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2.
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
3.
Int J Mol Sci ; 22(20)2021 Oct 10.
Article in English | MEDLINE | ID: covidwho-1463713

ABSTRACT

We report a lymphoma patient with profound B-cell deficiency after chemotherapy combined with anti-CD20 antibody successfully treated with remdesivir and convalescent plasma for prolonged SARS-CoV-2 infection. Viral clearance was likely attributed to the robust expansion and activation of TCR Vß2 CD8+ cytotoxic T cells and CD16 + CD56- NK cells. This is the first presentation of TCR-specific T cell oligoclonal response in COVID-19. Our study suggests that B-cell depleted patients may effectively respond to anti-SARS-CoV-2 treatment when NK and antigen-specific Tc cell response is induced.


Subject(s)
COVID-19/therapy , Killer Cells, Natural/immunology , T-Lymphocytes, Cytotoxic/immunology , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Aged , Alanine/analogs & derivatives , Alanine/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , B-Lymphocytes/metabolism , COVID-19/virology , Humans , Immunization, Passive , SARS-CoV-2/isolation & purification
4.
Sci Rep ; 11(1): 19817, 2021 10 06.
Article in English | MEDLINE | ID: covidwho-1454815

ABSTRACT

Recent studies have focused their attention on conjunctivitis as one of the symptoms of coronavirus disease 2019 (COVID-19). Therefore, tear samples were taken from COVID-19 patients and the presence of SARS-CoV-2 was evidenced using Real Time reverse transcription polymerase chain reaction. The main aim of this study was to analyze mRNA expression in the tears of patients with COVID-19 compared with healthy subjects using Next Generation Sequencing (NGS). The functional evaluation of the transcriptome highlighted 25 genes that differ statistically between healthy individuals and patients affected by COVID-19. In particular, the NGS analysis identified the presence of several genes involved in B cell signaling and keratinization. In particular, the genes involved in B cell signaling were downregulated in the tears of COVID-19 patients, while those involved in keratinization were upregulated. The results indicated that SARS-CoV-2 may induce a process of ocular keratinization and a defective B cell response.


Subject(s)
COVID-19/genetics , Eye Diseases/virology , Tears/metabolism , Transcriptome , Aged , B-Lymphocytes/metabolism , COVID-19/pathology , COVID-19/virology , Eye Diseases/genetics , Female , High-Throughput Nucleotide Sequencing/methods , Humans , Keratins/metabolism , Male , SARS-CoV-2/isolation & purification , Sequence Analysis, RNA/methods , Skin/metabolism , Skin/pathology , Skin/virology , Tears/virology
5.
Cell Rep ; 37(1): 109773, 2021 10 05.
Article in English | MEDLINE | ID: covidwho-1442298

ABSTRACT

SARS-CoV-2 infection in children is less severe than it is in adults. We perform a longitudinal analysis of the early innate responses in children and adults with mild infection within household clusters. Children display fewer symptoms than adults do, despite similar initial viral load, and mount a robust anti-viral immune signature typical of the SARS-CoV-2 infection and characterized by early interferon gene responses; increases in cytokines, such as CXCL10 and GM-CSF; and changes in blood cell numbers. When compared with adults, the antiviral response resolves faster (within a week of symptoms), monocytes and dendritic cells are more transiently activated, and genes associated with B cell activation appear earlier in children. Nonetheless, these differences do not have major effects on the quality of SARS-CoV-2-specific antibody responses. Our findings reveal that better early control of inflammation as observed in children may be key for rapidly controlling infection and limiting the disease course.


