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1.
Nat Commun ; 12(1): 1439, 2021 03 04.
Artículo en Inglés | MEDLINE | ID: mdl-33664251

RESUMEN

Treatment of advanced melanoma with combined PD-1/CTLA-4 blockade commonly causes serious immune-mediated complications. Here, we identify a subset of patients predisposed to immune checkpoint blockade-related hepatitis who are distinguished by chronic expansion of effector memory CD4+ T cells (TEM cells). Pre-therapy CD4+ TEM cell expansion occurs primarily during autumn or winter in patients with metastatic disease and high cytomegalovirus (CMV)-specific serum antibody titres. These clinical features implicate metastasis-dependent, compartmentalised CMV reactivation as the cause of CD4+ TEM expansion. Pre-therapy CD4+ TEM expansion predicts hepatitis in CMV-seropositive patients, opening possibilities for avoidance or prevention. 3 of 4 patients with pre-treatment CD4+ TEM expansion who received αPD-1 monotherapy instead of αPD-1/αCTLA-4 therapy remained hepatitis-free. 4 of 4 patients with baseline CD4+ TEM expansion given prophylactic valganciclovir and αPD-1/αCTLA-4 therapy remained hepatitis-free. Our findings exemplify how pathogen exposure can shape clinical reactions after cancer therapy and how this insight leads to therapeutic innovations.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Antígeno CTLA-4/antagonistas & inhibidores , Infecciones por Citomegalovirus/tratamiento farmacológico , Hepatitis A/prevención & control , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Antivirales/uso terapéutico , Linfocitos T CD4-Positivos/trasplante , Linfocitos T CD8-positivos/inmunología , Citomegalovirus/efectos de los fármacos , Citomegalovirus/inmunología , Hepatitis A/inmunología , Hepatitis A/virología , Humanos , Memoria Inmunológica/inmunología , Melanoma/tratamiento farmacológico , Valganciclovir/uso terapéutico , Carga Viral
2.
Front Immunol ; 12: 598778, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33717077

RESUMEN

Emerging infectious diseases (EIDs) caused by viruses are increasing in frequency, causing a high disease burden and mortality world-wide. The COVID-19 pandemic caused by the novel SARS-like coronavirus (SARS-CoV-2) underscores the need to innovate and accelerate the development of effective vaccination strategies against EIDs. Human leukocyte antigen (HLA) molecules play a central role in the immune system by determining the peptide repertoire displayed to the T-cell compartment. Genetic polymorphisms of the HLA system thus confer a strong variability in vaccine-induced immune responses and may complicate the selection of vaccine candidates, because the distribution and frequencies of HLA alleles are highly variable among different ethnic groups. Herein, we build on the emerging paradigm of rational epitope-based vaccine design, by describing an immunoinformatics tool (Predivac-3.0) for proteome-wide T-cell epitope discovery that accounts for ethnic-level variations in immune responsiveness. Predivac-3.0 implements both CD8+ and CD4+ T-cell epitope predictions based on HLA allele frequencies retrieved from the Allele Frequency Net Database. The tool was thoroughly assessed, proving comparable performances (AUC ~0.9) against four state-of-the-art pan-specific immunoinformatics methods capable of population-level analysis (NetMHCPan-4.0, Pickpocket, PSSMHCPan and SMM), as well as a strong accuracy on proteome-wide T-cell epitope predictions for HIV-specific immune responses in the Japanese population. The utility of the method was investigated for the COVID-19 pandemic, by performing in silico T-cell epitope mapping of the SARS-CoV-2 spike glycoprotein according to the ethnic context of the countries where the ChAdOx1 vaccine is currently initiating phase III clinical trials. Potentially immunodominant CD8+ and CD4+ T-cell epitopes and population coverages were predicted for each population (the Epitope Discovery mode), along with optimized sets of broadly recognized (promiscuous) T-cell epitopes maximizing coverage in the target populations (the Epitope Optimization mode). Population-specific epitope-rich regions (T-cell epitope clusters) were further predicted in protein antigens based on combined criteria of epitope density and population coverage. Overall, we conclude that Predivac-3.0 holds potential to contribute in the understanding of ethnic-level variations of vaccine-induced immune responsiveness and to guide the development of epitope-based next-generation vaccines against emerging pathogens, whose geographic distributions and populations in need of vaccinations are often well-defined for regional epidemics.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Epítopos de Linfocito T/metabolismo , Grupos Étnicos , Antígenos HLA/metabolismo , Proteómica/métodos , Glicoproteína de la Espiga del Coronavirus/metabolismo , /epidemiología , Enfermedades Transmisibles Emergentes , Epítopos de Linfocito T/genética , Antígenos HLA/genética , Humanos , Inmunogenicidad Vacunal , Aplicaciones de la Informática Médica , Pandemias/prevención & control , Polimorfismo Genético , Unión Proteica , Programas Informáticos , Glicoproteína de la Espiga del Coronavirus/genética
3.
Front Immunol ; 12: 640644, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33717195

