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1.
Front Cell Infect Microbiol ; 11: 624483, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33718270

RESUMEN

The immune response type organized against viral infection is determinant in the prognosis of some infections. This work has aimed to study Th polarization in acute COVID-19 and its possible association with the outcome through an observational prospective study. Fifty-eight COVID-19 patients were recruited in the Medicine Department of the hospital "12 de Octubre," 55 patients remaining after losses to follow-up. Four groups were established according to maximum degree of disease progression. T-helper cell percentages and phenotypes, analyzed by flow cytometer, and serum cytokines levels, analyzed by Luminex, were evaluated when the microbiological diagnosis (acute phase) of the disease was obtained. Our study found a significant reduction of %Th1 and %Th17 cells with higher activated %Th2 cells in the COVID-19 patients compared with reference population. A higher percent of senescent Th2 cells was found in the patients who died than in those who survived. Senescent Th2 cell percentage was an independent risk factor for death (OR: 13.88) accompanied by the numbers of total lymphocytes (OR: 0.15) with an AUC of 0.879. COVID-19 patients showed a profile of pro-inflammatory serum cytokines compared to controls, with higher levels of IL-2, IL-6, IL-15, and IP-10. IL-10 and IL-13 were also elevated in patients compared to controls. Patients who did not survive presented significantly higher levels of IL-15 than those who recovered. No significant differences were observed according to disease progression groups. The study has shown that increased levels of IL-15 and a high Th2 response are associated with a fatal outcome of the disease.


Asunto(s)
/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Adulto , Anciano , /patología , Citocinas/sangre , Progresión de la Enfermedad , Femenino , Humanos , Inmunidad , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estudios Prospectivos , Células TH1/inmunología , Células Th17/inmunología , Células Th2/inmunología
2.
Nat Commun ; 12(1): 1534, 2021 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-33750787

RESUMEN

Regulatory B cells (Bregs) contribute to immune regulation. However, the mechanisms of action of Bregs remain elusive. Here, we report that T cell immunoreceptor with Ig and ITIM domains (TIGIT) expressed on human memory B cells especially CD19+CD24hiCD27+CD39hiIgD-IgM+CD1c+ B cells is essential for effective immune regulation. Mechanistically, TIGIT on memory B cells controls immune response by directly acting on T cells and by arresting proinflammatory function of dendritic cells, resulting in the suppression of Th1, Th2, Th17, and CXCR5+ICOS+ T cell response while promoting immune regulatory function of T cells. TIGIT+ memory B cells are also superior to other B cells at expressing additional inhibitory molecules, including IL-10, TGFß1, granzyme B, PD-L1, CD39/CD73, and TIM-1. Lack or decrease of TIGIT+ memory B cells is associated with increased donor-specific antibody and TFH response, and decreased Treg response in renal and liver allograft patients. Therefore, TIGIT+ human memory B cells play critical roles in immune regulation.


Asunto(s)
Linfocitos B Reguladores/inmunología , Linfocitos B/inmunología , Receptores Inmunológicos/inmunología , Antígenos CD/metabolismo , Antígenos CD1 , Antígenos CD19 , Apirasa/metabolismo , Antígeno B7-H1 , Antígeno CD24/metabolismo , Glicoproteínas , Humanos , Inmunoglobulina D , Inmunoglobulina M , Proteína Coestimuladora de Linfocitos T Inducibles , Interleucina-10 , Receptores CXCR5 , Receptores Inmunológicos/genética , Células TH1 , Células Th17/inmunología , Células Th2 , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismo
3.
Microbiome ; 9(1): 39, 2021 02 06.
Artículo en Inglés | MEDLINE | ID: mdl-33549144

