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1.
Int J Mol Sci ; 22(20)2021 Oct 14.
Article in English | MEDLINE | ID: covidwho-1470890

ABSTRACT

Individuals with pre-existing chronic systemic low-grade inflammation are prone to develop severe COVID-19 and stronger anti-SARS-CoV-2 antibody responses. Whether this phenomenon reflects a differential expansion of antiviral B cells or a failure to regulate antibody synthesis remains unknown. Here, we compared the antiviral B cell repertoire of convalescent healthcare personnel to that of hospitalized patients with pre-existing comorbidities. Out of 277,500 immortalized B cell clones, antiviral B cell frequencies were determined by indirect immunofluorescence screening on SARS-CoV-2 infected cells. Surprisingly, frequencies of SARS-CoV-2 specific clones from the two groups were not statistically different, despite higher antibody levels in hospitalized patients. Moreover, functional analyses revealed that several B cell clones from healthcare personnel with low antibody levels had neutralizing properties. This study reveals for the first time a key qualitative defect of antibody synthesis in severe patients and calls for caution regarding estimated protective immunity based only on circulating antiviral antibodies.


Subject(s)
Antibodies, Viral/blood , B-Lymphocytes/immunology , COVID-19/pathology , SARS-CoV-2/immunology , Adult , Aged , Aged, 80 and over , Antibodies, Neutralizing/blood , Antibodies, Viral/immunology , Antibody Formation , B-Lymphocytes/cytology , B-Lymphocytes/metabolism , COVID-19/immunology , COVID-19/virology , Comorbidity , Female , Health Personnel , Humans , Male , Middle Aged , SARS-CoV-2/isolation & purification , SARS-CoV-2/metabolism , Severity of Illness Index , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology
2.
Cells ; 10(10)2021 09 26.
Article in English | MEDLINE | ID: covidwho-1438527

ABSTRACT

Specific memory B cells and antibodies are a reliable read-out of vaccine efficacy. We analysed these biomarkers after one and two doses of BNT162b2 vaccine. The second dose significantly increases the level of highly specific memory B cells and antibodies. Two months after the second dose, specific antibody levels decline, but highly specific memory B cells continue to increase, thus predicting a sustained protection from COVID-19. We show that although mucosal IgA is not induced by the vaccination, memory B cells migrate in response to inflammation and secrete IgA at mucosal sites. We show that the first vaccine dose may lead to an insufficient number of highly specific memory B cells and low concentration of serum antibodies, thus leaving vaccinees without the immune robustness needed to ensure viral elimination and herd immunity. We also clarify that the reduction of serum antibodies does not diminish the force and duration of the immune protection induced by vaccination. The vaccine does not induce sterilizing immunity. Infection after vaccination may be caused by the lack of local preventive immunity because of the absence of mucosal IgA.


Subject(s)
Antibodies, Viral/immunology , B-Lymphocytes/cytology , COVID-19 Vaccines/therapeutic use , COVID-19/immunology , COVID-19/prevention & control , Immunoglobulin A/immunology , Immunologic Memory , Adult , Antibodies, Neutralizing/blood , Antigens, Viral/immunology , B-Lymphocytes/immunology , Cryopreservation , Female , Health Personnel , Healthy Volunteers , Hospitals, Pediatric , Humans , Immunoglobulin G , Immunoglobulin M/immunology , Lactation , Male , Middle Aged , Mucous Membrane/immunology , Patient Safety , SARS-CoV-2 , Vaccination
3.
Front Immunol ; 12: 731643, 2021.
Article in English | MEDLINE | ID: covidwho-1412494

ABSTRACT

In the era of COVID-19, understanding how our immune system responds to viral infections is more pertinent than ever. Immunodeficiencies with very low or absent B cells offer a valuable model to study the role of humoral immunity against these types of infection. This review looks at the available evidence on viral infections in patients with B cell alymphocytosis, in particular those with X-linked agammaglobulinemia (XLA), Good's syndrome, post monoclonal-antibody therapy and certain patients with Common Variable Immune Deficiency (CVID). Viral infections are not as infrequent as previously thought in these conditions and individuals with very low circulating B cells seem to be predisposed to an adverse outcome. Particularly in the case of SARS-CoV2 infection, mounting evidence suggests that peripheral B cell alymphocytosis is linked to a poor prognosis.


