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1.
Int J Mol Sci ; 22(5)2021 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-33800363

RESUMEN

Quantitative and robust serology assays are critical measurements underpinning global COVID-19 response to diagnostic, surveillance, and vaccine development. Here, we report a proof-of-concept approach for the development of quantitative, multiplexed flow cytometry-based serological and neutralization assays. The serology assays test the IgG and IgM against both the full-length spike antigens and the receptor binding domain (RBD) of the spike antigen. Benchmarking against an RBD-specific SARS-CoV IgG reference standard, the anti-SARS-CoV-2 RBD antibody titer was quantified in the range of 37.6 µg/mL to 31.0 ng/mL. The quantitative assays are highly specific with no correlative cross-reactivity with the spike proteins of MERS, SARS1, OC43 and HKU1 viruses. We further demonstrated good correlation between anti-RBD antibody titers and neutralizing antibody titers. The suite of serology and neutralization assays help to improve measurement confidence and are complementary and foundational for clinical and epidemiologic studies.


Asunto(s)
/métodos , /sangre , Pruebas de Neutralización/métodos , Pruebas de Neutralización/normas , /inmunología , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Reacciones Cruzadas , Citometría de Flujo/métodos , Fluorescencia , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Inmunoglobulina M/sangre , Inmunoglobulina M/inmunología , Microesferas , Receptores Virales/química , Receptores Virales/inmunología , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/inmunología
2.
Viruses ; 13(3)2021 03 20.
Artículo en Inglés | MEDLINE | ID: mdl-33804667

RESUMEN

While SARS-CoV-2 specific neutralizing antibodies have been developed for therapeutic purposes, the specific viral triggers that drive the generation of SARS-CoV-2 specific IgG and IgM antibodies remain only partially characterized. Moreover, it is unknown whether endogenously derived antibodies drive viral clearance that might result in mitigation of clinical severity during natural infection. We developed a series of non-linear mathematical models to investigate whether SARS-CoV-2 viral and antibody kinetics are coupled or governed by separate processes. Patients with severe disease had a higher production rate of IgG but not IgM antibodies. Maximal levels of both isotypes were governed by their production rate rather than different saturation levels between people. Our results suggest that an exponential surge in IgG levels occurs approximately 5-10 days after symptom onset with no requirement for continual antigenic stimulation. SARS-CoV-2 specific IgG antibodies appear to have limited to no effect on viral dynamics but may enhance viral clearance late during primary infection resulting from the binding effect of antibody to virus, rather than neutralization. In conclusion, SARS-CoV-2 specific IgG antibodies may play only a limited role in clearing infection from the nasal passages despite providing long-term immunity against infection following vaccination or prior infection.


Asunto(s)
Anticuerpos Antivirales/inmunología , Inmunoglobulina G/inmunología , Nariz/virología , /fisiología , Anticuerpos Neutralizantes/inmunología , Humanos , Inmunoglobulina M/inmunología , Estudios Longitudinales , Nariz/inmunología , /inmunología , Esparcimiento de Virus
3.
Viruses ; 13(3)2021 03 23.
Artículo en Inglés | MEDLINE | ID: mdl-33806922

RESUMEN

Since the coronavirus disease (COVID-19) pandemic was first identified in early 2020, rare cases of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in pet cats have been reported worldwide. Some reports of cats with SARS-CoV-2 showed self-limiting respiratory or gastrointestinal disease after suspected human-to-feline transmission via close contact with humans with SARS-CoV-2. In the present study, we investigated a cat with SARS-CoV-2 that was presented to a private animal clinic in Northern Italy in May 2020 in a weak clinical condition due to an underlying intestinal B-cell lymphoma. The cat developed signs of respiratory tract disease, including a sneeze, a cough and ocular discharge, three days after an oropharyngeal swab tested positive for SARS-CoV-2 viral RNA using two real-time reverse transcriptase polymerase chain reaction (RT-qPCR) assays for the envelope (E) and RNA-dependent RNA polymerase (RdRp) gene. Thus, SARS-CoV-2 viral RNA was detectable prior to the onset of clinical signs. Five and six months after positive molecular results, the serological testing substantiated the presence of a SARS-CoV-2 infection in the cat with the detection of anti-SARS-CoV-2 receptor binding domain (RBD) immunoglobulin (IgG) antibodies and neutralizing activity in a surrogate virus neutralization assay (sVNT). To the best of our knowledge, this extends the known duration of seropositivity of SARS-CoV-2 in a cat. Our study provides further evidence that cats are susceptible to SARS-CoV-2 under natural conditions and strengthens the assumption that comorbidities may play a role in the development of clinical disease.