RESUMEN

Infection with SARS-CoV-2 can lead to Coronavirus disease-2019 (COVID-19) and result in severe acute respiratory distress syndrome (ARDS). Recent reports indicate an increased rate of fungal coinfections during COVID-19. With incomplete understanding of the pathogenesis and without any causative therapy available, secondary infections may be detrimental to the prognosis. We monitored 11 COVID-19 patients with ARDS for their immune phenotype, plasma cytokines, and clinical parameters on the day of ICU admission and on day 4 and day 7 of their ICU stay. Whole blood stimulation assays with lipopolysaccharide (LPS), heat-killed Listeria monocytogenes (HKLM), Aspergillus fumigatus, and Candida albicans were used to mimic secondary infections, and changes in immune phenotype and cytokine release were assessed. COVID-19 patients displayed an immune phenotype characterized by increased HLA-DR+CD38+ and PD-1+ CD4+ and CD8+ T cells, and elevated CD8+CD244+ lymphocytes, compared to healthy controls. Monocyte activation markers and cytokines IL-6, IL-8, TNF, IL-10, and sIL2Rα were elevated, corresponding to monocyte activation syndrome, while IL-1ß levels were low. LPS, HKLM and Aspergillus fumigatus antigen stimulation provoked an immune response that did not differ between COVID-19 patients and healthy controls, while COVID-19 patients showed an attenuated monocyte CD80 upregulation and abrogated release of IL-6, TNF, IL-1α, and IL-1ß toward Candida albicans. This study adds further detail to the characterization of the immune response in critically ill COVID-19 patients and hints at an increased susceptibility for Candida albicans infection.


Asunto(s)
Aspergillus fumigatus/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Candida albicans/inmunología , Listeria monocytogenes/inmunología , /fisiología , Anciano , Células Cultivadas , Citocinas/metabolismo , Susceptibilidad a Enfermedades , Femenino , Humanos , Tolerancia Inmunológica , Masculino , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/metabolismo
4.
Aging (Albany NY) ; 13(5): 6289-6297, 2021 03 12.
Artículo en Inglés | MEDLINE | ID: mdl-33711813

RESUMEN

OBJECTIVES: To retrospectively evaluate the clinical and immunological characteristics of patients who died of COVID-19 and to identify patients at high risk of death at an early stage and reduce their mortality. RESULTS: Total white blood cell count, neutrophil count and C-reactive protein were significantly higher in patients who died of COVID-19 than those who recovered from it (p < 0.05), but the total lymphocyte count, CD4 + T cells, CD8 + T cells, B cells and natural killer cells were significantly lower when compared in the same groups. Multiple logistic regression analysis showed that increased D-dimer, decreased CD4 + T cells and increased neutrophils were risk factors for mortality. Further multiple COX regression demonstrated that neutrophil ≥ 5.27 × 109/L increased the risk of death in COVID-19 patients after adjustment for age and gender. However, CD4 + T cells ≥ 260/µL appeared to reduce the risk of death. CONCLUSION: SARS-CoV-2 infection led to a significant decrease of lymphocytes, and decreased CD4 + T cell count was a risk factor for COVID-19 patients to develop severe disease and death. METHODS: This study included 190 hospitalized COVID-19 patients from January 30, 2020 to March 4, 2020 in Wuhan, China, of whom 85 died and 105 recovered. Two researchers independently collected the clinical and laboratory data from electronic medical records.