Subject(s)
Agammaglobulinemia/immunology , B-Lymphocytes/immunology , COVID-19/pathology , Common Variable Immunodeficiency/immunology , Genetic Diseases, X-Linked/immunology , Severe Combined Immunodeficiency/immunology , Thymoma/immunology , B-Lymphocytes/cytology , COVID-19/immunology , Humans , Lymphocyte Count , SARS-CoV-2/immunology , Thymoma/therapy
4.
Eur J Immunol ; 51(10): 2478-2484, 2021 10.
Article in English | MEDLINE | ID: covidwho-1340251

ABSTRACT

Treatment with convalescent plasma has been shown to be safe in coronavirus disease in 2019 (COVID-19) infection, although efficacy reported in immunocompetent patients varies. Nevertheless, neutralizing antibodies are a key requisite in the fight against viral infections. Patients depleted of antibody-producing B cells, such as those treated with rituximab (anti-CD20) for hematological malignancies, lack a fundamental part of their adaptive immunity. Treatment with convalescent plasma appears to be of general benefit in this particularly vulnerable cohort. We analyzed clinical course and inflammation markers of three B-cell-depleted patients suffering from COVID-19 who were treated with convalescent plasma. In addition, we measured serum antibody levels as well as peripheral blood CD38/HLA-DR-positive T-cells ex vivo and CD137-positive T-cells after in vitro stimulation with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-derived peptides in these patients. We observed that therapy with convalescent plasma was effective in all three patients and analysis of CD137-positive T-cells after stimulation with SARS-CoV-2 peptides showed an increase in peptide-specific T-cells after application of convalescent plasma. In conclusion, we here demonstrate efficacy of convalescent plasma therapy in three B-cell-depleted patients and present data that suggest that while application of convalescent plasma elevates systemic antibody levels only transiently, it may also boost specific T-cell responses.


Subject(s)
Antibodies, Viral/blood , B-Lymphocytes/immunology , COVID-19/therapy , T-Lymphocytes/immunology , Adolescent , Aged , Antibodies, Neutralizing/blood , B-Lymphocytes/cytology , Humans , Immunity, Cellular/immunology , Immunization, Passive/methods , Lymphocyte Count , Lymphocyte Depletion , Lymphoma, B-Cell/drug therapy , Lymphoma, Mantle-Cell/drug therapy , Male , Middle Aged , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Rituximab/adverse effects , SARS-CoV-2/immunology , Treatment Outcome , Tumor Necrosis Factor Receptor Superfamily, Member 9/metabolism
5.
Nature ; 596(7872): 417-422, 2021 08.
Article in English | MEDLINE | ID: covidwho-1287811

ABSTRACT

Although two-dose mRNA vaccination provides excellent protection against SARS-CoV-2, there is little information about vaccine efficacy against variants of concern (VOC) in individuals above eighty years of age1. Here we analysed immune responses following vaccination with the BNT162b2 mRNA vaccine2 in elderly participants and younger healthcare workers. Serum neutralization and levels of binding IgG or IgA after the first vaccine dose were lower in older individuals, with a marked drop in participants over eighty years old. Sera from participants above eighty showed lower neutralization potency against the B.1.1.7 (Alpha), B.1.351 (Beta) and P.1. (Gamma) VOC than against the wild-type virus and were more likely to lack any neutralization against VOC following the first dose. However, following the second dose, neutralization against VOC was detectable regardless of age. The frequency of SARS-CoV-2 spike-specific memory B cells was higher in elderly responders (whose serum showed neutralization activity) than in non-responders after the first dose. Elderly participants showed a clear reduction in somatic hypermutation of class-switched cells. The production of interferon-γ and interleukin-2 by SARS-CoV-2 spike-specific T cells was lower in older participants, and both cytokines were secreted primarily by CD4 T cells. We conclude that the elderly are a high-risk population and that specific measures to boost vaccine responses in this population are warranted, particularly where variants of concern are circulating.


