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1.
Front Immunol ; 12: 815404, 2021.
Article in English | MEDLINE | ID: covidwho-1674337

ABSTRACT

CVID patients have an increased susceptibility to vaccine-preventable infections. The question on the potential benefits of immunization of CVID patients against SARS-CoV-2 offered the possibility to analyze the defective mechanisms of immune responses to a novel antigen. In CVID, as in immunocompetent subjects, the role of B and T cells is different between infected and vaccinated individuals. Upon vaccination, variable anti-Spike IgG responses have been found in different CVID cohorts. Immunization with two doses of mRNA vaccine did not generate Spike-specific classical memory B cells (MBCs) but atypical memory B cells (ATM) with low binding capacity to Spike protein. Spike-specific T-cells responses were also induced in CVID patients with a variable frequency, differently from specific T cells produced after multiple exposures to viral antigens following influenza virus immunization and infection. The immune response elicited by SARS-CoV-2 infection was enhanced by subsequent immunization underlying the need to immunize convalescent COVID-19 CVID patients after recovery. In particular, immunization after SARS-Cov-2 infection generated Spike-specific classical memory B cells (MBCs) with low binding capacity to Spike protein and Spike-specific antibodies in a high percentage of CVID patients. The search for a strategy to elicit an adequate immune response post-vaccination in CVID patients is necessary. Since reinfection with SARS-CoV-2 has been documented, at present SARS-CoV-2 positive CVID patients might benefit from new preventing strategy based on administration of anti-SARS-CoV-2 monoclonal antibodies.


Subject(s)
Antibodies, Monoclonal/immunology , Antibodies, Viral/immunology , B-Lymphocyte Subsets/immunology , COVID-19 Vaccines/immunology , COVID-19/immunology , Common Variable Immunodeficiency/immunology , SARS-CoV-2/physiology , Adult , COVID-19/complications , Common Variable Immunodeficiency/complications , Female , Humans , Immunogenicity, Vaccine , Immunologic Memory , Male , Spike Glycoprotein, Coronavirus/immunology , Vaccination
2.
J Autoimmun ; 127: 102792, 2022 02.
Article in English | MEDLINE | ID: covidwho-1587359

ABSTRACT

The emergence and rapid global spread of the new Delta and, more recently, Omicron variants of SARS-CoV-2 pose a daunting public health emergency. Being an RNA virus, the Covid-19 virus is continuing to mutate, resulting in the emergence of new variants with high transmissibility, such as the recently discovered Omicron variant. In this paper, we consider the conditions that may facilitate viral mutations and the emergence of variants with the ability to evade immunity. Here, we have discussed the importance of vaccination with the currently available vaccines. These vaccines are highly effective at preventing serious disease, hospitalization, and death from Covid-19. However, the antibody response induced by these vaccines is short-lasting and there are reports of breakthrough infections. A stable and persistent interaction between T follicular helper cells and germinal center B cells is needed for robust B cell memory response. We discussed the potential reasons behind the breakthrough infections and underscored the importance of developing better second-generation vaccines that may not necessitate frequent booster immunizations and are preventive in nature. This may involve the development of multivalent vaccines and creating vaccines against other viral proteins including conserved proteins. Vaccine hesitancy remains a notable hurdle for implementing vaccination. Furthermore, we recommend different approaches to increase vaccine acceptance, which is a critical translational component of a successful vaccine strategy. These perspectives on overcoming the pandemic's current challenges provide strategies to contain SARS-CoV-2 globally.


