RESUMEN
Metabolism is a major regulator of immune cell function, but it remains difficult to study the metabolic status of individual cells. Here, we present Compass, an algorithm to characterize cellular metabolic states based on single-cell RNA sequencing and flux balance analysis. We applied Compass to associate metabolic states with T helper 17 (Th17) functional variability (pathogenic potential) and recovered a metabolic switch between glycolysis and fatty acid oxidation, akin to known Th17/regulatory T cell (Treg) differences, which we validated by metabolic assays. Compass also predicted that Th17 pathogenicity was associated with arginine and downstream polyamine metabolism. Indeed, polyamine-related enzyme expression was enhanced in pathogenic Th17 and suppressed in Treg cells. Chemical and genetic perturbation of polyamine metabolism inhibited Th17 cytokines, promoted Foxp3 expression, and remodeled the transcriptome and epigenome of Th17 cells toward a Treg-like state. In vivo perturbations of the polyamine pathway altered the phenotype of encephalitogenic T cells and attenuated tissue inflammation in CNS autoimmunity.
Asunto(s)
Autoinmunidad/inmunología , Modelos Biológicos , Células Th17/inmunología , Acetiltransferasas/metabolismo , Adenosina Trifosfato/metabolismo , Aerobiosis/efectos de los fármacos , Algoritmos , Animales , Autoinmunidad/efectos de los fármacos , Cromatina/metabolismo , Ciclo del Ácido Cítrico/efectos de los fármacos , Citocinas/metabolismo , Eflornitina/farmacología , Encefalomielitis Autoinmune Experimental/metabolismo , Encefalomielitis Autoinmune Experimental/patología , Epigenoma , Ácidos Grasos/metabolismo , Glucólisis/efectos de los fármacos , Histona Demetilasas con Dominio de Jumonji/metabolismo , Ratones Endogámicos C57BL , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Oxidación-Reducción/efectos de los fármacos , Putrescina/metabolismo , Análisis de la Célula Individual , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Células Th17/efectos de los fármacos , Transcriptoma/genéticaRESUMEN
The role of B cells in anti-tumour immunity is still debated and, accordingly, immunotherapies have focused on targeting T and natural killer cells to inhibit tumour growth1,2. Here, using high-throughput flow cytometry as well as bulk and single-cell RNA-sequencing and B-cell-receptor-sequencing analysis of B cells temporally during B16F10 melanoma growth, we identified a subset of B cells that expands specifically in the draining lymph node over time in tumour-bearing mice. The expanding B cell subset expresses the cell surface molecule T cell immunoglobulin and mucin domain 1 (TIM-1, encoded by Havcr1) and a unique transcriptional signature, including multiple co-inhibitory molecules such as PD-1, TIM-3, TIGIT and LAG-3. Although conditional deletion of these co-inhibitory molecules on B cells had little or no effect on tumour burden, selective deletion of Havcr1 in B cells both substantially inhibited tumour growth and enhanced effector T cell responses. Loss of TIM-1 enhanced the type 1 interferon response in B cells, which augmented B cell activation and increased antigen presentation and co-stimulation, resulting in increased expansion of tumour-specific effector T cells. Our results demonstrate that manipulation of TIM-1-expressing B cells enables engagement of the second arm of adaptive immunity to promote anti-tumour immunity and inhibit tumour growth.
