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Dupilumab is a monoclonal antibody approved for the treatment of atopic dermatitis (AD); however, its effects on molecular, cellular, and immunological levels remain to be elucidated. In this study, blood and dermal interstitial fluid (ISF) from nonlesional (NL) and lesional (L) skin were collected from eight patients with moderate to severe AD, before (visit 2-v2) and at the end of a 16-week treatment with dupilumab (visit 10-v10). Clinical treatment effect was demonstrated by significantly decreased AD severity scores at the end of treatment. At v10 versus v2, the percentages of CD4+ interleukin-producing cells showed a decreasing trend in ISF L and NL, unbound IL-4 levels in plasma were increased, IL-5 levels in ISF L reduced, and levels of factors involved in anti-inflammatory pathways and re-epithelization increased. At v2, ISF L showed that AD lesions might have altered amino acid pathways and lipid signaling compared to ISF NL. At v10, ISF L exhibited raised levels of long- and very-long-chain fatty acids and lipids compared to v2. Furthermore, dupilumab administration caused reduced expression of miR-155-5p and miR-378a-3p in ISF L. In conclusion, results from the present study provided novel knowledge by linking local immune and metabolic alterations to AD pathogenesis and treatment response.
Assuntos
Anticorpos Monoclonais Humanizados , Dermatite Atópica , Líquido Extracelular , Humanos , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/metabolismo , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Líquido Extracelular/efeitos dos fármacos , Líquido Extracelular/metabolismo , Masculino , Feminino , Adulto , Mediadores da Inflamação/metabolismo , Metaboloma/efeitos dos fármacos , Interleucina-4/metabolismo , MicroRNAs/metabolismo , MicroRNAs/genética , Pele/metabolismo , Pele/efeitos dos fármacos , Pele/irrigação sanguínea , Pessoa de Meia-Idade , Interleucina-5RESUMO
Cytomegalovirus (CMV) infection detrimentally influences graft survival in kidney transplant recipients, with the risk primarily determined by recipient and donor serostatus. However, recipient CD8+ T cells play a crucial role in CMV control. The optimal preventive strategy (prophylaxis vs. pre-emptive treatment), particularly for seropositive (intermediate risk) recipients, remains uncertain. We investigated CD8+ T cell subpopulation dynamics and CMV occurrence (DNAemia ≥ 100 IU/mL) in 65 kidney transplant recipients, collecting peripheral blood mononuclear cells before (T1) and 1 year after transplantation (T2). Comparing the two timepoints, we found an increase in granulocyte, monocyte and CD3+CD8+ T cells numbers, while FoxP3+CD25+, LAG-3+ and PD-1+ frequencies were reduced at T2. CMV DNAemia occurred in 33 recipients (55.8%) during the first year. Intermediate risk patients were disproportionally affected by posttransplant CMV (N = 29/45, 64.4%). Intermediate risk recipients developing CMV after transplantation exhibited lower leukocyte, monocyte, and granulocyte counts and higher FoxP3+CD25+ frequencies in CD3+CD8+ T cells pre-transplantation compared to patients staying CMV negative. Pre-transplant FoxP3+CD25+ in CD3+CD8+ T cells had the best discriminatory potential for CMV infection prediction within the first year after transplantation (AUC: 0.746). The FoxP3+CD25+ CD3+CD8+ T cell subset may aid in selecting intermediate risk kidney transplant recipients for CMV prophylaxis.
Assuntos
Linfócitos T CD8-Positivos , Infecções por Citomegalovirus , Fatores de Transcrição Forkhead , Subunidade alfa de Receptor de Interleucina-2 , Transplante de Rim , Humanos , Transplante de Rim/efeitos adversos , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/prevenção & controle , Feminino , Masculino , Linfócitos T CD8-Positivos/imunologia , Pessoa de Meia-Idade , Fatores de Transcrição Forkhead/metabolismo , Adulto , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Idoso , Complexo CD3/metabolismo , Citomegalovirus/imunologia , Fatores de Risco , Transplantados , Sobrevivência de Enxerto/imunologiaRESUMO
Hemodialysis patients (HD) are expected to have excess mortality in coronavirus disease 2019 (COVID-19). This was challenged by a recent study reporting HD patients to have comparable mortality and less ICU admissions when hospitalized with COVID-19. An altered immune system due to chronic inflammation might protect HD-patients from severe COVID-19. Therefore, we aimed to describe the peripheral blood immune phenotype in HD-patients and respective controls with COVID-19. Methods: Sixty-four patients (31 HD, 33 non-HD) with PCR-confirmed COVID-19 and 16 control patients (10 HD, 6 non-HD) were prospectively included. According to symptoms, COVID-19 patients were categorized as asymptomatic/mild, moderate or severe COVID-19 phenotypes. Cytokine profiling and immune phenotyping was performed. Results: Th1 and Th17 plasma cytokine levels were highly increased in HD patients without COVID-19 and were not significantly regulated during COVID-19. In non-HD COVID-19 patients these cytokines increased significantly with disease severity. While all patients with moderate or severe COVID-19 showed hallmarks of COVID-19 such as decreased CD3+, CD4+ and CD8+ and CD4+CD25hiFoxP3+ regulatory T cells, significantly increased CD38+CD8+ effector memory and CD38+CD8+ TEMRA T cells were detected in moderate/severe COVID-19 HD patients, which was not observed in non-HD patients with moderate or severe COVID-19. Furthermore, CD161+CD8+ T cells decreased significantly in non-HD COVID-19 patients dependent on disease severity, but not in HD patients. Dynamics of B cells and subtypes were comparable in HD and non-HD COVID-19 patients. Conclusions: HD patients might be protected from severe COVID-19 due to their chronic inflammatory state with increased CD38+CD8+ effector memory and TEMRA T cells as well as CD161+CD8+ T cells.