Asunto(s)
Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Enfermedades de los Gatos/inmunología , Linfoma de Células B/veterinaria , Animales , Formación de Anticuerpos , /virología , Enfermedades de los Gatos/virología , Gatos , Inmunoglobulina G/inmunología , Italia , Linfoma de Células B/inmunología , Linfoma de Células B/virología , Glicoproteína de la Espiga del Coronavirus
4.
Viruses ; 13(3)2021 03 05.
Artículo en Inglés | MEDLINE | ID: mdl-33807957

RESUMEN

Although antibody levels progressively decrease following SARS-CoV-2 infection, the immune memory persists for months. Thus, individuals who naturally contracted SARS-CoV-2 are expected to develop a more rapid and sustained response to COVID-19 vaccines than naïve individuals. In this study, we analyzed the dynamics of the antibody response to the BNT162b2 mRNA COVID-19 vaccine in six healthcare workers who contracted SARS-CoV-2 in March 2020, in comparison to nine control subjects without a previous infection. The vaccine was well tolerated by both groups, with no significant difference in the frequency of vaccine-associated side effects, with the exception of local pain, which was more common in previously infected subjects. Overall, the titers of neutralizing antibodies were markedly higher in response to the vaccine than after natural infection. In all subjects with pre-existing immunity, a rapid increase in anti-spike receptor-binding domain (RBD) IgG antibodies and neutralizing antibody titers was observed one week after the first dose, which seemed to act as a booster. Notably, in previously infected individuals, neutralizing antibody titers 7 days after the first vaccine dose were not significantly different from those observed in naïve subjects 7 days after the second vaccine dose. These results suggest that, in previously infected people, a single dose of the vaccine might be sufficient to induce an effective response.


Asunto(s)
Anticuerpos Antivirales/inmunología , /inmunología , ARN Mensajero/inmunología , ARN Viral/inmunología , /inmunología , Adulto , Formación de Anticuerpos , /virología , /genética , Femenino , Humanos , Inmunoglobulina G/inmunología , Masculino , Persona de Mediana Edad , ARN Mensajero/administración & dosificación , ARN Mensajero/genética , ARN Viral/administración & dosificación , ARN Viral/genética , /genética
5.
Front Immunol ; 12: 629185, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33833755

RESUMEN

The WHO declared the COVID-19 outbreak a public health emergency of international concern. The causative agent of this acute respiratory disease is a newly emerged coronavirus, named SARS-CoV-2, which originated in China in late 2019. Exposure to SARS-CoV-2 leads to multifaceted disease outcomes from asymptomatic infection to severe pneumonia, acute respiratory distress and potentially death. Understanding the host immune response is crucial for the development of interventional strategies. Humoral responses play an important role in defending viral infections and are therefore of particular interest. With the aim to resolve SARS-CoV-2-specific humoral immune responses at the epitope level, we screened clinically well-characterized sera from COVID-19 patients with mild and severe disease outcome using high-density peptide microarrays covering the entire proteome of SARS-CoV-2. Moreover, we determined the longevity of epitope-specific antibody responses in a longitudinal approach. Here we present IgG and IgA-specific epitope signatures from COVID-19 patients, which may serve as discriminating prognostic or predictive markers for disease outcome and/or could be relevant for intervention strategies.