Asunto(s)
Linfocitos B , Melanoma , Animales , Ratones , Linfocitos B/citología , Linfocitos B/inmunología , Linfocitos B/metabolismo , Activación de Linfocitos , Melanoma/inmunología , Melanoma/patología , Melanoma/prevención & control , Linfocitos T/citología , Linfocitos T/inmunología , Citometría de Flujo , Melanoma Experimental/inmunología , Melanoma Experimental/patología , Ganglios Linfáticos/citología , Ganglios Linfáticos/inmunología , Presentación de Antígeno , Receptores de Antígenos de Linfocitos B/genética , Análisis de Expresión Génica de una Sola Célula , Carga Tumoral , Interferón Tipo IRESUMEN
OBJECTIVE: Rheumatoid Arthritis (RA) is a systemic autoimmune disease involving pro-inflammatory cytokines that can be therapeutically targeted by antibodies or kinase inhibitors. Nevertheless, these drugs fail in a subset of patients independent of the abundance of the targeted cytokines. We aim to explore the cellular basis of this phenomenon by analyzing the relation of cytokine abundance and activation of downstream signaling pathways in RA. METHODS: The study included 62 RA patients and 9 healthy controls (HC). Phosphorylation of STAT 1-6 in various immune cell subsets was determined ex vivo using a novel robust flow cytometry-based protocol. Serum concentrations of IL-6, IL-10, IL-12p70, IL-17 A, interferon gamma, and TNFα in the same samples were measured using highly sensitive single molecule array (SIMOA). RESULTS: We found an increase in circulating cytokines in RA patients, while STAT activity was lower in RA patients compared to HC. Based on STAT activity we determined three endotypes in active RA patients (cDAI>10, n = 28): 1) those with active STAT5a/b signaling in T cells (n = 7/28), 2) those with a low STAT activity in all assessed cell types (n = 14/28), and 3) those with active STAT1 and STAT3 signaling mainly in myeloid cells (n = 7/28). Integrating intracellular STAT activation and cytokine analysis revealed diminished JAK/STAT signaling in a subset of patients (n = 8/20) despite elevated serum cytokine concentrations. CONCLUSION: Diminished JAK/STAT signaling in active RA may partly explain unresponsiveness to therapy targeting cytokine signaling. Analysis of JAK/STAT phosphorylation may identify patients at risk for non-response to these therapies.
Asunto(s)
Artritis Reumatoide , Citocinas , Quinasas Janus , Factores de Transcripción STAT , Transducción de Señal , Humanos , Artritis Reumatoide/sangre , Artritis Reumatoide/inmunología , Persona de Mediana Edad , Femenino , Masculino , Citocinas/sangre , Quinasas Janus/metabolismo , Adulto , Factores de Transcripción STAT/metabolismo , Anciano , Fosforilación , Factor de Transcripción STAT5/metabolismo , Leucocitos/metabolismo , Leucocitos/inmunología , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT1/sangreRESUMEN
Biradicals are important intermediates in the process of bond formation and breaking. While main-group-element-centered biradicals have been thoroughly studied, much less is known about tetraradicals, as their very low stability has hampered their isolation and use in small-molecule activation. Herein, we describe the search for persistent phosphorus-centered tetraradicals. Starting from an s-hydrindacenyl skeleton, we investigated the introduction of four phosphorus-based radical sites linked by an N-R unit and bridged by a benzene moiety. By varying the size of the substituent R, we finally succeeded in isolating a persistent P-centered singlet tetraradical, 2,6-diaza-1,3,5,7-tetraphospha-s-hydrindacene-1,3,5,7-tetrayl (1), in good yields. Furthermore, it was demonstrated that tetraradical 1 can be utilized for the activation of small molecules such as molecular hydrogen or alkynes. In addition to the synthesis of P-centered tetraradicals, the comparison with other known tetraradicals as well as biradicals is described on the basis of quantum mechanical calculations with respect to its multireference character, coupling of radical electrons, and aromaticity. The strong coupling of radical electrons enables selective discrimination between the first and the second activations of small molecules, which is shown by the example of H2 addition. The mechanism of hydrogen addition is investigated with parahydrogen-induced hyperpolarization NMR studies and DFT calculations.
