landward of magnetic anomaly M4, 230 km from the shelf break. Extrapolation of ages from chron M0 to the edge of interpreted oceanic crust suggests that the onset of seafloor spreading was ~138Ma (Valanginian) in the south (southern Newfoundland Basin) to ~125Ma (Barremian-Aptian boundary) in the north (Flemish Cap), comparable to those proposed for the conjugate margins.This work was funded by NSF grants OCE-9819053 and OCE-0326714 to Woods Hole Oceanographic Institution, NSERC (Canada) and the Danish Research Council. B. Tucholke also acknowledges support from the Henry Bryant Bigelow Chair in Oceanography at Woods Hole Oceanographic Institution

Crustal structure across the Grand Banks–Newfoundland Basin Continental Margin – I. Results from a seismic refraction profile

Author Posting. © Blackwell, 2006. This is the author's version of the work. It is posted here by permission of Blackwell for personal use, not for redistribution. The definitive version was published in Geophysical Journal International 167 (2006): 127-156, doi:10.1111/j.1365-246X.2006.02988.x.A P-wave velocity model along a 565-km-long profile across the Grand Banks/Newfoundland basin rifted margin is presented. Continental crust ~36-kmthick beneath the Grand Banks is divided into upper (5.8-6.25 km/s), middle (6.3- 6.53 km/s) and lower crust (6.77-6.9 km/s), consistent with velocity structure of Avalon zone Appalachian crust. Syn-rift sediment sequences 6-7-km thick occur in two primary layers within the Jeanne d’Arc and the Carson basins (~3 km/s in upper layer; ~5 km/s in lower layer). Abrupt crustal thinning (Moho dip ~ 35º) beneath the Carson basin and more gradual thinning seaward forms a 170-km-wide zone of rifted continental crust. Within this zone, lower and middle continental crust thin preferentially seaward until they are completely removed, while very thin (<3 km) upper crust continues ~60 km farther seaward. Adjacent to the continental crust, high velocity gradients (0.5-1.5 s-1) define an 80-km-wide zone of transitional basement that can be interpreted as exhumed, serpentinized mantle or anomalously thin oceanic crust, based on its velocity model alone. We prefer the exhumed-mantle interpretation after considering the non-reflective character of the basement and the low amplitude of associated magnetic anomalies, which are atypical of oceanic crust. Beneath both the transitional basement and thin (<6 km) continental crust, a 200-kmwide zone with reduced mantle velocities (7.6-7.9 km/s) is observed, which is interpreted as partially (<10%) serpentinized mantle. Seaward of the transitional basement, 2- to 6-km-thick crust with layer 2 (4.5-6.3 km/s) and layer 3 (6.3-7.2 km/s) velocities is interpreted as oceanic crust. Comparison of our crustal model with profile IAM-9 across the Iberia Abyssal Plain on the conjugate Iberia margin suggests asymmetrical continental breakup in which a wider zone of extended continental crust has been left on the Newfoundland side.This research was supported by National Science Foundation (NSF) grants OCE-9819053 and OCE-0326714, by the National Sciences and Engineering Research Council of Canada (NSERC), and by the Danish National Research Foundation. B. Tucholke also acknowledges support from the Henry Bryant Bigelow Chair in Oceanography from Woods Hole Oceanographic Institution

A deep seismic investigation of the Flemish Cap margin: implications for the origin of deep reflectivity and evidence for asymmetric break-up between Newfoundland and Iberia