RESUMEN

BACKGROUND: The gut microbiota plays a central role in host physiology and in several pathological mechanisms in humans. Antibiotics compromise the composition and functions of the gut microbiota inducing long-lasting detrimental effects on the host. Recent studies suggest that the efficacy of different clinical therapies depends on the action of the gut microbiota. Here, we investigated how different antibiotic treatments affect the ability of the gut microbiota to control intestinal inflammation upon fecal microbiota transplantation in an experimental colitis model and in ex vivo experiments with human intestinal biopsies. RESULTS: Murine fecal donors were pre-treated with different antibiotics, i.e., vancomycin, streptomycin, and metronidazole before FMT administration to colitic animals. The analysis of the gut microbiome, fecal metabolome, and the immunophenotyping of colonic lamina propria immune cells revealed that antibiotic pre-treatment significantly influences the capability of the microbiota to control intestinal inflammation. Streptomycin and vancomycin-treated microbiota failed to control intestinal inflammation and were characterized by the blooming of pathobionts previously associated with IBD as well as with metabolites related to the presence of oxidative stress and metabolism of simple sugars. On the contrary, the metronidazole-treated microbiota retained its ability to control inflammation co-occurring with the enrichment of Lactobacillus and of innate immune responses involving iNKT cells. Furthermore, ex vivo cultures of human intestinal lamina propria mononuclear cells and iNKT cell clones from IBD patients with vancomycin pre-treated sterile fecal water showed a Th1/Th17 skewing in CD4+ T-cell populations; metronidazole, on the other hand, induced the polarization of iNKT cells toward the production of IL10. CONCLUSIONS: Diverse antibiotic regimens affect the ability of the gut microbiota to control intestinal inflammation in experimental colitis by altering the microbial community structure and microbiota-derived metabolites. Video Abstract.


Asunto(s)
Antibacterianos/efectos adversos , Colitis/inducido químicamente , Colitis/microbiología , Modelos Animales de Enfermedad , Disbiosis/microbiología , Trasplante de Microbiota Fecal , Microbioma Gastrointestinal/efectos de los fármacos , Animales , Antibacterianos/farmacología , Colitis/inmunología , Colitis/patología , Disbiosis/inducido químicamente , Femenino , Microbioma Gastrointestinal/inmunología , Humanos , Masculino , Metronidazol/farmacología , Ratones , Células T Asesinas Naturales/efectos de los fármacos , Células T Asesinas Naturales/inmunología , Estreptomicina/efectos adversos , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células Th17/efectos de los fármacos , Células Th17/inmunología , Vancomicina/efectos adversos
5.
Sci Immunol ; 6(56)2021 02 23.
Artículo en Inglés | MEDLINE | ID: mdl-33622974

RESUMEN

Hyperinflammation contributes to lung injury and subsequent acute respiratory distress syndrome (ARDS) with high mortality in patients with severe coronavirus disease 2019 (COVID-19). To understand the underlying mechanisms involved in lung pathology, we investigated the role of the lung-specific immune response. We profiled immune cells in bronchoalveolar lavage fluid and blood collected from COVID-19 patients with severe disease and bacterial pneumonia patients not associated with viral infection. By tracking T cell clones across tissues, we identified clonally expanded tissue-resident memory-like Th17 cells (Trm17 cells) in the lungs even after viral clearance. These Trm17 cells were characterized by a a potentially pathogenic cytokine expression profile of IL17A and CSF2 (GM-CSF). Interactome analysis suggests that Trm17 cells can interact with lung macrophages and cytotoxic CD8+ T cells, which have been associated with disease severity and lung damage. High IL-17A and GM-CSF protein levels in the serum of COVID-19 patients were associated with a more severe clinical course. Collectively, our study suggests that pulmonary Trm17 cells are one potential orchestrator of the hyperinflammation in severe COVID-19.


Asunto(s)
/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Memoria Inmunológica , Pulmón/inmunología , Células Th17/metabolismo , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , /patología , Células Clonales , Humanos , Inflamación/etiología , Inflamación/inmunología , Pulmón/patología , Células Mieloides , Neumonía Bacteriana/inmunología , Células Th17/inmunología
6.
Front Immunol ; 12: 631044, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33613576

RESUMEN

The coronavirus disease 2019 (COVID-19) pandemic has been raging around the world since January 2020. Pregnancy places the women in a unique immune scenario which may allow severe COVID-19 disease. In this regard, the potential unknown effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on mothers and fetuses have attracted considerable attention. There is no clear consistent evidence of the changes in the immune status of pregnant women after recovery from COVID-19. In this study, we use multiparameter flow cytometry and Luminex assay to determine the immune cell subsets and cytokines, respectively, in the peripheral blood and umbilical cord blood from pregnant women recovering from COVID-19 about 3 months (n=5). Our results showed decreased percentages of Tc2, Tfh17, memory B cells, virus-specific NK cells, and increased percentages of naive B cells in the peripheral blood. Serum levels of IL-1ra and MCP-1 showed a decreased tendency in late recovery stage (LRS) patients. Meanwhile, there was no significant difference in immune cell subsets in the umbilical cord blood. The placentas from LRS patients showed increased CD68+ macrophages infiltration and mild hypoxic features. The inflammatory damage of the placenta may be related to the antiviral response. Since the receptors, ACE2 and TMPRSS2, utilized by SARS-CoV-2 are not co-expressed in the placenta, so it is extremely rare for SARS-CoV-2 to cause infection through this route and the impact on the fetus is negligible.