RESUMEN
Manganese-catalyzed hydrogenation reactions have aroused widespread interest in recent years. Among the catalytic systems described, especially PNP- and NNP-Mn pincer catalysts have been reported for the hydrogenation of aldehydes, ketones, nitriles, aldimines and esters. Furthermore, NNP-Mn pincer compounds are efficient catalysts for the hydrogenolysis of less reactive amides, ureas, carbonates, and carbamates. Herein, the synthesis and application of specific imidazolylaminophosphine ligands and the corresponding Mn pincer complexes are described. These new catalysts have been characterized and studied by a combination of experimental and theoretical investigations, and their catalytic activities have been tested in several hydrogenation reactions with good to excellent performance. Especially, the reduction of N-heterocycles can be performed under very mild conditions.
RESUMEN
Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has become pandemic. Cytokine release syndrome occurring in a minority of SARS-CoV-2 infections is associated with severe disease and high mortality. We profiled the composition, activation, and proliferation of T cells in 20 patients with severe or critical COVID-19 and 40 matched healthy controls by flow cytometry. Unsupervised hierarchical cluster analysis based on 18 T cell subsets resulted in separation of healthy controls and COVID-19 patients. Compared to healthy controls, patients suffering from severe and critical COVID-19 had increased frequencies of activated and proliferating CD38+Ki67+ CD4+ and CD8+ T cells, suggesting active antiviral T cell defense. Frequencies of CD38+Ki67+ Th1 and CD4+ cells correlated negatively with plasma IL-6. Thus, our data suggest that patients suffering from COVID-19 have a distinct T cell composition that is potentially modulated by IL-6.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , COVID-19/inmunología , Inmunidad Celular , SARS-CoV-2/inmunología , Células TH1/inmunología , ADP-Ribosil Ciclasa 1/inmunología , Adulto , Linfocitos T CD8-positivos/patología , COVID-19/epidemiología , COVID-19/patología , Femenino , Humanos , Inmunofenotipificación , Interleucina-6/inmunología , Antígeno Ki-67/inmunología , Masculino , Glicoproteínas de Membrana/inmunología , Pandemias , Estudios Retrospectivos , Células TH1/patologíaRESUMEN
OBJECTIVE: To compare structural findings between US, micro-CT (µCT) and histology in people with OA of the hands. METHODS: We analysed DIP and PIP joints of 31 fingers from 15 dissecting-room cadavers with OA of the hands. The occurrence of bone erosions and osteophytes were recorded by US, µCT and histology at 16 regions for each joint and compared for each method. RESULTS: In total, US (n = 558, 56.2% of 992 examined regions) and µCT (n = 493, 49.7%) detected a higher frequency of osteophytes at PIP and DIP joints than histology (n = 161, 23.4% of 689 histological examined regions; P = 0.01). We found a comparable number of erosions with each method [US, n = 52 (5.2%); µCT, n = 43 (4.3%); histology, n = 35 (5.2%)]. Both imaging techniques correlated moderately with each other regarding the detection of osteophytes (r = 0.54, P = 0.002) and erosions (r = 0.43, P = 0.017). Neither US nor µCT correlated with histology regarding erosions or osteophytes. With histology as the reference, US had a sensitivity of 80% and a specificity of 32% to detect osteophytes, whereas µCT had a sensitivity of 73% and a specificity of 27%. For erosions, sensitivities (US 10% and µCT 6%, respectively) were much lower. Microscopically, erosions contained fibrous myxoid tissue extending from subcortical cavities through the breach of cortical bone. CONCLUSIONS: The ability of US to identify osteophytes was comparable to that of µCT, yielding a good sensitivity when histology was used as the gold standard. The sensitivity of US and µCT to detecting erosions was low compared with histology.
Asunto(s)
Osteoartritis , Osteofito , Mano/patología , Humanos , Osteoartritis/diagnóstico por imagen , Osteoartritis/patología , Osteofito/diagnóstico por imagen , Osteofito/patología , Tomografía Computarizada por Rayos X , Ultrasonografía/métodosRESUMEN
A phosphine-oxide-promoted, cobalt-catalysed reductive etherification using syngas as a reductant is reported. This novel methodology was successfully used to prepare a broad range of unsymmetrical ethers from various aldehydes and alcohols containing diverse functional groups, and was scaled-up to multigram scale under comparably mild conditions. Mechanistic experiments support an acetalization-hydrogenation sequence.
