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1.
Exp Clin Transplant ; 18(3): 275-283, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32519618

RESUMEN

OBJECTIVES: COVID-19 is a great threat to the modern world and significant threat to immunocompromised patients, including patients with chronic renal failure. We evaluated COVID-19 incidence among our hemodialysis patients and investigated the most probable immune mechanisms against COVID-19. MATERIALS AND METHODS: Baskent University has 21 dialysis centers across Turkey, with 2420 patients on hemodialysis and 30 on peritoneal dialysis. Among these, we retrospectively evaluated 602 patients (257 female/345 male) with chronic renal failure receiving hemodialysis as renal replacement therapy; 7 patients (1.1%) were infected with SARS-CoV-2. We retrospectively collected patient demographic characteristics, clinical data, and immunological factors affecting the clinical course of the disease. We divided patients into groups and included 2 control groups (individuals with normal renal functions): group I included COVID-19-positive patients with normal renal function, group II included COVID-19-positive hemodialysis patients, group III included COVID-19-negative hemodialysis patients, and group IV included COVID-19-negative patients with normal renal function. Lymphocyte subsets in peripheral blood and typing of human leukocyte antigens were analyzed in all groups, with killer cell immunoglobulin like receptor genes analyzed only in COVID-19-positive patients and healthy controls. RESULTS: No deaths occurred among the 7 COVID-19-positive hemodialysis patients. Group I patients were significantly older than patients in groups II and III (P = .039, P = .030, respectively) but not significantly different from group IV (P = .060). Absolute counts of natural killer cells in healthy controls were higherthan in other groups (but not significantly). ActivatedT cells were significantly increased in both COVID-19-positive groups versus COVID-19-negative groups. Groups showed significant differences in C and DQ loci with respect to distribution of alleles in both HLA classes. CONCLUSIONS: Although immunocompromised patients are at greater risk for COVID-19, we found lower COVID-19 incidence in our hemodialysis patients, which should be further investigated in in vitro and molecular studies.


Asunto(s)
Betacoronavirus/inmunología , Infecciones por Coronavirus/epidemiología , Huésped Inmunocomprometido , Fallo Renal Crónico/terapia , Infecciones Oportunistas/epidemiología , Neumonía Viral/epidemiología , Diálisis Renal/efectos adversos , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Betacoronavirus/patogenicidad , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/virología , Femenino , Antígenos HLA/inmunología , Interacciones Huésped-Patógeno , Humanos , Incidencia , Fallo Renal Crónico/diagnóstico , Fallo Renal Crónico/epidemiología , Fallo Renal Crónico/inmunología , Células Asesinas Naturales/inmunología , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Infecciones Oportunistas/diagnóstico , Infecciones Oportunistas/inmunología , Infecciones Oportunistas/virología , Pandemias , Neumonía Viral/diagnóstico , Neumonía Viral/inmunología , Neumonía Viral/virología , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Linfocitos T/inmunología , Resultado del Tratamiento , Turquia/epidemiología , Adulto Joven
2.
In Vivo ; 34(3 Suppl): 1593-1596, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32503816

RESUMEN

The Covid-19 pandemic is a world-wide crisis without an effective therapy. While most approaches to therapy are using repurposed drugs that were developed for other diseases, it is thought that targeting the biology of the SARS-CoV-2 virus, which causes Covid-19, can result in an effective therapeutic treatment. The coronavirus RNA cap structure is methylated by two viral methyltransferases that transfer methyl groups from S-adenosylmethionine (SAM). The proper methylation of the virus depends on the level of methionine in the host to form SAM. Herein, we propose to restrict methionine availability by treating the patient with oral recombinant methioninase, aiming to treat Covid-19. By restricting methionine we not only interdict viral replication, which depends on the viral RNA cap methyaltion, but also inhibit the proliferation of the infected cells, which have an increased requirement for methionine. Most importantly, the virally-induced T-cell- and macrophage-mediated cytokine storm, which seems to be a significant cause for Covid-19 deaths, can also be inhibited by restricting methionine, since T-cell and macrophrage activation greatly increases the methionine requirement for these cells. The evidence reviewed here suggests that oral recombinant methioninase could be a promising treatment for coronavirus patients.