Subject(s)
Antibodies, Viral/immunology , COVID-19/genetics , COVID-19/immunology , Cytokines/metabolism , Immunity, Innate , SARS-CoV-2/immunology , Transcriptome , Adaptive Immunity , Adolescent , Adult , B-Lymphocytes/metabolism , COVID-19/virology , Chemokine CXCL10/metabolism , Child , Child, Preschool , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Humans , Infant , Inflammation/virology , Interferons/metabolism , Longitudinal Studies , Middle Aged , Monocytes/metabolism , Sequence Analysis, RNA , Viral Load , Young Adult
6.
J Exp Med ; 218(3)2021 03 01.
Article in English | MEDLINE | ID: covidwho-1406442

ABSTRACT

The identification of discrete subclasses within the immunoglobulin G (IgG) isotype by Grey and Kunkel (1964. J. Exp. Med.https://doi.org/10.1084/jem.120.2.253) provided the framework for our current understanding of differential IgG subclass activity in protective and self-reactive immune responses.


Subject(s)
Immunoglobulin G/metabolism , Antibody Formation/immunology , B-Lymphocytes/metabolism , COVID-19/immunology , Glycosylation , Humans , Multiple Myeloma/immunology , Multiple Myeloma/pathology
8.
Sci Rep ; 11(1): 17381, 2021 08 30.
Article in English | MEDLINE | ID: covidwho-1379332

ABSTRACT

Cancer patients are more susceptible to SARS-CoV-2 infection and generally have higher mortality rate. Anti-SARS-CoV-2 IgG is an important consideration for the patients in this COVID-19 pandemic. Recent researches suggested the rapid decay of anti-SARS-CoV-2 antibodies in the general population, but the decline rate of the antibodies in cancer patients was unknown. In this observational study, we reported the clinical features of the 53 cancer patients infected by SARS-CoV-2 from Wuhan, China and tracked the presence of anti-SARS-CoV-2 antibodies in the patients for more than 12 months. We found the duration (days) of anti-SARS-CoV-2 IgG in the patients was significant longer in chemotherapy (mean: 175; range: 75 to 315) and radiotherapy groups (mean: 168; range: 85 to 265) than in non-chemo- or radio-therapy group (mean: 58; range: 21 to 123) after their recovery from COVID-19. We also used single-cell RNA sequencing to track the immunologic changes in a representative patient recovered  from COVID-19 and found that CD8 + effective T cells, memory B cells and plasma cells were persistently activated in the patient undergoing chemotherapy. Together, our findings show that chemotherapy and radiotherapy might be beneficial to extend the duration of anti-SARS-CoV-2 IgG.


Subject(s)
COVID-19/blood , Immunoglobulin G/analysis , Neoplasms/immunology , Neoplasms/virology , SARS-CoV-2/immunology , Adult , Aged , Antibodies, Viral/analysis , B-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/metabolism , COVID-19/immunology , China , Drug Therapy , Female , Humans , Male , Middle Aged , Neoplasms/drug therapy , Neoplasms/radiotherapy , Plasma Cells/metabolism , Radiotherapy , SARS-CoV-2/genetics , Sequence Analysis, RNA , Single-Cell Analysis , Time Factors
9.
Viruses ; 13(9)2021 08 27.
Article in English | MEDLINE | ID: covidwho-1374536

ABSTRACT

SARS-CoV-2 is the virus responsible for the COVID-19 pandemic, causing respiratory syndrome and other manifestations. The clinical consequences of the SARS-CoV-2 infection are highly heterogeneous, ranging from asymptomatic and mild to severe and fatal conditions, with the highest mortality rate reached among elderly people. Such heterogeneity appears strongly influenced by the host immune response, which in turn is profoundly affected by aging. In fact, the occurrence of a low-grade inflammation and a decline in specific immune defense is generally reported in older people. Although the low ability of B cells to provide primary and secondary specific responses with a consequent increase in susceptibility to and severity of virus infections is generally described in elderly people, we would like to present here the particular case of a 100-year-old woman, who recovered well from COVID-19 and developed a long-term memory against SARS-CoV-2. Following the infection, the patient's blood was tested with both a classical ELISA and a specific Cell-ELISA addressed to measure the anti-spike S1 specific IgG released in plasma or produced in vitro by memory B cells, respectively. While showing negative on classical serological testing, the patient's blood was positive in Cell-ELISA up to 1 year after the infection. Our observation highlights a potential mechanism of B cell-dependent, long-term protection in response to SARS-CoV-2 infection, suggesting that in a case of successful aging, the absence of specific antibodies in serum does not necessarily mean the absence of immune memory.