RESUMEN
OBJECTIVE: To investigate peripheral lymphopenia, a frequent finding in primary Sjögren's syndrome (pSS) associated with higher disease activity and increased mortality. METHODS: Prospective, cross-sectional study of consecutive patients with pSS (n = 66) and healthy controls (n = 181). Lymphocyte subsets were analysed by flow cytometry, naïve (CD45RA+) and memory (CD45RO+) CD4+ T cells were purified by MACS technology. In vitro proliferation and senescence-associated ß-galactosidase (SABG) were assessed by flow cytometry. Telomere length and TCR excision circles (TREC) were measured by real-time PCR. Telomerase activity was analysed according to the telomeric repeat amplification protocols (TRAP). RESULTS: In pSS, lymphopenia mainly affected naïve CD4+ T cells. We noted a lower frequency of proliferating naïve CD4+ T cells ex vivo and decreased homeostatic proliferation in response to IL-7 stimulation in vitro. Furthermore, naïve CD4+ T cells exhibited signs of immune cell aging including shortened telomeres, a reduction in IL-7R expression and accumulation of SABG. The senescent phenotype could be explained by telomerase insufficiency and drastically reduced levels of T-cell receptor excision circles (TRECs), indicating a history of extensive post-thymic cell division. TRECs correlated with the number of naïve CD4+ T cells linking the extend of earlier proliferation to the inability to sustain normal cell numbers. CONCLUSION: In pSS, evidence for increased proliferation of naïve CD4+ T cells earlier in life is associated with a senescent phenotype unable to sustain homeostasis. The lack of naïve CD4+ T cells forms the basis of lymphopenia frequently observed in pSS.
Asunto(s)
Envejecimiento Prematuro/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfopenia/inmunología , Síndrome de Sjögren/inmunología , Subgrupos de Linfocitos T/inmunología , Envejecimiento Prematuro/etiología , Estudios Transversales , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Humanos , Linfopenia/complicaciones , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Síndrome de Sjögren/complicacionesRESUMEN
A disruption of the crucial balance between regulatory T-cells (Tregs) and Th17-cells was recently implicated in various autoimmune disorders. Tregs are responsible for the maintenance of self-tolerance, thus inhibiting autoimmunity, whereas pro-inflammatory Th17-cells contribute to the induction and propagation of inflammation. Distortion of the Th17/Treg balance favoring the pro-inflammatory Th17 side is hence suspected to contribute to exacerbation of autoimmune disorders. This review aims to summarize recent data and advances in targeted therapeutic modification of the Th17/Treg-balance, as well as information on the efficacy of candidate therapeutics with respect to the treatment of autoimmune diseases.