Assuntos
COVID-19/imunologia , Inflamação/imunologia , Diálise Renal , SARS-CoV-2 , Linfócitos T/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos B/imunologia , Citocinas/sangue , Feminino , Humanos , Inflamação/sangue , Masculino , Pessoa de Meia-Idade , Insuficiência Renal CrônicaRESUMO
BACKGROUND: The COVID-19 pandemic has major implications on kidney transplant recipients (KTRs) since they show increased mortality due to impaired immune responses to SARS-CoV-2 infection and a reduced efficacy of SARS-CoV-2 vaccination. Surprisingly, dialysis patients have shown superior seroconversion rates after vaccination compared to KTRs. Therefore, we investigated peripheral blood B cell (BC) composition before and after kidney transplantation (KT) and aimed to screen the BC compartment to explain impaired antibody generation. METHODS: A total of 105 patients were recruited, and multicolor flow cytometric phenotyping of peripheral venous blood BC subpopulations was performed before and 1 year after KT. Complete follow-up was available for 71 individuals. Anti-SARS-CoV-2 antibodies were collected retrospectively and were available for 40 subjects, who had received two doses of an mRNA-based vaccine (BNT162b2 or mRNA-1273). RESULTS: Overall, relative BC frequencies within lymphocytes decreased, and their absolute counts trended in the same direction 1 year after KT as compared to CKD G5 patients. Frequencies and absolute numbers of naïve BCs remained stable. Frequencies of double negative BCs, a heterogeneous subpopulation of antigen experienced BCs lacking CD27 expression, were increased after KT, yet their absolute counts were similar at both time points. Transitional BCs (TrBCs) and plasmablasts were significantly reduced after KT in absolute and relative terms. Memory BCs were affected differently since class-switched and IgM-only subsets decreased after KT, but unswitched and IgD-only memory BCs remained unchanged. CD86+ and CD5+ expression on BCs was downregulated after KT. Correlational analysis revealed that TrBCs were the only subset to correlate with titer levels after SARS-CoV-2 vaccination. Responders showed higher TrBCs, both absolute and relative, than non-responders. CONCLUSION: Together, after 1 year, KTRs showed persistent and profound compositional changes within the BC compartment. Low TrBCs, 1 year after KT, may account for the low serological response to SARS-CoV-2 vaccination in KTRs compared to dialysis patients. Our findings need confirmation in further studies as they may guide vaccination strategies.
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Although quasi-amorphous iridium oxohydroxides have been identified repeatedly as superior electrocatalysts for the oxygen evolution reaction (OER), an exact description of the performance-relevant species has remained a challenge. In this context, we report the characterization of hydrothermally prepared iridium(III/IV) oxohydroxides that exhibit exceptional OER performances. Holes in the O 2p states of the iridium(III/IV) oxohydroxides result in reactive OI- species, which are identified by characteristic near-edge X-ray absorption fine structure (NEXAFS) features. A prototypical titration reaction with CO as a probe molecule shows that these OI- species are highly susceptible to nucleophilic attack at room temperature. Similarly to the preactivated oxygen involved in the biological OER in photosystemâ II, the electrophilic OI- species evidenced in the iridium(III/IV) oxohydroxides are suggested to be precursors to species involved in the O-O bond formation during the electrocatalytic OER. The CO titration also highlights a link between the OER performance and the surface/subsurface mobility of the OI- species. Thus, the superior electrocatalytic properties of the iridium (III/IV) oxohydroxides are explained by their ability to accommodate preactivated electrophilic OI- species that can migrate within the lattice.
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Water splitting performed in acidic media relies on the exceptional performance of iridium-based materials to catalyze the oxygen evolution reaction (OER). In the present work, we use in situ X-ray photoemission and absorption spectroscopy to resolve the long-standing debate about surface species present in iridium-based catalysts during the OER. We find that the surface of an initially metallic iridium model electrode converts into a mixed-valent, conductive iridium oxide matrix during the OER, which contains OII- and electrophilic OI- species. We observe a positive correlation between the OI- concentration and the evolved oxygen, suggesting that these electrophilic oxygen sites may be involved in catalyzing the OER. We can understand this observation by analogy with photosystem II; their electrophilicity renders the OI- species active in O-O bond formation, i.e. the likely potential- and rate-determining step of the OER. The ability of amorphous iridium oxyhydroxides to easily host such reactive, electrophilic species can explain their superior performance when compared to plain iridium metal or crystalline rutile-type IrO2.
