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1.
Viruses ; 13(4)2021 03 26.
Artículo en Inglés | MEDLINE | ID: mdl-33810456

RESUMEN

A central feature of vertebrate immune systems is the ability to form antigen-specific immune memory in response to microbial challenge and so provide protection against future infection. In conflict with this process is the ability that many viruses have to mutate their antigens to escape infection- or vaccine-induced antibody memory responses. Mutable viruses such as dengue virus, influenza virus and of course coronavirus have a major global health impact, exacerbated by this ability to evade immune responses through mutation. There have been several outstanding recent studies on B-cell memory that also shed light on the potential and limitations of antibody memory to protect against viral antigen variation, and so promise to inform new strategies for vaccine design. For the purposes of this review, the current understanding of the different memory B-cell (MBC) populations, and their potential to recognize mutant antigens, will be described prior to some examples from antibody responses against the highly mutable RNA based flaviviruses, influenza virus and SARS-CoV-2.


Asunto(s)
Anticuerpos Antivirales/inmunología , Antígenos Virales/inmunología , Linfocitos B/inmunología , Virosis/inmunología , Virus/inmunología , Animales , Antígenos Virales/genética , Humanos , Memoria Inmunológica , Virosis/virología , Virus/genética
2.
FASEB J ; 35(5): e21577, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33831263

RESUMEN

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is an emerging respiratory pathogen that has rapidly spread in human populations. Severe forms of infection associate cytokine release syndrome and acute lung injury due to hyperinflammatory responses even though virus clearance is achieved. Key components of inflammation include immune cell recruitment in infected tissues, a step which is under the control of endothelial cells. Here, we review endothelial cell responses in inflammation and infection due to SARS-CoV-2 together with phenotypic and functional alterations of monocytes, T and B lymphocytes with which they interact. We surmise that endothelial cells function as an integrative and active platform for the various cells recruited, where fine tuning of immune responses takes place and which provides opportunities for therapeutic intervention.


Asunto(s)
Inmunidad Adaptativa/inmunología , /patología , Células Endoteliales/patología , Células Mieloides/inmunología , Animales , Linfocitos B/citología , Linfocitos B/inmunología , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/patología , Citocinas/inmunología , Humanos , Memoria Inmunológica , Células Mieloides/citología , Linfocitos T/citología , Linfocitos T/inmunología
3.
Science ; 372(6537)2021 04 02.
Artículo en Inglés | MEDLINE | ID: mdl-33795432

RESUMEN

Multivalent display of receptor-engaging antibodies or ligands can enhance their activity. Instead of achieving multivalency by attachment to preexisting scaffolds, here we unite form and function by the computational design of nanocages in which one structural component is an antibody or Fc-ligand fusion and the second is a designed antibody-binding homo-oligomer that drives nanocage assembly. Structures of eight nanocages determined by electron microscopy spanning dihedral, tetrahedral, octahedral, and icosahedral architectures with 2, 6, 12, and 30 antibodies per nanocage, respectively, closely match the corresponding computational models. Antibody nanocages targeting cell surface receptors enhance signaling compared with free antibodies or Fc-fusions in death receptor 5 (DR5)-mediated apoptosis, angiopoietin-1 receptor (Tie2)-mediated angiogenesis, CD40 activation, and T cell proliferation. Nanocage assembly also increases severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pseudovirus neutralization by α-SARS-CoV-2 monoclonal antibodies and Fc-angiotensin-converting enzyme 2 (ACE2) fusion proteins.


Asunto(s)
Anticuerpos/química , Anticuerpos/inmunología , Nanoestructuras , Ingeniería de Proteínas , Transducción de Señal , Angiopoyetinas/química , Angiopoyetinas/inmunología , Angiopoyetinas/metabolismo , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/química , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/química , Anticuerpos Antivirales/inmunología , Linfocitos B/inmunología , Antígenos CD40/química , Antígenos CD40/inmunología , Antígenos CD40/metabolismo , Línea Celular Tumoral , Proliferación Celular , Simulación por Computador , Genes Sintéticos , Humanos , Fragmentos Fc de Inmunoglobulinas/química , Activación de Linfocitos , Modelos Moleculares , Unión Proteica , Receptor TIE-2/metabolismo , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/inmunología , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Linfocitos T/inmunología , Linfocitos T/fisiología
4.
Signal Transduct Target Ther ; 6(1): 113, 2021 03 08.
Artículo en Inglés | MEDLINE | ID: mdl-33686064