Asunto(s)
/inmunología , Epítopos/inmunología , Proteoma/inmunología , /inmunología , Adulto , Anticuerpos Antivirales/inmunología , Femenino , Humanos , Inmunidad Humoral , Inmunoglobulina A/inmunología , Inmunoglobulina G/inmunología , Masculino
6.
Nat Commun ; 12(1): 2037, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33795692

RESUMEN

The hallmarks of COVID-19 are higher pathogenicity and mortality in the elderly compared to children. Examining baseline SARS-CoV-2 cross-reactive immunological responses, induced by circulating human coronaviruses (hCoVs), is needed to understand such divergent clinical outcomes. Here we show analysis of coronavirus antibody responses of pre-pandemic healthy children (n = 89), adults (n = 98), elderly (n = 57), and COVID-19 patients (n = 50) by systems serology. Moderate levels of cross-reactive, but non-neutralizing, SARS-CoV-2 antibodies are detected in pre-pandemic healthy individuals. SARS-CoV-2 antigen-specific Fcγ receptor binding accurately distinguishes COVID-19 patients from healthy individuals, suggesting that SARS-CoV-2 infection induces qualitative changes to antibody Fc, enhancing Fcγ receptor engagement. Higher cross-reactive SARS-CoV-2 IgA and IgG are observed in healthy elderly, while healthy children display elevated SARS-CoV-2 IgM, suggesting that children have fewer hCoV exposures, resulting in less-experienced but more polyreactive humoral immunity. Age-dependent analysis of COVID-19 patients, confirms elevated class-switched antibodies in elderly, while children have stronger Fc responses which we demonstrate are functionally different. These insights will inform COVID-19 vaccination strategies, improved serological diagnostics and therapeutics.


Asunto(s)
Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Formación de Anticuerpos/inmunología , /inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , /inmunología , Niño , Preescolar , Reacciones Cruzadas/inmunología , Humanos , Inmunoglobulina A/sangre , Inmunoglobulina A/inmunología , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Inmunoglobulina M/sangre , Inmunoglobulina M/inmunología , Persona de Mediana Edad , Receptores de IgG/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Adulto Joven
7.
Int J Mol Sci ; 22(6)2021 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-33802650

RESUMEN

As an essential modulator of IgG disposition, the neonatal Fc receptor (FcRn) governs the pharmacokinetics and functions many therapeutic modalities. In this review, we thoroughly reexamine the hitherto elucidated biological and thermodynamic properties of FcRn to provide context for our assessment of more recent advances, which covers antigen-binding fragment (Fab) determinants of FcRn affinity, transgenic preclinical models, and FcRn targeting as an immune-complex (IC)-clearing strategy. We further comment on therapeutic antibodies authorized for treating SARS-CoV-2 (bamlanivimab, casirivimab, and imdevimab) and evaluate their potential to saturate FcRn-mediated recycling. Finally, we discuss modeling and simulation studies that probe the quantitative relationship between in vivo IgG persistence and in vitro FcRn binding, emphasizing the importance of endosomal transit parameters.


Asunto(s)
Antígenos de Histocompatibilidad Clase I/química , Antígenos de Histocompatibilidad Clase I/metabolismo , Receptores Fc/química , Receptores Fc/metabolismo , Animales , Anticuerpos Monoclonales/metabolismo , Anticuerpos Monoclonales/farmacocinética , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Inmunoglobulina G/inmunología , Inmunoglobulina G/metabolismo , Receptores Fc/inmunología , Distribución Tisular/inmunología
8.
Nat Commun ; 12(1): 2055, 2021 04 06.
Artículo en Inglés | MEDLINE | ID: mdl-33824342

RESUMEN

Identification of protective T cell responses against SARS-CoV-2 requires distinguishing people infected with SARS-CoV-2 from those with cross-reactive immunity to other coronaviruses. Here we show a range of T cell assays that differentially capture immune function to characterise SARS-CoV-2 responses. Strong ex vivo ELISpot and proliferation responses to multiple antigens (including M, NP and ORF3) are found in 168 PCR-confirmed SARS-CoV-2 infected volunteers, but are rare in 119 uninfected volunteers. Highly exposed seronegative healthcare workers with recent COVID-19-compatible illness show T cell response patterns characteristic of infection. By contrast, >90% of convalescent or unexposed people show proliferation and cellular lactate responses to spike subunits S1/S2, indicating pre-existing cross-reactive T cell populations. The detection of T cell responses to SARS-CoV-2 is therefore critically dependent on assay and antigen selection. Memory responses to specific non-spike proteins provide a method to distinguish recent infection from pre-existing immunity in exposed populations.


