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1.
Nat Immunol ; 21(12): 1506-1516, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33028979

RESUMEN

A wide spectrum of clinical manifestations has become a hallmark of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) COVID-19 pandemic, although the immunological underpinnings of diverse disease outcomes remain to be defined. We performed detailed characterization of B cell responses through high-dimensional flow cytometry to reveal substantial heterogeneity in both effector and immature populations. More notably, critically ill patients displayed hallmarks of extrafollicular B cell activation and shared B cell repertoire features previously described in autoimmune settings. Extrafollicular activation correlated strongly with large antibody-secreting cell expansion and early production of high concentrations of SARS-CoV-2-specific neutralizing antibodies. Yet, these patients had severe disease with elevated inflammatory biomarkers, multiorgan failure and death. Overall, these findings strongly suggest a pathogenic role for immune activation in subsets of patients with COVID-19. Our study provides further evidence that targeted immunomodulatory therapy may be beneficial in specific patient subpopulations and can be informed by careful immune profiling.


Asunto(s)
Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Linfocitos B/inmunología , COVID-19/inmunología , SARS-CoV-2/inmunología , Humanos , Inmunofenotipificación
2.
Nature ; 611(7934): 139-147, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36044993

RESUMEN

Severe SARS-CoV-2 infection1 has been associated with highly inflammatory immune activation since the earliest days of the COVID-19 pandemic2-5. More recently, these responses have been associated with the emergence of self-reactive antibodies with pathologic potential6-10, although their origins and resolution have remained unclear11. Previously, we and others have identified extrafollicular B cell activation, a pathway associated with the formation of new autoreactive antibodies in chronic autoimmunity12,13, as a dominant feature of severe and critical COVID-19 (refs. 14-18). Here, using single-cell B cell repertoire analysis of patients with mild and severe disease, we identify the expansion of a naive-derived, low-mutation IgG1 population of antibody-secreting cells (ASCs) reflecting features of low selective pressure. These features correlate with progressive, broad, clinically relevant autoreactivity, particularly directed against nuclear antigens and carbamylated proteins, emerging 10-15 days after the onset of symptoms. Detailed analysis of the low-selection compartment shows a high frequency of clonotypes specific for both SARS-CoV-2 and autoantigens, including pathogenic autoantibodies against the glomerular basement membrane. We further identify the contraction of this pathway on recovery, re-establishment of tolerance standards and concomitant loss of acute-derived ASCs irrespective of antigen specificity. However, serological autoreactivity persists in a subset of patients with postacute sequelae, raising important questions as to the contribution of emerging autoreactivity to continuing symptomology on recovery. In summary, this study demonstrates the origins, breadth and resolution of autoreactivity in severe COVID-19, with implications for early intervention and the treatment of patients with post-COVID sequelae.


Asunto(s)
Autoanticuerpos , Linfocitos B , COVID-19 , Humanos , Autoanticuerpos/inmunología , Linfocitos B/inmunología , Linfocitos B/patología , COVID-19/inmunología , COVID-19/patología , COVID-19/fisiopatología , SARS-CoV-2/inmunología , SARS-CoV-2/patogenicidad , Inmunoglobulina G/inmunología , Análisis de la Célula Individual , Autoantígenos/inmunología , Membrana Basal/inmunología , Síndrome Post Agudo de COVID-19
3.
Nat Immunol ; 15(3): 275-82, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24441790

RESUMEN

While a number of extrinsic factors are known to promote the survival of plasma cells (PCs), the signaling intermediates involved remain poorly characterized. Here we identified inducible nitric oxide synthase (iNOS) as an intermediate that supported the survival of PCs. PCs deficient in iNOS (Nos2(-/-) PCs) showed enhanced death in vitro, after transfer into congenic adoptive hosts, and in chimeras made with wild-type and Nos2(-/-) bone marrow. The iNOS-mediated protection involved activation of protein kinase G and modulation of endoplasmic reticulum stress components. Activation of caspases was also diminished. We found that iNOS was required for PCs to respond to some prosurvival mediators associated with bone marrow stromal cells and that at least one mediator, interleukin 6, fed directly into this pathway by inducing iNOS.


