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1.
Eur J Neurol ; 29(11): 3317-3328, 2022 11.
Article in English | MEDLINE | ID: covidwho-1927583

ABSTRACT

BACKGROUND AND PURPOSE: Recent findings document a blunted humoral response to SARS-CoV-2 vaccination in patients on anti-CD20 treatment. Although most patients develop a cellular response, it is still important to identify predictors of seroconversion to optimize vaccine responses. METHODS: We determined antibody responses after SARS-CoV-2 vaccination in a real-world cohort of multiple sclerosis patients (n = 94) treated with anti-CD20, mainly rituximab, with variable treatment duration (median = 2.9, range = 0.4-9.6 years) and time from last anti-CD20 infusion to vaccination (median = 190, range = 60-1032 days). RESULTS: We find that presence of B cells and/or rituximab in blood predict seroconversion better than time since last infusion. Using multiple logistic regression, presence of >0.5% B cells increased probability of seroconversion with an odds ratio (OR) of 5.0 (95% confidence interval [CI] = 1.0-28.1, p = 0.055), whereas the corresponding OR for ≥6 months since last infusion was 1.45 (95% CI = 0.20-10.15, p = 0.705). In contrast, detectable rituximab levels were negatively associated with seroconversion (OR = 0.05, 95% CI = 0.002-0.392, p = 0.012). Furthermore, naïve and memory IgG+ B cells correlated with antibody levels. Although retreatment with rituximab at 4 weeks or more after booster depleted spike-specific B cells, it did not noticeably affect the rate of decline in antibody titers. Interferon-γ and/or interleukin-13 T-cell responses to the spike S1 domain were observed in most patients, but with no correlation to spike antibody levels. CONCLUSIONS: These findings are relevant for providing individualized guidance to patients and planning of vaccination schemes, in turn optimizing benefit-risk with anti-CD20.


Subject(s)
B-Lymphocytes , COVID-19 Vaccines , COVID-19 , Multiple Sclerosis , Antibodies, Viral , B-Lymphocytes/cytology , COVID-19/prevention & control , COVID-19 Vaccines/administration & dosage , Humans , Immunoglobulin G , Interferon-gamma , Interleukin-13 , Multiple Sclerosis/drug therapy , Rituximab/pharmacokinetics , Rituximab/therapeutic use , SARS-CoV-2 , Vaccination , Vaccine Efficacy
2.
Nature ; 604(7904): 141-145, 2022 04.
Article in English | MEDLINE | ID: covidwho-1684082

ABSTRACT

Germinal centres (GC) are lymphoid structures in which B cells acquire affinity-enhancing somatic hypermutations (SHM), with surviving clones differentiating into memory B cells (MBCs) and long-lived bone marrow plasma cells1-5 (BMPCs). SARS-CoV-2 mRNA vaccination induces a persistent GC response that lasts for at least six months in humans6-8. The fate of responding GC B cells as well as the functional consequences of such persistence remain unknown. Here, we detected SARS-CoV-2 spike protein-specific MBCs in 42 individuals who had received two doses of the SARS-CoV-2 mRNA vaccine BNT162b2 six month earlier. Spike-specific IgG-secreting BMPCs were detected in 9 out of 11 participants. Using a combined approach of sequencing the B cell receptors of responding blood plasmablasts and MBCs, lymph node GC B cells and plasma cells and BMPCs from eight individuals and expression of the corresponding monoclonal antibodies, we tracked the evolution of 1,540 spike-specific B cell clones. On average, early blood spike-specific plasmablasts exhibited the lowest SHM frequencies. By contrast, SHM frequencies of spike-specific GC B cells increased by 3.5-fold within six months after vaccination. Spike-specific MBCs and BMPCs accumulated high levels of SHM, which corresponded with enhanced anti-spike antibody avidity in blood and enhanced affinity as well as neutralization capacity of BMPC-derived monoclonal antibodies. We report how the notable persistence of the GC reaction induced by SARS-CoV-2 mRNA vaccination in humans culminates in affinity-matured long-term antibody responses that potently neutralize the virus.