Asunto(s)
Antivirales/uso terapéutico , Betacoronavirus/efectos de los fármacos , Liasas de Carbono-Azufre/uso terapéutico , Infecciones por Coronavirus/tratamiento farmacológico , Metionina/metabolismo , Neumonía Viral/tratamiento farmacológico , Caperuzas de ARN/efectos de los fármacos , Procesamiento Postranscripcional del ARN/efectos de los fármacos , ARN Viral/efectos de los fármacos , Administración Oral , Antivirales/administración & dosificación , Proteínas Bacterianas/administración & dosificación , Proteínas Bacterianas/uso terapéutico , Betacoronavirus/fisiología , Liasas de Carbono-Azufre/administración & dosificación , Ensayos Clínicos como Asunto , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/inmunología , Síndrome de Liberación de Citoquinas/prevención & control , Humanos , Activación de Linfocitos/efectos de los fármacos , Activación de Macrófagos/efectos de los fármacos , Metaanálisis como Asunto , Metilación/efectos de los fármacos , Pandemias , Neumonía Viral/complicaciones , Neumonía Viral/inmunología , Pseudomonas putida/enzimología , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/uso terapéutico , S-Adenosilmetionina/metabolismo , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/inmunología , Replicación Viral/efectos de los fármacos
3.
Nature ; 581(7807): 204-208, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32405000

RESUMEN

It has been speculated that brain activities might directly control adaptive immune responses in lymphoid organs, although there is little evidence for this. Here we show that splenic denervation in mice specifically compromises the formation of plasma cells during a T cell-dependent but not T cell-independent immune response. Splenic nerve activity enhances plasma cell production in a manner that requires B-cell responsiveness to acetylcholine mediated by the α9 nicotinic receptor, and T cells that express choline acetyl transferase1,2 probably act as a relay between the noradrenergic nerve and acetylcholine-responding B cells. We show that neurons in the central nucleus of the amygdala (CeA) and the paraventricular nucleus (PVN) that express corticotropin-releasing hormone (CRH) are connected to the splenic nerve; ablation or pharmacogenetic inhibition of these neurons reduces plasma cell formation, whereas pharmacogenetic activation of these neurons increases plasma cell abundance after immunization. In a newly developed behaviour regimen, mice are made to stand on an elevated platform, leading to activation of CeA and PVN CRH neurons and increased plasma cell formation. In immunized mice, the elevated platform regimen induces an increase in antigen-specific IgG antibodies in a manner that depends on CRH neurons in the CeA and PVN, an intact splenic nerve, and B cell expression of the α9 acetylcholine receptor. By identifying a specific brain-spleen neural connection that autonomically enhances humoral responses and demonstrating immune stimulation by a bodily behaviour, our study reveals brain control of adaptive immunity and suggests the possibility to enhance immunocompetency by behavioural intervention.


Asunto(s)
Conducta Animal/fisiología , Encéfalo/fisiología , Inmunidad Humoral/inmunología , Bazo/inmunología , Bazo/inervación , Acetilcolina/metabolismo , Acetilcolina/farmacología , Neuronas Adrenérgicas/metabolismo , Amígdala del Cerebelo/citología , Amígdala del Cerebelo/efectos de los fármacos , Amígdala del Cerebelo/metabolismo , Animales , Encéfalo/citología , Encéfalo/efectos de los fármacos , Colina O-Acetiltransferasa/metabolismo , Hormona Liberadora de Corticotropina/metabolismo , Hemocianinas/inmunología , Inmunoglobulina G/inmunología , Activación de Linfocitos , Masculino , Ratones , Núcleo Hipotalámico Paraventricular/citología , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Núcleo Hipotalámico Paraventricular/metabolismo , Células Plasmáticas/citología , Células Plasmáticas/efectos de los fármacos , Células Plasmáticas/inmunología , Receptores Nicotínicos/deficiencia , Receptores Nicotínicos/metabolismo , Bazo/citología , Bazo/efectos de los fármacos , Estrés Psicológico/inmunología , Estrés Psicológico/metabolismo , Linfocitos T/inmunología
4.
Scand J Immunol ; 92(1): e12886, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-32243615

RESUMEN

This study aimed to investigate the effect of long non-coding RNA XLOC_003810 on the activation of CD4+ T cells and expression of PD-1/PD-L1 in patients with myasthenia gravis-related thymoma (MG-T). Thymus specimens and thymic mononuclear cells were obtained from MG and MG-T patients or cardiac surgery patients undergoing thoracotomy who were selected as negative controls (NC). XLOC_003810 expression was examined using quantitative real-time PCR (qRT-PCR). Frequency of CD4+ T cells and proportion of CD4+ PD-1+ T cells and CD14+ PD-L1+ monocytes were quantified by flow cytometry. The release of inflammatory cytokines was measured by qRT-PCR and enzyme-linked immunosorbent assay. Compared with the NC group, expression of XLOC_003810, frequency of CD4+ T cells and the production of inflammatory cytokines were increased in patients with MG and MG-T. XLOC_003810 overexpression significantly increased the frequency of CD4+ T cells, facilitated the production of inflammatory cytokines and decreased the proportion of CD4+ PD-1+ T cells and CD14+ PD-L1+ monocytes in the thymic mononuclear cells. In contrast, XLOC_003810 knockdown exerted the opposite effect. Together, XLOC_003810 promotes T cell activation and inhibits PD-1/PD-L1 pathway in patients with MG-T.


