B Cell Subsets as Severity-Associated Signatures in COVID-19 Patients

Sosa-Hernández, Víctor Andrés; Torres-Ruíz, Jiram; Cervantes‐Díaz, Rodrigo; Romero‐Ramírez, Sandra; Páez-Franco, José C.; Meza-Sánchez, David Eduardo; Juárez‐Vega, Guillermo; Pérez-Fragoso, Alfredo; Ortı́z-Navarrete, Vianney; Ponce-de-León, Alfredo; Llorente, Luis Enrique Montiel; Berrón-Ruíz, Laura; Mejía‐Domínguez, Nancy R.; Gómez‐Martín, Diana; Maravillas-Montero, José Luis

doi:10.3389/fimmu.2020.611004

Cited by 125 publications

(152 citation statements)

References 56 publications

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“…Moreover, in these previously infected CVID patients, IgG response was boosted by the subsequent immunization. Interestingly, in all CVID patients, vaccination induced Trimeric Spike-specific B-cells inside the ATM and PB population, with low affinity for Trimeric Spike, possibly suggesting that the B-cell responses occurred mostly at extra-follicular sites [32] as recently demonstrated [33]. In line with this hypothesis, RBD+ B-cells were undetectable in CVID patients, whereas they represent 20% of the highly specific anti-Trimeric Spike response in HD (unpublished data) able to develop and successfully terminate the germinal center reaction [34].…”

Section: Discussionsupporting

confidence: 52%

SARS-CoV-2 Vaccine Induced Atypical Immune Responses in Antibody Defects: everybody does their best

Salinas

Mortari

Terreri

et al. 2021

Preprint

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Background. Patients with Primary Antibody Deficiencies (PAD) represent a potential at-risk group in the current COVID-19 pandemic. However, unexpectedly low cumulative incidence, low infection-fatality rate, and mild COVID-19 or asymptomatic SARS-CoV-2 infections were frequently reported in PAD. The discrepancy between clinical evidence and impaired antibody production requires in-depth studies on patients immune responses. Methods. Forty-one patients with Common Variable Immune Deficiencies (CVID), 6 patients with X-linked Agammaglobulinemia (XLA), and 28 healthy age-matched controls (HD) were analyzed for anti-Spike and anti-RBD antibody production, generation of low and high affinity Spike-specific memory B-cells, Spike-specific T-cells before and one week after the second dose of BNT162b2 vaccine. Results. HD produced antibodies, and generated memory B-cells with high affinity for Trimeric Spike. In CVID, the vaccine induced poor Spike-specific antibodies, and atypical B-cells with low affinity for Trimeric Spike, possibly by extra-follicular reactions or incomplete germinal center reactions. In HD, among Spike positive memory B-cells, we identified receptor-binding-domain-specific cells that were undetectable in CVID, indicating the incapability to generate this new specificity. Specific T-cell responses toward Spike-protein were evident in HD and defective in CVID. Due to the absence of B-cells, patients with XLA responded to immunization by specific T-cell responses only. Conclusions. We present detailed data on early non-canonical immune responses in PAD to a vaccine against an antigen never encountered before by humans. From our data, we expect that after BNT162b2 immunization, XLA patients might be protected by specific T-cells, while CVID patients might not be protected by immunization. Key words: Primary Antibody Deficiencies, Common Variable Immune Deficiencies, X-linked Agammaglobulinemia, COVID-19, SARS-CoV-2, BNT162b2 vaccine, memory cells, affinity, Trimeric Spike, receptor-binding-domain.

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Section: Discussionsupporting

confidence: 52%

SARS-CoV-2 Vaccine Induced Atypical Immune Responses in Antibody Defects: everybody does their best

Salinas

Mortari

Terreri

et al. 2021

Preprint

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“…DN B cells are suggested to be the precursors of antibody secreting cells in SLE patients and to develop outside the germinal center (36,37). While DN B cells can be detected in healthy individuals, they expand in patients with SLE (38), rheumatoid arthritis (39), nonsmall cell lung cancer (40), and COVID-19 (41). Furthermore, it has been reported that DN B cells increased in pediatric acute renal allograft rejection recipients who received steroid pulsing, compared to patients with stable graft function (42).…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of Bone Marrow-Derived Mesenchymal Stem Cells for Chronic Antibody-Mediated Rejection After Kidney Transplantation- A Single-Arm, Two-Dosing-Regimen, Phase I/II Study

Wei

Zhang

et al. 2021

Front. Immunol.