Subject(s)
Aging/immunology , COVID-19 Vaccines/immunology , Immunity , SARS-CoV-2/immunology , Adult , Aged , Aged, 80 and over , Aging/blood , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , Autoantibodies/immunology , B-Lymphocytes/cytology , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , COVID-19 Vaccines/administration & dosage , Female , Health Personnel , Humans , Immunity/genetics , Immunization, Secondary , Immunoglobulin A/immunology , Immunoglobulin Class Switching , Immunoglobulin G/genetics , Immunoglobulin G/immunology , Immunologic Memory/immunology , Inflammation/blood , Inflammation/immunology , Interferon-gamma/immunology , Interleukin-2/immunology , Male , Middle Aged , Somatic Hypermutation, Immunoglobulin , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes/immunology , Vaccination , Vaccines, Synthetic/administration & dosage , Vaccines, Synthetic/immunology
6.
Stem Cell Reports ; 16(5): 1165-1181, 2021 05 11.
Article in English | MEDLINE | ID: covidwho-1225410

ABSTRACT

SARS-CoV-2 infection is associated with lower blood oxygen levels, even in patients without hypoxia requiring hospitalization. This discordance illustrates the need for a more unifying explanation as to whether SARS-CoV-2 directly or indirectly affects erythropoiesis. Here, we show significantly enriched CD71+ erythroid precursors/progenitors in the blood circulation of COVID-19 patients. We found that these cells have distinctive immunosuppressive properties. In agreement, we observed a strong negative correlation between the frequency of these cells with T and B cell proportions in COVID-19 patients. The expansion of these CD71+ erythroid precursors/progenitors was negatively correlated with the hemoglobin levels. A subpopulation of abundant erythroid cells, CD45+ CD71+ cells, co-express ACE2, TMPRSS2, CD147, and CD26, and these can be infected with SARS-CoV-2. In turn, pre-treatment of erythroid cells with dexamethasone significantly diminished ACE2/TMPRSS2 expression and subsequently reduced their infectivity with SARS-CoV-2. This provides a novel insight into the impact of SARS-CoV-2 on erythropoiesis and hypoxia seen in COVID-19 patients.


Subject(s)
Adaptive Immunity/immunology , COVID-19/pathology , Erythroid Precursor Cells/virology , Erythropoiesis/physiology , Hemoglobins/analysis , Oxygen/blood , Adolescent , Adult , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme 2/metabolism , Animals , B-Lymphocytes/cytology , B-Lymphocytes/immunology , COVID-19/immunology , Dexamethasone/pharmacology , Erythroid Precursor Cells/immunology , Female , Humans , Lymphocyte Count , Male , Mice , Mice, Inbred BALB C , Middle Aged , SARS-CoV-2/immunology , Serine Endopeptidases/metabolism , T-Lymphocytes/cytology , T-Lymphocytes/immunology , Young Adult
7.
Cell ; 184(12): 3205-3221.e24, 2021 06 10.
Article in English | MEDLINE | ID: covidwho-1201121

ABSTRACT

Monoclonal antibodies (mAbs) are a focus in vaccine and therapeutic design to counteract severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants. Here, we combined B cell sorting with single-cell VDJ and RNA sequencing (RNA-seq) and mAb structures to characterize B cell responses against SARS-CoV-2. We show that the SARS-CoV-2-specific B cell repertoire consists of transcriptionally distinct B cell populations with cells producing potently neutralizing antibodies (nAbs) localized in two clusters that resemble memory and activated B cells. Cryo-electron microscopy structures of selected nAbs from these two clusters complexed with SARS-CoV-2 spike trimers show recognition of various receptor-binding domain (RBD) epitopes. One of these mAbs, BG10-19, locks the spike trimer in a closed conformation to potently neutralize SARS-CoV-2, the recently arising mutants B.1.1.7 and B.1.351, and SARS-CoV and cross-reacts with heterologous RBDs. Together, our results characterize transcriptional differences among SARS-CoV-2-specific B cells and uncover cross-neutralizing Ab targets that will inform immunogen and therapeutic design against coronaviruses.