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The synthesis of a highly active and yet stable electrocatalyst for the anodic oxygen evolution reaction (OER) remains a major challenge for acidic water splitting on an industrial scale. To address this challenge, we obtained an outstanding high-performance OER catalyst by loading Ir on conductive antimony-doped tin oxide (ATO)-nanoparticles by a microwave (MW)-assisted hydrothermal route. The obtained Ir phase was identified by using XRD as amorphous (XRD-amorphous), highly hydrated IrIII/IV oxohydroxide. To identify chemical and structural features responsible for the high activity and exceptional stability under acidic OER conditions with loadings as low as 20â µgIr cm-2 , we used stepwise thermal treatment to gradually alter the XRD-amorphous Ir phase by dehydroxylation and crystallization of IrO2 . This resulted in dramatic depletion of OER performance, indicating that the outstanding electrocatalytic properties of the MW-produced IrIII/IV oxohydroxide are prominently linked to the nature of the produced Ir phase. This finding is in contrast with the often reported stable but poor OER performance of crystalline IrO2 -based compounds produced through more classical calcination routes. Our investigation demonstrates the immense potential of Ir oxohydroxide-based OER electrocatalysts for stable high-current water electrolysis under acidic conditions.
Assuntos
Eletroquímica/métodos , Irídio/química , Água/química , Catálise , Cristalização , Eletrólise , Oxirredução , OxigênioRESUMO
The mechanism of C-H activation in selective oxidation reactions of short-chain alkane molecules over transition metal oxides is critically affected by the balance of acid-base and redox sites at the surface of the catalyst. Using the example of manganese tungstate we discuss how the relative abundance of these sites can be controlled via synthetic techniques. Phase-pure catalysts composed of the thermodynamic stable monoclinic MnWO4 phase have been prepared using hydrothermal synthesis. Variation of the initial pH value resulted in rod-shaped nano-crystalline MnWO4 catalysts composed of particles with varying aspect ratio. The synthesis products have been analysed using transmission electron microscopy, X-ray diffraction, infrared, and photoelectron spectroscopy. In situ Raman spectroscopy was used to investigate the dissolution-re-crystallization processes occurring under hydrothermal conditions. Ethanol oxidation was applied to probe the surface functionalities in terms of acid-base and redox properties. Changes in the aspect ratio of the primary catalyst particles are reflected in the product distribution induced by altering the fraction of acid-base and redox sites exposed at the surface of the catalysts in agreement with the proposed mechanism of particle growth by re-crystallization during ageing under hydrothermal conditions.
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The electronic and structural properties of vanadium-containing phases govern the formation of isolated active sites at the surface of these catalysts for selective alkane oxidation. This concept is not restricted to vanadium oxide. The deliberate use of hydrothermal techniques can turn the typical combustion catalyst manganese oxide into a selective catalyst for oxidative propane dehydrogenation. Nanostructured, crystalline MnWO4 serves as the support that stabilizes a defect-rich MnOx surface phase. Oxygen defects can be reversibly replenished and depleted at the reaction temperature. Terminating MnOx zigzag chains on the (010) crystal planes are suspected to bear structurally site-isolated oxygen defects that account for the unexpectedly good performance of the catalyst in propane activation.
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Tremendous effort has been devoted towards elucidating the fundamental reasons for the higher activity of hydrated amorphous IrIII/IV oxyhydroxides (IrO x ) in the oxygen evolution reaction (OER) in comparison with their crystalline counterpart, rutile-type IrO2, by focusing on the metal oxidation state. Here we demonstrate that, through an analogy to photosystem II, the nature of this reactive species is not solely a property of the metal but is intimately tied to the electronic structure of oxygen. We use a combination of synchrotron-based X-ray photoemission and absorption spectroscopies, ab initio calculations, and microcalorimetry to show that holes in the O 2p states in amorphous IrO x give rise to a weakly bound oxygen that is extremely susceptible to nucleophilic attack, reacting stoichiometrically with CO already at room temperature. As such, we expect this species to play the critical role of the electrophilic oxygen involved in O-O bond formation in the electrocatalytic OER on IrO x . We propose that the dynamic nature of the Ir framework in amorphous IrO x imparts the flexibility in Ir oxidation state required for the formation of this active electrophilic oxygen.
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Electrochemically grown cobalt on graphene exhibits exceptional performance as a catalyst for the oxygen evolution reaction (OER) and provides the possibility of controlling the morphology and the chemical properties during deposition. However, the detailed atomic structure of this hybrid material is not well understood. To elucidate the Co/graphene electronic structure, we have developed a flow cell closed by a graphene membrane that provides electronic and chemical information on the active surfaces under atmospheric pressure and in the presence of liquids by means of X-ray photoelectron spectroscopy (XPS). We found that cobalt is anchored on graphene via carbonyl-like species, namely Co(CO)x , promoting the reduction of Co(3+) to Co(2+), which is believed to be the active site of the catalyst.