Asunto(s)
Linfocitos B/inmunología , Sangre Fetal/inmunología , Centro Germinal/inmunología , Placenta/inmunología , Células Th17/inmunología , /metabolismo , Autoantígenos/metabolismo , Femenino , Citometría de Flujo , Humanos , Memoria Inmunológica , Inmunofenotipificación , Células Asesinas Naturales , Embarazo , Receptores de Interleucina-1/metabolismo , Serina Endopeptidasas/metabolismo
7.
Nat Commun ; 12(1): 481, 2021 01 20.
Artículo en Inglés | MEDLINE | ID: mdl-33473108

RESUMEN

T helper type 17 (Th17) cells have important functions in the pathogenesis of inflammatory and autoimmune diseases. Retinoid-related orphan receptor-γt (RORγt) is necessary for Th17 cell differentiation and functions. However, the transcriptional regulation of RORγt expression, especially at the enhancer level, is still poorly understood. Here we identify a novel enhancer of RORγt gene in Th17 cells, RORCE2. RORCE2 deficiency suppresses RORγt expression and Th17 differentiation, leading to reduced severity of experimental autoimmune encephalomyelitis. Mechanistically, RORCE2 is looped to RORγt promoter through SRY-box transcription factor 5 (SOX-5) in Th17 cells, and the loss of SOX-5 binding site in RORCE abolishes RORCE2 function and affects the binding of signal transducer and activator of transcription 3 (STAT3) to the RORγt locus. Taken together, our data highlight a molecular mechanism for the regulation of Th17 differentiation and functions, which may represent a new intervening clue for Th17-related diseases.


Asunto(s)
Diferenciación Celular , Encefalomielitis Autoinmune Experimental/metabolismo , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Factores de Transcripción SOXD/genética , Factores de Transcripción SOXD/metabolismo , Células Th17/metabolismo , Animales , Autoinmunidad , Diferenciación Celular/genética , Encefalomielitis Autoinmune Experimental/inmunología , Epigenómica , Regulación de la Expresión Génica , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Células Th17/inmunología
8.
Nat Commun ; 12(1): 76, 2021 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-33397953

RESUMEN

Full development of IL-17 producing CD4+ T helper cells (TH17 cells) requires the transcriptional activity of both orphan nuclear receptors RORα and RORγt. However, RORα is considered functionally redundant to RORγt; therefore, the function and therapeutic value of RORα in TH17 cells is unclear. Here, using mouse models of autoimmune and chronic inflammation, we show that expression of RORα is required for TH17 cell pathogenicity. T-cell-specific deletion of RORα reduces the development of experimental autoimmune encephalomyelitis (EAE) and colitis. Reduced inflammation is associated with decreased TH17 cell development, lower expression of tissue-homing chemokine receptors and integrins, and increased frequencies of Foxp3+ T regulatory cells. Importantly, inhibition of RORα with a selective small molecule antagonist mostly phenocopies our genetic data, showing potent suppression of the in vivo development of both chronic/progressive and relapsing/remitting EAE, but with no effect on overall thymic cellularity. Furthermore, use of the RORα antagonist effectively inhibits human TH17 cell differentiation and memory cytokine secretion. Together, these data suggest that RORα functions independent of RORγt in programming TH17 pathogenicity and identifies RORα as a safer and more selective therapeutic target for the treatment of TH17-mediated autoimmunity.


Asunto(s)
Inflamación/inmunología , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/antagonistas & inhibidores , Células Th17/inmunología , Animales , Autoinmunidad/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Enfermedad Crónica , Colon/patología , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental , Células HEK293 , Humanos , Inflamación/genética , Ratones Endogámicos C57BL , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Tamaño de los Órganos/efectos de los fármacos , Índice de Severidad de la Enfermedad , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Sulfonamidas/química , Sulfonamidas/farmacología , Tiofenos/química , Tiofenos/farmacología
9.
Life Sci ; 269: 119083, 2021 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-33482191

RESUMEN

Rheumatoid arthritis (RA) is an autoimmune disease that generally affects the joints. In the late stages of the disease, it can be associated with several complications. Although the exact etiology of RA is unknown, various studies have been performed to understand better the immunological mechanisms involved in the pathogenesis of RA. At the onset of the disease, various immune cells migrate to the joints and increase the recruitment of immune cells to the joints by several immunological mediators such as cytokines and chemokines. The function of specific immune cells in RA is well-established. The shift of immune responses to Th1 or Th17 is one of the most essential factors in the development of RA. Myeloid-derived suppressor cells (MDSCs), as a heterogeneous population of myeloid cells, play a regulatory role in the immune system that inhibits T cell activity through several mechanisms. Various studies have been performed on the function of these cells in RA, which in some cases have yielded conflicting results. Therefore, the purpose of this review article is to comprehensively understand the pro-inflammatory and anti-inflammatory functions of MDSCs in the pathogenesis of RA.