RESUMEN

The adaptive immunity that protects patients from coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is not well characterized. In particular, the asymptomatic patients have been found to induce weak and transient SARS-CoV-2 antibody responses, but the underlying mechanisms remain unknown; meanwhile, the protective immunity that guide the recovery of these asymptomatic patients is elusive. Here, we characterized SARS-CoV-2-specific B-cell and T-cell responses in 10 asymptomatic patients and 64 patients with other disease severity (mild, n = 10, moderate, n = 32, severe, n = 12) and found that asymptomatic or mild symptomatic patients failed to mount virus-specific germinal center (GC) B cell responses that result in robust and prolonged humoral immunity, assessed by GC response indicators including follicular helper T (TFH) cell and memory B cell responses as well as serum CXCL13 levels. Alternatively, these patients mounted potent virus-specific TH1 and CD8+ T cell responses. In sharp contrast, patients of moderate or severe disease induced vigorous virus-specific GC B cell responses and associated TFH responses; however, the virus-specific TH1 and CD8+ T cells were minimally induced in these patients. These results, therefore, uncovered the protective immunity in asymptomatic patients and also revealed the strikingly dichotomous and incomplete humoral and cellular immune responses in COVID-19 patients with different disease severity, providing important insights into rational design of effective COVID-19 vaccines.


Asunto(s)
Inmunidad Adaptativa , Linfocitos B/inmunología , Linfocitos T CD8-positivos/inmunología , /inmunología , Células TH1/inmunología , Adulto , Linfocitos B/patología , Linfocitos T CD8-positivos/patología , Femenino , Humanos , Masculino , Índice de Severidad de la Enfermedad , Células TH1/patología
5.
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
6.
BMC Immunol ; 22(1): 22, 2021 03 25.
Artículo en Inglés | MEDLINE | ID: mdl-33765919

RESUMEN

BACKGROUND: The spread of a novel coronavirus termed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in China and other countries is of great concern worldwide with no effective vaccine. This study aimed to design a novel vaccine construct against SARS-CoV-2 from the spike S protein and orf1ab polyprotein using immunoinformatics tools. The vaccine was designed from conserved epitopes interacted against B and T lymphocytes by the combination of highly immunogenic epitopes with suitable adjuvant and linkers. RESULTS: The proposed vaccine composed of 526 amino acids and was shown to be antigenic in Vaxigen server (0.6194) and nonallergenic in Allertop server. The physiochemical properties of the vaccine showed isoelectric point of 10.19. The instability index (II) was 31.25 classifying the vaccine as stable. Aliphatic index was 84.39 and the grand average of hydropathicity (GRAVY) was - 0.049 classifying the vaccine as hydrophilic. Vaccine tertiary structure was predicted, refined and validated to assess the stability of the vaccine via Ramachandran plot and ProSA-web servers. Moreover, solubility of the vaccine construct was greater than the average solubility provided by protein sol and SOLpro servers indicating the solubility of the vaccine construct. Disulfide engineering was performed to reduce the high mobile regions in the vaccine to enhance stability. Docking of the vaccine construct with TLR4 demonstrated efficient binding energy with attractive binding energy of - 338.68 kcal/mol and - 346.89 kcal/mol for TLR4 chain A and chain B respectively. Immune simulation significantly provided high levels of immunoglobulins, T-helper cells, T-cytotoxic cells and INF-γ. Upon cloning, the vaccine protein was reverse transcribed into DNA sequence and cloned into pET28a(+) vector to ensure translational potency and microbial expression. CONCLUSION: A unique vaccine construct from spike S protein and orf1ab polyprotein against B and T lymphocytes was generated with potential protection against the pandemic. The present study might assist in developing a suitable therapeutics protocol to combat SARSCoV-2 infection.