Subject(s)
COVID-19 Vaccines , COVID-19/prevention & control , Pandemics/prevention & control , SARS-CoV-2/immunology , Antibodies, Viral/biosynthesis , Antibodies, Viral/immunology , B-Lymphocyte Subsets/immunology , COVID-19/transmission , COVID-19 Vaccines/immunology , Host-Pathogen Interactions/immunology , Humans , Immunogenicity, Vaccine , Immunologic Memory , SARS-CoV-2/genetics , T-Lymphocytes/immunology , Vaccination
3.
Front Immunol ; 12: 803742, 2021.
Article in English | MEDLINE | ID: covidwho-1581314

ABSTRACT

Immunocompromised patients are considered high-risk and prioritized for vaccination against COVID-19. We aimed to analyze B-cell subsets in these patients to identify potential predictors of humoral vaccination response. Patients (n=120) suffering from hematologic malignancies or other causes of immunodeficiency and healthy controls (n=79) received a full vaccination series with an mRNA vaccine. B-cell subsets were analyzed prior to vaccination. Two independent anti-SARS-CoV-2 immunoassays targeting the receptor-binding domain (RBD) or trimeric S protein (TSP) were performed three to four weeks after the second vaccination. Seroconversion occurred in 100% of healthy controls, in contrast to 67% (RBD) and 82% (TSP) of immunocompromised patients, while only 32% (RBD) and 22% (TSP) achieved antibody levels comparable to those of healthy controls. The number of circulating CD19+IgD+CD27- naïve B cells was strongly associated with antibody levels (ρ=0.761, P<0.001) and the only independent predictor for achieving antibody levels comparable to healthy controls (OR 1.07 per 10-µL increase, 95%CI 1.02-1.12, P=0.009). Receiver operating characteristic analysis identified a cut-off at ≥61 naïve B cells per µl to discriminate between patients with and without an optimal antibody response. Consequently, measuring of naïve B cells in immunocompromised hematologic patients could be useful in predicting their humoral vaccination response.


Subject(s)
B-Lymphocyte Subsets/immunology , COVID-19 Vaccines/immunology , COVID-19/prevention & control , Immunocompromised Host/immunology , Immunogenicity, Vaccine/immunology , Adult , Aged , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Female , Humans , Male , Middle Aged , SARS-CoV-2 , Vaccines, Synthetic/immunology , /immunology
4.
Mucosal Immunol ; 14(5): 1144-1159, 2021 09.
Article in English | MEDLINE | ID: covidwho-1550272

ABSTRACT

Increased IgE is a typical feature of allergic rhinitis. Local class-switch recombination has been intimated but B cell precursors and mechanisms remain elusive. Here we describe the dynamics underlying the generation of IgE-antibody secreting cells (ASC) in human nasal polyps (NP), mucosal tissues rich in ASC without germinal centers (GC). Using VH next generation sequencing, we identified an extrafollicular (EF) mucosal IgD+ naïve-like intermediate B cell population with high connectivity to the mucosal IgE ASC. Mucosal IgD+ B cells, express germline epsilon transcripts and predominantly co-express IgM. However, a small but significant fraction co-express IgG or IgA instead which also show connectivity to ASC IgE. Phenotypically, NP IgD+ B cells display an activated profile and molecular evidence of BCR engagement. Transcriptionally, mucosal IgD+ B cells reveal an intermediate profile between naïve B cells and ASC. Single cell IgE ASC analysis demonstrates lower mutational frequencies relative to IgG, IgA, and IgD ASC consistent with IgE ASC derivation from mucosal IgD+ B cell with low mutational load. In conclusion, we describe a novel mechanism of GC-independent, extrafollicular IgE ASC formation at the nasal mucosa whereby activated IgD+ naïve B cells locally undergo direct and indirect (through IgG and IgA), IgE class switch.


Subject(s)
Antibody Formation/immunology , B-Lymphocyte Subsets/immunology , B-Lymphocyte Subsets/metabolism , Immunoglobulin D/immunology , Immunoglobulin E/immunology , Nasal Mucosa/immunology , Nasal Mucosa/metabolism , Adult , Antibody Formation/genetics , Antibody-Producing Cells/immunology , Antibody-Producing Cells/metabolism , Computational Biology , Gene Expression Profiling , Germinal Center/immunology , High-Throughput Nucleotide Sequencing , Humans , Hypersensitivity/etiology , Hypersensitivity/metabolism , Immunoglobulin Class Switching/genetics , Immunoglobulin Class Switching/immunology , Immunoglobulin Isotypes/genetics , Immunoglobulin Isotypes/immunology , Immunophenotyping , Nasal Polyps/etiology , Nasal Polyps/metabolism , Nasal Polyps/pathology , Pollen/immunology , Seasons , Somatic Hypermutation, Immunoglobulin
5.
Cell Res ; 31(12): 1244-1262, 2021 12.
Article in English | MEDLINE | ID: covidwho-1493090

