Maintenance of cytomegalovirus-specific CD4pos T-cell response in rheumatoid arthritis patients receiving anti-tumor necrosis factor treatments

International audienceINTRODUCTION: Anti-tumor necrosis factor (TNF)-α biotherapies have considerably changed the treatment of rheumatoid arthritis (RA). However, serious infections are a major concern in patients with rheumatic diseases treated with anti-TNF-α. Little is known about viral, especially latent, infections in anti-TNF-α treatments. Infections by cytomegalovirus (CMV), a β-herpes virus, are frequent and induce a strong CD4pos T-cell immunity, which participates in the control of infection. We thus have chosen to analyze the CD4pos T-cell response to CMV antigens as a model of antiviral response in RA patients treated with anti-TNF-α. CD28 expression was evaluated. METHODS: We have measured the CD4pos response to CMV antigens in RA patients, before and after initiation of treatment with an anti-TNF-α agent. The intracellular production of interferon (IFN)-γ in total and CD28neg CD4pos T cells in response to CMV antigens (Ags) was evaluated with flow cytometry. The proliferation of total CD4pos T cells in the presence of CMV antigens was measured with 3H-thymidine incorporation. RESULTS: Anti-TNF-α treatments impaired neither the anti-CD4pos anti-CMV IFN-γ response nor the proliferative response in patients. The percentage of CD28neg CD4pos cells remained constant. CONCLUSIONS: Our data suggest that the CD4pos T-cell response against CMV is not altered by anti-TNF-α treatments and that infection remains controlled in treated RA patients latently infected with CMV. Our observation brings new insight into the current knowledge of the risks of infection in patients treated with anti-TNF-α biotherapies

Crystal structure, NIR luminescence and X-ray computed tomography of Nd3+:Ba0.3Lu0.7F2.7 nanospheres

Uniform, hydrophilic 50 nm diameter Nd3+-doped Ba0.3Lu0.7F2.7 nanospheres are synthesized at 120 °C using a singular one-pot method based on the use of ethylene glycol as solvent, in the absence of any additive. The composition and crystal structure of the undoped material are analyzed in detail using ICP and XRD, which reveals a BaF2 cubic crystal structure that is able to incorporate 70 mol% of Lu ions. This finding contrasts with the reported phase diagram of the system, where the maximum solubility is around 30 mol% Lu. XRD proves as well that the Ba0.3Lu0.7F2.7 structure is able to incorporate Nd3+ ions up to, at least 10 mol%, without altering the uniform particles morphology. The Nd-doped particles exhibit nearinfrared luminescence when excited at 810 nm. The maximum emission intensity with the minimum concentration quenching effect is obtained at 1.5% Nd doping level. X-ray computed tomography experiments are carried out on powder samples of the latter composition. The sample significantly absorbs X-ray photons, thus demonstrating that the Nd3+-doped Ba0.3Lu0.7F2.7 nanospheres are good candidates as contrast agents in computed tomography.Ministerio de Economía y Competitividad MAT2014-54852-R, MAT2012-34919Consejo Superior de Investigaciones Científicas 201560E056, 201460E00

Interacting internal waves explain global patterns of interior ocean mixing

Across the stable density stratification of the abyssal ocean, deep dense water is slowly propelled upward by sustained, though irregular, turbulent mixing. The resulting mean upwelling is key to setting large-scale oceanic circulation properties, such as heat and carbon transport. It is generally accepted that in the ocean interior, this turbulent mixing is caused mainly by breaking internal waves, which are predominantly generated by winds and tides, interact nonlinearly, thereby fluxing energy down to ever smaller scales, and finally become unstable, break and mix the water column. This paradigm forms the conceptual backbone of the widely used Finescale Parameterization. This formula estimates small-scale mixing from the readily observable internal wave activity at larger scales and theoretical scaling laws for the downscale nonlinear energy flux, but has never been fully explained theoretically. Here, we close this gap using wave-wave interaction theory with input from both localized high-resolution experiments and combined global observational datasets. We find near-ubiquitous agreement between our predictions, derived from first-principles alone, and the observed mixing patterns in the global ocean interior. Our findings lay the foundations for a new type of wave-driven mixing parameterization for ocean general circulation models that is entirely physics-based, which is key to reliably represent climate states that differ substantially from today's