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ObjectiveTo investigate the efficacy and safety of bone marrow-derived mesenchymal stem cells (BM-MSCs) on chronic active antibody-mediated rejection (cABMR) in the kidney allograft.MethodsKidney recipients with biopsy-proven cABMR were treated with allogeneic third-party BM-MSCs in this open-label, single-arm, single-center, two-dosing-regimen phase I/II clinical trial. In Regimen 1 (n=8), BM-MSCs were administered intravenously at a dose of 1.0×106 cells/kg monthly for four consecutive months, while in Regimen 2 (n=15), the BM-MSCs dose was 1.0×106 cells/kg weekly during four consecutive weeks. The primary endpoints were the absolute change of estimated glomerular filtration rate (eGFR) from baseline (delta eGFR) and the incidence of adverse events associated with BM-MSCs administration 24 months after the treatment. Contemporaneous cABMR patients who did not receive BM-MSCs were retrospectively analyzed as the control group (n =30).ResultsTwenty-three recipients with cABMR received BM-MSCs. The median delta eGFR of the total BM-MSCs treated patients was -4.3 ml/min per 1.73m2 (interquartile range, IQR -11.2 to 1.2) 2 years after BM-MSCs treatment (P=0.0233). The median delta maximum donor-specific antibody (maxDSA) was -4310 (IQR -9187 to 1129) at 2 years (P=0.0040). The median delta eGFR of the control group was -12.7 ml/min per 1.73 m2 (IQR -22.2 to -3.5) 2 years after the diagnosis, which was greater than that of the BM-MSCs treated group (P=0.0342). The incidence of hepatic enzyme elevation, BK polyomaviruses (BKV) infection, cytomegalovirus (CMV) infection was 17.4%, 17.4%, 8.7%, respectively. There was no fever, anaphylaxis, phlebitis or venous thrombosis, cardiovascular complications, or malignancy after BM-MSCs administration. Flow cytometry analysis showed a significant decreasing trend of CD27-IgD- double negative B cells subsets and trend towards the increase of CD3+CD4+PD-1+/lymphocyte population after MSCs therapy. Multiplex analysis found TNF-α, CXCL10, CCL4, CCL11 and RANTES decreased after MSCs treatment.ConclusionKidney allograft recipients with cABMR are tolerable to BM-MSCs. Immunosuppressive drugs combined with intravenous BM-MSCs can delay the deterioration of allograft function, probably by decreasing DSA level and reducing DSA-induced injury. The underlying mechanism may involve immunomodulatory effect of MSCs on peripheral B and T cells subsets.

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“…This indicates a critical role of immune cells, which are primarily hematopoietic, in the development of severe COVID-19 [16][17][18][19] . To profile the cell-cell interactions underlying severe COVID-19 from a genetic perspective, we constructed a cell correlation matrix based on the overlap of RefMap genes between cell types ( Fig.…”

Section: Refmap Analysis Of Common Variants Uncovers Cell-type-specific Genetic Basis Of Covid-19 Severitymentioning

confidence: 98%

“…Profiles of the immune response associated with severe COVID-19 have produced a number of conflicting observations. These studies have variously linked COVID-19 severity to CD8 T cells 16 , CD19 B cells 17 , eosinophils 18 , and myeloid cells 19 . Single-cell omic profiling has demonstrated the differential function of various immune cell types in severe disease as opposed to mild disease or non-infected condition [20][21][22][23][24][25] .…”

Section: Introductionmentioning

confidence: 99%

Common and rare variant analyses combined with single-cell multiomics reveal cell-type-specific molecular mechanisms of COVID-19 severity

Zhang

Cooper‐Knock

Weimer

et al. 2021

Preprint

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The determinants of severe COVID-19 in non-elderly adults are poorly understood, which limits opportunities for early intervention and treatment. Here we present novel machine learning frameworks for identifying common and rare disease-associated genetic variation, which outperform conventional approaches. By integrating single-cell multiomics profiling of human lungs to link genetic signals to cell-type-specific functions, we have discovered and validated over 1,000 risk genes underlying severe COVID-19 across 19 cell types. Identified risk genes are overexpressed in healthy lungs but relatively downregulated in severely diseased lungs. Genetic risk for severe COVID-19, within both common and rare variants, is particularly enriched in natural killer (NK) cells, which places these immune cells upstream in the pathogenesis of severe disease. Mendelian randomization indicates that failed NKG2D-mediated activation of NK cells leads to critical illness. Network analysis further links multiple pathways associated with NK cell activation, including type-I-interferon-mediated signalling, to severe COVID-19. Our rare variant model, PULSE, enables sensitive prediction of severe disease in non-elderly patients based on whole-exome sequencing; individualized predictions are accurate independent of age and sex, and are consistent across multiple populations and cohorts. Risk stratification based on exome sequencing has the potential to facilitate post-exposure prophylaxis in at-risk individuals, potentially based around augmentation of NK cell function. Overall, our study characterizes a comprehensive genetic landscape of COVID-19 severity and provides novel insights into the molecular mechanisms of severe disease, leading to new therapeutic targets and sensitive detection of at-risk individuals.

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B Cell Subsets as Severity-Associated Signatures in COVID-19 Patients

Cited by 125 publications

References 56 publications

SARS-CoV-2 Vaccine Induced Atypical Immune Responses in Antibody Defects: everybody does their best

SARS-CoV-2 Vaccine Induced Atypical Immune Responses in Antibody Defects: everybody does their best

Efficacy and Safety of Bone Marrow-Derived Mesenchymal Stem Cells for Chronic Antibody-Mediated Rejection After Kidney Transplantation- A Single-Arm, Two-Dosing-Regimen, Phase I/II Study

Common and rare variant analyses combined with single-cell multiomics reveal cell-type-specific molecular mechanisms of COVID-19 severity

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