ABSTRACT

The infusion of coronavirus disease 2019 (COVID-19) patients with mesenchymal stem cells (MSCs) potentially improves clinical symptoms, but the underlying mechanism remains unclear. We conducted a randomized, single-blind, placebo-controlled (29 patients/group) phase II clinical trial to validate previous findings and explore the potential mechanisms. Patients treated with umbilical cord-derived MSCs exhibited a shorter hospital stay (P = 0.0198) and less time required for symptoms remission (P = 0.0194) than those who received placebo. Based on chest images, both severe and critical patients treated with MSCs showed improvement by day 7 (P = 0.0099) and day 21 (P = 0.0084). MSC-treated patients had fewer adverse events. MSC infusion reduced the levels of C-reactive protein, proinflammatory cytokines, and neutrophil extracellular traps (NETs) and promoted the maintenance of SARS-CoV-2-specific antibodies. To explore how MSCs modulate the immune system, we employed single-cell RNA sequencing analysis on peripheral blood. Our analysis identified a novel subpopulation of VNN2+ hematopoietic stem/progenitor-like (HSPC-like) cells expressing CSF3R and PTPRE that were mobilized following MSC infusion. Genes encoding chemotaxis factors - CX3CR1 and L-selectin - were upregulated in various immune cells. MSC treatment also regulated B cell subsets and increased the expression of costimulatory CD28 in T cells in vivo and in vitro. In addition, an in vivo mouse study confirmed that MSCs suppressed NET release and reduced venous thrombosis by upregulating kindlin-3 signaling. Together, our results underscore the role of MSCs in improving COVID-19 patient outcomes via maintenance of immune homeostasis.


Subject(s)
COVID-19/therapy , Immunomodulation , Mesenchymal Stem Cell Transplantation , Aged , Animals , Antibodies, Viral/blood , B-Lymphocyte Subsets/cytology , B-Lymphocyte Subsets/immunology , B-Lymphocyte Subsets/metabolism , C-Reactive Protein/analysis , COVID-19/immunology , COVID-19/virology , Cytokines/genetics , Cytokines/metabolism , Cytoskeletal Proteins/metabolism , Disease Models, Animal , Extracellular Traps/metabolism , Female , Humans , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/metabolism , Male , Mice , Mice, Inbred C57BL , Middle Aged , SARS-CoV-2/isolation & purification , T-Lymphocytes/cytology , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Venous Thrombosis/metabolism , Venous Thrombosis/pathology
6.
J Immunol ; 207(10): 2581-2588, 2021 11 15.
Article in English | MEDLINE | ID: covidwho-1450886

ABSTRACT

SARS-CoV-2 is a respiratory pathogen that can cause severe disease in at-risk populations but results in asymptomatic infections or a mild course of disease in the majority of cases. We report the identification of SARS-CoV-2-reactive B cells in human tonsillar tissue obtained from children who were negative for coronavirus disease 2019 prior to the pandemic and the generation of mAbs recognizing the SARS-CoV-2 Spike protein from these B cells. These Abs showed reduced binding to Spike proteins of SARS-CoV-2 variants and did not recognize Spike proteins of endemic coronaviruses, but subsets reacted with commensal microbiota and exhibited SARS-CoV-2-neutralizing potential. Our study demonstrates pre-existing SARS-CoV-2-reactive Abs in various B cell populations in the upper respiratory tract lymphoid tissue that may lead to the rapid engagement of the pathogen and contribute to prevent manifestations of symptomatic or severe disease.