Asunto(s)
Antígeno B7-H1/biosíntesis , Linfocitos T CD4-Positivos/inmunología , Miastenia Gravis/genética , ARN Largo no Codificante/genética , Timoma/genética , Neoplasias del Timo/genética , Recuento de Linfocito CD4 , Citocinas/metabolismo , Femenino , Citometría de Flujo , Humanos , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Masculino , Persona de Mediana Edad , Miastenia Gravis/inmunología , Miastenia Gravis/patología , Receptores Colinérgicos/inmunología , Timoma/inmunología , Timo/inmunología , Timo/patología , Neoplasias del Timo/inmunología
6.
Scand J Immunol ; 91(6): e12881, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32243636

RESUMEN

Increasing prevalence of allergic and autoimmune diseases urges clinicians and researchers to search for new and efficient treatments. Strategies that activate antigen-specific immune tolerance and simultaneously maintain immune reactivity to all other antigens deserve special attention. Accordingly, antigen-presenting cells (APCs) seem to be the best suited for orchestrating these mechanisms by directing T cell immune responses towards a tolerant subtype. Recent advances in understanding cell-to-cell communication via extracellular vesicles (EVs) make the latter promising candidates for reprogramming APCs towards a tolerant phenotype, and for mediating tolerogenic APC function. Thus, comprehensive studies have been undertaken to describe the interactions of APCs and EVs naturally occurring during immune tolerance induction, as well as to develop EV-based manoeuvres enabling the induction of immune tolerance in an antigen-specific manner. In this review, we summarize the findings of relevant studies, with a special emphasis on future perspectives on their translation to clinical practice.


Asunto(s)
Enfermedades Autoinmunes/inmunología , Linfocitos B/inmunología , Vesículas Extracelulares/inmunología , Hipersensibilidad/inmunología , Linfocitos T/inmunología , Animales , Autoantígenos/inmunología , Autoinmunidad , Epítopos , Humanos , Activación de Linfocitos , Especificidad del Receptor de Antígeno de Linfocitos T
7.
Scand J Immunol ; 91(6): e12888, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32281665

RESUMEN

We propose a framework to explain how T cells achieve specificity and sensitivity, how the affinity of the TcR peptide/MHC interaction controls positive and negative thymic selection and mature T cell survival, and whether antigen-dependent activation and inactivation takes place. Two distinct types of signalling can lead to mature T cell multiplication. One requires the TcR to recognize with a certain affinity an antigen-derived peptide, an agonist peptide, bound to an MHC molecule. The other, the tonic signal, leads to naïve T cell survival and modest proliferation if the T cell successfully competes for endogenous, self-peptide/MHC ligands, involving lower affinity TCR/ligand interactions. Many suggest lymphopenia contributes to autoimmunity by increasing the strength of TcR-tonic signalling, and so activation of anti-self T cells. We suggest T cell activation requires antigen-mediated cooperation between T cells. Increased tonic signalling under lymphopenic conditions facilitates T cell proliferation and so antigen-dependent cooperation and activation of anti-self T cells.


Asunto(s)
Linfopenia/inmunología , Especificidad del Receptor de Antígeno de Linfocitos T , Linfocitos T/inmunología , Animales , Presentación de Antígeno , Autoantígenos/inmunología , Autoantígenos/metabolismo , Autoinmunidad , Comunicación Celular , Diferenciación Celular , Supervivencia Celular , Antígenos de Histocompatibilidad/metabolismo , Humanos , Activación de Linfocitos , Modelos Inmunológicos , Fragmentos de Péptidos/inmunología , Fragmentos de Péptidos/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal
8.
Nat Commun ; 11(1): 1114, 2020 02 28.
Artículo en Inglés | MEDLINE | ID: mdl-32111837

