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Cyclosporine A has long been known to suppress T cell responses by inhibiting the production of IL-2, which drives T cell proliferation, enabling its use as a therapeutic for ...transplantation or autoimmunity. However, cyclosporine A also impacts on innate immune cells including dendritic cells, macrophages and neutrophils. In dendritic cells, which are essential for T cell priming, cyclosporine A can modulate both expression of surface molecules that engage with T cells and cytokine secretion, leading to altered induction of T cell responses. In macrophages and neutrophils, which play key antimicrobial roles, cyclosporine A reduces the production of cytokines that can play protective roles against pathogens. Some of these molecules, if produced in the context of chronic disease, can also contribute to pathology. There have been a number of elegant recent studies addressing the mechanisms by which cyclosporine A can modulate innate immunity. In particular, cyclosporine A inhibits the release of mitochondrial factors that stimulate the production of type 1 interferons by innate immune cells. This review addresses the emerging literature on modulation of innate immune responses by cyclosporine A, its resultant impact on adaptive immune responses and how this offers potential for new therapeutic applications.
Dispersion of the tracer sulphur hexafluoride (SF6) during the Southern Ocean Iron Enrichment Experiment (SOIREE) provided an estimate of vertical exchange at the base of the surface mixed layer (60 ...m) at 61°S 140°E. Budget analysis confirmed that the SF6 patch was well constrained by surface mapping, with the decline in total SF6 showing good agreement with that predicted from wind speed parameterizations. Two approaches were used to calculate the mean effective vertical diffusivity Kz from the diapycnal transfer of SF6, with complementary error function and second‐moment fits to the SF6 depth profiles indicating that Kz was less than 0.3 × 10−4 m2s−1. This result was examined using a three‐dimensional diffusion model that incorporated lateral dispersion and air‐sea exchange losses, which confirmed that vertical shear and subpycnocline dispersion did not influence the Kz estimate. Current shear at the base of the mixed layer was generated by wind‐driven inertial oscillation, with a decrease in wind speed and increasing stratification in the latter half of the experiment reducing diapycnal transfer of SF6. A compilation was used to examine the potential of both N (Brunt‐Väisäla frequency) and Ri (gradient Richardson number) on the basis of parameterizations of Kz in the seasonal pycnocline. Application of Kz to nutrient gradients in the seasonal pycnocline suggests that vertical diffusion represents a significant pathway for silicic acid supply in late summer. Furthermore, use of the mean effective Kz (0.11 ± 0.2 × 10−4 m2s−1) indicates that vertical diffusion supplies a large proportion of the iron required for new production in this region.
Measurements of air‐sea gas exchange rates are reported from two deliberate tracer experiments in the southern North Sea during February 1992 and 1993. A conservative tracer, spores of the bacterium ...Bacillus globigii var. Niger, was used for the first time in an in situ air‐sea gas exchange experiment. This nonvolatile tracer is used to correct for dispersive dilution of the volatile tracers and allows three estimations of the transfer velocity for the same time period. The first estimation of the power dependence of gas transfer on molecular diffusivity in the marine environment is reported. This allows the impact of bubbles on estimates of the transfer velocity derived from changes in the helium/sulphur hexafluoride ratio to be assessed. Data from earlier dual tracer experiments are reinterpreted, and findings suggest that results from all dual tracer experiments are mutually consistent. The complete data set is used to test published parameterizations of gas transfer with wind speed. A gas ex‐ change relationship that shows a dependence on wind speed intermediate between those ofLiss and Merlivat 1986 and Wanninkhof 1992 is found to be optimal. The dual tracer data are shown to be reasonably consistent with global estimates of gas exchange based on the uptake of natural and bomb‐derived radiocarbon. The degree of scatter in the data when plotted against wind speed suggests that parameters not scaling with wind speed are also influencing gas exchange rates.
Despite being in the midst of a global pandemic of infections caused by the pathogen Chlamydia trachomatis, a vaccine capable of inducing protective immunity remains elusive. Given the C. trachomatis ...mucosal port of entry, a formulation compatible with mucosal administration and capable of eliciting potent genital tract immunity is highly desirable. While subunit vaccines are considered safer and better tolerated, these are typically poorly immunogenic and require co-formulation with immune-potentiating adjuvants. However, of the adjuvants licensed for use in humans, very few drive robust cellular responses, a pre-requisite for protection against C. trachomatis infection. Recently, the cationic adjuvant formulations (CAF) have been shown to induce robust humoral and cellular immunity in pre-clinical models of chlamydia, malaria and tuberculosis (TB). Here, we demonstrate that CAF01 induces potent immune responses when combined with the major outer membrane protein (MOMP) of C. trachomatis following parenteral immunisation and also as part of a heterologous prime/boost regime. We show that a subcutaneous prime with CAF01-adjuvanted recombinant MOMP licenses antigen-specific immunity at distant mucosal sites which can be activated following oral antigen re-encounter in the absence of concomitant adjuvant stimulation. Finally, we shed light on the mechanism(s) through which CAF01 elicits robust antigen-specific immunity to co-formulated MOMP via type I interferon (IFN) signalling.