Subject(s)
Adenoids/immunology , B-Lymphocyte Subsets/immunology , B-Lymphocytes/immunology , COVID-19/immunology , Mucous Membrane/immunology , Receptors, Antigen, B-Cell/genetics , Respiratory System/immunology , SARS-CoV-2/physiology , Antibodies, Viral/metabolism , Child , HEK293 Cells , Humans , Immunologic Memory , Lymphocyte Activation , Single-Cell Analysis , Spike Glycoprotein, Coronavirus/immunology , Transcriptome
7.
Viruses ; 13(10)2021 09 30.
Article in English | MEDLINE | ID: covidwho-1444330

ABSTRACT

BACKGROUND: The immunological changes associated with COVID-19 are largely unknown. METHODS: Patients with COVID-19 showing moderate (n = 18; SpO2 > 93%, respiratory rate > 22 per minute, CRP > 10 mg/L) and severe (n = 23; SpO2 < 93%, respiratory rate >30 per minute, PaO2/FiO2 ≤ 300 mmHg, permanent oxygen therapy, qSOFA > 2) infection, and 37 healthy donors (HD) were enrolled. Circulating T- and B-cell subsets were analyzed by flow cytometry. RESULTS: CD4+Th cells were skewed toward Th2-like phenotypes within CD45RA+CD62L- (CM) and CD45RA-CD62L- (EM) cells in patients with severe COVID-19, while CM CCR6+ Th17-like cells were decreased if compared with HD. Within CM Th17-like cells "classical" Th17-like cells were increased and Th17.1-like cells were decreased in severe COVID-19 cases. Circulating CM follicular Th-like (Tfh) cells were decreased in all COVID-19 patients, and Tfh17-like cells represented the most predominant subset in severe COVID-19 cases. Both groups of patients showed increased levels of IgD-CD38++ B cells, while the levels of IgD+CD38- and IgD-CD38- were decreased. The frequency of IgD+CD27+ and IgD-CD27+ B cells was significantly reduced in severe COVID-19 cases. CONCLUSIONS: We showed an imbalance within almost all circulating memory Th subsets during acute COVID-19 and showed that altered Tfh polarization led to a dysregulated humoral immune response.


Subject(s)
B-Lymphocyte Subsets/immunology , COVID-19/immunology , Immunity , SARS-CoV-2 , ADP-ribosyl Cyclase 1 , Adult , Aged , B-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/immunology , Female , Flow Cytometry , Humans , Immunoglobulin D , Male , Middle Aged , Oxygen , Receptors, CCR6 , T-Lymphocytes/metabolism , Th17 Cells/immunology
8.
Am J Trop Med Hyg ; 105(5): 1255-1260, 2021 09 27.
Article in English | MEDLINE | ID: covidwho-1441316

ABSTRACT

It is essential to examine the longevity of the defensive immune response engendered by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. We examined the SARS-CoV-2-specific antibody responses and ex vivo memory B-cell subsets in seven groups of individuals with COVID-19 classified based on days since reverse-transcription polymerase chain reaction confirmation of SARS-CoV-2 infection. Our data showed that the levels of IgG and neutralizing antibodies started increasing from days 15 to 30 to days 61 to 90, and plateaued thereafter. The frequencies of naive B cells and atypical memory B cells decreased from days 15 to 30 to days 61 to 90, and plateaued thereafter. In contrast, the frequencies of immature B cells, classical memory B cells, activated memory B cells, and plasma cells increased from days 15 to 30 to days 61 to 90, and plateaued thereafter. Patients with severe COVID-19 exhibited increased frequencies of naive cells, atypical memory B cells, and activated memory B cells, and lower frequencies of immature B cells, central memory B cells, and plasma cells when compared with patients with mild COVID-19. Therefore, our data suggest modifications in memory B-cell subset frequencies and persistence of humoral immunity in convalescent individuals with COVID-19.