Asunto(s)
Artritis Reumatoide/inmunología , Artritis Reumatoide/patología , Células Supresoras de Origen Mieloide/inmunología , Células TH1/inmunología , Células Th17/inmunología , Animales , Artritis Reumatoide/metabolismo , Citocinas/metabolismo , Humanos
10.
Biomed Pharmacother ; 133: 111028, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33378943

RESUMEN

Aspirin is one of the most commonly prescribed medications. Evidence shows that it can even treat and prevent intestinal tumors. However, it has also caused a great deal of controversy due to its intestinal side effects. We therefore explored whether aspirin was beneficial or harmful to the intestines. We used aspirin continuously interfered with C57BL/6 J mice for 48 weeks, examining their intestinal tissues at 13, 26 and 48 weeks to determine the drug's effect on the intestines. In addition, we used flow cytometry (FCM) used to detect T cells and expression of T-cell immunoreceptor with immunoglobulin (Ig)- and tyrosine-based inhibitory motif (ITIM) domain (TIGIT) on their surfaces to determine aspirin's immunomodulatory effects. The results showed that long-term aspirin intervention could reverse damage to the intestines, an effect related to the drug's significant inhibitory effect on TIGIT. The change in TIGIT level could regulate T-cell subsets, so that counts of Cluster of Differentiation 4 (CD4)+/chemokine (C-X3-C motif) receptor 3 (CXCR3)+ T-helper 1 (Th1) cells and CD4+/interleukin-4 (IL-4)+ Th2 cells increased, while those of CD4+/C-C chemokine receptor type 6 (CCR6)+ Th17 cells and CD4+/CD25+ regulatory T cells (Tregs) decreased. In summary, we demonstrated that long-term aspirin intervention could inhibit TIGIT, regulating T cells to reverse damage to the intestines. Furthermore, aspirin is a potential therapy for diseases related to an increase in TIGIT.


Asunto(s)
Aspirina/toxicidad , Colon/efectos de los fármacos , Receptores Inmunológicos/metabolismo , Recto/efectos de los fármacos , Subgrupos de Linfocitos T/efectos de los fármacos , Animales , Colon/inmunología , Colon/metabolismo , Colon/patología , Regulación hacia Abajo , Masculino , Ratones Endogámicos C57BL , Fenotipo , Recto/inmunología , Recto/metabolismo , Recto/patología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células TH1/metabolismo , Células Th17/efectos de los fármacos , Células Th17/inmunología , Células Th17/metabolismo , Células Th2/efectos de los fármacos , Células Th2/inmunología , Células Th2/metabolismo , Factores de Tiempo
11.
PLoS Pathog ; 16(12): e1009096, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33315936

RESUMEN

Bacille Calmette-Guerin (BCG), an attenuated whole cell vaccine based on Mycobacterium bovis, is the only licensed vaccine against Mycobacterium tuberculosis (Mtb), but its efficacy is suboptimal and it fails to protect against pulmonary tuberculosis. We previously reported that Mtb lacking the virulence genes lprG and rv1410c (ΔLprG) was highly attenuated in immune deficient mice. In this study, we show that attenuated ΔLprG Mtb protects C57BL/6J, Balb/cJ, and C3HeB/FeJ mice against Mtb challenge and is as attenuated as BCG in SCID mice. In C3HeB/FeJ mice, ΔLprG vaccination resulted in innate peripheral cytokine production and induced high polyclonal PPD-specific cytokine-secreting CD4+ T lymphocytes in peripheral blood. The ΔLprG vaccine afforded protective efficacy in the lungs of C3H/FeJ mice following both H37Rv and Erdman aerosolized Mtb challenges. Vaccine efficacy correlated with antigen-specific PD-1-negative CD4+ T lymphocytes as well as with serum IL-17 levels after vaccination. We hypothesize that induction of Th17 cells in lung is critical for vaccine protection, and we show a serum cytokine biomarker for IL-17 shortly after vaccination may predict protective efficacy.