Asunto(s)
Óxido Nítrico Sintasa de Tipo II/inmunología , Células Plasmáticas/inmunología , Transducción de Señal/inmunología , Traslado Adoptivo , Animales , Supervivencia Celular/inmunología , Citometría de Flujo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Óxido Nítrico Sintasa de Tipo II/metabolismo , Células Plasmáticas/enzimología , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
4.
Immunol Rev ; 309(1): 40-63, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35801537

RESUMEN

Infection with SARS-CoV-2, the etiology of the ongoing COVID-19 pandemic, has resulted in over 450 million cases with more than 6 million deaths worldwide, causing global disruptions since early 2020. Memory B cells and durable antibody protection from long-lived plasma cells (LLPC) are the mainstay of most effective vaccines. However, ending the pandemic has been hampered by the lack of long-lived immunity after infection or vaccination. Although immunizations offer protection from severe disease and hospitalization, breakthrough infections still occur, most likely due to new mutant viruses and the overall decline of neutralizing antibodies after 6 months. Here, we review the current knowledge of B cells, from extrafollicular to memory populations, with a focus on distinct plasma cell subsets, such as early-minted blood antibody-secreting cells and the bone marrow LLPC, and how these humoral compartments contribute to protection after SARS-CoV-2 infection and immunization.


Asunto(s)
COVID-19 , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Humanos , Inmunidad Humoral , Pandemias/prevención & control , Células Plasmáticas , SARS-CoV-2 , Vacunación
5.
Waste Manag Res ; : 734242X231188664, 2023 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-37519292

RESUMEN

Plastic waste circularity is a priority at a global level. Sustainable development goals (SDGs) set the ways to go, and the circular economy principles underlined the 'green' strategies to be employed. However, in practice, there is still much to do, especially in developing countries, where open burning and open dumping still represent the common way of plastic waste disposal. This review aims to analyse current plastic waste circular approaches in low-middle income settings. Seven countries were selected based on the economic level and data availability from the authors, and analysed to collect and critically discuss the actions implemented at a city level. Examples of waste minimization and recycling strategies, selective collection systems and public campaigns are reported from Africa, Asia and Latin America. First, a background analysis related to physical and governance aspects of municipal solid waste management systems of the chosen settings was conducted. The assessment was focused on the treatment processes or minimization actions. Then, the applicability of the projects to achieve the SDGs was commented on. The outcomes of the research underline the need to: (1) scale up small-scale and pilot projects, (2) disseminate good practices in more low- to middle-income settings, (3) create synergies among international partners for further replications in cities. Urgent solutions to plastic waste pollution are needed. The review presented practical actions to be implemented now to boost plastic waste circularity in developing cities.

7.
Front Cell Dev Biol ; 10: 895162, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36518540

RESUMEN

Mammalian cardiomyocyte maturation entails phenotypic and functional optimization during the late fetal and postnatal phases of heart development, both processes driven and coordinated by complex gene regulatory networks. Cardiomyocytes derived from human induced pluripotent stem cells (iPSCs) are heterogenous and immature, barely resembling their adult in vivo counterparts. To characterize relevant developmental programs and maturation states during human iPSC-cardiomyocyte differentiation, we performed single-cell transcriptomic sequencing, which revealed six cardiomyocyte subpopulations, whose heterogeneity was defined by cell cycle and maturation states. Two of those subpopulations were characterized by a mature, non-proliferative transcriptional profile. To further investigate the proliferation-maturation transition in cardiomyocytes, we induced loss-of-function of LMNB2, which represses cell cycle progression in primary cardiomyocytes in vivo. This resulted in increased maturation in LMNB2-inactivated cardiomyocytes, characterized by transcriptional profiles related to myofibril structure and energy metabolism. Furthermore, we identified maturation signatures and maturational trajectories unique for control and LMNB2-inactivated cardiomyocytes. By comparing these datasets with single-cell transcriptomes of human fetal hearts, we were able to define spatiotemporal maturation states in human iPSC-cardiomyocytes. Our results provide an integrated approach for comparing in vitro-differentiated cardiomyocytes with their in vivo counterparts and suggest a strategy to promote cardiomyocyte maturation.