Subject(s)
Antibodies, Viral/blood , B-Lymphocyte Subsets/immunology , COVID-19/immunology , Convalescence , /immunology , Acute Disease , Adolescent , Adult , Aged , Antibodies, Neutralizing/blood , Cross-Sectional Studies , Female , Humans , Immunity, Humoral , India , Male , Middle Aged , Young Adult
9.
Cell Rep ; 37(2): 109823, 2021 10 12.
Article in English | MEDLINE | ID: covidwho-1433047

ABSTRACT

Although both infections and vaccines induce memory B cell (MBC) populations that participate in secondary immune responses, the MBCs generated in each case can differ. Here, we compare SARS-CoV-2 spike receptor binding domain (S1-RBD)-specific primary MBCs that form in response to infection or a single mRNA vaccination. Both primary MBC populations have similar frequencies in the blood and respond to a second S1-RBD exposure by rapidly producing plasmablasts with an abundant immunoglobulin (Ig)A+ subset and secondary MBCs that are mostly IgG+ and cross-react with the B.1.351 variant. However, infection-induced primary MBCs have better antigen-binding capacity and generate more plasmablasts and secondary MBCs of the classical and atypical subsets than do vaccine-induced primary MBCs. Our results suggest that infection-induced primary MBCs have undergone more affinity maturation than vaccine-induced primary MBCs and produce more robust secondary responses.


Subject(s)
COVID-19 Vaccines/immunology , Plasma Cells/immunology , SARS-CoV-2/immunology , Adult , Animals , Antibodies, Viral/immunology , B-Lymphocyte Subsets/immunology , B-Lymphocytes/immunology , COVID-19/immunology , COVID-19/metabolism , Cross Reactions/immunology , Female , HEK293 Cells , Humans , Immunization/methods , Immunologic Memory , Male , Mice , Mice, Inbred C57BL , Middle Aged , RNA, Messenger/immunology , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism , Vaccination/methods , Vaccines/immunology
11.
J Clin Invest ; 131(8)2021 04 15.
Article in English | MEDLINE | ID: covidwho-1186423

ABSTRACT

Dysregulated immune profiles have been described in symptomatic patients infected with SARS-CoV-2. Whether the reported immune alterations are specific to SARS-CoV-2 infection or also triggered by other acute illnesses remains unclear. We performed flow cytometry analysis on fresh peripheral blood from a consecutive cohort of (a) patients hospitalized with acute SARS-CoV-2 infection, (b) patients of comparable age and sex hospitalized for another acute disease (SARS-CoV-2 negative), and (c) healthy controls. Using both data-driven and hypothesis-driven analyses, we found several dysregulations in immune cell subsets (e.g., decreased proportion of T cells) that were similarly associated with acute SARS-CoV-2 infection and non-COVID-19-related acute illnesses. In contrast, we identified specific differences in myeloid and lymphocyte subsets that were associated with SARS-CoV-2 status (e.g., elevated proportion of ICAM-1+ mature/activated neutrophils, ALCAM+ monocytes, and CD38+CD8+ T cells). A subset of SARS-CoV-2-specific immune alterations correlated with disease severity, disease outcome at 30 days, and mortality. Our data provide an understanding of the immune dysregulation specifically associated with SARS-CoV-2 infection among acute care hospitalized patients. Our study lays the foundation for the development of specific biomarkers to stratify SARS-CoV-2-positive patients at risk of unfavorable outcomes and to uncover candidate molecules to investigate from a therapeutic perspective.


Subject(s)
COVID-19/immunology , Leukocytes/classification , Leukocytes/immunology , SARS-CoV-2 , Acute Disease , Adult , Aged , B-Lymphocyte Subsets/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/epidemiology , COVID-19/mortality , Case-Control Studies , Cohort Studies , Female , Hospitalization , Humans , Lymphocyte Activation , Male , Middle Aged , Models, Immunological , Monocytes/immunology , Multivariate Analysis , Neutrophils/immunology , Pandemics , Prognosis , Prospective Studies , Quebec/epidemiology , Risk Factors , SARS-CoV-2/immunology , Severity of Illness Index
12.
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
13.
PLoS One ; 16(1): e0244855, 2021.
Article in English | MEDLINE | ID: covidwho-1052436