Asunto(s)
Vacunas contra la Tuberculosis/genética , Vacunas contra la Tuberculosis/inmunología , Vacunas Atenuadas/genética , Vacunas Atenuadas/inmunología , Factores de Virulencia/genética , Animales , Genes Bacterianos/genética , Interleucina-17/inmunología , Ratones , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/inmunología , Células Th17/inmunología , Tuberculosis Pulmonar/inmunología , Tuberculosis Pulmonar/prevención & control
12.
PLoS Pathog ; 16(12): e1009176, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33347509

RESUMEN

Multiple sclerosis (MS) is a highly disabling neurodegenerative autoimmune condition in which an unbalanced immune response plays a critical role. Although the mechanisms remain poorly defined, helminth infections are known to modulate the severity and progression of chronic inflammatory diseases. The tyrosine kinase receptors TYRO3, AXL, and MERTK (TAM) have been described as inhibitors of the immune response in various inflammatory settings. We show here that patients with concurrent natural helminth infections and MS condition (HIMS) had an increased expression of the negative regulatory TAM receptors in antigen-presenting cells and their agonist GAS6 in circulating CD11bhigh and CD4+ T cells compared to patients with only MS. The Th17 subset was reduced in patients with HIMS with a subsequent downregulation of its pathogenic genetic program. Moreover, these CD4+ T cells promoted lower levels of the co-stimulatory molecules CD80, CD86, and CD40 on dendritic cells compared with CD4+ T cells from patients with MS, an effect that was GAS6-dependent. IL-10+ cells from patients with HIMS showed higher GAS6 expression levels than Th17 cells, and inhibition of phosphatidylserine/GAS6 binding led to an expansion of Th17 effector genes. The addition of GAS6 on activated CD4+ T cells from patients with MS restrains the Th17 gene expression signature. This cohort of patients with HIMS unravels a promising regulatory mechanism to dampen the Th17 inflammatory response in autoimmunity.


Asunto(s)
Helmintiasis/complicaciones , Helmintiasis/inmunología , Péptidos y Proteínas de Señalización Intercelular/inmunología , Esclerosis Múltiple Recurrente-Remitente/inmunología , Esclerosis Múltiple Recurrente-Remitente/parasitología , Células Th17/inmunología , Adulto , Animales , Femenino , Humanos , Masculino
13.
Viruses ; 12(12)2020 12 13.
Artículo en Inglés | MEDLINE | ID: mdl-33322218

RESUMEN

The aims of this study were to determine the involvement of interleukin 17 (IL-17) and IL-17-producing cells in dengue pathogenesis. Blood samples from dengue virus (DENV)-infected patients were collected on different days after the onset of symptoms. Patients were classified according to 1997 World Health Organization guidelines. Our study examined 152 blood samples from dengue fever (DF, n = 109) and dengue hemorrhagic fever (DHF, n = 43) patients and 90 blood samples from healthy controls (HC). High serum concentrations of IL-17A and IL-22 were also associated with DHF (IL-17A [DHF vs. DF, p < 0.01; DHF vs. HC, p < 0.0001]; IL-22 [DHF vs. DF, p < 0.05; DHF vs. HC, p < 0.0001]). Moreover, there was a positive correlation between serum levels of IL-17A and IL-23, a key cytokine that promotes IL-17-based immune responses (r = 0.4089, p < 0.0001). Consistent with the IL-17-biased immune response in DHF patients, we performed ex vivo activation of peripheral blood mononuclear cells (PBMCs) from DHF patients and flow cytometry analysis showed a robust IL-17-biased immune response, characterized by a high frequency of CD4+IL-17+ producing cells. Our results suggests IL-17-producing cells and their related cytokines can play a prominent role in this viral disease.


Asunto(s)
Linfocitos T CD4-Positivos/metabolismo , Virus del Dengue/fisiología , Dengue/etiología , Dengue/metabolismo , Interleucina-17/metabolismo , Células Th17/metabolismo , Adolescente , Adulto , Anciano , Linfocitos T CD4-Positivos/inmunología , Niño , Citocinas/sangre , Citocinas/metabolismo , Dengue/diagnóstico , Susceptibilidad a Enfermedades , Femenino , Humanos , Interleucina-17/sangre , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Células Th17/inmunología , Adulto Joven
14.
Front Immunol ; 11: 596553, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33324414