Subject(s)
B-Lymphocytes , BNT162 Vaccine , Germinal Center , Vaccination , Antibodies, Monoclonal , Antibodies, Viral , B-Lymphocytes/cytology , B-Lymphocytes/immunology , BNT162 Vaccine/administration & dosage , BNT162 Vaccine/immunology , COVID-19/immunology , COVID-19/prevention & control , COVID-19/virology , Germinal Center/cytology , Germinal Center/immunology , Humans , RNA, Messenger/genetics , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology
3.
Inflamm Res ; 71(1): 131-140, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1544398

ABSTRACT

OBJECTIVES: The role of B cells in COVID-19, beyond the production of specific antibodies against SARS-CoV-2, is still not well understood. Here, we describe the novel landscape of circulating double-negative (DN) CD27- IgD- B cells in COVID-19 patients, representing a group of atypical and neglected subpopulations of this cell lineage. METHODS: Using multiparametric flow cytometry, we determined DN B cell subset amounts from 91 COVID-19 patients, correlated those with cytokines, clinical and laboratory parameters, and segregated them by principal components analysis. RESULTS: We detected significant increments in the DN2 and DN3 B cell subsets, while we found a relevant decrease in the DN1 B cell subpopulation, according to disease severity and patient outcomes. These DN cell numbers also appeared to correlate with pro- or anti-inflammatory signatures, respectively, and contributed to the segregation of the patients into disease severity groups. CONCLUSION: This study provides insights into DN B cell subsets' potential role in immune responses against SARS-CoV-2, particularly linked to the severity of COVID-19.


Subject(s)
COVID-19/blood , COVID-19/immunology , Immunoglobulin D/blood , SARS-CoV-2 , Tumor Necrosis Factor Receptor Superfamily, Member 7/blood , Adult , Aged , Aged, 80 and over , B-Lymphocytes/cytology , COVID-19/diagnosis , COVID-19/virology , Cell Lineage , Computational Biology , Disease Progression , Female , Humans , Male , Middle Aged , Principal Component Analysis , Prognosis , Respiration, Artificial , Severity of Illness Index , Young Adult
5.
Int J Mol Sci ; 22(22)2021 Nov 19.
Article in English | MEDLINE | ID: covidwho-1524027

ABSTRACT

Severe outcomes of COVID-19 are associated with pathological response of the immune system to the SARS-CoV-2 infection. Emerging evidence suggests that an interaction may exist between COVID-19 pathogenesis and a broad range of xenobiotics, resulting in significant increases in death rates in highly exposed populations. Therefore, a better understanding of the molecular basis of the interaction between SARS-CoV-2 infection and chemical exposures may open opportunities for better preventive and therapeutic interventions. We attempted to gain mechanistic knowledge on the interaction between SARS-CoV-2 infection and chemical exposures using an in silico approach, where we identified genes and molecular pathways affected by both chemical exposures and SARS-CoV-2 in human immune cells (T-cells, B-cells, NK-cells, dendritic, and monocyte cells). Our findings demonstrate for the first time that overlapping molecular mechanisms affected by a broad range of chemical exposures and COVID-19 are linked to IFN type I/II signaling pathways and the process of antigen presentation. Based on our data, we also predict that exposures to various chemical compounds will predominantly impact the population of monocytes during the response against COVID-19.


Subject(s)
COVID-19/immunology , Immunity, Innate/drug effects , Xenobiotics/pharmacology , B-Lymphocytes/cytology , B-Lymphocytes/drug effects , B-Lymphocytes/metabolism , COVID-19/pathology , COVID-19/virology , Humans , Interferons/metabolism , SARS-CoV-2/isolation & purification , Signal Transduction/drug effects , T-Lymphocytes/cytology , T-Lymphocytes/drug effects , T-Lymphocytes/metabolism
6.
J Clin Invest ; 131(24)2021 12 15.
Article in English | MEDLINE | ID: covidwho-1495792

ABSTRACT

Acute COVID-19, caused by SARS-CoV-2, is characterized by diverse clinical presentations, ranging from asymptomatic infection to fatal respiratory failure, and often associated with varied longer-term sequelae. Over the past 18 months, it has become apparent that inappropriate immune responses contribute to the pathogenesis of severe COVID-19. Researchers working at the intersection of COVID-19 and autoimmunity recently gathered at an American Autoimmune Related Diseases Association Noel R. Rose Colloquium to address the current state of knowledge regarding two important questions: Does established autoimmunity predispose to severe COVID-19? And, at the same time, can SARS-CoV-2 infection trigger de novo autoimmunity? Indeed, work to date has demonstrated that 10% to 15% of patients with critical COVID-19 pneumonia exhibit autoantibodies against type I interferons, suggesting that preexisting autoimmunity underlies severe disease in some patients. Other studies have identified functional autoantibodies following infection with SARS-CoV-2, such as those that promote thrombosis or antagonize cytokine signaling. These autoantibodies may arise from a predominantly extrafollicular B cell response that is more prone to generating autoantibody-secreting B cells. This Review highlights the current understanding, evolving concepts, and unanswered questions provided by this unique opportunity to determine mechanisms by which a viral infection can be exacerbated by, and even trigger, autoimmunity. The potential role of autoimmunity in post-acute sequelae of COVID-19 is also discussed.