Asunto(s)
Enfermedades Autoinmunes/tratamiento farmacológico , Factores de Transcripción Forkhead/inmunología , Factores Inmunológicos/uso terapéutico , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Células Th17/efectos de los fármacos , Animales , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Factores de Transcripción Forkhead/antagonistas & inhibidores , Factores de Transcripción Forkhead/genética , Regulación de la Expresión Génica , Humanos , Inflamación , Interleucina-17/antagonistas & inhibidores , Interleucina-17/genética , Interleucina-17/inmunología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/antagonistas & inhibidores , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Piperidinas/uso terapéutico , Pirimidinas/uso terapéutico , Pirroles/uso terapéutico , Transducción de Señal , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/patología , Células Th17/inmunología , Células Th17/patología , Ustekinumab/uso terapéuticoRESUMEN
OBJECTIVE: To investigate the possible occurrence of early thymic failure and premature senescence of naïve and memory T-cells in patients with axial spondyloarthritis (aSpA). METHODS: Prospective, cross-sectional study of consecutive patients with aSpA (n=51), rheumatoid arthritis (RA, n=51) and healthy controls (HCs, n=50). Demographic, clinical and laboratory parameters were collected in all patients and we isolated naïve (CD45RA(+)) and memory (CD45RO(+)) CD4(+) and CD8(+) T-cell subsets by MACS technology. T-cell receptor rearrangement excision circle (TREC) and telomere length were measured by real-time PCR. We used TRECs as a surrogate for thymus function and telomere length as an indicator of cellular senescence. Telomerase activity was analysed with the Telomeric Repeat Amplification Protocols. RESULTS: We observed a premature decline of thymic output in patients with aSpA and patients with RA compared with HCs as indicated by a reduction of TREC levels in naive T-cells (aSpA: age adjusted regression coefficient (regcoeff) for CD4(+)CD45RA(+) T-cells -2.566, p=0.023; RA regcoeff=-2.844, p=0.008). Telomere length of all CD4(+) and CD8(+) T-cell subsets was reduced in young patients with aSpA compared with HCs, whereas data for patients with RA were comparable with HCs. Telomerase activity was inversely correlated with telomere length in HCs (correlation coefficient (corcoeff)=-0.532, p<0.001) but not in patients with aSpA (corcoeff=-0.056, p=0.697) and RA (corcoeff=-0.003, p=0.982). CONCLUSIONS: Our data indicate an age-inappropriate shrinkage of thymic output, an inappropriate shortening of telomeres in young patients with aSpA and an impaired telomerase enzyme in patients with aSpA and RA.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Senescencia Celular/inmunología , Espondilitis Anquilosante/inmunología , Telómero/genética , Adulto , Anciano , Artritis Reumatoide/genética , Artritis Reumatoide/inmunología , Estudios de Casos y Controles , Senescencia Celular/genética , Estudios Transversales , Femenino , Citometría de Flujo , Humanos , Antígenos Comunes de Leucocito/inmunología , Modelos Lineales , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estudios Prospectivos , Receptores de Antígenos de Linfocitos T/genética , Espondiloartropatías/genética , Espondiloartropatías/inmunología , Espondilitis Anquilosante/genética , Subgrupos de Linfocitos T/inmunología , Adulto JovenRESUMEN
BACKGROUND: Endoplasmic reticulum (ER) stress is a key feature of lipid-laden macrophages and contributes to the development of atherosclerotic plaques. Blood platelets are known to interact with macrophages and fine-tune effector functions such as inflammasome activation and phagocytosis. However, the effect of platelets on ER stress induction is unknown. OBJECTIVES: The objective of this study is to elucidate the potential of platelets in regulating ER stress in macrophages in vitro. METHODS: Bone marrow-derived macrophages and RAW 264.7 cells were incubated with isolated murine platelets, and ER stress and inflammation markers were determined by reverse transcription-quantitative polymerase chain reaction, Western blotting, and enzyme-linked immunosorbent assay. ER morphology was investigated by electron microscopy. Cell viability, lipid accumulation, and activation were measured by flow cytometry. To gain mechanistic insights, coincubation experiments were performed with platelet decoys/releasates as well as lipopolysaccharide, blocking antibodies, and TLR4 inhibitors. RESULTS: Coincubation of platelets and macrophages led to elevated levels of ER stress markers (BIP, IRE1α, CHOP, and XBP1 splicing) in murine and human macrophages, which led to a pronounced enlargement of the ER. Macrophage ER stress was accompanied by increased release of proinflammatory cytokines and intracellular lipid accumulation, but not cell death. Platelet decoys, but not platelet releasates or lysate from other cells, phenocopied the effect of platelets. Blocking TLR4 inhibited inflammatory activation of macrophages but did not affect ER stress induction by platelet coincubation. CONCLUSION: To our knowledge, this study is the first to demonstrate that platelets induce ER stress and unfolded protein response in macrophages by heat-sensitive membrane proteins, independent of inflammatory activation of macrophages.