RESUMEN

The severity of SARS-CoV-2 infection has been related to uncontrolled inflammatory innate responses and impaired adaptive immune responses mostly due to exhausted T lymphocytes and lymphopenia. In this work we have characterized the nature of the lymphopenia and demonstrate a set of factors that hinder the effective control of virus infection and the activation and arming of effector cytotoxic T CD8 cells and showing signatures defining a high-risk population. We performed immune profiling of the T helper (Th) CD4+ and T CD8+ cell compartments in peripheral blood of 144 COVID-19 patients using multiparametric flow cytometry analysis. On the one hand, there was a consistent lymphopenia with an overrepresentation of non-functional T cells, with an increased percentage of naive Th cells (CD45RA+, CXCR3-, CCR4-, CCR6-, CCR10-) and persistently low frequency of markers associated with Th1, Th17, and Th1/Th17 memory-effector T cells compared to healthy donors. On the other hand, the most profound alteration affected the Th1 subset, which may explain the poor T cells responses and the persistent blood virus load. Finally, the decrease in Th1 cells may also explain the low frequency of CD4+ and CD8+ T cells that express the HLA-DR and CD38 activation markers observed in numerous patients who showed minimal or no lymphocyte activation response. We also identified the percentage of HLA-DR+CD4+ T cells, PD-1+CD+4/CD8+ T cells in blood, and the neutrophil/lymphocyte ratio as useful factors for predicting critical illness and fatal outcome in patients with confirmed COVID-19.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , /inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Células TH1/inmunología , ADP-Ribosil Ciclasa 1/inmunología , ADP-Ribosil Ciclasa 1/metabolismo , Anciano , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Diferenciación Celular/inmunología , Femenino , Antígenos HLA-DR/inmunología , Antígenos HLA-DR/metabolismo , Humanos , Activación de Linfocitos/inmunología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Linfocitos T Colaboradores-Inductores/metabolismo , Células TH1/metabolismo , Células Th17/inmunología , Células Th17/metabolismo
15.
Nihon Saikingaku Zasshi ; 75(2): 185-194, 2020.
Artículo en Japonés | MEDLINE | ID: mdl-33361654

RESUMEN

Countless numbers of bacteria inhabit the intestinal tract. One of the important functions of gut microbiota is the "colonization resistance" against infection by pathogenic microorganisms. However, detailed mechanism of the colonization resistance of intestinal bacteria is still largely unknown. We tried to identify molecular and cellular mechanism of it and found that antigen presentation by dendritic cells is required for the induction of intestinal segmented filamentous bacteria (SFB)-induced T helper 17 (Th17) cells that contribute to the protection against infection by Citrobacter rodentium. We further identified that gut Th17 cells selectively recognize antigens derived from SFB. We also revealed that SFB induce α1,2-fucose, one of carbohydrate chains, expressed on the intestinal epithelial cells mediated by group 3 innate lymphoid cells. Epithelial α1,2-fucose protected against infection by pathogenic bacterium Salmonella typhimurium. Furthermore, it was found that intestinal bacteria inhibit colonization of the pathogenic fungus Candida albicans as well as pathogenic bacteria. From these studies, detailed mechanism of "colonization resistance" against pathogenic microorganisms by intestinal bacteria has been clarified.


Asunto(s)
Candida albicans/patogenicidad , Citrobacter rodentium/patogenicidad , Microbioma Gastrointestinal/inmunología , Microbioma Gastrointestinal/fisiología , Interacciones Microbiota-Huesped/inmunología , Sistema Inmunológico/inmunología , Mucosa Intestinal/microbiología , Salmonella typhimurium/patogenicidad , Células Th17/inmunología , Animales , Presentación de Antígeno , Antígenos Bacterianos/inmunología , Adhesión Bacteriana/inmunología , Candida albicans/inmunología , Citrobacter rodentium/inmunología , Células Dendríticas/inmunología , Fucosa/metabolismo , Humanos , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Ratones , Salmonella typhimurium/inmunología
16.
Nat Commun ; 11(1): 5406, 2020 10 26.
Artículo en Inglés | MEDLINE | ID: mdl-33106495

RESUMEN

Mutations in nucleotide-binding oligomerization domain-containing protein 2 (NOD2) cause Blau syndrome, an inflammatory disorder characterized by uveitis. The antimicrobial functions of Nod2 are well-established, yet the cellular mechanisms by which dysregulated Nod2 causes uveitis remain unknown. Here, we report a non-conventional, T cell-intrinsic function for Nod2 in suppression of Th17 immunity and experimental uveitis. Reconstitution of lymphopenic hosts with Nod2-/- CD4+ T cells or retina-specific autoreactive CD4+ T cells lacking Nod2 reveals a T cell-autonomous, Rip2-independent mechanism for Nod2 in uveitis. In naive animals, Nod2 operates downstream of TCR ligation to suppress activation of memory CD4+ T cells that associate with an autoreactive-like profile involving IL-17 and Ccr7. Interestingly, CD4+ T cells from two Blau syndrome patients show elevated IL-17 and increased CCR7. Our data define Nod2 as a T cell-intrinsic rheostat of Th17 immunity, and open new avenues for T cell-based therapies for Nod2-associated disorders such as Blau syndrome.