The air–water exchange of gases can be substantially enhanced by wave breaking and specifically by bubble-mediated transfer. A feature of bubble-mediated transfer is the additional pressure on ...bubbles resulting from the hydrostatic forces on a submerged bubble and from surface tension and curvature. This peculiarity results in asymmetry of bubble-mediated gas transfer and equilibrium supersaturations of dissolved gases in a bubbly ocean. A second peculiarity is the finite capacity of bubbles, so that the composition of a bubble may change during the exchange. The result is that gas transfer mediated by bubbles is characterized by an altered dependence on the molecular properties of the dissolved gas compared to direct transfer across the main air–water interface. A related phenomenon for bubble plumes with a high void fraction (air volume to total volume ratio) is that the composition of the dissolved gas within the interstitial water of a plume may alter during the exchange process and only mix into the full water reservoir later. Three asymptotes are identified for gas exchange mediated by high-void-fraction bubble plumes and a semi-empirical parameterization of bubble-mediated gas transfer is devised on the basis of these asymptotes, which describes the dependence of the overall transfer velocity on plume properties and molecular properties of the gas.
These models are confronted with data from laboratory experiments. The experiments use artificial aeration with the gas source switched during each run. Measurements of the bubble distribution enable calculation of the theoretical transfer of the gases. A parameterization fits the theoretical transfer satisfactorily. Gas measurements are used to test if the actual transfer of gases is similar to the theoretical transfer. The experimental method enables separation of bubble-mediated transfer from transfer directly across the main air–water interface. The agreement between gas and bubble-derived values of transfer velocity is sufficient to generally validate the theory, but is imprecise. The results suggest that the interstitial water plays a significant role in limiting gas transfer–in particular, limiting transfer of helium–despite the fact that typical void fractions were low (<
0.1%). It should be possible to predict gas transfer velocities in the field by simulating oceanic bubble plumes sufficient to constrain that part of the transfer, but targets of 10% or 20% may be beyond reach especially for the most poorly soluble gases (for which the bubble-mediated mechanism is particularly important). These simulations require accurate bubble distributions, void fractions and a good description of the entire plume dynamics. Such simulations are particularly important for interpreting dual tracer and nitrogen/oxygen experiments in stormy conditions, where the relative transfer of different gases is a non-trivial problem.
We report the results of an experiment in the Northeast Atlantic in which sulphur hexafluoride (SF sub(6)) was released within an eddy and the behaviour of trace gases, nutrients and productivity ...followed within a Lagrangian framework over a period of 24 days. Measurements were also made in the air above the eddy in order to estimate air-sea exchange rates for some components. The physical, biological and biogeochemical properties of the eddy resemble those of other eddies studied in this area, suggesting that the results we report may be applicable beyond the specific eddy studied. During a period of low wind speed at the start of the experiment, we are able to quantitatively describe and balance the nutrient and carbon budgets for the eddy. We also report concentrations of various trace gases in the region which are similar to those observed in other studies and we estimate exchange rates for several trace gases. We show that the importance of gas exchange over other loss terms varies with time and also varies for the different gases. We show that the various trace gases considered (CO sub(2), dimethyl sulphide (DMS), N sub(2)O, CH sub(4), non-methane-hydrocarbons, methyl bromide, methyl iodide and volatile selenium species) are all influenced by physical and biological processes, but the overall distribution and temporal variability of individual gases are different to one another. A storm disrupted the stratification in the eddy during the experiment, resulting in enhanced nutrient supply to surface waters, enhanced gas exchange rates and a change in plankton community, which we quantify, although overall productivity was little changed. Emphasis is placed on the regularity of storms in the temperate ocean and the importance of these stochastic processes in such systems.
This study explores the changes in the surface water fugacity of carbon dioxide (
fCO
2) and biological carbon uptake in two Southern Ocean iron fertilisation experiments with different hydrographic ...regimes. The Southern Ocean Iron Release Experiment (SOIREE) experiment was carried out south of the Antarctic Polar Front (APF) at 61°S, 141°E in February 1999 in a stable hydrographic setting. The EisenEx experiment was conducted in a cyclonic eddy north of the APF at 48°S, 21°E in November 2000 and was characterised by a rapid succession of low to storm-force wind speeds and dynamic hydrographic conditions. The iron additions promoted algal blooms in both studies. They alleviated algal iron limitation during the 13-day SOIREE experiment and probably during the first 12 days of EisenEx. The
fCO
2 in surface water decreased at a constant rate of 3.8
μatm
day
−1 from 4 to 5 days onwards in SOIREE. The
fCO
2 reduction was 35
μatm after 13 days. The evolution of surface water
fCO
2 in the iron-enriched waters (or ‘patch’) displayed a saw tooth pattern in EisenEx, in response to algal carbon uptake in calm conditions and deep mixing and horizontal dispersion during storms. The maximum
fCO
2 reduction was 18–20
μatm after 12 and 21 days with lower values in between. The iron-enriched waters in EisenEx absorbed four times more atmospheric CO
2 than in SOIREE between 5 and 12 days, as a result of stronger winds. The total biological uptake of inorganic carbon across the patch was 1389
ton C (±10%) in SOIREE and 1433
ton C (±27%) in EisenEx after 12 days (1
ton=10
6
g). This similarity probably reflects the comparable size of the iron additions, as well as algal growth at a similar near-maximum growth rate in these regions. The findings imply that the different mixing regimes had less effect on the overall biological carbon uptake across the iron-enriched waters than suggested by the evolution of
fCO
2 in surface water.
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