ABSTRACT

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of the pandemic human respiratory illness COVID-19, is a global health emergency. While severe acute disease has been linked to an expansion of antibody-secreting plasmablasts, we sought to identify B cell responses that correlated with positive clinical outcomes in convalescent patients. We characterized the peripheral blood B cell immunophenotype and plasma antibody responses in 40 recovered non-hospitalized COVID-19 subjects that were enrolled as donors in a convalescent plasma treatment study. We observed a significant negative correlation between the frequency of peripheral blood memory B cells and the duration of symptoms for convalescent subjects. Memory B cell subsets in convalescent subjects were composed of classical CD24+ class-switched memory B cells, but also activated CD24-negative and natural unswitched CD27+ IgD+ IgM+ subsets. Memory B cell frequency was significantly correlated with both IgG1 and IgM responses to the SARS-CoV-2 spike protein receptor binding domain (RBD) in most seropositive subjects. IgM+ memory, but not switched memory, directly correlated with virus-specific antibody responses, and remained stable over 3 months. Our findings suggest that the frequency of memory B cells is a critical indicator of disease resolution, and that IgM+ memory B cells may play an important role in SARS-CoV-2 immunity.


Subject(s)
B-Lymphocyte Subsets/immunology , COVID-19/immunology , Adult , Aged , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Antibody Formation , B-Lymphocytes/immunology , Convalescence , Disease Progression , Female , Humans , Immunity/immunology , Immunoglobulin G/immunology , Immunoglobulin M/metabolism , Immunophenotyping/methods , Male , Middle Aged , Recovery of Function/immunology , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification
14.
Int Arch Allergy Immunol ; 182(3): 195-209, 2021.
Article in English | MEDLINE | ID: covidwho-1042227

ABSTRACT

We report perhaps the most comprehensive study of subsets of CD4+ and CD8+ and subsets of B cells in a mild symptomatic SARS-CoV-2+ immunocompetent patient and a common variable immunodeficiency disease (CVID) patient who had normal absolute lymphocyte counts and remained negative for SARS-CoV-2 IgG antibodies. Naïve (TN), central memory (TCM), effector memory (TEM), and terminally differentiated effector memory (TEMRA) subsets of CD4+ and CD8+ T cells, subsets of T follicular helper cells (cTFH, TFH1, TFH2, TFH17, TFH1/TFH17, and TFR), CD4 Treg, CD8 Treg, mature B cells, transitional B cells, marginal zone B cells, germinal center (GC) B cells, CD21low B cells, antibody-secreting cells (plasmablasts), and Breg cells were examined in patients and age-matched controls with appropriate monoclonal antibodies and isotype controls using multicolor flow cytometry. Different patterns of abnormalities (often contrasting) were observed in the subsets of CD4+ T, CD8+ T, B-cell subsets, and regulatory lymphocytes among the immunocompetent patient and CVID patient as compared to corresponding healthy controls. Furthermore, when data were analyzed between the 2 patients, the immunocompetent patient demonstrated greater changes in various subsets as compared to the CVID patient. These data demonstrate different immunological responses to SARS-CoV-2 infection in an immunocompetent patient and the CVID patient. A marked decrease in GC B cells and plasmablasts may be responsible for failure to make SARS-CoV-2 antibodies. The lack of SARS-CoV-2 antibodies with mild clinical disease suggests an important role of T-cell response in defense against SARS-CoV-2 infection.


Subject(s)
COVID-19/immunology , Common Variable Immunodeficiency/immunology , SARS-CoV-2/immunology , T-Lymphocyte Subsets/immunology , Adult , B-Lymphocyte Subsets/immunology , Female , Humans , Immunocompetence , Male , Middle Aged
15.
Front Immunol ; 11: 611004, 2020.
Article in English | MEDLINE | ID: covidwho-993360