Asunto(s)
/sangre , Linfocitos/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Linfocitos B/inmunología , Proteína C-Reactiva/análisis , Proteína C-Reactiva/inmunología , Linfocitos T CD4-Positivos/inmunología , /mortalidad , Femenino , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Productos de Degradación de Fibrina-Fibrinógeno/inmunología , Humanos , Células Asesinas Naturales/inmunología , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Neutrófilos/inmunología , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , /aislamiento & purificación
5.
Sci Rep ; 11(1): 4954, 2021 03 02.
Artículo en Inglés | MEDLINE | ID: mdl-33654181

RESUMEN

The prophylactic vaccines available to protect against infections by HPV are well tolerated and highly immunogenic. People with HIV have a higher risk of developing HPV infection and HPV-associated cancers due to a lower immune response, and due to viral interactions. We performed a systematic review of RCTs to assess HPV vaccines efficacy and safety on HIV-infected people compared to placebo or no intervention in terms of seroconversion, infections, neoplasms, adverse events, CD4+ T-cell count and HIV viral load. The vaccine-group showed a seroconversion rate close to 100% for each vaccine and a significantly higher level of antibodies against HPV vaccine types, as compared to the placebo group (MD = 4333.3, 95% CI 2701.4; 5965.1 GMT EL.U./ml for HPV type 16 and MD = 1408.8, 95% CI 414.8; 2394.7 GMT EL.U./ml for HPV type 18). There were also no differences in terms of severe adverse events (RR = 0.6, 95% CI 0.2; 1.6) and no severe adverse events (RR = 0.6, 95% CI 0.9; 1.2) between vaccine and placebo groups. Secondary outcomes, such as CD4 + T-cell count and HIV viral load, did not differ between groups (MD = 14.8, 95% CI - 35.1; 64.6 cells/µl and MD = 0.0, 95% CI - 0.3; 0.3 log10 RNA copies/ml, respectively). Information on the remaining outcomes was scarce and that did not allow us to combine the data. The results support the use of the HPV vaccine in HIV-infected patients and highlight the need of further RCTs assessing the effectiveness of the HPV vaccine on infections and neoplasms.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Infecciones por VIH/inmunología , Infecciones por Papillomavirus/prevención & control , Vacunas contra Papillomavirus/inmunología , Seguridad del Paciente , Adolescente , Adulto , Anticuerpos Antivirales , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/virología , Femenino , Humanos , Masculino , Infecciones por Papillomavirus/virología , Vacunas contra Papillomavirus/efectos adversos , Salud Pública , Ensayos Clínicos Controlados Aleatorios como Asunto , Riesgo , Resultado del Tratamiento , Carga Viral , Esparcimiento de Virus , Adulto Joven
6.
Methods Mol Biol ; 2265: 645-654, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33704745

RESUMEN

Expression of chimeric antigen receptors can redirect T cell specificity and allow for MHC-independent recognition of melanoma associated antigens. Retroviral transduction is used to express chimeric antigen receptor constructs in murine CD4+ and CD8+ T cells. Here we describe the production of retroviral supernatants and the activation, transduction, expansion, and selection of murine T cells expressing the chimeric-PD1 receptor. This protocol can be modified for any murine chimeric antigen receptor construct.


Asunto(s)
Linfocitos T CD4-Positivos , Linfocitos T CD8-positivos , Inmunoterapia Adoptiva , Melanoma Experimental , Receptores Quiméricos de Antígenos , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/trasplante , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/trasplante , Humanos , Melanoma Experimental/inmunología , Melanoma Experimental/metabolismo , Ratones , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/inmunología
7.
PLoS One ; 16(3): e0248061, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33730022

RESUMEN

Developing an efficacious vaccine for SARS-CoV-2 infection is critical to stemming COVID-19 fatalities and providing the global community with immune protection. We have used a bioinformatic approach to aid in designing an epitope peptide-based vaccine against the spike protein of the virus. Five antigenic B cell epitopes with viable antigenicity and a total of 27 discontinuous B cell epitopes were mapped out structurally in the spike protein for antibody recognition. We identified eight CD8+ T cell 9-mers and 12 CD4+ T cell 14-15-mer as promising candidate epitopes putatively restricted by a large number of MHC I and II alleles, respectively. We used this information to construct an in silico chimeric peptide vaccine whose translational rate was highly expressed when cloned in pET28a (+) vector. With our In silico test, the vaccine construct was predicted to elicit high antigenicity and cell-mediated immunity when given as a homologous prime-boost, triggering of toll-like receptor 5 by the adjuvant linker. The vaccine was also characterized by an increase in IgM and IgG and an array of Th1 and Th2 cytokines. Upon in silico challenge with SARS-CoV-2, there was a decrease in antigen levels using our immune simulations. We, therefore, propose that potential vaccine designs consider this approach.