RESUMEN

Little is known regarding lymph node (LN)-homing of immune cells via afferent lymphatics. Here, we show, using a photo-convertible Dendra-2 reporter, that recently activated CD4 T cells enter downstream LNs via afferent lymphatics at high frequencies. Intra-lymphatic immune cell transfer and live imaging data further show that activated T cells come to an instantaneous arrest mediated passively by the mechanical 3D-sieve barrier of the LN subcapsular sinus (SCS). Arrested T cells subsequently migrate randomly on the sinus floor independent of both chemokines and integrins. However, chemokine receptors are imperative for guiding cells out of the SCS, and for their subsequent directional translocation towards the T cell zone. By contrast, integrins are dispensable for LN homing, yet still contribute by increasing the dwell time within the SCS and by potentially enhancing T cell sensing of chemokine gradients. Together, these findings provide fundamental insights into mechanisms that control homing of lymph-derived immune cells.


Asunto(s)
Linfocitos T CD4-Positivos/fisiología , Movimiento Celular/inmunología , Quimiocinas/metabolismo , Integrinas/metabolismo , Ganglios Linfáticos/fisiología , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Endotelio Linfático/fisiología , Integrinas/genética , Linfa/citología , Ganglios Linfáticos/citología , Activación de Linfocitos , Ratones , Receptores de Quimiocina/genética , Receptores de Quimiocina/metabolismo , Receptores Mensajeros de Linfocitos/metabolismo
9.
Scand J Immunol ; 91(5): e12865, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32185817

RESUMEN

Plasmacytoid dendritic cells (pDCs) regulate immunity and promote tolerance in asthma. Notch signalling is a highly conserved pathway that regulates the immune response; however, its role in pDC-mediated asthmatic airway inflammation is unclear. This study clarified the effects of Notch signalling on pDC-mediated airway inflammation using murine models of ovalbumin-sensitized allergic asthma. RBP-J-deficient pDCs (RBP-J-/- pDCs) were co-cultured with naïve CD4+ T cells and supernatants and T cell subtypes were analysed. RBP-J-/- pDCs were intranasally transferred to the airways of ovalbumin-sensitized recipient mice. Lung samples of all mice were subjected to tests for histopathology, cytokine profile of bronchoalveolar lavage fluid, airway hyperactivity and expression of T helper type 1 (Th1)/Th2 cells, regulatory T cells and type 2 innate lymphoid cells (ILC2s). The results showed that pDCs with and without RBP-J deficiency significantly differed in expression levels of cluster of differentiation 83 (CD83), but not CD80, CD86 and major histocompatibility complex class II. Co-culturing pDCs with naïve T cells revealed a poorer immunosuppressive effect of RBP-J-/- pDCs. This may be attributed to the lower expression levels of inducible co-stimulator ligand and lower production of interleukin 10 in RBP-J-/- pDCs than in control pDCs, which impeded T cell activation and Treg suppression. RBP-J-/- pDCs were associated with high ILC2 expression and severe Th2 immune responses and airway inflammation. Therefore, Notch signalling is critical for pDC-dependent immunoregulation, and RBP-J deficiency reduces pDC-based immunosuppression via T cell activation and Th cell differentiation. Thus, this pathway may be a therapeutic target for pDC-based anti-asthma immunotherapy.


Asunto(s)
Diferenciación Celular , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Inmunomodulación , Receptores Notch/metabolismo , Transducción de Señal , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Animales , Asma/etiología , Asma/metabolismo , Asma/patología , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Femenino , Expresión Génica , Humanos , Ligando Coestimulador de Linfocitos T Inducibles/genética , Ligando Coestimulador de Linfocitos T Inducibles/metabolismo , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Ratones , Células Th2/inmunología , Células Th2/metabolismo
10.
Nat Immunol ; 21(4): 400-411, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32123373

RESUMEN

Mucosal-associated invariant T (MAIT) cells are activated by microbial riboflavin-based metabolite antigens when presented by MR1. How modifications to the potent antigen 5-OP-RU affect presentation by MR1 and MAIT cell activation remains unclear. Here we design 20 derivatives, termed altered metabolite ligands (AMLs), to dissect the impact of different antigen components on the human MAIT-MR1 axis. Analysis of 11 crystal structures of MAIT T cell antigen receptor (TCR)-MR1-AML ternary complexes, along with biochemical and functional assays, shows that MR1 cell-surface upregulation is influenced by ribityl and non-ribityl components of the ligand and the hydrophobicity of the MR1-AML interface. The polar ribityl chain of the AML strongly influences MAIT cell activation potency through dynamic compensatory interactions within a MAIT TCR-MR1-AML interaction triad. We define the basis by which the MAIT TCR can differentially recognize AMLs, thereby providing insight into MAIT cell antigen specificity and potency.