Author Posting. © Blacwell, 2006. This article is posted here by permission of Blackwell for personal use, not for redistribution. The definitive version was published in Geophysical Journal International 164 (2006): 501–515, doi:10.1111/j.1365-246X.2006.02800.x.Seismic reflection and refraction data were acquired along the southeast margin of Flemish Cap at a position conjugate to drilling and geophysical surveys across the Galicia Bank margin. The data document first-order asymmetry during final break-up between Newfoundland and Iberia. An abrupt necking profile of continental crust observed off Flemish Cap contrasts strongly with gradual tapering on the conjugate margin. There is no evidence beneath Flemish Cap for a final phase of continental extension that resulted in thin continental crust underlain by a strong 'S'-like reflection, which indicates that this mode of extension occurred only on the Galicia Bank margin. Compelling evidence for a broad zone of exhumed mantle or for peridotite ridges is also lacking along the Flemish Cap margin. Instead, anomalously thin, 3–4-km-thick oceanic crust is observed. This crust is highly tectonized and broken up by high-angle normal faulting. The thin crust and rift structures that resemble the abandoned spreading centre in the Labrador sea suggest that initial seafloor spreading was affected by processes observed in present-day ultra-slow spreading environments. Landwards, Flemish Cap is underlain by a highly reflective lower crust. The reflectivity most likely originates from older Palaeozoic orogenic structures that are unrelated to extension and break-up tectonics.This work was supported by the Danish National Research Foundation, U.S. National Science Foundation grants OCE-9819053 and OCE-0326714, and the Natural Science and Engineering Research Council of Canada. Additional support for Hopper was provided by the German Research Foundation grant MO-961/4-1. Tucholke also acknowledges support from Henry Bryant Bigelow Chair in Oceanography at Woods Hole Oceanographic Institution

Influence of deformation and fluids on Ar retention in white mica: Dating the Dover Fault, Newfoundland Appalachians

White mica 40Ar/39Ar analyses may provide useful constraints on the timing of tectonic processes, but complex geological and thermal histories can perturb Ar systematics in a variety of ways. Ductile shear zones represent excellent case studies for exploring the link(s) between dynamic re-/neo-crystallization of white mica and coeval enhanced fluid flow, and their effect on 40Ar/39Ar dates. White mica 40Ar/39Ar dates were collected from compositionally similar granites that record different episodes of deformation with proximity to the Dover Fault, a terrane-bounding strike-slip shear zone in the Appalachian orogen, Newfoundland, Canada. 40Ar/39Ar data were collected in situ by laser ablation and by step heating single crystals. Results were compared to each other and against complementary U-Pb zircon and monazite, and K-Ar fault gouge analysis. Although step-heat 40Ar/39Ar is a widely applied method in orogenic settings, this dataset shows that relatively flat step-heat 40Ar/39Ar spectra are in contradiction with wide spreads in in-situ 40Ar/39Ar dates from the same samples, and that plateau dates in some cases yielded mixed dates of equivocal geological significance. This result indicates that the step-wise release of Ar from white mica likely homogenizes and obscures spatially-controlled Ar isotope reservoirs in white mica from sheared rocks. In contrast, in situ laser ablation 40Ar/39Ar analysis preserves the spatial resolution of 40Ar reservoirs that have been variably reset by deformation and fluid interaction. This study therefore suggests that laser ablation is the best method for dating the timing of deformation recorded by white mica. Final interpretation of results should be guided by microstructural analysis, estimation of deformation temperature, chemical characterization of white mica, and complementary chronometers. Overall the dataset shows that granitic protoliths were emplaced between 430-422 Ma (U-Pb zircon). High strain deformation along the Wing Pond Shear Zone occurred between ca. 422-405 Ma (U-Pb monazite and 40Ar/39Ar). Subsequent patchy Ar loss in white mica occurred locally during low T shear (40Ar/39Ar). K-Ar dating of authigenic illite in fault gouge from the broadly co-linear brittle Hermitage Bay Fault indicates that slip along the terrane boundary persisted until at least the Mississippian

IL-4Rα-Independent Expression of Mannose Receptor and Ym1 by Macrophages Depends on their IL-10 Responsiveness

