Severity of SARS-CoV-2 infection is linked to double-negative (CD27− IgD−) B cell subset numbers

Cervantes‐Díaz, Rodrigo; Sosa-Hernández, Víctor Andrés; Torres-Ruíz, Jiram; Romero‐Ramírez, Sandra; Cañez-Hernández, Mariana; Pérez-Fragoso, Alfredo; Páez-Franco, José C.; Meza-Sánchez, David Eduardo; Pescador-Rojas, Miriam; Sosa-Hernández, Víctor Adrián; Gómez‐Martín, Diana; Maravillas‐Montero, José Luis

doi:10.1007/s00011-021-01525-3

Cited by 21 publications

(20 citation statements)

References 32 publications

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“…DN cells are a relatively minor population within the total B cell population ( Figure 1D ) and quantification of the DN1 subset did not reveal any significant differences in the frequency of DN1 cells amongst CD19+ cells with severe SARS-CoV-2 infection compared to other individuals ( Figure 1E ). Importantly, we observed a significant increase in DN2 and DN3 cells within the total B cell population with severe SARS-CoV-2 infection compared to heathy controls, individuals immunized against SARS-CoV-2 or subjects with mild infection ( Figure 1E ), in accordance with previous reports ( 22 , 23 ).…”

Section: Resultssupporting

confidence: 93%

“…Expansion of the DN3 subset correlated with a variety of clinical parameters including increased respiratory rate and increased levels of D-dimer and CRP ( 11 ), suggesting a possible role for DN3 cells in disease pathogenesis. Furthermore, individuals who recovered from infection had a higher frequency of DN1 cells than individuals who succumbed to infection ( 23 ), indicating DN1 cells may play a protective role in viral infection. Despite these reports on DN subset frequency and correlation with disease parameters, there is still limited information on DN cells in both healthy controls and during SARS-CoV-2 infection.…”

Section: Introductionmentioning

confidence: 99%

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Autoantibodies elicited with SARS-CoV-2 infection are linked to alterations in double negative B cells

et al. 2022

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Double negative (DN) B cells (CD27-IgD-) comprise a heterogenous population of DN1, DN2, and the recently described DN3 and DN4 subsets. In autoimmune disease, DN2 cells are reported to be precursors to autoreactive antibody secreting cells and expansion of DN2 cells is linked to elevated interferon levels. Severe SARS-CoV-2 infection is characterized by elevated systemic levels of pro-inflammatory cytokines and serum autoantibodies and expansion of the DN2 subset in severe SARS-CoV-2 infection has been reported. However, the activation status, functional capacity and contribution to virally-induced autoantibody production by DN subsets is not established. Here, we validate the finding that severe SARS-CoV-2 infection is associated with a reduction in the frequency of DN1 cells coinciding with an increase in the frequency of DN2 and DN3 cells. We further demonstrate that with severe viral infection DN subsets are at a heightened level of activation, display changes in immunoglobulin class isotype frequency and have functional BCR signaling. Increases in overall systemic inflammation (CRP), as well as specific pro-inflammatory cytokines (TNFα, IL-6, IFNγ, IL-1β), significantly correlate with the skewing of DN1, DN2 and DN3 subsets during severe SARS-CoV-2 infection. Importantly, the reduction in DN1 cell frequency and expansion of the DN3 population during severe infection significantly correlates with increased levels of serum autoantibodies. Thus, systemic inflammation during SARS-CoV-2 infection drives changes in Double Negative subset frequency, likely impacting their contribution to generation of autoreactive antibodies.

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Section: Resultssupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Autoantibodies elicited with SARS-CoV-2 infection are linked to alterations in double negative B cells

et al. 2022

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“…In particular, such populations are characterized by CD19 + CD27 + CD38 hi antibody-producing cells, as well as CD11 + activated naïve B cells that differentiate in effector B cells lacking naïve (IgD) and memory (CD27) markers, i.e. CD19 + CD27 -CD38 -CD24 -IgD -CD11c + CD21 -, also called double-negative B cells (113,117). The expansion of B cells lacking memory markers has been described in several studies and has been referred to as atypical memory B cells (CD21 lo CD27 -CD10 -) (118).…”

Section: Antigen-specific B Cell and Humoral Responsesmentioning

confidence: 99%

Hallmarks of Severe COVID-19 Pathogenesis: A Pas de Deux Between Viral and Host Factors

et al. 2022

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Two years into Coronavirus Disease 2019 (COVID-19) pandemic, a comprehensive characterization of the pathogenesis of severe and critical forms of COVID-19 is still missing. While a deep dysregulation of both the magnitude and functionality of innate and adaptive immune responses have been described in severe COVID-19, the mechanisms underlying such dysregulations are still a matter of scientific debate, in turn hampering the identification of new therapies and of subgroups of patients that would most benefit from individual clinical interventions. Here we review the current understanding of viral and host factors that contribute to immune dysregulation associated with COVID-19 severity in the attempt to unfold and broaden the comprehension of COVID-19 pathogenesis and to define correlates of protection to further inform strategies of targeted therapeutic interventions.