Asunto(s)
/inmunología , Epítopos de Linfocito T/inmunología , Inmunogenicidad Vacunal/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Vacunas de Subunidad/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Biología Computacional/métodos , Citocinas/inmunología , Epítopos de Linfocito B/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Humanos , Inmunidad Celular/inmunología , Inmunoglobulina G/inmunología , Inmunoglobulina M/inmunología , Simulación del Acoplamiento Molecular , Péptidos/inmunología
8.
Cell Rep ; 34(11): 108852, 2021 03 16.
Artículo en Inglés | MEDLINE | ID: mdl-33730580

RESUMEN

As the global COVID-19 pandemic progresses, it is paramount to gain knowledge on adaptive immunity to SARS-CoV-2 in children to define immune correlates of protection upon immunization or infection. We analyzed anti-SARS-CoV-2 antibodies and their neutralizing activity (PRNT) in 66 COVID-19-infected children at 7 (±2) days after symptom onset. Individuals with specific humoral responses presented faster virus clearance and lower viral load associated with a reduced in vitro infectivity. We demonstrated that the frequencies of SARS-CoV-2-specific CD4+CD40L+ T cells and Spike-specific B cells were associated with the anti-SARS-CoV-2 antibodies and the magnitude of neutralizing activity. The plasma proteome confirmed the association between cellular and humoral SARS-CoV-2 immunity, and PRNT+ patients show higher viral signal transduction molecules (SLAMF1, CD244, CLEC4G). This work sheds lights on cellular and humoral anti-SARS-CoV-2 responses in children, which may drive future vaccination trial endpoints and quarantine measures policies.


Asunto(s)
Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , /inmunología , Inmunidad Adaptativa/inmunología , Linfocitos B/inmunología , Linfocitos T CD4-Positivos/inmunología , Niño , Humanos , Inmunidad Humoral/inmunología , Proteoma/inmunología , Transducción de Señal/inmunología , Carga Viral/inmunología
9.
Exp Parasitol ; 223: 108082, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33581108

RESUMEN

Leishmaniasis is a complex vector-borne disease mediated by Leishmania parasite and a strong and long-lasting CD4+ Th1 and CD8+-T cell immunity is required to control the infection. Thus far multivalent subunit vaccines have met this requirement more promisingly. However several full protein sequences cannot be easily arranged in one construct. Instead, new emerging immune-informatics based epitope formulations surpass this restriction. Herein, we aimed to examine the protective potential of a dendritic cell based vaccine presenting epitopes to CD8+ and CD4+-T cells in combination with DNA vaccine encoding the same epitopes against murine cutaneous leishmaniasis. Immature DCs were loaded with epitopes (selected from parasite proteome) in vitro with or without CpG oligonucleotides and were used to immunize BALB/c mice. Peptide coding DNA was used to boost the system and immunological responses were evaluated after Leishmania (L.) major infectious challenge. The pre-challenge response to included epitopes was Th1 polarized which potentially lowered the infection at early time points post-challenge but not at later weeks. Collectively, DC prime-DNA boost was found to be a promising approach for Th1 polarization however the constituent epitopes undoubtedly make a significant contribution in the protection outcome of the vaccine.


Asunto(s)
Células de la Médula Ósea/inmunología , Linfocitos T CD8-positivos/inmunología , Células Dendríticas/inmunología , Leishmania major/inmunología , Leishmaniasis Cutánea/prevención & control , Vacunas Antiprotozoos , Secuencia de Aminoácidos , Animales , Linfocitos T CD4-Positivos/inmunología , Citocinas/metabolismo , Epítopos/química , Epítopos/inmunología , Femenino , Ratones , Ratones Endogámicos BALB C , Óxido Nítrico/metabolismo , Proteoma/química , Vacunas de ADN
10.
Nat Commun ; 12(1): 1162, 2021 02 19.
Artículo en Inglés | MEDLINE | ID: mdl-33608522