Asunto(s)
/inmunología , Epítopos de Linfocito B , Epítopos de Linfocito T , Glicoproteína de la Espiga del Coronavirus , Proteínas Virales , Linfocitos B/inmunología , /química , /inmunología , Epítopos de Linfocito B/química , Epítopos de Linfocito B/genética , Epítopos de Linfocito B/inmunología , Epítopos de Linfocito T/química , Epítopos de Linfocito T/genética , Epítopos de Linfocito T/inmunología , Humanos , Poliproteínas/química , Poliproteínas/genética , Poliproteínas/inmunología , /genética , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/inmunología , Linfocitos T/inmunología , Proteínas Virales/química , Proteínas Virales/genética , Proteínas Virales/inmunología
7.
Einstein (Sao Paulo) ; 19: eRB6077, 2021.
Artículo en Inglés, Portugués | MEDLINE | ID: mdl-33681888

RESUMEN

Follicular helper T lymphocytes are a subpopulation of CD4+ T lymphocytes initially identified in germinal centers of follicles found in secondary lymphoid organs. The primary function of follicular helper T lymphocytes is to help B lymphocytes' antibody production. Changing of antibody class and affinity, B cell differentiation and memory generation depend on cooperation between follicular helper T lymphocytes and B cells. In blood, follicular helper T lymphocytes are called circulating follicular helper T lymphocytes. They are considered to have specificities similar to those developed in the secondary lymphoid organs. The phenotype of human follicular helper T lymphocytes is given by simultaneous expression of the markers CXCR5, Bcl-6, CD40L, PD-1, and ICOS. In germinal centers, follicular helper T lymphocytes synthesize interleukin 21 as predominant cytokine. In blood, subpopulations of circulating follicular helper T lymphocytes can be recognized, with different expressions of the classical follicular helper T lymphocytes markers and, in addition, can express other markers such as CXCR3 and CCR6. Presently, there is great interest in follicular helper T lymphocytes and circulating follicular helper T lymphocytes in vaccination studies as indicators of immunization efficacy. In addition, follicular helper T lymphocytes are investigated as possible markers of activity in many diseases and potential therapeutic intervention. This short review describes aspects of immunobiology and quantification of follicular helper T lymphocytes and circulating follicular helper T lymphocytes, and presents a few examples of related findings in systemic lupus erythematosus, rheumatoid arthritis, HIV infection and vaccination.


Asunto(s)
Formación de Anticuerpos , Centro Germinal/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos B/inmunología , Humanos
8.
J Immunother Cancer ; 9(3)2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33707314

RESUMEN

While vaccines directed against the SARS-CoV-2 spike protein will have varying degrees of effectiveness in preventing SARS-CoV-2 infections, the severity of infection will be determined by multiple host factors including the ability of immune cells to lyse virus-infected cells. This review will discuss the complexity of both adaptive and innate immunomes and how a flow-based assay can detect up to 158 distinct cell subsets in the periphery. This assay has been employed to show the effect of age on differences in specific immune cell subsets, and the differences in the immunome between healthy donors and age-matched cancer patients. Also reviewed are the numerous soluble factors, in addition to cytokines, that may vary in the pathogenesis of SARS-CoV-2 infections and may also be employed to help define the effectiveness of a given vaccine or other antiviral agents. Various steroids have been employed in the management of autoimmune adverse events in cancer patients receiving immunotherapeutics and may be employed in the management of SARS-CoV-2 infections. The influence of steroids on multiple immune cells subsets will also be discussed.


Asunto(s)
Inmunidad Adaptativa/inmunología , Linfocitos B/inmunología , Células Dendríticas/inmunología , Inmunidad Innata/inmunología , Células Asesinas Naturales/inmunología , Neoplasias/inmunología , Linfocitos T/inmunología , Factores de Edad , Antígeno B7-H1/inmunología , Ligando de CD40/inmunología , /uso terapéutico , Citocinas/inmunología , Susceptibilidad a Enfermedades , Glucocorticoides/uso terapéutico , Granzimas/inmunología , Humanos , Inmunosenescencia/inmunología , Células Supresoras de Origen Mieloide/inmunología , Neoplasias/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/inmunología , Proteoma , Índice de Severidad de la Enfermedad , Subgrupos de Linfocitos T/inmunología , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunología
9.
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
10.
Int J Mol Sci ; 22(4)2021 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-33673271

RESUMEN

Senescent cells accumulate in the adipose tissue (AT) of individuals with obesity and secrete multiple factors that constitute the senescence-associated secretory phenotype (SASP). This paper aimed at the identification of B cells with a SASP phenotype in the AT, as compared to the peripheral blood, of individuals with obesity. Our results show increased expression of SASP markers in AT versus blood B cells, a phenotype associated with a hyper-metabolic profile necessary to support the increased immune activation of AT-derived B cells as compared to blood-derived B cells. This hyper-metabolic profile is needed for the secretion of the pro-inflammatory mediators (cytokines, chemokines, micro-RNAs) that fuel local and systemic inflammation.