8.
medRxiv ; 2021 Jul 27.
Artículo en Inglés | MEDLINE | ID: mdl-33106819

RESUMEN

An emerging feature of COVID-19 is the identification of autoreactivity in patients with severe disease that may contribute to disease pathology, however the origin and resolution of these responses remain unclear. Previously, we identified strong extrafollicular B cell activation as a shared immune response feature between both severe COVID-19 and patients with advanced rheumatic disease. In autoimmune settings, this pathway is associated with relaxed peripheral tolerance in the antibody secreting cell compartment and the generation of de novo autoreactive responses. Investigating these responses in COVID-19, we performed single-cell repertoire analysis on 7 patients with severe disease. In these patients, we identify the expansion of a low-mutation IgG1 fraction of the antibody secreting cell compartment that are not memory derived, display low levels of selective pressure, and are enriched for autoreactivity-prone IGHV4-34 expression. Within this compartment, we identify B cell lineages that display specificity to both SARS-CoV-2 and autoantigens, including pathogenic autoantibodies against glomerular basement membrane, and describe progressive, broad, clinically relevant autoreactivity within these patients correlated with disease severity. Importantly, we identify anti-carbamylated protein responses as a common hallmark and candidate biomarker of broken peripheral tolerance in severe COVID-19. Finally, we identify the contraction of this pathway upon recovery, and re-establishment of tolerance standards coupled with a concomitant loss of acute-derived ASCs irrespective of antigen specificity. In total, this study reveals the origins, breadth, and resolution of acute-phase autoreactivity in severe COVID-19, with significant implications in both early interventions and potential treatment of patients with post-COVID sequelae.

9.
HGG Adv ; 2(3)2021 07 08.
Artículo en Inglés | MEDLINE | ID: mdl-34888534

RESUMEN

Bicuspid aortic valve (BAV) with ~1%-2% prevalence is the most common congenital heart defect (CHD). It frequently results in valve disease and aorta dilation and is a major cause of adult cardiac surgery. BAV is genetically linked to rare left-heart obstructions (left ventricular outflow tract obstructions [LVOTOs]), including hypoplastic left heart syndrome (HLHS) and coarctation of the aorta (CoA). Mouse and human studies indicate LVOTO is genetically heterogeneous with a complex genetic etiology. Homozygous mutation in the Pcdha protocadherin gene cluster in mice can cause BAV, and also HLHS and other LVOTO phenotypes when accompanied by a second mutation. Here we show two common deletion copy number variants (delCNVs) within the PCDHA gene cluster are associated with LVOTO. Analysis of 1,218 white individuals with LVOTO versus 463 disease-free local control individuals yielded odds ratios (ORs) at 1.47 (95% confidence interval [CI], 1.13-1.92; p = 4.2 × 10-3) for LVOTO, 1.47 (95% CI, 1.10-1.97; p = 0.01) for BAV, 6.13 (95% CI, 2.75-13.7; p = 9.7 × 10-6) for CoA, and 1.49 (95% CI, 1.07-2.08; p = 0.019) for HLHS. Increased OR was observed for all LVOTO phenotypes in homozygous or compound heterozygous PCDHA delCNV genotype comparison versus wild type. Analysis of an independent white cohort (381 affected individuals, 1,352 control individuals) replicated the PCDHA delCNV association with LVOTO. Generalizability of these findings is suggested by similar observations in Black and Chinese individuals with LVOTO. Analysis of Pcdha mutant mice showed reduced PCDHA expression at regions of cell-cell contact in aortic smooth muscle and cushion mesenchyme, suggesting potential mechanisms for BAV pathogenesis and aortopathy. Together, these findings indicate common variants causing PCDHA deficiency play a significant role in the genetic etiology of common and rare LVOTO-CHD.

10.
Immunohorizons ; 5(5): 322-335, 2021 05 17.
Artículo en Inglés | MEDLINE | ID: mdl-34001652

RESUMEN

SARS-CoV-2 has caused over 100,000,000 cases and almost 2,500,000 deaths globally. Comprehensive assessment of the multifaceted antiviral Ab response is critical for diagnosis, differentiation of severity, and characterization of long-term immunity, especially as COVID-19 vaccines become available. Severe disease is associated with early, massive plasmablast responses. We developed a multiplex immunoassay from serum/plasma of acutely infected and convalescent COVID-19 patients and prepandemic and postpandemic healthy adults. We measured IgA, IgG, and/or IgM against SARS-CoV-2 nucleocapsid (N), spike domain 1 (S1), S1-receptor binding domain (RBD) and S1-N-terminal domain. For diagnosis, the combined [IgA + IgG + IgM] or IgG levels measured for N, S1, and S1-RBD yielded area under the curve values ≥0.90. Virus-specific Ig levels were higher in patients with severe/critical compared with mild/moderate infections. A strong prozone effect was observed in sera from severe/critical patients-a possible source of underestimated Ab concentrations in previous studies. Mild/moderate patients displayed a slower rise and lower peak in anti-N and anti-S1 IgG levels compared with severe/critical patients, but anti-RBD IgG and neutralization responses reached similar levels at 2-4 mo after symptom onset. Measurement of the Ab responses in sera from 18 COVID-19-vaccinated patients revealed specific responses for the S1-RBD Ag and none against the N protein. This highly sensitive, SARS-CoV-2-specific, multiplex immunoassay measures the magnitude, complexity, and kinetics of the Ab response and can distinguish serum Ab responses from natural SARS-CoV-2 infections (mild or severe) and mRNA COVID-19 vaccines.