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“…Moreover, transitional (TR) B-cell subsets increased in mild and moderate cases, whereas the memory B compartment decreased in severe and critical cases, while the ASCs increased in accordance with the disease severity ( Sosa-Hernandez et al., 2020 ). Similarly, there have been significant increments in the double-negative (DN) CD27 − IgD − B-cell subsets (DN2 and DN3), alongside a relevant decrease in the DN1 B-cell subpopulation in conjunction with COVID-19 case severity and the patient’s outcome ( Cervantes-Diaz et al., 2022 ). These DN cell numbers also appeared to correlate with pro- or anti-inflammatory signatures, respectively ( Cervantes-Diaz et al., 2022 ).…”

Section: Introductionmentioning

confidence: 99%

“…Similarly, there have been significant increments in the double-negative (DN) CD27 − IgD − B-cell subsets (DN2 and DN3), alongside a relevant decrease in the DN1 B-cell subpopulation in conjunction with COVID-19 case severity and the patient’s outcome ( Cervantes-Diaz et al., 2022 ). These DN cell numbers also appeared to correlate with pro- or anti-inflammatory signatures, respectively ( Cervantes-Diaz et al., 2022 ). These pathogenic changes in the B-cell compartment previously observed in SLE, hepatitis C, and HIV infection ( Holla et al., 2021 ; Sanz et al., 2019 ) have now similarly been observed COVID-19 ( Sosa-Hernandez et al., 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Acute Surge of Atypical Memory and Plasma B-Cell Subsets Driven by an Extrafollicular Response in Severe COVID-19

Lee

Kim

et al. 2022

Front. Cell. Infect. Microbiol.

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BackgroundDespite the use of vaccines and therapeutics against the coronavirus disease 2019 (COVID-19) pandemic, this severe disease has been a critical burden on public health, whereas the pathogenic mechanism remains elusive. Recently, accumulating evidence underscores the potential role of the aberrant B-cell response and humoral immunity in disease progression, especially in high-risk groups.MethodsUsing single-cell RNA (scRNA) sequencing analysis, we investigated transcriptional features of B-cell population in peripheral blood from COVID-19 patients and compared them, according to clinical severity and disease course, against a public B-cell dataset.ResultsWe confirmed that acute B cells differentiate into plasma cells, particularly in severe patients, potentially through enhanced extrafollicular (EF) differentiation. In severe groups, the elevated plasma B-cell response displayed increased B-cell receptor (BCR) diversity, as well as higher levels of anti–severe acute respiratory syndrome coronavirus 2 (anti–SARS-CoV-2) spike antibodies in plasma, than those in moderate cases, suggesting more robust and heterogeneous plasma cell response in severe COVID-19 patients. Trajectory analysis identified a differentiation pathway for the EF B-cell response from active naïve to atypical memory B cells (AM2), in addition to the emergence of an aberrant plasma cell subset (PC2), which was associated with COVID-19 progression and severity. The AM2 and PC2 subsets surged in the acute phase of the severe disease and presented multiple inflammatory features, including higher cytokine expression and humoral effector function, respectively. These features differ from other B-cell subsets, suggesting a pathogenic potential for disease progression.ConclusionThe acute surge of AM2 and PC2 subsets with lower somatic hypermutation and higher inflammatory features may be driven by the EF B-cell response during the acute phase of severe COVID-19 and may represent one of the critical drivers in disease severity.

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Severity of SARS-CoV-2 infection is linked to double-negative (CD27− IgD−) B cell subset numbers

Cited by 21 publications

References 32 publications

Autoantibodies elicited with SARS-CoV-2 infection are linked to alterations in double negative B cells

Autoantibodies elicited with SARS-CoV-2 infection are linked to alterations in double negative B cells

Hallmarks of Severe COVID-19 Pathogenesis: A Pas de Deux Between Viral and Host Factors

Acute Surge of Atypical Memory and Plasma B-Cell Subsets Driven by an Extrafollicular Response in Severe COVID-19

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