Asunto(s)
Antivirales/farmacología , /virología , Reacciones Cruzadas/inmunología , Inmunoensayo/métodos , Linfocitos T/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Proliferación Celular , Citocinas/metabolismo , Células HEK293 , Personal de Salud , Humanos , Inmunoglobulina G/inmunología , Memoria Inmunológica , Interferón gamma/metabolismo , Pandemias , Péptidos/metabolismo , /efectos de los fármacos
10.
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
11.
Int J Nanomedicine ; 16: 1819-1836, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33707942

RESUMEN

Background: The development of vaccines is a promising and cost-effective strategy to prevent emerging multidrug-resistant (MDR) Acinetobacter baumannii (A. baumannii) infections. The purpose of this study was to prepare a multiepitope peptide nanovaccine and evaluate its immunogenicity and protective effect in BALB/c mice. Methods: The B-cell and T-cell epitopes of Omp22 from A. baumannii were predicted using bioinformatics methods and identified by immunological experiments. The optimal epitopes were conjugated in series by 6-aminocaproic acid and chemically synthesized multiepitope polypeptide rOmp22. Then, rOmp22 was encapsulated by chitosan (CS) and poly (lactic-co-glycolic) acid (PLGA) to prepare CS-PLGA-rOmp22 nanoparticles (NPs). The immunogenicity and immunoprotective efficacy of the vaccine were evaluated in BALB/c mice. Results: CS-PLGA-rOmp22 NPs were small (mean size of 272.83 nm) with apparently spherical structures, positively charged (4.39 mV) and nontoxic to A549 cells. A high encapsulation efficiency (54.94%) and a continuous slow release pattern were achieved. Compared with nonencapsulated rOmp22, CS-PLGA-rOmp22 immunized BALB/c mice induced higher levels of rOmp22-specific IgG in serum and IFN-γ in splenocyte supernatant. Additionally, lung injury and bacterial burdens in the lung and blood were suppressed, and potent protection (57.14%-83.3%) against acute lethal intratracheal A. baumannii challenge was observed in BALB/c mice vaccinated with CS-PLGA-rOmp22. Conclusion: CS-PLGA-rOmp22 NPs elicited specific IgG antibodies, Th1 cellular immunity and protection against acute lethal intratracheal A. baumannii challenge. Our results indicate that this nanovaccine is a desirable candidate for preventing A. baumannii infection.


Asunto(s)
Infecciones por Acinetobacter/inmunología , Acinetobacter baumannii/inmunología , Vacunas Bacterianas/inmunología , Quitosano/química , Epítopos/inmunología , Nanopartículas/química , Péptidos/inmunología , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Células A549 , Infecciones por Acinetobacter/sangre , Infecciones por Acinetobacter/microbiología , Secuencia de Aminoácidos , Animales , Anticuerpos Antibacterianos/inmunología , Carga Bacteriana , Peso Corporal , Epítopos/química , Femenino , Humanos , Inmunidad Humoral , Inmunización , Inmunoglobulina G/inmunología , Interferón gamma/metabolismo , Interleucina-4/metabolismo , Pulmón/inmunología , Pulmón/microbiología , Pulmón/patología , Ratones , Ratones Endogámicos BALB C , Nanopartículas/ultraestructura , Péptidos/química , Proteínas Recombinantes/aislamiento & purificación , Bazo/patología , Análisis de Supervivencia
12.
Front Immunol ; 12: 632814, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33763078