Subject(s)
Antibodies, Viral/immunology , COVID-19/immunology , COVID-19/virology , Host-Pathogen Interactions/immunology , Immunologic Memory , SARS-CoV-2/immunology , Age Factors , Aged, 80 and over , Antibodies, Viral/blood , Antibody Formation/immunology , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , COVID-19/blood , COVID-19/diagnosis , Enzyme-Linked Immunosorbent Assay , Female , Humans , Immunoglobulin G/blood , Immunoglobulin G/immunology , Radiography, Thoracic
10.
Sci Immunol ; 6(62)2021 08 10.
Article in English | MEDLINE | ID: covidwho-1352519

ABSTRACT

To understand how a protective immune response against SARS-CoV-2 develops over time, we integrated phenotypic, transcriptional and repertoire analyses on PBMCs from mild and severe COVID-19 patients during and after infection, and compared them to healthy donors (HD). A type I IFN-response signature marked all the immune populations from severe patients during the infection. Humoral immunity was dominated by IgG production primarily against the RBD and N proteins, with neutralizing antibody titers increasing post infection and with disease severity. Memory B cells, including an atypical FCRL5+ T-BET+ memory subset, increased during the infection, especially in patients with mild disease. A significant reduction of effector memory, CD8+ T cells frequency characterized patients with severe disease. Despite such impairment, we observed robust clonal expansion of CD8+ T lymphocytes, while CD4+ T cells were less expanded and skewed toward TCM and TH2-like phenotypes. MAIT cells were also expanded, but only in patients with mild disease. Terminally differentiated CD8+ GZMB+ effector cells were clonally expanded both during the infection and post-infection, while CD8+ GZMK+ lymphocytes were more expanded post-infection and represented bona fide memory precursor effector cells. TCR repertoire analysis revealed that only highly proliferating T cell clonotypes, which included SARS-CoV-2-specific cells, were maintained post-infection and shared between the CD8+ GZMB+ and GZMK+ subsets. Overall, this study describes the development of immunity against SARS-CoV-2 and identifies an effector CD8+ T cell population with memory precursor-like features.


Subject(s)
COVID-19/genetics , COVID-19/immunology , Host-Pathogen Interactions/immunology , Immunophenotyping , SARS-CoV-2/immunology , Transcriptome , Adult , Aged , Antibodies, Viral/immunology , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Biomarkers , COVID-19/virology , Cell Plasticity/genetics , Cell Plasticity/immunology , Clonal Evolution/immunology , Female , Gene Expression Profiling , Humans , Immunoglobulin Isotypes/immunology , Immunologic Memory , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/metabolism , Lymphocyte Count , Male , Middle Aged , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism
11.
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
12.
Nat Cell Biol ; 23(6): 620-630, 2021 06.
Article in English | MEDLINE | ID: covidwho-1263492

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection often causes severe complications and even death. However, asymptomatic infection has also been reported, highlighting the difference in immune responses among individuals. Here we performed single-cell chromatin accessibility and T cell-receptor analyses of peripheral blood mononuclear cells collected from individuals convalescing from COVID-19 and healthy donors. Chromatin remodelling was observed in both innate and adaptive immune cells in the individuals convalescing from COVID-19. Compared with healthy donors, recovered individuals contained abundant TBET-enriched CD16+ and IRF1-enriched CD14+ monocytes with sequential trained and activated epigenomic states. The B-cell lineage in recovered individuals exhibited an accelerated developmental programme from immature B cells to antibody-producing plasma cells. Finally, an integrated analysis of single-cell T cell-receptor clonality with the chromatin accessibility landscape revealed the expansion of putative SARS-CoV-2-specific CD8+ T cells with epigenomic profiles that promote the differentiation of effector or memory cells. Overall, our data suggest that immune cells of individuals convalescing from COVID-19 exhibit global remodelling of the chromatin accessibility landscape, indicative of the establishment of immunological memory.