Asunto(s)
Plaquetas , Estrés del Retículo Endoplásmico , Macrófagos , Ratones Endogámicos C57BL , Proteínas Serina-Treonina Quinasas , Proteína 1 de Unión a la X-Box , Animales , Plaquetas/metabolismo , Macrófagos/metabolismo , Humanos , Ratones , Células RAW 264.7 , Proteína 1 de Unión a la X-Box/metabolismo , Proteína 1 de Unión a la X-Box/genética , Receptor Toll-Like 4/metabolismo , Retículo Endoplásmico/metabolismo , Endorribonucleasas/metabolismo , Citocinas/metabolismo , Chaperón BiP del Retículo Endoplásmico , Factor de Transcripción CHOP/metabolismo , Transducción de Señal , Lipopolisacáridos/farmacología , Proteínas de Choque Térmico/metabolismo , Metabolismo de los Lípidos , Mediadores de Inflamación/metabolismo , Inflamación/metabolismo , Supervivencia CelularRESUMEN
OBJECTIVE: To investigate functional expression of NKG2D on CD4 and CD8 T-cells in patients with giant cell arteritis (GCA) and polymyalgia rheumatica (PMR). METHODS: Peripheral blood was drawn from patients with GCA (n=16), PMR (n=78) and healthy controls (HC, n=64). Tissue samples were obtained from GCA patients and controls. Proliferation and cytokine production assays were performed using CFSE and intracellular IFN-γ or TNF-α staining, respectively, and flow cytometry analysis. Immunofluorescence and immunohistology were applied to analyse the presence of NKG2D-expressing T-cells and NKG2D-ligands in temporal arteries, respectively. mRNA levels of NKG2D-ligands were determined by RT-PCR. RESULTS: In both GCA and PMR patients, NKG2D was preferentially expressed on senescent CD4CD28(-) and CD8CD28(-), as well as on CD8CD28 T-cells. Frequencies of senescent T-cells were increased in GCA and PMR patients compared to HC. In GCA tissue samples, infiltrating T-cells were predominately CD28(-). NKG2D expressing T-cells concentrated around the vasa vasorum of the adventitia. Antigenic stimulation induced rapid up-regulation of NKG2D on CD4CD28(-) and CD4CD28 T-cells, whereas TNF-α and interleukin-15 enhanced NKG2D expression on senescent CD4 and CD8 T-cells only. NKG2D cross-linkage augmented anti-CD3 triggered proliferation, IFN-γ and TNF-α production of CD8 T-cells. In CD4CD28(-) T-cells, NKG2D ligation resulted in increased IFN-γ production only. NKG2D ligands were expressed in temporal arteries from GCA patients, particularly in the adventitial and medial layers of affected vessels. CONCLUSIONS: NKG2D is functionally expressed on CD4CD28(-) and CD8 T-cells in GCA and PMR. NKG2D-ligands are present in temporal arteries and may co-stimulate NKG2D expressing T-cells.
Asunto(s)
Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Arteritis de Células Gigantes/metabolismo , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismo , Polimialgia Reumática/metabolismo , Anciano , Anciano de 80 o más Años , Autoinmunidad , Estudios de Casos y Controles , Senescencia Celular , Femenino , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/metabolismo , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Interferón gamma/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Masculino , Persona de Mediana Edad , Reacción en Cadena en Tiempo Real de la Polimerasa , Transducción de Señal , Arterias Temporales/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Regulación hacia ArribaRESUMEN
An efficient and general cascade synthesis of pyrroles from nitroarenes using an acid-tolerant homogeneous iron catalyst is presented. Initial (transfer) hydrogenation using the commercially available iron-Tetraphos catalyst is followed by acid catalysed Paal-Knorr condensation. Both formic acid and molecular hydrogen can be used as green reductants in this process. Particularly, under transfer hydrogenation conditions, the homogeneous catalyst shows remarkable reactivity at low temperatures, high functional group tolerance and excellent chemoselectivity transforming a wide variety of substrates. Compared to classical heterogeneous catalysts, this system presents complementing reactivity, showing none of the typical side reactions such as dehalogenation, debenzylation, arene or olefin hydrogenation. It thereby enhances the chemical toolbox in terms of orthogonal reactivity. The methodology was successfully applied to the late-stage modification of multi-functional drug(-like) molecules as well as to the one-pot synthesis of the bioactive agent BM-635.