RESUMEN

Increasing evidence suggests that dysregulated immune responses are associated with the clinical outcome of coronavirus disease 2019 (COVID-19). Nucleocapsid protein (NP)-, spike (S)-, receptor binding domain (RBD)- specific immunoglobulin (Ig) isotypes, IgG subclasses and neutralizing antibody (NAb) were analyzed in 123 serum from 63 hospitalized patients with severe, moderate, mild or asymptomatic COVID-19. Mild to modest correlations were found between disease severity and antigen specific IgG subclasses in serum, of which IgG1 and IgG3 were negatively associated with viral load in nasopharyngeal swab. Multiple cytokines were significantly related with antigen-specific Ig isotypes and IgG subclasses, and IL-1ß was positively correlated with most antibodies. Furthermore, the old patients (≥ 60 years old) had higher levels of chemokines, increased NAb activities and SARS-CoV-2 specific IgG1, and IgG3 responses and compromised T cell responses compared to the young patients (≤ 18 years old), which are related with more severe cases. Higher IgG1 and IgG3 were found in COVID-19 patients with comorbidities while biological sex had no effect on IgG subclasses. Overall, we have identified diseases severity was related to higher antibodies, of which IgG subclasses had weakly negative correlation with viral load, and cytokines were significantly associated with antibody response. Further, advancing age and comorbidities had obvious effect on IgG1 and IgG3.


Asunto(s)
Anticuerpos Antivirales/inmunología , Inmunoglobulina G/inmunología , /fisiología , Adolescente , Adulto , /virología , Niño , China , Citocinas/inmunología , Femenino , Humanos , Inmunoglobulina A/inmunología , Inmunoglobulina M/inmunología , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Linfocitos T/inmunología , Adulto Joven
13.
Indian J Public Health ; 65(1): 5-10, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33753682

RESUMEN

Background: Multiple serosurveillance studies have focused on the presence of antibodies against severe acute respiratory syndrome coronavirus 2 in the general population and confirmed cases. However, seroprevalence of immunoglobulin G (IgG) among contacts of confirmed cases can add further value to the scientific findings. Objectives: The objective is to estimate COVID-19 seropositivity among contacts of COVID-19 cases and to compare the seropositivity between types of contact for the assessment of differential risk and transmission dynamics. Methods: Large scale population-based serosurveillance on contacts of COVID-19 cases was carried out during the second half of August 2020 in Ahmedabad using the COVID-Kavach. The seropositivity among contacts was estimated and correlated-compared with type of contact and other demographic factors. Results: With 1268 positive for IgG antibodies from 3973 samples, the seropositivity against COVID-19 among contacts of cases in Ahmedabad was 31.92% (95% confidence interval 30.48%-33.38%). The seropositivity among family contacts was significantly higher (39.36%) as compared to other contacts (28.72%) (Z = 6.60, P < 0.01). This trend is seen across all age groups and both the sex groups. The seropositivity has increasing trend with increasing age and is significantly higher among females (35.11%) than males (28.95%) (Z = 4.16, P < 0.01). Conclusion: Seropositivity of 31.92% among contacts indicates that a large proportion of contacts have already acquired immunity on account of their contact with the case. Higher seropositivity among family contacts justifies the risk categorization and testing strategy adopted for the contacts of the cases. This also reaffirms the need for contact tracing strategy for controlling the inevitable spread of pandemic.


Asunto(s)
/epidemiología , Trazado de Contacto/métodos , Inmunoglobulina G/inmunología , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Familia , Femenino , Humanos , India/epidemiología , Lactante , Masculino , Persona de Mediana Edad , Estudios Seroepidemiológicos , Factores Sexuales , Factores Socioeconómicos , Adulto Joven
14.
Cell Rep ; 34(13): 108915, 2021 03 30.
Artículo en Inglés | MEDLINE | ID: mdl-33761319

RESUMEN

To fully decipher the immunogenicity of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike protein, it is essential to assess which part is highly immunogenic in a systematic way. We generate a linear epitope landscape of the Spike protein by analyzing the serum immunoglobulin G (IgG) response of 1,051 coronavirus disease 2019 (COVID-19) patients with a peptide microarray. We reveal two regions rich in linear epitopes, i.e., C-terminal domain (CTD) and a region close to the S2' cleavage site and fusion peptide. Unexpectedly, we find that the receptor binding domain (RBD) lacks linear epitope. We reveal that the number of responsive peptides is highly variable among patients and correlates with disease severity. Some peptides are moderately associated with severity and clinical outcome. By immunizing mice, we obtain linear-epitope-specific antibodies; however, no significant neutralizing activity against the authentic virus is observed for these antibodies. This landscape will facilitate our understanding of SARS-CoV-2-specific humoral responses and might be useful for vaccine refinement.