Asunto(s)
Antígenos/inmunología , Células T Invariantes Asociadas a Mucosa/inmunología , Línea Celular Tumoral , Humanos , Células Jurkat , Ligandos , Activación de Linfocitos/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Riboflavina/inmunología
11.
Science ; 367(6483): 1255-1260, 2020 03 13.
Artículo en Inglés | MEDLINE | ID: mdl-32165587

RESUMEN

T cells maintain a quiescent state prior to activation. As inappropriate T cell activation can cause disease, T cell quiescence must be preserved. Despite its importance, the mechanisms underlying the "quiescent state" remain elusive. Here, we identify BTG1 and BTG2 (BTG1/2) as factors responsible for T cell quiescence. BTG1/2-deficient T cells show an increased proliferation and spontaneous activation due to a global increase in messenger RNA (mRNA) abundance, which reduces the threshold to activation. BTG1/2 deficiency leads to an increase in polyadenylate tail length, resulting in a greater mRNA half-life. Thus, BTG1/2 promote the deadenylation and degradation of mRNA to secure T cell quiescence. Our study reveals a key mechanism underlying T cell quiescence and suggests that low mRNA abundance is a crucial feature for maintaining quiescence.


Asunto(s)
Proteínas Inmediatas-Precoces/fisiología , Activación de Linfocitos , Proteínas de Neoplasias/fisiología , Estabilidad del ARN , ARN Mensajero/química , Linfocitos T/inmunología , Proteínas Supresoras de Tumor/fisiología , Animales , Células Cultivadas , Proteínas Inmediatas-Precoces/genética , Ratones , Ratones Noqueados , Proteínas de Neoplasias/genética , Poliadenilación , Proteínas Supresoras de Tumor/genética
12.
Nat Immunol ; 21(4): 388-399, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32205878

RESUMEN

Understanding the mechanisms that modulate helper T lymphocyte functions is crucial to decipher normal and pathogenic immune responses in humans. To identify molecular determinants influencing the pathogenicity of T cells, we separated ex vivo-isolated primary human memory T lymphocytes on the basis of their ability to produce high levels of inflammatory cytokines. We found that the inflammatory, cytokine-producing phenotype of memory T lymphocytes was defined by a specific core gene signature and was mechanistically regulated by the constitutive activation of the NF-κB pathway and by the expression of the transcriptional repressor BHLHE40. BHLHE40 attenuated the expression of anti-inflammatory factors, including miR-146a, a negative regulator of NF-κB activation and ZC3H12D, an RNase of the Regnase-1 family able to degrade inflammatory transcripts. Our data reveal a molecular network regulating the proinflammatory phenotype of human memory T lymphocytes, with the potential to contribute to disease.


Asunto(s)
Regulación de la Expresión Génica/inmunología , Memoria Inmunológica/inmunología , Inflamación/inmunología , Línea Celular , Línea Celular Tumoral , Citocinas/inmunología , Células HEK293 , Humanos , Células Jurkat , Activación de Linfocitos/inmunología , FN-kappa B/inmunología , Fenotipo , Linfocitos T/inmunología
13.
Adv Exp Med Biol ; 1248: 7-32, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32185705

RESUMEN

Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is an inhibitory receptor belonging to the CD28 immunoglobulin subfamily, expressed primarily by T-cells. Its ligands, CD80 and CD86, are typically found on the surface of antigen-presenting cells and can either bind CD28 or CTLA-4, resulting in a costimulatory or a co-inhibitory response, respectively. Because of its dampening effect, CTLA-4 is a crucial regulator of T-cell homeostasis and self-tolerance. The mechanisms by which CTLA-4 exerts its inhibitory function can be categorized as either cell-intrinsic (affects the CTLA-4 expressing T-cell) or cell-extrinsic (affects secondary cells). Research from the last decade has shown that CTLA-4 mainly acts in a cell-extrinsic manner via its competition with CD28, CTLA-4-mediated trans-endocytosis of CD80 and CD86, and its direct tolerogenic effects on the interacting cell. Nonetheless, intrinsic CTLA-4 signaling has been implicated in T-cell motility and the regulation of CTLA-4 its subcellular localization amongst others. CTLA-4 is well recognized as a key immune checkpoint and has gained significant momentum as a therapeutic target in the field of autoimmunity and cancer. In this chapter, we describe the role of costimulation in immune response induction as well as the main mechanisms by which CTLA-4 can inhibit this process.