Asunto(s)
Proteína Adaptadora de Señalización NOD2/inmunología , Células Th17/inmunología , Uveítis/inmunología , Uveítis/prevención & control , Animales , Artritis/genética , Artritis/inmunología , Linfocitos T CD4-Positivos/inmunología , Femenino , Humanos , Interleucina-17/genética , Interleucina-17/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Proteína Adaptadora de Señalización NOD2/genética , Receptores CCR7/genética , Receptores CCR7/inmunología , Sarcoidosis , Sinovitis/genética , Sinovitis/inmunología , Uveítis/genética
17.
Nat Commun ; 11(1): 5173, 2020 10 14.
Artículo en Inglés | MEDLINE | ID: mdl-33057068

RESUMEN

In ovarian cancer (OC), IL-17-producing T cells (Th17s) predict improved survival, whereas regulatory T cells predict poorer survival. We previously developed a vaccine whereby patient-derived dendritic cells (DCs) are programmed to induce Th17 responses to the OC antigen folate receptor alpha (FRα). Here we report the results of a single-arm open-label phase I clinical trial designed to determine vaccine safety and tolerability (primary outcomes) and recurrence-free survival (secondary outcome). Immunogenicity is also evaluated. Recruitment is complete with a total of 19 Stage IIIC-IV OC patients in first remission after conventional therapy. DCs are generated using our Th17-inducing protocol and are pulsed with HLA class II epitopes from FRα. Mature antigen-loaded DCs are injected intradermally. All patients have completed study-related interventions. No grade 3 or higher adverse events are seen. Vaccination results in the development of Th1, Th17, and antibody responses to FRα in the majority of patients. Th1 and antibody responses are associated with prolonged recurrence-free survival. Antibody-dependent cell-mediated cytotoxic activity against FRα is also associated with prolonged RFS. Of 18 patients evaluable for efficacy, 39% (7/18) remain recurrence-free at the time of data censoring, with a median follow-up of 49.2 months. Thus, vaccination with Th17-inducing FRα-loaded DCs is safe, induces antigen-specific immunity, and is associated with prolonged remission.


Asunto(s)
Vacunas contra el Cáncer/administración & dosificación , Células Dendríticas/trasplante , Recurrencia Local de Neoplasia/epidemiología , Neoplasias Ováricas/terapia , Células Th17/inmunología , Anciano , Vacunas contra el Cáncer/efectos adversos , Vacunas contra el Cáncer/inmunología , Supervivencia sin Enfermedad , Femenino , Receptor 1 de Folato/inmunología , Humanos , Inmunidad Humoral , Inyecciones Intradérmicas , Interferón gamma/metabolismo , Interleucina-17/metabolismo , Persona de Mediana Edad , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/prevención & control , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/mortalidad , Células Th17/metabolismo , Trasplante Autólogo/efectos adversos , Trasplante Autólogo/métodos
18.
Front Immunol ; 11: 588724, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33117402

RESUMEN

SARS-CoV-2 infection is a new threat to global public health in the 21st century (2020), which has now rapidly spread around the globe causing severe pneumonia often linked to Acute Respiratory Distress Syndrome (ARDS) and hyperinflammatory syndrome. SARS-CoV-2 is highly contagious through saliva droplets. The structural analysis suggests that the virus enters human cells through the ligation of the spike protein to angiotensin-converting enzyme 2 (ACE2). The progression of Covid-19 has been divided into three main stages: stage I-viral response, stage II-pulmonary phase, and stage III-hyperinflammation phase. Once the patients enter stage III, it will likely need ventilation and it becomes difficult to manage. Thus, it will be of paramount importance to find therapies to prevent or slow down the progression of the disease toward stage III. The key event leading to hyperinflammation seems to be the activation of Th-17 immunity response and Cytokine storm. B2-adrenergic receptors (B2ARs) are expressed on airways and on all the immune cells such as macrophages, dendritic cells, B and T lymphocytes. Blocking (B2AR) has been proven, also in clinical settings, to reduce Th-17 response and negatively modulate inflammatory cytokines including IL-6 while increasing IFNγ. Non-selective beta-blockers are currently used to treat several diseases and have been proven to reduce stress-induced inflammation and reduce anxiety. For these reasons, we speculate that targeting B2AR in the early phase of Covid-19 might be beneficial to prevent hyperinflammation.