Asunto(s)
/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Adulto , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Antígenos Virales/inmunología , /genética , China/epidemiología , Modelos Animales de Enfermedad , Mapeo Epitopo/métodos , Epítopos/inmunología , Femenino , Humanos , Inmunoglobulina G/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/metabolismo
15.
Medicine (Baltimore) ; 100(9): e24372, 2021 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-33655912

RESUMEN

RATIONALE: Severe refractory idiopathic inflammatory myopathy (IIM) represents a challenge for the clinician. The lack of efficacy of available tools reflects our incomplete insight into the molecular events sustaining the inflammatory tissue damage in these patients. We present the first case of refractory IIM treated with anti-dipeptidyl peptidase-4 (DPP-4)/cluster of differentiation 26 (CD26) monoclonal antibody. PATIENT CONCERNS: A 55-year old man presented with proximal muscle weakness, diffuse erythematous skin lesions which rapidly evolved into ulcerations, dysphagia and dysphonia. DIAGNOSIS: Increased serum creatine kinase levels and histological findings at muscle and skin biopsies were compatible with the diagnosis of dermatomyositis (DM). Several lines of treatment failed to control the disease including steroids, mycophenolate mofetil, tacrolimus, intravenous immunoglobulins and rituximab. Despite therapy, the patient also had recurrent intestinal vasculitis causing bowel perforation. Concurrently, DPP-4/CD26 expression in the patient's skin and skeletal muscle was observed. INTERVENTIONS: The patient was treated with begelomab, a murine immunoglobulin G2b monoclonal antibody against DPP-4/CD26. OUTCOMES: Dysphagia, skin lesions and intestinal vasculitis resolved and the patient experienced a significant improvement of his quality of life. CONCLUSION: Blockade of DPP-4/CD26, which is expressed on T cells and mediates T cell activation and function, is safe and might be effective in patients with refractory DM.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Dermatomiositis/tratamiento farmacológico , Dipeptidil Peptidasa 4/inmunología , Inhibidores de la Dipeptidil-Peptidasa IV/inmunología , Inmunoglobulina G/inmunología , Dermatomiositis/inmunología , Humanos , Masculino , Persona de Mediana Edad
16.
Sci Rep ; 11(1): 5563, 2021 03 10.
Artículo en Inglés | MEDLINE | ID: mdl-33692457

RESUMEN

While there are various attempts to administer COVID-19-convalescent plasmas to SARS-CoV-2-infected patients, neither appropriate approach nor clinical utility has been established. We examined the presence and temporal changes of the neutralizing activity of IgG fractions from 43 COVID-19-convalescent plasmas using cell-based assays with multiple endpoints. IgG fractions from 27 cases (62.8%) had significant neutralizing activity and moderately to potently inhibited SARS-CoV-2 infection in cell-based assays; however, no detectable neutralizing activity was found in 16 cases (37.2%). Approximately half of the patients (~ 41%), who had significant neutralizing activity, lost the neutralization activity within ~ 1 month. Despite the rapid decline of neutralizing activity in plasmas, good amounts of SARS-CoV-2-S1-binding antibodies were persistently seen. The longer exposure of COVID-19 patients to greater amounts of SARS-CoV-2 elicits potent immune response to SARS-CoV-2, producing greater neutralization activity and SARS-CoV-2-S1-binding antibody amounts. The dilution of highly-neutralizing plasmas with poorly-neutralizing plasmas relatively readily reduced neutralizing activity. The presence of good amounts of SARS-CoV-2-S1-binding antibodies does not serve as a surrogate ensuring the presence of good neutralizing activity. In selecting good COVID-19-convalescent plasmas, quantification of neutralizing activity in each plasma sample before collection and use is required.