Subject(s)
Antibodies, Neutralizing/immunology , B-Lymphocytes/metabolism , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/chemistry , Antibodies, Viral/blood , Antibodies, Viral/chemistry , Antibodies, Viral/immunology , Antigen-Antibody Complex/chemistry , Antigen-Antibody Complex/metabolism , Antigen-Antibody Reactions , B-Lymphocytes/cytology , B-Lymphocytes/virology , COVID-19/pathology , COVID-19/virology , Cryoelectron Microscopy , Crystallography, X-Ray , Gene Expression Profiling , Humans , Immunoglobulin A/immunology , Immunoglobulin Variable Region/chemistry , Immunoglobulin Variable Region/genetics , Protein Domains/immunology , Protein Multimerization , Protein Structure, Quaternary , SARS-CoV-2/isolation & purification , SARS-CoV-2/metabolism , Sequence Analysis, RNA , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism
8.
J Med Virol ; 93(3): 1589-1598, 2021 03.
Article in English | MEDLINE | ID: covidwho-1196482

ABSTRACT

A novel member of human coronavirus, named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has been recently recognized in China and rapidly spread worldwide. Studies showed the decreasing of peripheral blood lymphocytes in a majority of patients. In this study, we have reported the clinical features, laboratory characteristics, the frequency of peripheral blood lymphocyte subpopulations, and their apoptosis pattern in Iranian coronavirus infectious disease (COVID-19) patients. Demographic and clinical data of 61 hospitalized confirmed cases with COVID-19 at Imam Khomeini Hospital were collected and analyzed. Peripheral blood mononuclear cells were isolated from all samples and the apoptosis pattern was evaluated using Annexin V/propidium iodide method. The frequency of lymphocyte subsets, including T-CD4+ , T-CD8+ , NK, B cells, and monocytes, was measured in all patients and 31 controls by flow cytometry. Our findings demonstrated that the percentage of lymphocytes, CD4+ , and CD8+ T cells were decreased in COVID-19 patients compared with the control group. Regarding the clinical severity, the number of lymphocytes, CD4+ , CD8+ T cells, and NK cells were also decreased in severe cases when compared with mild cases. Finally, our data have also indicated the increase in apoptosis of mononuclear cells from COVID-19 patients which was more remarkable in severe clinical cases. The frequency of immune cells is a useful indicator for prediction of severity and prognosis of COVID-19 patients. These results could help to explain the immunopathogenesis of SARS-CoV-2 and introducing novel biomarkers, therapeutic strategies, and vaccine candidates.


Subject(s)
B-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/cytology , Immunophenotyping/methods , Killer Cells, Natural/cytology , SARS-CoV-2/immunology , Adult , Aged , Apoptosis/immunology , Biomarkers/blood , COVID-19/immunology , Female , Flow Cytometry , Humans , Iran , Lymphocyte Count , Lymphopenia/immunology , Male , Middle Aged
9.
BMC Pediatr ; 21(1): 181, 2021 04 17.
Article in English | MEDLINE | ID: covidwho-1190064

ABSTRACT

BACKGROUND: Early diagnostic indicators and the identification of possible progression to severe or critical COVID-19 in children are unknown. To investigate the immune characteristics of early SARS-CoV-2 infection in children and possible key prognostic factors for early identification of critical COVID-19, a retrospective study including 121 children with COVID-19 was conducted. Peripheral blood lymphocyte subset counts, T cell-derived cytokine concentrations, inflammatory factor concentrations, and routine blood counts were analyzed statistically at the initial presentation. RESULTS: The T lymphocyte subset and natural killer cell counts decreased with increasing disease severity. Group III (critical cases) had a higher Th/Tc ratio than groups I and II (common and severe cases); group I had a higher B cell count than groups II and III. IL-6, IL-10, IFN-γ, SAA, and procalcitonin levels increased with increasing disease severity. Hemoglobin concentration, and RBC and eosinophil counts decreased with increasing disease severity. Groups II and III had significantly lower lymphocyte counts than group I. T, Th, Tc, IL-6, IL-10, RBC, and hemoglobin had relatively high contribution and area under the curve values. CONCLUSIONS: Decreased T, Th, Tc, RBC, hemoglobin and increased IL-6 and IL-10 in early SARS-CoV-2 infection in children are valuable indices for early diagnosis of severe disease. The significantly reduced Th and Tc cells and significantly increased IL-6, IL-10, ferritin, procalcitonin, and SAA at this stage in children with critical COVID-19 may be closely associated with the systemic cytokine storm caused by immune dysregulation.


Subject(s)
COVID-19/diagnosis , Systemic Inflammatory Response Syndrome/diagnosis , Adolescent , B-Lymphocytes/cytology , Child , Child, Preschool , Cytokine Release Syndrome/virology , Cytokines/blood , Female , Humans , Immunity , Infant , Killer Cells, Natural/cytology , Lymphocyte Count , Male , Prognosis , Retrospective Studies , Severity of Illness Index , T-Lymphocyte Subsets/cytology
10.
FASEB J ; 35(5): e21577, 2021 05.
Article in English | MEDLINE | ID: covidwho-1172658

ABSTRACT

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.