Asunto(s)
Anticuerpos Antivirales , Vacunas contra la COVID-19/administración & dosificación , COVID-19 , SARS-CoV-2 , Índice de Severidad de la Enfermedad , Vacunación , Adulto , Anciano , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , COVID-19/sangre , COVID-19/inmunología , COVID-19/prevención & control , Femenino , Humanos , Inmunoensayo , Masculino , Persona de Mediana Edad , SARS-CoV-2/inmunología , SARS-CoV-2/metabolismo
11.
medRxiv ; 2020 Jun 22.
Artículo en Inglés | MEDLINE | ID: mdl-32511635

RESUMEN

A wide clinical spectrum has become a hallmark of the SARS-CoV-2 (COVID-19) pandemic, although its immunologic underpinnings remain to be defined. We have performed deep characterization of B cell responses through high-dimensional flow cytometry to reveal substantial heterogeneity in both effector and immature populations. More notably, critically ill patients displayed hallmarks of extrafollicular B cell activation as previously described in autoimmune settings. Extrafollicular activation correlated strongly with large antibody secreting cell expansion and early production of high levels of SARS-CoV-2-specific antibodies. Yet, these patients fared poorly with elevated inflammatory biomarkers, multi-organ failure, and death. Combined, the findings strongly indicate a major pathogenic role for immune activation in subsets of COVID-19 patients. Our study suggests that, as in autoimmunity, targeted immunomodulatory therapy may be beneficial in specific patient subpopulations that can be identified by careful immune profiling.

12.
Sci Adv ; 6(31): eabb0806, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32832688

RESUMEN

Aging results in profound immune dysfunction, resulting in the decline of vaccine responsiveness previously attributed to irreversible defects in the immune system. In addition to increased interleukin-6 (IL-6), we found aged mice exhibit increased systemic IL-10 that requires forkhead box P3-negative (FoxP3-), but not FoxP3+, CD4+T cells. Most IL-10-producing cells manifested a T follicular helper (Tfh) phenotype and required the Tfh cytokines IL-6 and IL-21 for their accrual, so we refer to them as Tfh10 cells. IL-21 was also required to maintain normal serum levels of IL-6 and IL-10. Notably, antigen-specific Tfh10 cells arose after immunization of aged mice, and neutralization of IL-10 receptor signaling significantly restored Tfh-dependent antibody responses, whereas depletion of FoxP3+ regulatory and follicular regulatory cells did not. Thus, these data demonstrate that immune suppression with age is reversible and implicate Tfh10 cells as an intriguing link between "inflammaging" and impaired immune responses with age.