RESUMEN
B-cell depleting therapies result in diminished humoral immunity following vaccination against COVID-19, but our understanding on the impact on cellular immune responses is limited. Here, we performed a detailed analysis of cellular immunity following mRNA vaccination in patients receiving B-cell depleting therapy using ELISpot assay and flow cytometry. Anti-SARS-CoV-2 spike receptor-binding domain antibody assays were performed to elucidate B-cell responses. To complement our cellular analysis, we performed immunophenotyping for T- and B-cell subsets. We show that SARS-CoV-2 vaccination using mRNA vaccines elicits cellular T-cell responses in patients under B-cell depleting therapy. Some facets of this immune response including TNFα production of CD4+ T-cells and granzyme B production of CD8+ T-cells, however, are distinctly diminished in these patients. Consequently, it appears that the finely coordinated process of T-cell activation with a uniform involvement of CD4+ and CD8+ T-cells as seen in HCs is disturbed in autoimmune patients. In addition, we observed that immune cell composition does impact cellular immunity as well as sustainability of anti-spike antibody titers. Our data suggest disturbed cellular immunity following mRNA vaccination in patients treated with B-cell depleting therapy. Immune cell composition may be an important determinant for vaccination efficacy.
Asunto(s)
Autoinmunidad , COVID-19 , Humanos , SARS-CoV-2 , Linfocitos T CD8-positivos , Vacunas contra la COVID-19 , Inmunidad Celular , Anticuerpos Antivirales , VacunaciónRESUMEN
Immunosenescence is a state of dysregulated leukocyte function characterised by arrested cell cycle, telomere shortening, expression of markers of cellular stress, and secretion of pro-inflammatory mediators. Immunosenescence principally develops during aging, but it may also be induced in other pathological settings, such as chronic viral infections and autoimmune diseases. Appearance of senescent immune cells has been shown to potentially cause chronic inflammation and tissue damage, suggesting an important role for this process in organismal homeostasis. In particular, the presence of senescent T lymphocytes has been reported in neurological diseases, with some works pointing towards a direct connection between T cell senescence, inflammation and neuronal damage. In this minireview, we provide an overview on the role of T cell senescence in neurological disorders, in particular in multiple sclerosis and Alzheimer disease. We also discuss recent literature investigating how metabolic remodelling controls the development of a senescence phenotype in T cells. Targeting metabolic pathways involved in the induction of senescent T cells may indeed represent a novel approach to limit their inflammatory activity and prevent neuroinflammation and neurodegeneration.
Asunto(s)
Inmunosenescencia/inmunología , Degeneración Nerviosa/inmunología , Enfermedades Neuroinflamatorias/inmunología , Linfocitos T/patología , Animales , Humanos , Degeneración Nerviosa/patología , Enfermedades Neuroinflamatorias/patología , Linfocitos T/inmunologíaRESUMEN
BACKGROUND AND PURPOSE: The outbreak of the COVID-19 pandemic has resulted in an overall decline in fractures. However, the amount of hip fractures has remained relatively stable throughout the period. The objective of this study is to investigate the impact of perioperative COVID-19 infections on mortality among hip fracture patients. METHODS: A meta-analysis was performed by collecting current data available through a systematic literature search in the PubMed database. The search was performed Oct 18 2020. RESULTS: The meta-analysis was conducted on a trial population consisting of 1.272 hip fracture patients with a pooled prevalence of COVID-19 of 18%. Mortality among hip fracture patients without a perioperative COVID-19 infection was 7.49%. Mortality among hip fracture patients infected with COVID-19 perioperatively was associated with an odds ratio of 6.70 [(95% CI 4.64-9.68), p < 0.00001, I2 = 41%]. A sensitivity analysis showed no major impact of assumptions regarding varying definitions of COVID-19 statuses among the included studies. CONCLUSION: Perioperative infections with COVID-19 in hip fracture patients are correlated with a significantly increased mortality. The meta-analysis showed a pooled odds ratio of 6.70 [(95% CI 4.64-9.68), p < 0.00001, I2 = 41%].