Asunto(s)
Antígeno CTLA-4/inmunología , Antígeno CTLA-4/metabolismo , Animales , Antígeno B7-1/metabolismo , Antígeno B7-2/metabolismo , Antígenos CD28/metabolismo , Humanos , Activación de Linfocitos
14.
Mol Cell ; 77(5): 930-931, 2020 03 05.
Artículo en Inglés | MEDLINE | ID: mdl-32142689

RESUMEN

Okazaki and colleagues report that PD-1 signaling mainly restrains effector function at the early stage of T cell activation. The authors find that cytokine genes require strong antigen stimulation and are more susceptible to PD-1 inhibition.


Asunto(s)
Receptor de Muerte Celular Programada 1/genética , Linfocitos T/inmunología , Activación de Linfocitos , Transducción de Señal , Transcriptoma
15.
J Antimicrob Chemother ; 75(7): 1667-1670, 2020 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-32196083

RESUMEN

A novel coronavirus disease (COVID-19), caused by infection with SARS-CoV-2, has swept across 31 provinces in China and over 40 countries worldwide. The transition from first symptoms to acute respiratory distress syndrome (ARDS) is highly likely to be due to uncontrolled cytokine release. There is an urgent need to identify safe and effective drugs for treatment. Chloroquine (CQ) exhibits a promising inhibitory effect. However, the clinical use of CQ can cause severe side effects. We propose that hydroxychloroquine (HCQ), which exhibits an antiviral effect highly similar to that of CQ, could serve as a better therapeutic approach. HCQ is likely to attenuate the severe progression of COVID-19, inhibiting the cytokine storm by suppressing T cell activation. It has a safer clinical profile and is suitable for those who are pregnant. It is cheaper and more readily available in China. We herein strongly urge that clinical trials are performed to assess the preventive effects of HCQ in both disease infection and progression.


Asunto(s)
Infecciones por Coronavirus/tratamiento farmacológico , Hidroxicloroquina/uso terapéutico , Neumonía Viral/tratamiento farmacológico , Betacoronavirus , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Síndrome de Liberación de Citoquinas/prevención & control , Progresión de la Enfermedad , Humanos , Hidroxicloroquina/efectos adversos , Activación de Linfocitos/efectos de los fármacos , Pandemias , Síndrome de Dificultad Respiratoria del Adulto/tratamiento farmacológico , Síndrome de Dificultad Respiratoria del Adulto/prevención & control , Síndrome de Dificultad Respiratoria del Adulto/virología , Linfocitos T/efectos de los fármacos
16.
Exerc Immunol Rev ; 26: 116-131, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32139354

RESUMEN

Type 1 diabetes (T1D) is a T cell mediated autoimmune disease that targets and destroys insulin-secreting pancreatic beta cells. Although T cell mediated, a number of other immune cells are also critically involved in coordinating the events leading to T1D. Specifically, innate subsets play an important role in the pathogenesis of T1D. NK cells are one of the first cell types to infiltrate the pancreas, causing damage and release of beta cell antigens. Previous work in our group has shown differential mobilisation of highly differentiated CD8+ T cells during vigorous intensity exercise in T1D compared to a control cohort. Here, we aimed to explore exercise-induced mobilisation of other cell types involved in T1D pathogenesis. In this study, we investigated the effects of a single bout of vigorous (80% predicted VO2max) intensity exercise on innate cell mobilisation in T1D and control participants. T1D (N=12, mean age 33.2yrs, predicted VO2max 32.2 ml.kg.min⁻¹, BMI 25.3 kg.m⁻²) and control (N=12, mean age 29.4yrs, predicted VO2 max 38.5 ml.kg.min⁻¹, BMI 23.7 kg.m⁻² male participants completed a 30-minute bout of cycling at 80% predicted VO2 max in a fasted state. Peripheral blood was collected at baseline, immediately post-exercise, and 1 hour post-exercise. NK cell subsets mobilised during vigorous intensity exercise in both control and T1D participants. However, mature NK cells, defined as the CD56dimCD16bright subset, displayed a lower percentage increase following vigorous intensity exercise in T1D participants (Control: 185.12%, T1D: 97.06%). This blunted mobilisation was specific to early mature NK cells (KIR+) but not later differentiated NK cells (KIR+CD57+). Myeloid lineage subsets mobilised to a similar extent in both control and T1D participants. In conclusion, vigorous exercise mobilises innate immune cells in people with T1D albeit to a different extent to those without T1D. This mobilisation of innate immune cells provides a mechanistic argument to support exercise in people with T1D where it has the potential to improve surveillance for infection and to modulate the autoimmune response to the beta cell.