Subject(s)
COVID-19/genetics , Epigenesis, Genetic , Epigenomics , Genes, T-Cell Receptor , Immunologic Memory , Lymphocyte Subsets/immunology , Monocytes/immunology , SARS-CoV-2/immunology , Single-Cell Analysis , Adaptive Immunity , Adolescent , Adult , Aged , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , B-Lymphocytes/virology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/virology , COVID-19/immunology , COVID-19/metabolism , COVID-19/virology , Case-Control Studies , Cell Differentiation , Chromatin Assembly and Disassembly , Female , Gene Expression Profiling , Host-Pathogen Interactions , Humans , Immunity, Innate , Lymphocyte Subsets/metabolism , Lymphocyte Subsets/virology , Male , Middle Aged , Monocytes/metabolism , Monocytes/virology , SARS-CoV-2/pathogenicity , Young Adult
13.
Nat Commun ; 12(1): 3501, 2021 06 09.
Article in English | MEDLINE | ID: covidwho-1263489

ABSTRACT

The characteristics of COVID-19 patients with persistent SARS-CoV-2 infection are not yet well described. Here, we compare the clinical and molecular features of patients with long duration of viral shedding (LDs) with those from patients with short duration patients (SDs), and healthy donors (HDs). We find that several cytokines and chemokines, such as interleukin (IL)-2, tumor necrosis factor (TNF) and lymphotoxin α (LT-α) are present at lower levels in LDs than SDs. Single-cell RNA sequencing shows that natural killer (NK) cells and CD14+ monocytes are reduced, while regulatory T cells are increased in LDs; moreover, T and NK cells in LDs are less activated than in SDs. Importantly, most cells in LDs show reduced expression of ribosomal protein (RP) genes and related pathways, with this inversed correlation between RP levels and infection duration further validated in 103 independent patients. Our results thus indicate that immunosuppression and low RP expression may be related to the persistence of the viral infection in COVID-19 patients.


Subject(s)
COVID-19/immunology , SARS-CoV-2/pathogenicity , B-Lymphocytes/metabolism , B-Lymphocytes/pathology , COVID-19/virology , Cytokines/blood , Gene Expression Profiling , Humans , Killer Cells, Natural/metabolism , Killer Cells, Natural/pathology , Leukocytes, Mononuclear/pathology , Lymphocyte Activation/genetics , Lymphocyte Subsets/metabolism , Lymphocyte Subsets/pathology , Ribosomal Proteins/genetics , SARS-CoV-2/isolation & purification , Signal Transduction/genetics , T-Lymphocytes/metabolism , T-Lymphocytes/pathology , Virus Shedding
14.
Viruses ; 13(6)2021 05 21.
Article in English | MEDLINE | ID: covidwho-1244141

ABSTRACT

Patients with coronavirus disease 2019 (COVID-19) predominantly have a respiratory tract infection with various symptoms and high mortality is associated with respiratory failure second to severe disease. The risk factors leading to severe disease remain unclear. Here, we reanalyzed a published single-cell RNA-Seq (scRNA-Seq) dataset and found that bronchoalveolar lavage fluid (BALF) of patients with severe disease compared to those with mild disease contained decreased TH17-type cells, decreased IFNA1-expressing cells with lower expression of toll-like receptor 7 (TLR7) and TLR8, increased IgA-expressing B cells, and increased hyperactive epithelial cells (and/or macrophages) expressing matrix metalloproteinases (MMPs), hyaluronan synthase 2 (HAS2), and plasminogen activator inhibitor-1 (PAI-1), which may together contribute to the pulmonary pathology in severe COVID-19. We propose IFN-I (and TLR7/TLR8) and PAI-1 as potential biomarkers to predict the susceptibility to severe COVID-19.