Subject(s)
Adaptive Immunity/immunology , COVID-19/immunology , COVID-19/pathology , Endothelial Cells/pathology , Myeloid Cells/immunology , Animals , B-Lymphocytes/cytology , B-Lymphocytes/immunology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/pathology , Cytokines/immunology , Humans , Immunologic Memory , Myeloid Cells/cytology , T-Lymphocytes/cytology , T-Lymphocytes/immunology
11.
Virology ; 558: 13-21, 2021 06.
Article in English | MEDLINE | ID: covidwho-1123073

ABSTRACT

India is one of the most affected countries by COVID-19 pandemic; but little is understood regarding immune responses to SARS-CoV-2 in this region. Herein we examined SARS-CoV-2 neutralizing antibodies, IgG, IgM, IgA and memory B cells in COVID-19 recovered individual from India. While a vast majority of COVID-19 recovered individuals showed SARS-CoV-2 RBD-specific IgG, IgA and IgM antibodies (38/42, 90.47%; 21/42, 50%; 33/42, 78.57% respectively), only half of them had appreciable neutralizing antibody titers. RBD-specific IgG, but not IgA or IgM titers, correlated with neutralizing antibody titers and RBD-specific memory B cell frequencies. These findings have timely significance for identifying potential donors for plasma therapy using RBD-specific IgG assays as surrogate measurement for neutralizing antibodies in India. Further, this study provides useful information needed for designing large-scale studies towards understanding of inter-individual variation in immune memory to SARS CoV-2 natural infection for future vaccine evaluation and implementation efforts.


Subject(s)
Antibodies, Neutralizing/analysis , Antibodies, Viral/analysis , B-Lymphocytes , COVID-19/immunology , Spike Glycoprotein, Coronavirus/immunology , Adolescent , Adult , Aged , B-Lymphocytes/cytology , B-Lymphocytes/immunology , COVID-19/epidemiology , Humans , Immunity, Humoral , Immunoglobulin Isotypes/analysis , India/epidemiology , Male , Middle Aged , Pandemics , Young Adult
14.
Cell ; 184(7): 1821-1835.e16, 2021 04 01.
Article in English | MEDLINE | ID: covidwho-1095899

ABSTRACT

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.


Subject(s)
Antibodies, Monoclonal/administration & dosage , Antibodies, Neutralizing/administration & dosage , Antibodies, Viral/administration & dosage , B-Lymphocytes/immunology , COVID-19 , Convalescence , 3T3 Cells , Animals , Antibodies, Monoclonal/isolation & purification , Antibodies, Neutralizing/isolation & purification , Antibodies, Viral/isolation & purification , B-Lymphocytes/cytology , COVID-19/immunology , COVID-19/prevention & control , COVID-19/therapy , Chlorocebus aethiops , Disease Models, Animal , Female , HEK293 Cells , Humans , Immunoglobulin Fc Fragments/immunology , Male , Mice , Spike Glycoprotein, Coronavirus/immunology , Vero Cells
16.
Nature ; 591(7851): 639-644, 2021 03.
Article in English | MEDLINE | ID: covidwho-1065898

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected 78 million individuals and is responsible for over 1.7 million deaths to date. Infection is associated with the development of variable levels of antibodies with neutralizing activity, which can protect against infection in animal models1,2. Antibody levels decrease with time, but, to our knowledge, the nature and quality of the memory B cells that would be required to produce antibodies upon reinfection has not been examined. Here we report on the humoral memory response in a cohort of 87 individuals assessed at 1.3 and 6.2 months after infection with SARS-CoV-2. We find that titres of IgM and IgG antibodies against the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 decrease significantly over this time period, with IgA being less affected. Concurrently, neutralizing activity in plasma decreases by fivefold in pseudotype virus assays. By contrast, the number of RBD-specific memory B cells remains unchanged at 6.2 months after infection. Memory B cells display clonal turnover after 6.2 months, and the antibodies that they express have greater somatic hypermutation, resistance to RBD mutations and increased potency, indicative of continued evolution of the humoral response. Immunofluorescence and PCR analyses of intestinal biopsies obtained from asymptomatic individuals at 4 months after the onset of coronavirus disease 2019 (COVID-19) revealed the persistence of SARS-CoV-2 nucleic acids and immunoreactivity in the small bowel of 7 out of 14 individuals. We conclude that the memory B cell response to SARS-CoV-2 evolves between 1.3 and 6.2 months after infection in a manner that is consistent with antigen persistence.