Asunto(s)
/inmunología , Inmunoglobulina G/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Femenino , Humanos , Inmunización Pasiva/métodos , Masculino , Persona de Mediana Edad , Pandemias/prevención & control , Plasma/química , Receptores Virales/metabolismo , /patogenicidad
17.
Emerg Microbes Infect ; 10(1): 664-676, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33734013

RESUMEN

Seasonal human coronaviruses (HCoVs) including HCoV-229E, -OC43, -NL63, and -HKU1 widely spread in global human populations. However, the relevance of humoral response against seasonal HCoVs to COVID-19 pathogenesis is elusive. In this study, we profiled the temporal changes of IgG antibody against spike proteins (S-IgG) of SARS-CoV-2 and seasonal HCoVs in 838 plasma samples collected from 344 COVID-19 patients. We tested the antigenic cross-reactivities of S protein between SARS-CoV-2 and seasonal HCoVs and evaluated the correlations between the levels of HCoV-OC43 S-IgG and the disease severity in COVID-19 patients. We found that SARS-CoV-2 S-IgG titres mounted until days 22-28, whereas HCoV-OC43 antibody titres increased until days 15-21 and then plateaued until day 46. However, IgG titres against HCoV-NL63, -229E, and -HKU1 showed no significant increase. A two-way cross-reactivity was identified between SARS-CoV-2 and HCoV-OC43. Neutralizing antibodies against SARS-CoV-2 were not detectable in healthy controls who were positive for HCoV-OC43 S-IgG. HCoV-OC43 S-IgG titres were significantly higher in patients with severe disease than those in mild patients at days 1-21 post symptom onset (PSO). Higher levels of HCoV-OC43 S-IgG were also observed in patients requiring mechanical ventilation. At days 1-10 PSO, HCoV-OC43 S-IgG titres correlated to disease severity in the age group over 60. Our data indicate that there is a correlation between cross-reactive antibody against HCoV-OC43 spike protein and disease severity in COVID-19 patients.


Asunto(s)
Anticuerpos Antivirales/sangre , Coronavirus Humano OC43/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Reacciones Cruzadas/inmunología , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Adulto Joven
18.
Medicine (Baltimore) ; 100(12): e25165, 2021 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-33761691

RESUMEN

RATIONALE: Rosai-Dorfman disease (RDD) is a rare and self-limiting condition caused by the non-neoplastic proliferation of histiocytes/phagocytes in the sinusoids of lymph nodes and in extranodal tissues. Of the extranodal involvement, laryngeal involvement is extremely rare. Because of its rarity and nonspecific clinicoradiologic features, RDD is often difficult to differentiate from other benign or malignant lymphoproliferative diseases. We present a case of RDD with infiltration of IgG4-bearing plasma cells manifesting laryngeal and nasal masses with cervical lymphadenopathy. PATIENT CONCERNS: A 45-year-old male patient presented with recurrent epistaxis and airway disturbance. DIAGNOSES: On endoscopy, there were submucosal masses in both nasal cavities and both sides of subglottic larynx. On neck CT, there were well-defined, enhancing soft tissue masses in both nasal cavities and both sides of subglottic larynx, resulting in mild airway narrowing. In addition, multiple enlarged lymph nodes showing homogeneous enhancement were noted in both parotid glands and both internal jugular chains. All lesions demonstrated marked FDG-uptake on PET/CT. Therefore, the initial radiologic differential diagnoses included lymphoma and IgG4-related disease. Biopsy was performed on the nasal and laryngeal lesions, and they revealed RDD with infiltration of IgG4-bearing plasma cells. INTERVENTION: The patient underwent surgical resection of the masses in the nasal cavity and larynx to relieve airway narrowing. OUTCOMES: After surgery, airway obstruction was much improved and the patient was asymptomatic. On outpatient follow-up, he exhibited a stable condition and had no dyspnea on exercise. LESSONS: Clinical awareness and suspicion are important for the accurate diagnosis and management of patients with homogeneous masses in the larynx or nasal cavity, even if there is no combined cervical lymphadenopathy.