RESUMEN

The durability of infection-induced SARS-CoV-2 immunity has major implications for reinfection and vaccine development. Here, we show a comprehensive profile of antibody, B cell and T cell dynamics over time in a cohort of patients who have recovered from mild-moderate COVID-19. Binding and neutralising antibody responses, together with individual serum clonotypes, decay over the first 4 months post-infection. A similar decline in Spike-specific CD4+ and circulating T follicular helper frequencies occurs. By contrast, S-specific IgG+ memory B cells consistently accumulate over time, eventually comprising a substantial fraction of circulating the memory B cell pool. Modelling of the concomitant immune kinetics predicts maintenance of serological neutralising activity above a titre of 1:40 in 50% of convalescent participants to 74 days, although there is probably additive protection from B cell and T cell immunity. This study indicates that SARS-CoV-2 immunity after infection might be transiently protective at a population level. Therefore, SARS-CoV-2 vaccines might require greater immunogenicity and durability than natural infection to drive long-term protection.


Asunto(s)
Anticuerpos Antivirales/inmunología , Formación de Anticuerpos , Inmunidad Celular , Memoria Inmunológica , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/sangre , Linfocitos B/inmunología , Linfocitos T CD4-Positivos/inmunología , Humanos , Inmunoglobulina G/inmunología , Estudios Longitudinales , Modelos Teóricos , Pruebas de Neutralización , Linfocitos T Colaboradores-Inductores/inmunología
11.
Front Immunol ; 12: 603563, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33603759

RESUMEN

The high infection rate and rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) make it a world-wide pandemic. Individuals infected by the virus exhibited different degrees of symptoms, and most convalescent individuals have been shown to develop both cellular and humoral immune responses. However, virus-specific adaptive immune responses in severe patients during acute phase have not been thoroughly studied. Here, we found that in a group of COVID-19 patients with acute respiratory distress syndrome (ARDS) during hospitalization, most of them mounted SARS-CoV-2-specific antibody responses, including neutralizing antibodies. However, compared to healthy controls, the percentages and absolute numbers of both NK cells and CD8+ T cells were significantly reduced, with decreased IFNγ expression in CD4+ T cells in peripheral blood from severe patients. Most notably, their peripheral blood lymphocytes failed in producing IFNγ against viral proteins. Thus, severe COVID-19 patients at acute infection stage developed SARS-CoV-2-specific antibody responses but were impaired in cellular immunity, which emphasizes on the role of cellular immunity in COVID-19.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Células Asesinas Naturales/inmunología , /inmunología , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Recuento de Células , Células Cultivadas , Progresión de la Enfermedad , Femenino , Humanos , Inmunidad Celular , Interferón gamma/metabolismo , Masculino , Persona de Mediana Edad
12.
Viruses ; 13(2)2021 02 09.
Artículo en Inglés | MEDLINE | ID: mdl-33572146

RESUMEN

B-cell follicles constitute large reservoirs of infectious HIV/SIV associated to follicular dendritic cells and infecting follicular helper (TFH) and regulatory (TFR) T-cells in germinal centers (GCs). Thus, follicular and GC B-cells are persistently exposed to viral antigens. Despite recent development of potent HIV immunogens, numerous questions are still open regarding GC reaction during early HIV/SIV infection. Here, we dissect the dynamics of B- and T-cells in GCs of macaques acutely infected by SIV (Group SIV+) or vaccinated with Tetanus Toxoid (Group TT), a T-dependent model antigen. Systemic inflammation and mobilization of antigen-presenting cells in inguinal lymph nodes and spleen are lower in Group TT than in Group SIV+. Despite spleen GC reaction of higher magnitude in Group SIV+, the development of protective immunity could be limited by abnormal helper functions of TFH massively polarized into TFH1-like cells, by inflammation-induced recruitment of fCD8 (either regulatory or cytotoxic) and by low numbers of TFR limiting TFH/TFR competition for high affinity B-cells. Increased GC B-cells apoptosis and accumulation of CD21lo memory B-cells, unable to further participate to GC reaction, likely contribute to eliminate SIV-specific B-cells and decrease antibody affinity maturation. Surprisingly, functional GCs and potent TT-specific antibodies develop despite low levels of CXCL13.