Asunto(s)
Tejido Adiposo/inmunología , Linfocitos B/inmunología , Senescencia Celular/inmunología , Obesidad/inmunología , Tejido Adiposo/patología , Adulto , Linfocitos B/patología , Citocinas/inmunología , Femenino , Humanos , Inflamación/inmunología , Inflamación/patología , Mediadores de Inflamación/inmunología , Masculino , Persona de Mediana Edad , Obesidad/patología
11.
Cell ; 184(6): 1401, 2021 03 18.
Artículo en Inglés | MEDLINE | ID: mdl-33740443

RESUMEN

The first two vaccines proven to be effective for inhibiting COVID-19 illness were both mRNA, achieving 95% efficacy (and safety) among 74,000 participants (half receiving placebo) after intramuscular delivery of two shots, 3-4 weeks apart. To view this Bench to Bedside, open or download the PDF.


Asunto(s)
/inmunología , /inmunología , /inmunología , Vacunas Sintéticas/inmunología , Vacunas Sintéticas/uso terapéutico , Células Presentadoras de Antígenos/inmunología , Linfocitos B/inmunología , Sistemas de Liberación de Medicamentos/métodos , Humanos , Liposomas , Nanopartículas , Glicoproteína de la Espiga del Coronavirus/inmunología , Linfocitos T/inmunología , Resultado del Tratamiento
12.
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
13.
mSphere ; 6(2)2021 03 10.
Artículo en Inglés | MEDLINE | ID: mdl-33692194

RESUMEN

The concept of original antigenic sin (OAS) was put forth many years ago to explain how humoral memory responses generated against one set of antigens can affect the nature of antibody responses elicited to challenge infections or vaccinations containing a similar but not identical array of antigens. Here, we highlight the link between OAS and the germinal center reaction (GCR), a process unique to activated B cells undergoing somatic hypermutation and class switch recombination. It is the powerful response of activated memory B cells and the accompanying GCR that establish the foundations of OAS. We apply these concepts to the current COVID-19 pandemic and put forth several possible scenarios whereby OAS may result in either beneficial or harmful outcomes depending, hypothetically, on prior exposure to antigens shared between SARS-CoV-2 and seasonal human coronaviruses (hCoVs) that include betacoronaviruses (e.g., HCoV-OC43 and HCoV-HKU1) and alphacoronaviruses (e.g., HCoV-NL63 and HCoV-HKU1) (E. M. Anderson, E. C. Goodwin, A. Verma, C. P. Arevalo, et al., medRxiv, 2020, https://doi.org/10.1101/2020.11.06.20227215; S. M. Kissler, C. Tedijanto, E. Goldstein, Y. H. Grad, and M. Lipsitch, Science 368:860-868, 2020, https://doi.org/10.1126/science.abb5793).


Asunto(s)
/inmunología , Memoria Inmunológica/inmunología , /inmunología , Formación de Anticuerpos , Linfocitos B/inmunología , Centro Germinal/inmunología , Humanos
15.
Ugeskr Laeger ; 183(11)2021 03 15.
Artículo en Danés | MEDLINE | ID: mdl-33734074

RESUMEN

The duration of immunity after SARS-CoV-2 infection or vaccination is uncertain, but major advances have been made in the understanding of SARS-CoV-2 B- and T-cell protection. In this review, key data from studies of re-infection as well as B- and T-cell immunity after infection and vaccination are presented.