Subject(s)
COVID-19/pathology , Lung/pathology , B-Lymphocytes/metabolism , B-Lymphocytes/pathology , Biomarkers/metabolism , Bronchoalveolar Lavage Fluid/immunology , COVID-19/immunology , COVID-19/metabolism , Databases, Genetic , Humans , Hyaluronan Synthases/metabolism , Immunoglobulin A/metabolism , Interferon-alpha/metabolism , Lung/immunology , Lung/metabolism , Matrix Metalloproteinases/metabolism , Mucin-1/metabolism , Plasminogen Activator Inhibitor 1/metabolism , RNA-Seq , SARS-CoV-2 , Th17 Cells/metabolism , Th17 Cells/pathology
15.
Immunity ; 54(6): 1290-1303.e7, 2021 06 08.
Article in English | MEDLINE | ID: covidwho-1237724

ABSTRACT

Dissecting the evolution of memory B cells (MBCs) against SARS-CoV-2 is critical for understanding antibody recall upon secondary exposure. Here, we used single-cell sequencing to profile SARS-CoV-2-reactive B cells in 38 COVID-19 patients. Using oligo-tagged antigen baits, we isolated B cells specific to the SARS-CoV-2 spike, nucleoprotein (NP), open reading frame 8 (ORF8), and endemic human coronavirus (HCoV) spike proteins. SARS-CoV-2 spike-specific cells were enriched in the memory compartment of acutely infected and convalescent patients several months post symptom onset. With severe acute infection, substantial populations of endemic HCoV-reactive antibody-secreting cells were identified and possessed highly mutated variable genes, signifying preexisting immunity. Finally, MBCs exhibited pronounced maturation to NP and ORF8 over time, especially in older patients. Monoclonal antibodies against these targets were non-neutralizing and non-protective in vivo. These findings reveal antibody adaptation to non-neutralizing intracellular antigens during infection, emphasizing the importance of vaccination for inducing neutralizing spike-specific MBCs.


Subject(s)
Antibodies, Viral/immunology , Antibody Formation/immunology , B-Lymphocytes/immunology , COVID-19/immunology , Host-Pathogen Interactions/immunology , Immunodominant Epitopes/immunology , SARS-CoV-2/immunology , Antibodies, Neutralizing/immunology , Antibody Formation/genetics , B-Lymphocytes/metabolism , Computational Biology/methods , Cross Reactions/immunology , Epitope Mapping , Female , Gene Expression Profiling , High-Throughput Nucleotide Sequencing , Host-Pathogen Interactions/genetics , Humans , Immunodominant Epitopes/genetics , Immunologic Memory , Male , Neutralization Tests , Single-Cell Analysis/methods , Spike Glycoprotein, Coronavirus/immunology , Transcriptome
16.
Front Immunol ; 12: 639329, 2021.
Article in English | MEDLINE | ID: covidwho-1219713

ABSTRACT

Background: Infection with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a wide range of symptoms including gastrointestinal manifestations, and intestinal epithelial cells are a target of the virus. However, it is unknown how the intestinal immune system contributes to systemic immune responses in coronavirus disease 2019 (COVID-19). Methods: We characterized peripheral blood lymphocytes from patients with active COVID-19 and convalescent patients as well as healthy controls by flow cytometry. Results: The frequency and absolute number of circulating memory T and B cells expressing the gut homing integrin α4ß7 integrin was reduced during COVID-19, whether gastrointestinal symptoms were present or not. While total IgA-expressing B cells were increased, gut-imprinted B cells with IgA expression were stable. Conclusion: COVID-19 is associated with a decrease in circulating adaptive immune cells expressing the key gut homing marker α4ß7 suggesting that these cells are preferentially recruited to extra-intestinal tissues independently of α4ß7 or that the systemic immune response against SARS-CoV-2 is at least numerically dominated by extraintestinal, particularly pulmonary, immune cell priming.