Asunto(s)
Antagonistas de Receptores Adrenérgicos beta 2/uso terapéutico , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/patología , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/patología , Receptores Adrenérgicos beta 2/efectos de los fármacos , /tratamiento farmacológico , Betacoronavirus/efectos de los fármacos , Síndrome de Liberación de Citoquinas/patología , Humanos , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Inflamación/patología , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Pandemias , /virología , Células Th17/inmunología
19.
Front Immunol ; 11: 2056, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32973814

RESUMEN

The pandemic of coronavirus disease 2019 (COVID-19), a disease which causes severe lung injury and multiple organ damage, presents an urgent need for new drugs. The case severity and fatality of COVID-19 are associated with excessive inflammation, namely, a cytokine storm. Metformin, a widely used drug to treat type 2 diabetes (T2D) mellitus and metabolic syndrome, has immunomodulatory activity that reduces the production of proinflammatory cytokines using macrophages and causes the formation of neutrophil extracellular traps (NETs). Metformin also inhibits the cytokine production of pathogenic Th1 and Th17 cells. Importantly, treatment with metformin alleviates various lung injuries in preclinical animal models. In addition, a recent proteomic study revealed that metformin has the potential to directly inhibit SARS-CoV-2 infection. Furthermore, retrospective clinical studies have revealed that metformin treatment reduces the mortality of T2D with COVID-19. Therefore, metformin has the potential to be repurposed to treat patients with COVID-19 at risk of developing severe illness. This review summarizes the immune pathogenesis of SARS-CoV-2 and addresses the effects of metformin on inhibiting cytokine storms and preventing SARS-CoV-2 infection, as well as its side effects.


Asunto(s)
Antivirales/uso terapéutico , Betacoronavirus , Infecciones por Coronavirus/tratamiento farmacológico , Factores Inmunológicos/uso terapéutico , Lesión Pulmonar/tratamiento farmacológico , Metformina/uso terapéutico , Neumonía Viral/tratamiento farmacológico , Animales , Antivirales/efectos adversos , Antivirales/farmacología , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/virología , Citocinas/antagonistas & inhibidores , Reposicionamiento de Medicamentos/métodos , Trampas Extracelulares/efectos de los fármacos , Humanos , Factores Inmunológicos/efectos adversos , Factores Inmunológicos/farmacología , Inflamación/tratamiento farmacológico , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Metformina/efectos adversos , Metformina/farmacología , Pandemias , Neumonía Viral/inmunología , Neumonía Viral/virología , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células Th17/efectos de los fármacos , Células Th17/inmunología
20.
Mol Immunol ; 127: 107-111, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32950755

RESUMEN

BACKGROUND: T helper 17 (Th17) cell responses were involved in the pathophysiology of primary Sjögren's syndrome (pSS). IL-38 has been reported to inhibit the secretion of chemokines involved in Th17 pathway. This study aimed to explore the regulation of Th17 response by IL-38 in pSS. METHODS: Twenty-four pSS patients, 15 non-pSS control, and 13 health subjects were recruited. The expression of IL-38 and Th17 cytokines were detected and compared between pSS and controls. Human peripheral blood mononuclear cells (PBMCs) and minor salivary gland mononuclear cells (MSGMs) were purified and stimulated by IL-38. The differentiation and function of Th17 cells were evaluated by PCR and enzyme-linked immunosorbent assay (ELISA). RESULTS: The pSS patients presented with significantly lower expression of IL-38 and higher Th17 cytokines (IL-17 and IL-23) compared with both non-pSS and healthy controls. The IL-38 inhibited the differentiation and function of Th17 responses from PBMCs and MSGMs. The IL-38 treatment could inhibit the Th17 response in mice model. CONCLUSIONS: IL-38 inhibits T helper 17 type responses in pSS, suggesting that IL-38 may be used as potential treatment target in pSS.


Asunto(s)
Interleucinas/metabolismo , Síndrome de Sjögren/inmunología , Células Th17/inmunología , Adulto , Animales , Autoanticuerpos/sangre , Estudios de Casos y Controles , Diferenciación Celular , Citocinas/metabolismo , Femenino , Humanos , Interleucina-17/metabolismo , Interleucina-23/metabolismo , Interleucinas/genética , Leucocitos Mononucleares/metabolismo , Masculino , Ratones , Persona de Mediana Edad , ARN Mensajero/genética , ARN Mensajero/metabolismo , Saliva/metabolismo , Glándulas Salivales/patología , Transducción de Señal , Síndrome de Sjögren/sangre
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