Subject(s)
Autoantibodies/chemistry , Autoimmunity/immunology , COVID-19/immunology , COVID-19/physiopathology , Signal Transduction , Animals , Autoimmune Diseases , B-Lymphocytes/cytology , Cytokines/metabolism , Disease Progression , Female , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Humans , Inflammation , Interleukin-1/metabolism , Interleukin-6/metabolism , Macrophage Activation , Male , Mice , Phospholipids/metabolism , SARS-CoV-2
7.
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
8.
Sci Immunol ; 6(66): eabl5842, 2021 Dec 10.
Article in English | MEDLINE | ID: covidwho-1467664

ABSTRACT

Initial exposure to a pathogen elicits an adaptive immune response to control and eradicate the threat. Interrogating the abundance and specificity of the naive B cell repertoire drives understanding of how to mount protective responses. Here, we isolated naive B cells from eight seronegative human donors targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor binding domain (RBD). Single-cell B cell receptor (BCR) sequencing identified diverse gene usage and no restriction on complementarity determining region length. A subset of recombinant antibodies produced by naive B cell precursors bound to SARS-CoV-2 RBD and engaged circulating variants including B.1.1.7, B.1.351, and B.1.617.2, as well as preemergent bat-derived coronaviruses RaTG13, SHC104, and WIV1. By structural characterization of a naive antibody in complex with SARS-CoV-2 spike, we identified a conserved mode of recognition shared with infection-induced antibodies. We found that representative naive antibodies could signal in a B cell activation assay, and by using directed evolution, we could select for a higher-affinity RBD interaction, conferred by a single amino acid change. The minimally mutated, affinity-matured antibodies also potently neutralized SARS-CoV-2. Understanding the SARS-CoV-2 RBD­specific naive repertoire may inform potential responses capable of recognizing future SARS-CoV-2 variants or emerging coronaviruses, enabling the development of pan-coronavirus vaccines aimed at engaging protective germline responses.


Subject(s)
B-Lymphocytes/cytology , B-Lymphocytes/immunology , Coronavirus/immunology , SARS-CoV-2/immunology , Antibodies, Neutralizing/immunology , Antigens, Viral/immunology , B-Lymphocytes/metabolism , COVID-19/immunology , COVID-19 Vaccines/immunology , Epitopes , Humans , Lymphocyte Activation , SARS-CoV-2/classification , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism
9.
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
10.
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
11.
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
12.
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
13.
Cell Rep Med ; 2(6): 100313, 2021 06 15.
Article in English | MEDLINE | ID: covidwho-1240648

ABSTRACT

The continual emergence of novel coronaviruses (CoV), such as severe acute respiratory syndrome-(SARS)-CoV-2, highlights the critical need for broadly reactive therapeutics and vaccines against this family of viruses. From a recovered SARS-CoV donor sample, we identify and characterize a panel of six monoclonal antibodies that cross-react with CoV spike (S) proteins from the highly pathogenic SARS-CoV and SARS-CoV-2, and demonstrate a spectrum of reactivity against other CoVs. Epitope mapping reveals that these antibodies recognize multiple epitopes on SARS-CoV-2 S, including the receptor-binding domain, the N-terminal domain, and the S2 subunit. Functional characterization demonstrates that the antibodies mediate phagocytosis-and in some cases trogocytosis-but not neutralization in vitro. When tested in vivo in murine models, two of the antibodies demonstrate a reduction in hemorrhagic pathology in the lungs. The identification of cross-reactive epitopes recognized by functional antibodies expands the repertoire of targets for pan-coronavirus vaccine design strategies.


Subject(s)
Antibodies, Monoclonal/immunology , Epitopes/immunology , Immunoglobulin Fc Fragments/metabolism , Spike Glycoprotein, Coronavirus/immunology , Animals , Antigen-Antibody Reactions , B-Lymphocytes/cytology , B-Lymphocytes/metabolism , COVID-19/pathology , COVID-19/virology , Cell Line , Cross Reactions/immunology , Epitope Mapping , Female , Humans , Immunoglobulin Fc Fragments/immunology , Mice , Mice, Inbred BALB C , Phagocytosis , Protein Subunits/immunology , SARS Virus/immunology , SARS Virus/metabolism , SARS-CoV-2/isolation & purification , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism
14.
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
15.
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
16.
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
17.
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
18.
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
19.
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
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