IL-4Rα-dependent responses are essential for granuloma formation and host survival during acute schistosomiasis. Previously, we demonstrated that mice deficient for macrophage-specific IL-4Rα (LysMcreIl4ra−/lox) developed increased hepatotoxicity and gut inflammation; whereas inflammation was restricted to the liver of mice lacking T cell-specific IL-4Rα expression (iLckcreIl4ra−/lox). In the study presented here we further investigated their role in liver granulomatous inflammation. Frequencies and numbers of macrophage, lymphocyte or granulocyte populations, as well as Th1/Th2 cytokine responses were similar in Schistosoma mansoni-infected LysMcreIl4ra−/lox liver granulomas, when compared to Il4ra−/lox control mice. In contrast, a shift to Th1 responses with high IFN-γ and low IL-4, IL-10 and IL-13 was observed in the severely disrupted granulomas of iLckcreIl4ra−/lox and Il4ra−/− mice. As expected, alternative macrophage activation was reduced in both LysMcreIl4ra−/lox and iLckcreIl4ra−/lox granulomas with low arginase 1 and heightened nitric oxide synthase RNA expression in granuloma macrophages of both mouse strains. Interestingly, a discrete subpopulation of SSChighCD11b+I-A/I-EhighCD204+ macrophages retained expression of mannose receptor (MMR) and Ym1 in LysMcreIl4ra−/lox but not in iLckcreIl4ra−/lox granulomas. While aaMφ were in close proximity to the parasite eggs in Il4ra−/lox control mice, MMR+Ym1+ macrophages in LysMcreIl4ra−/lox mice were restricted to the periphery of the granuloma, indicating that they might have different functions. In vivo IL-10 neutralisation resulted in the disappearance of MMR+Ym1+ macrophages in LysMcreIl4ra−/lox mice. Together, these results show that IL-4Rα-responsive T cells are essential to drive alternative macrophage activation and to control granulomatous inflammation in the liver. The data further suggest that in the absence of macrophage-specific IL-4Rα signalling, IL-10 is able to drive mannose receptor- and Ym1-positive macrophages, associated with control of hepatic granulomatous inflammation

Helios Is Associated with CD4 T Cells Differentiating to T Helper 2 and Follicular Helper T Cells In Vivo Independently of Foxp3 Expression

Although in vitro IL-4 directs CD4 T cells to produce T helper 2 (Th2)-cytokines, these cytokines can be induced in vivo in the absence of IL-4-signalling. Thus, mechanism(s), different from the in vitro pathway for Th2-induction, contribute to in vivo Th2-differentiation. The pathway for in vivo IL-4-independent Th2-differentiation has yet to be characterized. - upregulate Th1 features - T-bet and IFN-γ - but not Helios. In addition, CD4 T cells induced to produce Th2 cytokines in vitro do not express Helios. The kinetics of Helios mRNA and protein induction mirrors that of GATA-3. The induction of IL-4, IL-13 and CXCR5 by alumOVA requires NF-κB1 and this is also needed for Helios upregulation. Importantly, Helios is induced in Th2 and TFh cells without parallel upregulation of Foxp3. These findings suggested a key role for Helios in Th2 and TFh development in response to alum-protein vaccines. We tested this possibility using Helios-deficient OTII cells and found this deficiency had no discernable impact on Th2 and TFh differentiation in response to alumOVA.Helios is selectively upregulated in CD4 T cells during Th2 and TFh responses to alum-protein vaccines in vivo, but the functional significance of this upregulation remains uncertain

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Three billion years of crustal evolution in eastern Canada: constraints from receiver functions

The geological record of SE Canada spans more than 2.5 Ga, making it a natural laboratory for the study of crustal formation and evolution over time. We estimate the crustal thickness, Poisson's ratio, a proxy for bulk crustal composition, and shear velocity (Vs) structure from receiver functions at a network of seismograph stations recently deployed across the Archean Superior Craton, the Proterozoic Grenville, and the Phanerozoic Appalachian provinces. The bulk seismic crustal properties and shear velocity structure reveal a correlation with tectonic provinces of different ages: the post-Archean crust becomes thicker, faster, more heterogeneous, and more compositionally evolved. This secular variation pattern is consistent with a growing consensus that crustal growth efficiency increased at the end of the Archean. A lack of correlation among elevation, Moho topography, and gravity anomalies within the Proterozoic belt is better explained by buoyant mantle support rather than by compositional variations driven by lower crustal metamorphic reactions. A ubiquitous ∼20 km thick high-Vs lower crustal layer is imaged beneath the Proterozoic belt. The strong discontinuity at 20 km may represent the signature of extensional collapse of an orogenic plateau, accommodated by lateral crustal flow. Wide anorthosite massifs inferred to fractionate from a mafic mantle source are abundant in Proterozoic geology and are underlain by high-Vs lower crust and a gradational Moho. Mafic underplating may have provided a source for these intrusions and could have been an important post-Archean process stimulating mafic crustal growth in a vertical sense