ABSTRACT

Background: SARS-CoV-2 infection represents a global health problem that has affected millions of people. The fine host immune response and its association with the disease course have not yet been fully elucidated. Consequently, we analyze circulating B cell subsets and their possible relationship with COVID-19 features and severity. Methods: Using a multiparametric flow cytometric approach, we determined B cell subsets frequencies from 52 COVID-19 patients, grouped them by hierarchical cluster analysis, and correlated their values with clinical data. Results: The frequency of CD19+ B cells is increased in severe COVID-19 compared to mild cases. Specific subset frequencies such as transitional B cell subsets increase in mild/moderate cases but decrease with the severity of the disease. Memory B compartment decreased in severe and critical cases, and antibody-secreting cells are increased according to the severity of the disease. Other non-typical subsets such as double-negative B cells also showed significant changes according to disease severity. Globally, these differences allow us to identify severity-associated patient clusters with specific altered subsets. Finally, respiratory parameters, biomarkers of inflammation, and clinical scores exhibited correlations with some of these subpopulations. Conclusions: The severity of COVID-19 is accompanied by changes in the B cell subpopulations, either immature or terminally differentiated. Furthermore, the existing relationship of B cell subset frequencies with clinical and laboratory parameters suggest that these lymphocytes could serve as potential biomarkers and even active participants in the adaptive antiviral response mounted against SARS-CoV-2.


Subject(s)
B-Lymphocyte Subsets , COVID-19 , SARS-CoV-2 , Adult , Aged , Aged, 80 and over , B-Lymphocyte Subsets/immunology , B-Lymphocyte Subsets/metabolism , B-Lymphocyte Subsets/pathology , COVID-19/blood , COVID-19/immunology , COVID-19/pathology , Female , Flow Cytometry , Humans , Male , Middle Aged , SARS-CoV-2/immunology , SARS-CoV-2/metabolism , Severity of Illness Index
16.
Science ; 369(6508)2020 09 04.
Article in English | MEDLINE | ID: covidwho-981641

ABSTRACT

Coronavirus disease 2019 (COVID-19) is currently a global pandemic, but human immune responses to the virus remain poorly understood. We used high-dimensional cytometry to analyze 125 COVID-19 patients and compare them with recovered and healthy individuals. Integrated analysis of ~200 immune and ~50 clinical features revealed activation of T cell and B cell subsets in a proportion of patients. A subgroup of patients had T cell activation characteristic of acute viral infection and plasmablast responses reaching >30% of circulating B cells. However, another subgroup had lymphocyte activation comparable with that in uninfected individuals. Stable versus dynamic immunological signatures were identified and linked to trajectories of disease severity change. Our analyses identified three immunotypes associated with poor clinical trajectories versus improving health. These immunotypes may have implications for the design of therapeutics and vaccines for COVID-19.


Subject(s)
B-Lymphocytes/immunology , Betacoronavirus/immunology , Coronavirus Infections/immunology , Pneumonia, Viral/immunology , T-Lymphocytes/immunology , Adaptive Immunity , Adult , Aged , Aged, 80 and over , Antibodies, Viral/blood , B-Lymphocyte Subsets/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19 , Cytokines/blood , Female , Humans , Immunologic Memory , Lymphocyte Activation , Male , Middle Aged , Pandemics , Plasma Cells/immunology , SARS-CoV-2 , Severity of Illness Index , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Helper-Inducer/immunology , Time Factors , Young Adult
17.
Immunity ; 53(6): 1136-1150, 2020 12 15.
Article in English | MEDLINE | ID: covidwho-978309

ABSTRACT

Activated B cells participate in either extrafollicular (EF) or germinal center (GC) responses. Canonical responses are composed of a short wave of plasmablasts (PBs) arising from EF sites, followed by GC producing somatically mutated memory B cells (MBC) and long-lived plasma cells. However, somatic hypermutation (SHM) and affinity maturation can take place at both sites, and a substantial fraction of MBC are produced prior to GC formation. Infection responses range from GC responses that persist for months to persistent EF responses with dominant suppression of GCs. Here, we review the current understanding of the functional output of EF and GC responses and the molecular switches promoting them. We discuss the signals that regulate the magnitude and duration of these responses, and outline gaps in knowledge and important areas of inquiry. Understanding such molecular switches will be critical for vaccine development, interpretation of vaccine efficacy and the treatment for autoimmune diseases.