Asunto(s)
COVID-19 , Fracturas de Cadera , Periodo Perioperatorio/mortalidad , SARS-CoV-2/aislamiento & purificación , COVID-19/diagnóstico , COVID-19/epidemiología , Comorbilidad , Fracturas de Cadera/epidemiología , Fracturas de Cadera/cirugía , Humanos , Mortalidad , Medición de RiesgoRESUMEN
Immunocompromised patients are considered high-risk and prioritized for vaccination against COVID-19. We aimed to analyze B-cell subsets in these patients to identify potential predictors of humoral vaccination response. Patients (n=120) suffering from hematologic malignancies or other causes of immunodeficiency and healthy controls (n=79) received a full vaccination series with an mRNA vaccine. B-cell subsets were analyzed prior to vaccination. Two independent anti-SARS-CoV-2 immunoassays targeting the receptor-binding domain (RBD) or trimeric S protein (TSP) were performed three to four weeks after the second vaccination. Seroconversion occurred in 100% of healthy controls, in contrast to 67% (RBD) and 82% (TSP) of immunocompromised patients, while only 32% (RBD) and 22% (TSP) achieved antibody levels comparable to those of healthy controls. The number of circulating CD19+IgD+CD27- naïve B cells was strongly associated with antibody levels (ρ=0.761, P<0.001) and the only independent predictor for achieving antibody levels comparable to healthy controls (OR 1.07 per 10-µL increase, 95%CI 1.02-1.12, P=0.009). Receiver operating characteristic analysis identified a cut-off at ≥61 naïve B cells per µl to discriminate between patients with and without an optimal antibody response. Consequently, measuring of naïve B cells in immunocompromised hematologic patients could be useful in predicting their humoral vaccination response.
Asunto(s)
Subgrupos de Linfocitos B/inmunología , Vacunas contra la COVID-19/inmunología , COVID-19/prevención & control , Huésped Inmunocomprometido/inmunología , Inmunogenicidad Vacunal/inmunología , Adulto , Anciano , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , SARS-CoV-2 , Vacunas Sintéticas/inmunología , Vacunas de ARNm/inmunologíaRESUMEN
(1) Background: Psoriatic Arthritis (PsA) is a painful disease of the joints and spine. Recent reports observed distinct enteric dysbiosis in PsA; intake of probiotic strains is considered to ameliorate enteric dysbiosis. If probiotics are effective in PsA is elusive. (2) Methods: In this pilot open-label study we enrolled 10 PsA patients with low to medium disease activity who received probiotics for 12 weeks. Analysis of faecal zonulin, α1-antitrypsin and calprotectin, as well as peripheral immune phenotyping was performed at baseline, after 12 weeks and 12 weeks after termination of probiotic intake. (3) Results: All patients showed increased levels of the enteric permeability marker zonulin which correlated with the frequency of peripheral Th17 cells. Calprotectin, a marker for intestinal inflammation was elevated in 6 out of 10 patients. Probiotic intake resulted in a reduction of disease activity and gut permeability. These effects, however, were not sustained beyond termination of probiotic intake. (4) Conclusions: PsA patients suffer from enhanced enteric permeability and inflammation. Probiotics may ameliorate disease activity in PsA by targeting these alterations.