Subject(s)
Antibodies, Viral/immunology , COVID-19/immunology , Immunity, Humoral/immunology , SARS-CoV-2/immunology , Adolescent , Adult , Aged , Antibodies, Monoclonal/blood , Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/genetics , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/genetics , Antigens, Viral/chemistry , Antigens, Viral/genetics , Antigens, Viral/immunology , B-Lymphocytes/cytology , B-Lymphocytes/immunology , Biopsy , COVID-19/blood , Cohort Studies , Fluorescent Antibody Technique , Humans , Immunity, Humoral/genetics , Immunoglobulin A/immunology , Immunoglobulin G/immunology , Immunoglobulin M/immunology , Immunologic Memory/immunology , Intestines/immunology , Middle Aged , Mutation , Somatic Hypermutation, Immunoglobulin , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Time Factors , Young Adult
17.
Sci Rep ; 10(1): 20836, 2020 11 30.
Article in English | MEDLINE | ID: covidwho-1059918

ABSTRACT

Impaired immune responses have been hypothesised to be a possible trigger of unfavourable outcomes in coronavirus disease 2019 (COVID-19). We aimed to characterise IgM memory B cells in patients with COVID-19 admitted to an internal medicine ward in Northern Italy. Overall, 66 COVID-19 patients (mean age 74 ± 16.6 years; 29 females) were enrolled. Three patients (4.5%; 1 female) had been splenectomised and were excluded from further analyses. Fifty-five patients (87.3%) had IgM memory B cell depletion, and 18 (28.6%) died during hospitalisation (cumulative incidence rate 9.26/100 person-week; 5.8-14.7 95% CI). All patients who died had IgM memory B cell depletion. A superimposed infection was found in 6 patients (9.5%), all of them having IgM memory B cell depletion (cumulative incidence rate 3.08/100 person-week; 1.3-6.8 95% CI). At bivariable analyses, older age, sex, number of comorbidities, and peripheral blood lymphocyte count < 1500/µl were not correlated with IgM memory B cell depletion. A discrete-to-marked reduction of the B-cell compartment was also noticed in autoptic spleen specimens of two COVID-19 patients. We conclude that IgM memory B cells are commonly depleted in COVID-19 patients and this correlates with increased mortality and superimposed infections.


Subject(s)
B-Lymphocytes/cytology , COVID-19/mortality , Hospital Mortality , Immunologic Memory/immunology , Lymphocyte Depletion , Adult , Aged , Aged, 80 and over , B-Lymphocyte Subsets/cytology , B-Lymphocyte Subsets/immunology , B-Lymphocytes/immunology , COVID-19/pathology , Female , Humans , Immunoglobulin M/blood , Longitudinal Studies , Lymphocyte Count , Male , Middle Aged , Prospective Studies , SARS-CoV-2/immunology , Spleen/cytology , Spleen/immunology
18.
Nat Med ; 27(1): 125-135, 2021 01.
Article in English | MEDLINE | ID: covidwho-1023963

ABSTRACT

Most of what we know about adaptive immunity has come from inbred mouse studies, using methods that are often difficult or impossible to confirm in humans. In addition, vaccine responses in mice are often poorly predictive of responses to those same vaccines in humans. Here we use human tonsils, readily available lymphoid organs, to develop a functional organotypic system that recapitulates key germinal center features in vitro, including the production of antigen-specific antibodies, somatic hypermutation and affinity maturation, plasmablast differentiation and class-switch recombination. We use this system to define the essential cellular components necessary to produce an influenza vaccine response. We also show that it can be used to evaluate humoral immune responses to two priming antigens, rabies vaccine and an adenovirus-based severe acute respiratory syndrome coronavirus 2 vaccine, and to assess the effects of different adjuvants. This system should prove useful for studying critical mechanisms underlying adaptive immunity in much greater depth than previously possible and to rapidly test vaccine candidates and adjuvants in an entirely human system.