Subject(s)
B-Lymphocyte Subsets/immunology , B-Lymphocytes/immunology , Germinal Center/immunology , Immunity/immunology , Animals , Autoimmune Diseases/immunology , Humans , Immunoglobulin Class Switching , Infections/etiology , Infections/immunology , Lymphocyte Activation , Plasma Cells/immunology , Vaccines/immunology
19.
Nat Med ; 26(10): 1623-1635, 2020 10.
Article in English | MEDLINE | ID: covidwho-717130

ABSTRACT

Improved understanding and management of COVID-19, a potentially life-threatening disease, could greatly reduce the threat posed by its etiologic agent, SARS-CoV-2. Toward this end, we have identified a core peripheral blood immune signature across 63 hospital-treated patients with COVID-19 who were otherwise highly heterogeneous. The signature includes discrete changes in B and myelomonocytic cell composition, profoundly altered T cell phenotypes, selective cytokine/chemokine upregulation and SARS-CoV-2-specific antibodies. Some signature traits identify links with other settings of immunoprotection and immunopathology; others, including basophil and plasmacytoid dendritic cell depletion, correlate strongly with disease severity; while a third set of traits, including a triad of IP-10, interleukin-10 and interleukin-6, anticipate subsequent clinical progression. Hence, contingent upon independent validation in other COVID-19 cohorts, individual traits within this signature may collectively and individually guide treatment options; offer insights into COVID-19 pathogenesis; and aid early, risk-based patient stratification that is particularly beneficial in phasic diseases such as COVID-19.


Subject(s)
Antibodies, Viral/immunology , B-Lymphocytes/immunology , Coronavirus Infections/immunology , Cytokines/immunology , Dendritic Cells/immunology , Pneumonia, Viral/immunology , T-Lymphocytes/immunology , Aged , B-Lymphocyte Subsets/immunology , Basophils/immunology , Betacoronavirus , COVID-19 , Case-Control Studies , Cell Cycle , Chemokine CXCL10/immunology , Chemokines/immunology , Cohort Studies , Coronavirus Infections/blood , Disease Progression , Female , Flow Cytometry , Hospitalization , Humans , Immunologic Memory , Immunophenotyping , Interleukin-10/immunology , Interleukin-6/immunology , Leukocyte Count , Lymphocyte Activation/immunology , Male , Middle Aged , Pandemics , Pneumonia, Viral/blood , Prognosis , SARS-CoV-2 , Severity of Illness Index , T-Lymphocyte Subsets/immunology , Up-Regulation
20.
Sci Immunol ; 5(49)2020 07 15.
Article in English | MEDLINE | ID: covidwho-646575

ABSTRACT

Although critical illness has been associated with SARS-CoV-2-induced hyperinflammation, the immune correlates of severe COVID-19 remain unclear. Here, we comprehensively analyzed peripheral blood immune perturbations in 42 SARS-CoV-2 infected and recovered individuals. We identified extensive induction and activation of multiple immune lineages, including T cell activation, oligoclonal plasmablast expansion, and Fc and trafficking receptor modulation on innate lymphocytes and granulocytes, that distinguished severe COVID-19 cases from healthy donors or SARS-CoV-2-recovered or moderate severity patients. We found the neutrophil to lymphocyte ratio to be a prognostic biomarker of disease severity and organ failure. Our findings demonstrate broad innate and adaptive leukocyte perturbations that distinguish dysregulated host responses in severe SARS-CoV-2 infection and warrant therapeutic investigation.


Subject(s)
B-Lymphocyte Subsets/immunology , Betacoronavirus/immunology , Coronavirus Infections/immunology , Neutrophils/immunology , Pneumonia, Viral/immunology , T-Lymphocytes/immunology , Aged , COVID-19 , Clonal Selection, Antigen-Mediated/immunology , Coronavirus Infections/pathology , Cytokines/metabolism , Female , Humans , Immunity, Innate/immunology , Immunologic Memory/immunology , Lymphocyte Activation/immunology , Lymphocyte Count , Male , Middle Aged , Pandemics , Pneumonia, Viral/pathology , SARS-CoV-2
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