Tumor necrosis factor alpha and adalimumab differentially regulate CD36 expression in human monocytes

In chronic inflammatory diseases, such as rheumatoid arthritis, inflammation acts as an independent cardiovascular risk factor and the use of anti-inflammatory drugs, such as anti-tumor necrosis factor alpha (anti-TNFα), may decrease this risk. The phagocytosis of oxidized low density lipoproteins (LDLs) accumulated in the subendothelium by mononuclear cells influences atherosclerosis and depends on CD36 expression. We investigated the role of TNFα and adalimumab, a human anti-TNFα monoclonal antibody widely used in human pathology, in CD36 expression in human monocytes. Human monocytes were prepared by adherence from whole-blood buffy-coat fractions from healthy donors. CD36 expression was assessed by RT-PCR and flow cytometry, with various TNFα or adalimumab concentrations. Implication of peroxisome proliferator-activated receptor (PPAR)γ in the regulation of CD36 expression was assessed using specific inhibitor or gel shift assays. The impact of redox signaling was investigated using quantification of reactive oxygen species, antioxidant and a NADPH oxidase inhibitor. The F(ab')2 fragment of adalimumab was isolated and its effect was analyzed. TNFα inhibits both CD36 membrane expression and mRNA expression. This inhibition involves a reduction in PPARγ activation. In contrast, adalimumab increases both CD36 membrane expression and mRNA expression. This induction is independent of the Fc portion of adalimumab and involves redox signaling via NADPH oxidase activation. CD36 expression on human monocytes is inhibited by TNFα and independently increased by adalimumab. These data highlight that pro-inflammatory cytokines and their specific neutralization influence the expression of cellular receptors implicated in atherosclerosis. Further studies are needed to investigate the clinical implications of these results in accelerated atherosclerosis observed in rheumatoid arthritis

A new classification of HLA-DRB1 alleles differentiates predisposing and protective alleles for autoantibody production in rheumatoid arthritis

The HLA-DRB1 gene was reported to be associated with anticitrullinated protein/peptide autoantibody (ACPA) production in rheumatoid arthritis (RA) patients. A new classification of HLA-DRB1 alleles, reshaping the shared epitope (SE) hypothesis, was recently found relevant in terms of RA susceptibility and structural severity

Polarization of Rheumatoid Macrophages by TNF Targeting Through an IL-10/STAT3 Mechanism

Macrophages contribute to the pathogenesis of rheumatoid arthritis (RA). They can display different states of activation or “polarization,” notably the so-called inflammatory “M1” and the various alternative “M2” polarizations, characterized by distinct functions. Data regarding the effects of RA anti-cytokine biological disease-modifying anti-rheumatic drugs (bDMARDs) on macrophage polarization are scarce. We aimed to assess in vitro modulation of macrophage polarization by bDMARDs targeting pro-inflammatory cytokines in RA. We generated monocyte derived macrophages using blood samples from 20 RA patients with active RA and 30 healthy controls. We evaluated in vitro the impact on M1 inflammatory macrophages of: etanercept (ETA), adalimumab (ADA), certolizumab (CZP), tocilizumab (TCZ), and rituximab (RTX). We assessed the impact on macrophage polarization using flow cytometry and RTqPCR to study the expression of surface markers and perform functional studies of cytokine production, phagocytosis, and negative feedback control of inflammation. Among evaluated bDMARDs, anti-TNF agents modulated the polarization of inflammatory macrophages by decreasing inflammatory surface markers (CD40, CD80) and favoring alternative markers (CD16, CD163, MerTK). Anti-TNF agents also induced alternative functions in macrophages activated in inflammatory condition with (i) the inhibition of inflammatory cytokines (TNF, IL-6, IL-12), (ii) an increase in phagocytosis. These findings were mechanistically related to an increase in early IL-10 production, responsible for higher negative feedback control of inflammation involving SOCS3 and Gas6. This IL-10 effect was STAT3-dependent. Anti-TNF agents not only inhibit in vitro inflammatory functions of macrophages, but also favor resolution of inflammation through polarization toward alternative features specifically involving the IL-10/STAT3 axis