Asunto(s)
Diabetes Mellitus Tipo 1/inmunología , Ejercicio Físico , Células Asesinas Naturales/citología , Activación de Linfocitos , Adulto , Antígeno CD56 , Proteínas Ligadas a GPI , Humanos , Masculino , Receptores de IgG
17.
Ann Rheum Dis ; 79(4): 518-524, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32114510

RESUMEN

BACKGROUND: Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease characterised by aberrant B cell hyperactivation, whose mechanism is partially understood. METHODS: We performed whole transcriptome sequencing of B cells from three pSS patients and three matched healthy controls (HC). Differentially expression genes (DEGs) were confirmed with B cells from 40 pSS patients and 40 HC by quantitative PCR and western blot. We measured the proliferation potential and immunoglobulins production of siRNA-transfected or plasmid-transfected B cells stimulated with cytosine-phosphate-guanine (CpG) or anti-IgM. We also explored Toll-like receptor 9 (TLR9) signalling to reveal the potential mechanism of B cell hyperactivation in pSS. RESULTS: We identified 77 upregulated and 32 downregulated DEGs in pSS B cells. We confirmed that epithelial stromal interaction (EPST1) expression in pSS B cells was significantly higher than that from HCs. EPSTI1-silencing B cells stimulated with CpG were less proliferated and produced lower level of IgG and IgM comparing with control B cells. EPSTI1-silencing B cells expressed lower level of p-p65 and higher level of IκBα, and B cells with overexpressed EPSTI1 showed higher level of p-p65 and lower level of IκBα. Finally, IκBα degradation inhibitor Dehydrocostus Lactone treatment attenuated p65 phosphorylation promoted by EPSTI1. CONCLUSION: Elevated EPSTI1 expression in pSS B cells promoted TLR9 signalling activation and contributed to the abnormal B cell activation, which was promoted by facilitating p65 phosphorylation and activation of NF-κB signalling via promoting IκBα degradation. EPSTI1 might be implicated in pSS pathogenesis and was a potential therapeutic target of pSS.


Asunto(s)
Linfocitos B/inmunología , Activación de Linfocitos/inmunología , FN-kappa B/inmunología , Proteínas de Neoplasias/inmunología , Síndrome de Sjögren/inmunología , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Lactonas , Masculino , Persona de Mediana Edad , Inhibidor NF-kappaB alfa/inmunología , Inhibidor NF-kappaB alfa/metabolismo , FN-kappa B/metabolismo , Proteínas de Neoplasias/metabolismo , Fosforilación , ARN Interferente Pequeño , Sesquiterpenos , Síndrome de Sjögren/metabolismo , Receptor Toll-Like 9/inmunología , Receptor Toll-Like 9/metabolismo , Factor de Transcripción ReIA/inmunología , Factor de Transcripción ReIA/metabolismo , Adulto Joven
18.
Scand J Immunol ; 91(6): e12880, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32219875

RESUMEN

Synthetic Toll-like receptor (TLR) 7 agonists have been suggested as immune modulators in a range of conditions. In contrast, self-derived TLR7 activators, such as RNA-containing immune complexes (RNA-IC), can contribute to autoimmune diseases due to endogenous immune activation. The exact difference in immune cell response between synthetic and endogenous TLR7 triggers is only partly known. An understanding of these differences could aid in the development of new therapeutic agents and provide insights into autoimmune disease mechanisms. We therefore compared the stimulatory capacity of two TLR7 agonists, RNA-IC and a synthetic small molecule DSR-6434, on blood leucocytes, plasmacytoid dendritic cells (pDCs) and B cells from healthy individuals. IFN-α, IL-6, IL-8 and TNF levels were measured by immunoassays, and gene expression in pDCs was analysed by an expression array. DSR-6434 triggered 20-fold lower levels of IFN-α by pDCs, but higher production of IL-6, IL-8 and TNF, compared to RNA-IC. Furthermore, IFN-α and TNF production were increased with exogenous IFN-α2b priming, whereas IL-8 synthesis by B cells was reduced for both stimuli. Cocultivation of pDCs and B cells increased the RNA-IC-stimulated IFN-α and TNF levels, while only IL-6 production was enhanced in the DSR-6434-stimulated cocultures. When comparing pDCs stimulated with RNA-IC and DSR-6434, twelve genes were differentially expressed (log2 fold change >2, adjusted P-value <.05). In conclusion, RNA-IC, which mimics an endogenous TLR7 stimulator, and the synthetic TLR7 agonist DSR-6434 trigger distinct inflammatory profiles in immune cells. This demonstrates the importance of using relevant stimuli when targeting the TLR7 pathway for therapeutic purposes.