Asunto(s)
Centro Germinal/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/inmunología , Animales , Receptor del Factor Activador de Células B/metabolismo , Linfocitos B/inmunología , Linfocitos B/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Inmunidad Humoral , Memoria Inmunológica , Inflamación , Macaca mulatta , Masculino , Bazo/inmunología , /metabolismo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Toxoide Tetánico/administración & dosificación , Toxoide Tetánico/inmunología , Proteína Activadora Transmembrana y Interactiva del CAML/metabolismo
13.
Nat Commun ; 12(1): 755, 2021 02 02.
Artículo en Inglés | MEDLINE | ID: mdl-33531483

RESUMEN

Fecal microbiota transplantation (FMT) is a successful therapeutic strategy for treating recurrent Clostridioides difficile infection. Despite remarkable efficacy, implementation of FMT therapy is limited and the mechanism of action remains poorly understood. Here, we demonstrate a critical role for the immune system in supporting FMT using a murine C. difficile infection system. Following FMT, Rag1 heterozygote mice resolve C. difficile while littermate Rag1-/- mice fail to clear the infection. Targeted ablation of adaptive immune cell subsets reveal a necessary role for CD4+ Foxp3+ T-regulatory cells, but not B cells or CD8+ T cells, in FMT-mediated resolution of C. difficile infection. FMT non-responsive mice exhibit exacerbated inflammation, impaired engraftment of the FMT bacterial community and failed restoration of commensal bacteria-derived secondary bile acid metabolites in the large intestine. These data demonstrate that the host's inflammatory immune status can limit the efficacy of microbiota-based therapeutics to treat C. difficile infection.


Asunto(s)
/patogenicidad , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Infecciones por Clostridium/inmunología , Infecciones por Clostridium/metabolismo , Heces/microbiología , Factores de Transcripción Forkhead/metabolismo , Proteínas de Homeodominio/metabolismo , Inflamación/inmunología , Inflamación/metabolismo , Ratones , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo
14.
Immunity ; 54(2): 340-354.e6, 2021 02 09.
Artículo en Inglés | MEDLINE | ID: mdl-33567252

RESUMEN

Cellular and humoral immunity to SARS-CoV-2 is critical to control primary infection and correlates with severity of disease. The role of SARS-CoV-2-specific T cell immunity, its relationship to antibodies, and pre-existing immunity against endemic coronaviruses (huCoV), which has been hypothesized to be protective, were investigated in 82 healthy donors (HDs), 204 recovered (RCs), and 92 active COVID-19 patients (ACs). ACs had high amounts of anti-SARS-CoV-2 nucleocapsid and spike IgG but lymphopenia and overall reduced antiviral T cell responses due to the inflammatory milieu, expression of inhibitory molecules (PD-1, Tim-3) as well as effector caspase-3, -7, and -8 activity in T cells. SARS-CoV-2-specific T cell immunity conferred by polyfunctional, mainly interferon-γ-secreting CD4+ T cells remained stable throughout convalescence, whereas humoral responses declined. Immune responses toward huCoV in RCs with mild disease and strong cellular SARS-CoV-2 T cell reactivity imply a protective role of pre-existing immunity against huCoV.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Inmunidad Celular/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Femenino , Humanos , Inmunidad Humoral/inmunología , Masculino , Persona de Mediana Edad , Adulto Joven
15.
Nat Commun ; 12(1): 897, 2021 02 09.
Artículo en Inglés | MEDLINE | ID: mdl-33563974

RESUMEN

The dynamics, duration, and nature of immunity produced during SARS-CoV-2 infection are still unclear. Here, we longitudinally measured virus-neutralising antibody, specific antibodies against the spike (S) protein, receptor-binding domain (RBD), and the nucleoprotein (N) of SARS-CoV-2, as well as T cell responses, in 25 SARS-CoV-2-infected patients up to 121 days post-symptom onset (PSO). All patients seroconvert for IgG against N, S, or RBD, as well as IgM against RBD, and produce neutralising antibodies (NAb) by 14 days PSO, with the peak levels attained by 15-30 days PSO. Anti-SARS-CoV-2 IgG and NAb remain detectable and relatively stable 3-4 months PSO, whereas IgM antibody rapidly decay. Approximately 65% of patients have detectable SARS-CoV-2-specific CD4+ or CD8+ T cell responses 3-4 months PSO. Our results thus provide critical evidence that IgG, NAb, and T cell responses persist in the majority of patients for at least 3-4 months after infection.