Internal wave activity in the deep Gulf of Mexico

Internal wave activity in the Gulf of Mexico (GoM) is investigated using a fleet of profiling floats. The floats continuously measured temperature and salinity as they drifted at a parking depth of 1500 dbar, allowing for the reconstruction of 2615 time series of isopycnal displacements. Thanks to the dense sampling of the eastern part of the GoM (east of 90°W), the geographical distribution of the internal waves displacement variance and available potential energy (APE) is revealed. The Loop Current (LC) influence region, between the Yucatan shelf to the west and the southern West Florida shelf to the east exhibits increased displacement variance and APE both in the continuum and near-inertial bands, while the north-eastern and central GoM show reduced internal wave activity. As the LC position fluctuates between a retracted and extended mode, we assessed the impact of the presence or absence of the LC in the increased internal wave activity region. It is shown that in the LC influence region, APE is increased (decreased) when the LC is present (absent), suggesting a strong control of the LC on deep internal waves activity. The 1500 dbar flow velocity, bottom roughness, and float altitude also seem to contribute to increased internal waves APE, but their influence is more subtle. Oppositely, no correlation with wind speed or wind intermittency is found

Double diffusion, shear instabilities, and heat impacts of a pacific summer water intrusion in the Beaufort Sea

© The Author(s), 2022. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Fine, E., MacKinnon, J., Alford, M., Middleton, L., Taylor, J., Mickett, J., Cole, S., Couto, N., Boyer, A., & Peacock, T. Double diffusion, shear instabilities, and heat impacts of a pacific summer water intrusion in the Beaufort Sea. Journal of Physical Oceanography, 52(2), (2022): 189–203, https://doi.org/10.1175/jpo-d-21-0074.1.Pacific Summer Water eddies and intrusions transport heat and salt from boundary regions into the western Arctic basin. Here we examine concurrent effects of lateral stirring and vertical mixing using microstructure data collected within a Pacific Summer Water intrusion with a length scale of ∼20 km. This intrusion was characterized by complex thermohaline structure in which warm Pacific Summer Water interleaved in alternating layers of O(1) m thickness with cooler water, due to lateral stirring and intrusive processes. Along interfaces between warm/salty and cold/freshwater masses, the density ratio was favorable to double-diffusive processes. The rate of dissipation of turbulent kinetic energy (ε) was elevated along the interleaving surfaces, with values up to 3 × 10−8 W kg−1 compared to background ε of less than 10−9 W kg−1. Based on the distribution of ε as a function of density ratio Rρ, we conclude that double-diffusive convection is largely responsible for the elevated ε observed over the survey. The lateral processes that created the layered thermohaline structure resulted in vertical thermohaline gradients susceptible to double-diffusive convection, resulting in upward vertical heat fluxes. Bulk vertical heat fluxes above the intrusion are estimated in the range of 0.2–1 W m−2, with the localized flux above the uppermost warm layer elevated to 2–10 W m−2. Lateral fluxes are much larger, estimated between 1000 and 5000 W m−2, and set an overall decay rate for the intrusion of 1–5 years.This work was supported by ONR Grant N00014-16-1-2378 and NSF Grants PLR 14-56705 and PLR-1303791, NSF Graduate Research Fellowship Grant DGE-1650112, as well as by the Postdoctoral Scholar Program at Woods Hole Oceanographic Institution, with funding provided by the Weston Howland Jr. Postdoctoral Scholarship

Broad emission lines for negatively spinning black holes

We present an extended scheme for the calculation of the profiles of emission lines from accretion discs around rotating black holes. The scheme includes discs with angular momenta which are parallel and antiparallel with respect to the black hole's angular momentum, as both configurations are assumed to be stable (King et al., 2005). We discuss line shapes for such discs and present a code for modelling observational data with this scheme in X-ray data analysis programs. Based on a Green's function approach, an arbitrary radius dependence of the disc emissivity and arbitrary limb darkening laws can be easily taken into account, while the amount of precomputed data is significantly reduced with respect to other available models.Comment: 7 pages, 6 figures; accepted by MNRAS for Publication, now matches the proof read versio