Asunto(s)
Adenina/farmacología , Complejo Antígeno-Anticuerpo/farmacología , Linfocitos B/inmunología , Células Dendríticas/inmunología , Complejos Multiproteicos/farmacología , ARN/farmacología , Receptor Toll-Like 7/metabolismo , Adenina/análogos & derivados , Adenina/química , Complejo Antígeno-Anticuerpo/química , Diferenciación Celular , Células Cultivadas , Citocinas/metabolismo , Perfilación de la Expresión Génica , Humanos , Mediadores de Inflamación/metabolismo , Activación de Linfocitos , Estructura Molecular , Complejos Multiproteicos/química , ARN/química , Receptor Toll-Like 7/agonistas
19.
Am J Pathol ; 190(6): 1224-1235, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32201264

RESUMEN

Intratracheal instillation of apoptotic cells enhances resolution of experimental lung inflammation by incompletely understood mechanisms. We report that this intervention induces functional regulatory T lymphocytes (Tregs) in mouse lung experimentally inflamed by intratracheal administration of lipopolysaccharide. Selective depletion demonstrated that Tregs were necessary for maximal apoptotic cell-directed enhancement of resolution, and adoptive transfer of additional Tregs was sufficient to promote resolution without administering apoptotic cells. After intratracheal instillation, labeled apoptotic cells were observed in most CD11c+CD103+ myeloid dendritic cells migrating to mediastinal draining lymph nodes and bearing migratory and immunoregulatory markers, including increased CCR7 and ß8 integrin (ITGB8) expression. In mice deleted for αv integrin in the myeloid line to reduce phagocytosis of dying cells by CD103+ dendritic cells, exogenous apoptotic cells failed to induce transforming growth factor-ß1 expression or Treg accumulation and failed to enhance resolution of lipopolysaccharide-induced lung inflammation. We conclude that in murine lung, myeloid phagocytes encountering apoptotic cells can deploy αv integrin-mediated mechanisms to induce Tregs and enhance resolution of acute inflammation.


Asunto(s)
Apoptosis/fisiología , Integrina alfaV/metabolismo , Neumonía/metabolismo , Linfocitos T Reguladores/metabolismo , Traslado Adoptivo , Animales , Factores de Transcripción Forkhead/metabolismo , Activación de Linfocitos , Depleción Linfocítica , Ratones , Fagocitosis/fisiología , Neumonía/patología
20.
Nat Commun ; 11(1): 1187, 2020 03 04.
Artículo en Inglés | MEDLINE | ID: mdl-32132528

RESUMEN

Induction of antigen-specific immune activation by the maturation of dendritic cells (DCs) is a strategy used for cancer immunotherapy. In this study, we find that FimH, which is an Escherichia coli adhesion portion, induces toll-like receptor 4-dependent and myeloid differentiation protein 2-independent DC maturation in mice in vivo. A combined treatment regimen with FimH and antigen promotes antigen-specific immune activation, including proliferation of T cells, production of IFN-γ and TNF-α, and infiltration of effector T cells into tumors, which consequently inhibits tumor growth in mice in vivo against melanoma and carcinoma. In addition, combined therapeutic treatment of anti-PD-L1 antibodies and FimH treatment efficiently inhibits CT26 tumor growth in BALB/c mice. Finally, FimH promotes human peripheral blood DC activation and syngeneic T-cell proliferation and activation. Taken together, these findings demonstrate that FimH can be a useful adjuvant for cancer immunotherapy.


Asunto(s)
Adhesinas de Escherichia coli/administración & dosificación , Adyuvantes Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/administración & dosificación , Células Dendríticas/inmunología , Proteínas Fimbrias/administración & dosificación , Inmunoterapia Adoptiva/métodos , Neoplasias/terapia , Adhesinas de Escherichia coli/inmunología , Animales , Línea Celular Tumoral/trasplante , Proliferación Celular , Células Dendríticas/metabolismo , Modelos Animales de Enfermedad , Proteínas Fimbrias/inmunología , Humanos , Activación de Linfocitos , Ratones , Neoplasias/inmunología , Neoplasias/patología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Receptores Quiméricos de Antígenos/inmunología , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/inmunología , Linfocitos T/inmunología , Receptor Toll-Like 4/metabolismo
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