Asunto(s)
Anticuerpos Antivirales/inmunología , /virología , Linfocitos T/inmunología , Adulto , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Femenino , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Inmunoglobulina M/sangre , Inmunoglobulina M/inmunología , Memoria Inmunológica , Interferón gamma/metabolismo , Cinética , Antígenos Comunes de Leucocito/metabolismo , Masculino , Persona de Mediana Edad , Fenotipo , Receptores CCR7/metabolismo
16.
Medicine (Baltimore) ; 100(6): e24619, 2021 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-33578573

RESUMEN

ABSTRACT: CD4+T cell epitopes plays a key role in anti-tuberculosis (TB) immunity, CD4+T cell epitopes suitable for the domestic population are lacking. Therefore, we predicted and identified novel CD4+T cell epitopes.The bioinformatics software, namely, DNAStar (DNASTAR of the United States), SYFPEITHI (INTERFACTORS INSTITUT Für ZELL Biologie of Germany), RANKPEP, and NetMHC IIpan (National Cancer Institute, United States of America), were used to comprehensively predict the CD4+T cell immune epitope of Mycobacterium TB, and the predicted epitope polypeptide was synthesized by the standard Fmoc scheme. The proliferation of PBMC and CD4+T cells stimulated by peptides was preliminarily detected by the CCK8 method. Then, the candidate polypeptides screened out by the CCK8 method were verified again by the BrdU assay, and flow cytometry was performed to analyze further the extent of their stimulation on the proliferation of CD4+T cells. The changes in the secreted cytokines IFN-γ, TNF-α, IL-2, and IL-10 before and after the candidate polypeptide stimulation of CD4+T lymphocytes were detected by ELISA. The preliminary humoral immunity test was conducted by indirect ELISA to evaluate the serological diagnostic value of the CD4+T cell epitope polypeptide.In this study, 5 novel candidate CD4+T cell epitope polypeptides with the amino acid sequences of LQGQWRGAAGTAAQA, PVTLAETGSTLLYPL, AAAWGGSGSEAYQGV, QFVYAGAMSGLLDPS, and KAALTRTASNMNAAA and others that have not been reported in the research were predicted. For convenience, the 5 candidates were successively named as P39, P50, P40, P185, and P62. P39, P62, and the mixed peptide P39+P62 could effectively induce the proliferation of CD4+T cells and increase the secretion of IFN-γ, TNF-α, and IL-2 from the CD4+T cells, while reducing the content of IL-10. The serological test showed that the sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) of P39 were 75%, 67.71%, and 0.844, respectively. The sensitivity, specificity, and AUC of P62 were 91.66%, 46.87%, and 0.649, respectively. The sensitivity of the mixed peptide P39+P62 was 95.83%, the specificity was 97.91%, and the AUC was 0.793.The P39 and P62 polypeptides were predicted and identified as potential CD4+T cell immune epitope polypeptides of M. TB. The polypeptide had better diagnosis effect, which provided potential candidate epitope polypeptides for the development of TB-specific diagnosis reagents and novel TB epitope vaccines.


Asunto(s)
Antígenos Bacterianos/inmunología , Linfocitos T CD4-Positivos/inmunología , Epítopos de Linfocito T/inmunología , Mycobacterium tuberculosis/inmunología , Ensayo de Inmunoadsorción Enzimática , Humanos , Sensibilidad y Especificidad
17.
Nat Commun ; 12(1): 907, 2021 02 10.
Artículo en Inglés | MEDLINE | ID: mdl-33568645

RESUMEN

Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are two distinct autoimmune diseases that manifest with chronic synovial inflammation. Here, we show that CD4+ T cells from patients with RA and PsA have increased expression of the pore-forming calcium channel component ORAI3, thereby increasing the activity of the arachidonic acid-regulated calcium-selective (ARC) channel and making T cells sensitive to arachidonic acid. A similar increase does not occur in T cells from patients with systemic lupus erythematosus. Increased ORAI3 transcription in RA and PsA T cells is caused by reduced IKAROS expression, a transcriptional repressor of the ORAI3 promoter. Stimulation of the ARC channel with arachidonic acid induces not only a calcium influx, but also the phosphorylation of components of the T cell receptor signaling cascade. In a human synovium chimeric mouse model, silencing ORAI3 expression in adoptively transferred T cells from patients with RA attenuates tissue inflammation, while adoptive transfer of T cells from healthy individuals with reduced expression of IKAROS induces synovitis. We propose that increased ARC activity due to reduced IKAROS expression makes T cells more responsive and contributes to chronic inflammation in RA and PsA.