Asunto(s)
Linfocitos B/inmunología , /inmunología , /inmunología , Linfocitos T/inmunología , /inmunología , Humanos , Vacunación
16.
Cell ; 184(7): 1821-1835.e16, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33667349

RESUMEN

Human monoclonal antibodies are safe, preventive, and therapeutic tools that can be rapidly developed to help restore the massive health and economic disruption caused by the coronavirus disease 2019 (COVID-19) pandemic. By single-cell sorting 4,277 SARS-CoV-2 spike protein-specific memory B cells from 14 COVID-19 survivors, 453 neutralizing antibodies were identified. The most potent neutralizing antibodies recognized the spike protein receptor-binding domain, followed in potency by antibodies that recognize the S1 domain, the spike protein trimer, and the S2 subunit. Only 1.4% of them neutralized the authentic virus with a potency of 1-10 ng/mL. The most potent monoclonal antibody, engineered to reduce the risk of antibody-dependent enhancement and prolong half-life, neutralized the authentic wild-type virus and emerging variants containing D614G, E484K, and N501Y substitutions. Prophylactic and therapeutic efficacy in the hamster model was observed at 0.25 and 4 mg/kg respectively in absence of Fc functions.


Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Neutralizantes/administración & dosificación , Anticuerpos Antivirales/administración & dosificación , Linfocitos B/inmunología , Convalecencia , Células 3T3 , Animales , Anticuerpos Monoclonales/aislamiento & purificación , Anticuerpos Neutralizantes/aislamiento & purificación , Anticuerpos Antivirales/aislamiento & purificación , Linfocitos B/citología , /prevención & control , Chlorocebus aethiops , Modelos Animales de Enfermedad , Femenino , Células HEK293 , Humanos , Fragmentos Fc de Inmunoglobulinas/inmunología , Masculino , Ratones , Glicoproteína de la Espiga del Coronavirus/inmunología , Células Vero
17.
Cell ; 184(7): 1790-1803.e17, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33735607

RESUMEN

The long non-coding RNA (lncRNA) XIST establishes X chromosome inactivation (XCI) in female cells in early development and thereafter is thought to be largely dispensable. Here, we show XIST is continually required in adult human B cells to silence a subset of X-linked immune genes such as TLR7. XIST-dependent genes lack promoter DNA methylation and require continual XIST-dependent histone deacetylation. XIST RNA-directed proteomics and CRISPRi screen reveal distinctive somatic cell-type-specific XIST complexes and identify TRIM28 that mediates Pol II pausing at promoters of X-linked genes in B cells. Single-cell transcriptome data of female patients with either systemic lupus erythematosus or COVID-19 infection revealed XIST dysregulation, reflected by escape of XIST-dependent genes, in CD11c+ atypical memory B cells (ABCs). XIST inactivation with TLR7 agonism suffices to promote isotype-switched ABCs. These results indicate cell-type-specific diversification and function for lncRNA-protein complexes and suggest expanded roles for XIST in sex-differences in biology and medicine.


Asunto(s)
Linfocitos B/inmunología , Lupus Eritematoso Sistémico , ARN Largo no Codificante/fisiología , Receptor Toll-Like 7/inmunología , Inactivación del Cromosoma X , /genética , Línea Celular , Metilación de ADN , Femenino , Silenciador del Gen , Humanos , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunología
18.
Front Immunol ; 12: 636768, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33777028

RESUMEN

Understanding the causes of the diverse outcome of COVID-19 pandemic in different geographical locations is important for the worldwide vaccine implementation and pandemic control responses. We analyzed 42 unexposed healthy donors and 28 mild COVID-19 subjects up to 5 months from the recovery for SARS-CoV-2 specific immunological memory. Using HLA class II predicted peptide megapools, we identified SARS-CoV-2 cross-reactive CD4+ T cells in around 66% of the unexposed individuals. Moreover, we found detectable immune memory in mild COVID-19 patients several months after recovery in the crucial arms of protective adaptive immunity; CD4+ T cells and B cells, with a minimal contribution from CD8+ T cells. Interestingly, the persistent immune memory in COVID-19 patients is predominantly targeted towards the Spike glycoprotein of the SARS-CoV-2. This study provides the evidence of both high magnitude pre-existing and persistent immune memory in Indian population. By providing the knowledge on cellular immune responses to SARS-CoV-2, our work has implication for the development and implementation of vaccines against COVID-19.


Asunto(s)
Linfocitos B/inmunología , Linfocitos T CD4-Positivos/inmunología , Memoria Inmunológica , Glicoproteína de la Espiga del Coronavirus/inmunología , Adulto , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Linfocitos B/virología , Linfocitos T CD4-Positivos/virología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/virología , /diagnóstico , Estudios de Casos y Controles , Femenino , Humanos , Inmunidad Celular , Masculino , Persona de Mediana Edad , Factores de Tiempo , Adulto Joven
19.
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
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