Subject(s)
B-Lymphocytes/metabolism , COVID-19/immunology , Integrin alpha4/metabolism , Integrins/metabolism , SARS-CoV-2/immunology , T-Lymphocytes/metabolism , Adult , B-Lymphocytes/immunology , Biomarkers/analysis , COVID-19/pathology , Female , Humans , Immunologic Memory/immunology , Intestinal Mucosa/cytology , Intestinal Mucosa/immunology , Lymphocyte Count , Male , Middle Aged , T-Lymphocytes/immunology
17.
Front Immunol ; 12: 665522, 2021.
Article in English | MEDLINE | ID: covidwho-1211818

ABSTRACT

COVID-19 is characterized by a severe pulmonary disease due to severe acute respiratory syndrome (SARS)-CoV-2 infection. For clinicians involved in the management of patients with chronic autoimmune diseases the risk linked to the conditions itself and to drug-induced immunosuppression during the COVID-19 pandemic is a major topic. Pemphigus is a rare autoimmune blistering disease (AIBD) of the skin and mucous membranes caused by autoantibodies to desmosomal components, desmoglein 1 and 3. Among immunosuppressant therapies, rituximab (RTX) is considered a highly effective treatment with a favorable safety profile, but it induces a prolonged B-cell depletion that can lead to higher susceptibility to infections. For this reason, concerns about its use during the pandemic have been raised. We describe a case of a pemphigus patient in which RTX-induced B cell depletion led to the severe inflammatory phase, whereas corticosteroid treatment allowed a favorable outcome.


Subject(s)
Adrenal Cortex Hormones/therapeutic use , B-Lymphocytes/immunology , COVID-19/drug therapy , Pemphigus/immunology , Rituximab/adverse effects , Adrenal Cortex Hormones/adverse effects , B-Lymphocytes/metabolism , COVID-19/complications , COVID-19/physiopathology , Female , Fever , Humans , Immunoglobulin G/immunology , Inflammation/drug therapy , Middle Aged , Oxygen Inhalation Therapy , Pemphigus/complications , Pemphigus/drug therapy , Rituximab/therapeutic use
18.
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
19.
Intern Emerg Med ; 16(8): 2181-2191, 2021 11.
Article in English | MEDLINE | ID: covidwho-1173991

ABSTRACT

Evaluating the effect of convalescent plasma (CP) on some cytokine storm indices in severe COVID-19 patients. Totally, 62 patients were randomly assigned into two groups for this clinical trial. Patients in the intervention group received one unit (500 mL) plasma on the admission day plus standard drugs while the controls merely received standard treatments. Eventually, primary and secondary outcomes were evaluated. In the CP group, compared with controls, the mean levels of lymphocytes and IL-10 significantly increased while the levels of IL-6, TNF-α, and IFN-γ decreased (p < 0.05). The length of in-hospital stay, and mortality rate did not significantly reduce in the CP group compared with controls (p > 0.05) while WHO severity scores remarkably improved (p = 0.01), despite the higher frequency of underlying diseases among the CP group (66.7%) vs. controls (33.3%). Although CP has a remarkable immunomodulatory and antiviral potential to improve the cytokine storm and disease severity in COVID-19 patients, it did not considerably affect the mortality rate.


Subject(s)
Blood Component Transfusion , COVID-19/therapy , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/therapy , Adult , B-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/metabolism , COVID-19/immunology , Critical Illness/therapy , Female , Humans , Immunization, Passive , Interleukin-10/blood , Interleukin-6/blood , Length of Stay , Male , Middle Aged , Severity of Illness Index , Treatment Outcome
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