Asunto(s)
Ácido Araquidónico/inmunología , Artritis Reumatoide/inmunología , Linfocitos T CD4-Positivos/inmunología , Membrana Sinovial/inmunología , Anciano , Artritis Psoriásica/genética , Artritis Psoriásica/inmunología , Artritis Reumatoide/genética , Calcio/inmunología , Canales de Calcio/genética , Canales de Calcio/inmunología , Señalización del Calcio , Femenino , Humanos , Masculino , Persona de Mediana Edad
18.
Medicine (Baltimore) ; 100(5): e24075, 2021 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-33592861

RESUMEN

BACKGROUND: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a life-threatening syndrome with high mortality. Biomarkers are urgently needed to predict the prognosis of HBV-ACLF. Recent evidence suggests a key role for immune system in the pathology of HBV-ACLF. Here, we analyzed the correlation between peripheral blood T lymphocytes and the severity and prognosis in HBV-ACLF patients. METHOD: Sixty-six patients with HBV-ACLF received conventional medical treatments for 4 weeks. Twenty-five healthy subjects and 20 HBV patients were enrolled for comparison. We determined white blood cell count, lymphocytes, CD3+, CD4+ and CD8+ T cells, and CD4+CD25+ Treg cells in the blood of all subjects. Their associations with laboratory parameters before or after treatments were statistically analyzed. RESULT: The results showed that compare normal subjects and chronic hepatitis B patients, HBV-ACLF patients had significantly increased white blood count, CD4+ T cells and decreased lymphocytes, CD3+ T cells, and Treg cells. Correlation analysis showed that white blood cell, lymphocytes, and peripheral T lymphocytes were correlated with prothrombin activity (PTA) and model for end-stage liver disease (MELD) scores. After treatment, white blood cell, lymphocytes, and peripheral T lymphocytes were also correlated with PTA and MELD scores. Additionally, total bilirubin (TBIL), alanine aminotransferase (ALT), international standard ratio (INR), MELD, and white blood cell count were potential prognostic criteria for HBV-ACLF patients. CONCLUSION: HBV-ACLF patients had depletion and dysfunction of immune system. Changes of peripheral T lymphocytes were closely related to the pathogenesis and prognosis of disease. Our results may contribute to predict the severity of HBV-ACLF, and provide a prognosis response to improve the treatment of HBV-ACLF.


Asunto(s)
Insuficiencia Hepática Crónica Agudizada , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Hepatitis B Crónica/complicaciones , Recuento de Linfocitos/métodos , Linfocitos T Reguladores/inmunología , Insuficiencia Hepática Crónica Agudizada/sangre , Insuficiencia Hepática Crónica Agudizada/diagnóstico , Insuficiencia Hepática Crónica Agudizada/etiología , Insuficiencia Hepática Crónica Agudizada/mortalidad , China/epidemiología , Correlación de Datos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Índice de Severidad de la Enfermedad
20.
Science ; 371(6529)2021 02 05.
Artículo en Inglés | MEDLINE | ID: mdl-33408181

RESUMEN

Understanding immune memory to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for improving diagnostics and vaccines and for assessing the likely future course of the COVID-19 pandemic. We analyzed multiple compartments of circulating immune memory to SARS-CoV-2 in 254 samples from 188 COVID-19 cases, including 43 samples at ≥6 months after infection. Immunoglobulin G (IgG) to the spike protein was relatively stable over 6+ months. Spike-specific memory B cells were more abundant at 6 months than at 1 month after symptom onset. SARS-CoV-2-specific CD4+ T cells and CD8+ T cells declined with a half-life of 3 to 5 months. By studying antibody, memory B cell, CD4+ T cell, and CD8+ T cell memory to SARS-CoV-2 in an integrated manner, we observed that each component of SARS-CoV-2 immune memory exhibited distinct kinetics.


Asunto(s)
Anticuerpos Antivirales/sangre , Memoria Inmunológica , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Neutralizantes/sangre , Linfocitos B/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Estudios Transversales , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Glicoproteína de la Espiga del Coronavirus/inmunología , Estados Unidos , Adulto Joven
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