Asunto(s)
Histiocitosis Sinusal/inmunología , Histiocitosis Sinusal/patología , Inmunoglobulina G/inmunología , Laringe/patología , Linfadenopatía/patología , Cavidad Nasal/patología , Células Plasmáticas/inmunología , Obstrucción de las Vías Aéreas/etiología , Obstrucción de las Vías Aéreas/cirugía , Biopsia , Diagnóstico Diferencial , Endoscopía , Epistaxis/etiología , Radioisótopos de Flúor , Histiocitosis Sinusal/complicaciones , Histiocitosis Sinusal/cirugía , Humanos , Laringe/cirugía , Linfadenopatía/etiología , Linfadenopatía/cirugía , Masculino , Persona de Mediana Edad , Cavidad Nasal/cirugía , Cuello , Tomografía Computarizada por Tomografía de Emisión de Positrones , Recurrencia
19.
Nat Commun ; 12(1): 1961, 2021 03 30.
Artículo en Inglés | MEDLINE | ID: mdl-33785765

RESUMEN

The pathogenesis of severe COVID-19 reflects an inefficient immune reaction to SARS-CoV-2. Here we analyze, at the single cell level, plasmablasts egressed into the blood to study the dynamics of adaptive immune response in COVID-19 patients requiring intensive care. Before seroconversion in response to SARS-CoV-2 spike protein, peripheral plasmablasts display a type 1 interferon-induced gene expression signature; however, following seroconversion, plasmablasts lose this signature, express instead gene signatures induced by IL-21 and TGF-ß, and produce mostly IgG1 and IgA1. In the sustained immune reaction from COVID-19 patients, plasmablasts shift to the expression of IgA2, thereby reflecting an instruction by TGF-ß. Despite their continued presence in the blood, plasmablasts are not found in the lungs of deceased COVID-19 patients, nor does patient IgA2 binds to the dominant antigens of SARS-CoV-2. Our results thus suggest that, in severe COVID-19, SARS-CoV-2 triggers a chronic immune reaction that is instructed by TGF-ß, and is distracted from itself.


Asunto(s)
Anticuerpos Antivirales/inmunología , /inmunología , Factor de Crecimiento Transformador beta/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Inmunoglobulina A/inmunología , Inmunoglobulina G/inmunología , Interleucinas/inmunología , Masculino , Persona de Mediana Edad , Células Plasmáticas/inmunología , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/inmunología
20.
Anal Chem ; 93(12): 5259-5266, 2021 03 30.
Artículo en Inglés | MEDLINE | ID: mdl-33733739

RESUMEN

Lung-secreted IgG and IgM antibodies are valuable biomarkers for monitoring the local immune response against respiratory infections. These biomarkers are found in lower airway secretions that need to be liquefied prior to analysis. Traditional methods for sample liquefaction rely on reducing disulfide bonds, which may damage the structure of the biomarkers and hamper their immunodetection. Here, we propose an alternative enzymatic method that uses O2 bubbles generated by endogenous catalase enzymes in order to liquefy respiratory samples. The proposed method is more efficient for liquefying medium- and high-viscosity samples and does not fragment the antibodies. This prevents damage to antigen recognition domains and recognition sites for secondary antibodies that can decrease the signal of immunodetection techniques. The suitability of the enzymatic method for detecting antibodies in respiratory samples is demonstrated by detecting anti-SARS-CoV-2 IgG and IgM to viral N-protein with gold standard ELISA in bronchial aspirate specimens from a multicenter cohort of 44 COVID-19 patients. The enzymatic detection sharply increases the sensitivity toward IgG and IgM detection compared to the traditional approach based on liquefying samples with dithiothreitol. This improved performance could reveal new mechanisms of the early local immune response against respiratory infections that may have gone unnoticed with current sample treatment methods.


Asunto(s)
Anticuerpos Antivirales/inmunología , Inmunoglobulina G/inmunología , Inmunoglobulina M/inmunología , Pulmón/inmunología , /inmunología , Ensayo de Inmunoadsorción Enzimática , Humanos , Límite de Detección
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