13.
bioRxiv ; 2020 Dec 06.
Artículo en Inglés | MEDLINE | ID: mdl-33299998

RESUMEN

BACKGROUND: SARS-CoV-2 has caused over 36,000,000 cases and 1,000,000 deaths globally. Comprehensive assessment of the multifaceted anti-viral antibody response is critical for diagnosis, differentiation of severe disease, and characterization of long-term immunity. Initial observations suggest that severe disease is associated with higher antibody levels and greater B cell/plasmablast responses. A multi-antigen immunoassay to define the complex serological landscape and clinical associations is essential. METHODS: We developed a multiplex immunoassay and evaluated serum/plasma from adults with RT-PCR-confirmed SARS-CoV-2 infections during acute illness (N=52) and convalescence (N=69); and pre-pandemic (N=106) and post-pandemic (N=137) healthy adults. We measured IgA, IgG, and/or IgM against SARS-CoV-2 Nucleocapsid (N), Spike domain 1 (S1), receptor binding domain (S1-RBD) and S1-N-terminal domain (S1-NTD). RESULTS: To diagnose infection, the combined [IgA+IgG+IgM] or IgG for N, S1, and S1-RBD yielded AUC values -0.90 by ROC curves. From days 6-30 post-symptom onset, the levels of antigen-specific IgG, IgA or [IgA+IgG+IgM] were higher in patients with severe/critical compared to mild/moderate infections. Consistent with excessive concentrations of antibodies, a strong prozone effect was observed in sera from severe/critical patients. Notably, mild/moderate patients displayed a slower rise and lower peak in anti-N and anti-S1 IgG levels compared to severe/critical patients, but anti-RBD IgG and neutralization responses reached similar levels at 2-4 months. CONCLUSION: This SARS-CoV-2 multiplex immunoassay measures the magnitude, complexity and kinetics of the antibody response against multiple viral antigens. The IgG and combined-isotype SARS-CoV-2 multiplex assay is highly diagnostic of acute and convalescent disease and may prognosticate severity early in illness. ONE SENTENCE SUMMARY: In contrast to patients with moderate infections, those with severe COVID-19 develop prominent, early antibody responses to S1 and N proteins.

14.
Indian J Tuberc ; 64(3): 232-234, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28709496

RESUMEN

Invasive candidiasis coexisting with drug-resistant Mycobacterium tuberculosis (DR-TB) in the immunocompetent patient is a rare entity. We report a 30-year-old woman, nondiabetic, who presented to us with complaints of acute onset cough, breathlessness, and fever since 20 days. On thorough investigations, she was diagnosed to be suffering from coexisting drug-resistant tuberculosis and invasive candidiasis. Prompt treatment initiated at right time helped us in saving her life. The unique presentation of this case and that too in an immunocompetent female makes it an interesting case.


Asunto(s)
Candidiasis Invasiva/complicaciones , Tuberculosis Resistente a Múltiples Medicamentos/complicaciones , Adulto , Candidiasis Invasiva/diagnóstico , Candidiasis Invasiva/tratamiento farmacológico , Femenino , Humanos , Inmunocompetencia , Tomografía Computarizada por Rayos X , Tuberculosis Resistente a Múltiples Medicamentos/diagnóstico , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico
15.
Am J Med Sci ; 348(5): 377-81, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-24762754

RESUMEN

BACKGROUND: A better understanding of the factors affecting the outcome of inpatient cardiopulmonary resuscitation (CPR) is crucial in making key clinical decisions. We aim to study the impact of various patient-related and hospital-related variables in a community-based teaching setup that could affect the prognosis of in-hospital cardiac arrests. METHODS: We analyzed the data on all patients who experienced cardiac arrest while hospitalized at a community teaching hospital in Youngstown, Ohio. A multivariable logistic regression was performed to identify patient- and system-based variables associated with mortality in inpatient cardiac arrest. RESULTS: A total of 417 in-hospital cardiopulmonary arrests were recorded during the study period. We analyzed 299 events in our final sample. One hundred sixty-four patients (54.8%) achieved return of spontaneous circulation and 137 (48.5%) survived the cardiopulmonary arrest for at least 24 hours. The duration of CPR, age, initial rhythm, witnessed events and sex were strongly associated with mortality in our univariate analysis. After adjustment for age, location and whether the code was witnessed, the timing of the week, initial rhythm, the duration of CPR and the sex of the patient retained prognostic significance in predicting the mortality. CONCLUSIONS: In our study, we report a 17.4% survival to hospital discharge after an in-hospital cardiopulmonary arrest and subsequent CPR, similar to rates reported in larger multicenter studies. Prolonged duration of CPR (>10 minutes) and male sex were found to be associated with worse outcomes. We report the impact of system-based variables such as physician and nursing staffing during different days of the week, on survival in these patients.


Asunto(s)
Reanimación Cardiopulmonar/tendencias , Paro Cardíaco/terapia , Hospitalización/tendencias , Adulto , Anciano , Anciano de 80 o más Años , Reanimación Cardiopulmonar/mortalidad , Femenino , Paro Cardíaco/diagnóstico , Paro Cardíaco/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Alta del Paciente/tendencias , Estudios Retrospectivos , Tasa de Supervivencia/tendencias , Resultado del Tratamiento , Adulto Joven
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