Subject(s)
Influenza Vaccines/immunology , Palatine Tonsil/immunology , Adjuvants, Immunologic , B-Lymphocytes/cytology , B-Lymphocytes/immunology , COVID-19 Vaccines/immunology , Germinal Center/cytology , Hemagglutinin Glycoproteins, Influenza Virus , Humans , In Vitro Techniques , Lymphoid Tissue/immunology , Measles-Mumps-Rubella Vaccine/immunology , Organoids/cytology , Organoids/immunology , Rabies Vaccines/immunology , T-Lymphocytes/immunology
19.
Cells ; 9(12)2020 12 05.
Article in English | MEDLINE | ID: covidwho-967600

ABSTRACT

Cell response to novel coronavirus disease 19 (COVID-19) is currently a widely researched topic. The assessment of leukocytes population and the maturation of both B and T lymphocytes may be important in characterizing the immunological profile of COVID-19 patients. The aim of the present study was to evaluate maturation of B and T cells in COVID-19 patients with interstitial lesions on chest X-ray (COVID-19 X-ray (+)), without changes on X-ray (COVID-19 X-ray (-)) and in healthy control. The study group consisted of 23 patients divided on two groups: COVID-19 X-ray (+) n = 14 and COVID-19 X-ray (-) n = 9 and control n = 20. The flow cytometry method was performed. We observed a significantly higher percentage of plasmablasts and lower CD4+ lymphocytes in COVID-19 X-ray (+) patients than in COVID-19 X-ray (-) and control. In the COVID-19 X-ray (+) patients, there was a lower proportion of effector CD4+ T cells, naïve CD8+ T cells and higher central memory CD4+ cells and effector CD8+ T cells than control. The above results showed that the assessment of selected cells of B and T lymphocytes by flow cytometry can distinguish patients with COVID-19 and differentiate patients with and without changes on chest X-ray.


Subject(s)
B-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/cytology , COVID-19/pathology , Adult , Aged , Aged, 80 and over , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , COVID-19/immunology , COVID-19/virology , Case-Control Studies , Female , Flow Cytometry , Humans , Immunophenotyping , Male , Middle Aged , SARS-CoV-2/isolation & purification
20.
Sci Rep ; 10(1): 17718, 2020 10 19.
Article in English | MEDLINE | ID: covidwho-880700

ABSTRACT

COVID-19 has been widely spreading. We aimed to examine adaptive immune cells in non-severe patients with persistent SARS-CoV-2 shedding. 37 non-severe patients with persistent SARS-CoV-2 presence that were transferred to Zhongnan hospital of Wuhan University were retrospectively recruited to the PP (persistently positive) group, which was further allocated to PPP group (n = 19) and PPN group (n = 18), according to their testing results after 7 days (N = negative). Epidemiological, demographic, clinical and laboratory data were collected and analyzed. Data from age- and sex-matched non-severe patients at disease onset (PA [positive on admission] patients, n = 37), and lymphocyte subpopulation measurements from matched 54 healthy subjects were extracted for comparison (HC). Compared with PA patients, PP patients had much improved laboratory findings. The absolute numbers of CD3+ T cells, CD4+ T cells, and NK cells were significantly higher in PP group than that in PA group, and were comparable to that in healthy controls. PPP subgroup had markedly reduced B cells and T cells compared to PPN group and healthy subjects. Finally, paired results of these lymphocyte subpopulations from 10 PPN patients demonstrated that the number of T cells and B cells significantly increased when the SARS-CoV-2 tests turned negative. Persistent SARS-CoV-2 presence in non-severe COVID-19 patients is associated with reduced numbers of adaptive immune cells. Monitoring lymphocyte subpopulations could be clinically meaningful in identifying fully recovered COVID-19 patients.


Subject(s)
B-Lymphocytes/cytology , Coronavirus Infections/pathology , Pneumonia, Viral/pathology , T-Lymphocytes/cytology , Adult , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Betacoronavirus/isolation & purification , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , COVID-19 , Case-Control Studies , Coronavirus Infections/immunology , Coronavirus Infections/virology , Female , Humans , Killer Cells, Natural/cytology , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Male , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Retrospective Studies , SARS-CoV-2 , Severity of Illness Index , T-Lymphocytes/immunology , T-Lymphocytes/metabolism
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