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

Víctor A. Sosa‐Hernández1,2, Jiram Torres-Ruíz3,4, Rodrigo Cervantes‐Díaz5,2, Sandra Romero‐Ramírez5,2, José C. Páez-Franco2, David Eduardo Meza-Sánchez2, Guillermo Juárez‐Vega2, Alfredo Pérez‐Fragoso4, Vianney Ortiz‐Navarrete1, Alfredo Ponce‐de‐León6, Luis Enrique Montiel Llorente4, Laura Berrón-Ruíz7, Nancy R. Mejía‐Domínguez2, Diana Gómez‐Martín4, José Luis Maravillas‐Montero2
1Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico City, Mexico
2Red de Apoyo a La Investigación, Universidad Nacional Autónoma de México E Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
3Departamento de Atención Institucional Continua y Urgencias, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
4Departamento de Inmunología y Reumatología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
5Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico
6Departamento de Infectología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
7Unidad de Investigación en Inmunodeficiencias, Instituto Nacional de Pediatría, Mexico City, Mexico

Tóm tắt

BackgroundSARS-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.MethodsUsing 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.ResultsThe 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.ConclusionsThe 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.

Từ khóa


Tài liệu tham khảo

Wang, 2020, The genetic sequence, origin, and diagnosis of SARS-CoV-2, Eur J Clin Microbiol Infect Dis, 39, 10.1007/s10096-020-03899-4

Chan, 2020, A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster, Lancet, 395, 10.1016/S0140-6736(20)30154-9

Huang, 2020, Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China, Lancet, 395, 497, 10.1016/S0140-6736(20)30183-5

Docherty, 2020, Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study, BMJ, 369, 10.1136/bmj.m1985

Lechien, 2020, Clinical and epidemiological characteristics of 1420 European patients with mild-to-moderate coronavirus disease 2019, J Intern Med, 288, 10.1111/joim.13089

Wu, 2020, A new coronavirus associated with human respiratory disease in China, Nature, 579, 10.1038/s41586-020-2008-3

Driggin, 2020, Cardiovascular Considerations for Patients, Health Care Workers, and Health Systems During the COVID-19 Pandemic, J Am Coll Cardiol, 75, 10.1016/j.jacc.2020.03.031

Arachchillage, 2020, Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia, J Thromb Haemost, 18, 10.1111/jth.14820

Cui, 2020, Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia, J Thromb Haemost, 18, 10.1111/jth.14830

Teuwen, 2020, COVID-19: the vasculature unleashed, Nat Rev Immunol, 20, 10.1038/s41577-020-0343-0

Chen, 2020, Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study, Lancet, 395, 10.1016/S0140-6736(20)30211-7

Nicholls, 2003, Lung pathology of fatal severe acute respiratory syndrome, Lancet, 361, 10.1016/S0140-6736(03)13413-7

Li, 2010, Murine coronavirus induces type I interferon in oligodendrocytes through recognition by RIG-I and MDA5, J Virol, 84, 10.1128/JVI.00016-10

Li, 2013, Extraordinary GU-rich single-strand RNA identified from SARS coronavirus contributes an excessive innate immune response, Microbes Infect, 15, 88, 10.1016/j.micinf.2012.10.008

Totura, 2015, Toll-Like Receptor 3 Signaling via TRIF Contributes to a Protective Innate Immune Response to Severe Acute Respiratory Syndrome Coronavirus Infection, mBio, 6, 10.1128/mBio.00638-15

Channappanavar, 2017, Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology, Semin Immunopathol, 39, 10.1007/s00281-017-0629-x

Grifoni, 2020, Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals, Cell, 181, 1489, 10.1016/j.cell.2020.05.015

Weiskopf, 2020, Phenotype and kinetics of SARS-CoV-2-specific T cells in COVID-19 patients with acute respiratory distress syndrome, Sci Immunol, 5, 1, 10.1126/sciimmunol.abd2071

Zhao, 2020, Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019, Clin Infect Dis, 71, 10.2139/ssrn.3546052

Prompetchara, 2020, Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic, Asian Pac J Allergy Immunol, 38, 1, 10.12932/AP-200220-0772

Abbott, 2020, Factors in B cell competition and immunodominance, Immunol Rev, 296, 10.1111/imr.12861

Romero-Ramirez, 2019, Innate-like B cell subsets during immune responses: Beyond antibody production, J Leukoc Biol, 105, 10.1002/JLB.MR0618-227R

Glass, 2020, An Integrated Multi-omic Single-Cell Atlas of Human B Cell Identity, Immunity, 53, 217, 10.1016/j.immuni.2020.06.013

Sanz, 2019, Challenges and Opportunities for Consistent Classification of Human B Cell and Plasma Cell Populations, Front Immunol, 10, 10.3389/fimmu.2019.02458

Wei, 2007, A new population of cells lacking expression of CD27 represents a notable component of the B cell memory compartment in systemic lupus erythematosus, J Immunol, 178, 10.4049/jimmunol.178.10.6624

Liu, 2020, Analysis of factors associated with disease outcomes in hospitalized patients with 2019 novel coronavirus disease, Chin Med J (Engl), 133, 10.1097/CM9.0000000000000775

Fan, 2020, Comparison of severity scores for COVID-19 patients with pneumonia: a retrospective study, Eur Respir J, 56, 1, 10.1183/13993003.02113-2020

Chen, 2020, Clinical and immunological features of severe and moderate coronavirus disease 2019, J Clin Invest, 130, 10.1172/JCI137244

Lynch, 2020, Magnitude and kinetics of anti-SARS-CoV-2 antibody responses and their relationship to disease severity, Clin Infect Dis, 1, 10.1101/2020.06.03.20121525

Zhang, 2020, Immune Phenotyping Based on the Neutrophil-to-Lymphocyte Ratio and IgG Level Predicts Disease Severity and Outcome for Patients With COVID-19, Front Mol Biosci, 7, 10.3389/fmolb.2020.00157

Jesenak, 2020, Immune Parameters and COVID-19 Infection - Associations With Clinical Severity and Disease Prognosis, Front Cell Infect Microbiol, 10, 10.3389/fcimb.2020.00364

Hadjadj, 2020, Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients, Science, 369, 10.1126/science.abc6027

Lucas, 2020, Longitudinal analyses reveal immunological misfiring in severe COVID-19, Nature, 584, 10.1038/s41586-020-2588-y

Li, 2018, Marked elevation of circulating CD19(+)CD38(hi)CD24(hi) transitional B cells give protection against neonatal sepsis, Pediatr Neonatol, 59, 296, 10.1016/j.pedneo.2017.10.005

Piper, 2018, CD19(+)CD24(hi)CD38(hi) B Cells Are Expanded in Juvenile Dermatomyositis and Exhibit a Pro-Inflammatory Phenotype After Activation Through Toll-Like Receptor 7 and Interferon-alpha, Front Immunol, 9, 10.3389/fimmu.2018.01372

Sambleben, 2018, Increased proportions of B cells with spontaneous production of interleukin-10 in HIV-infected individuals are normalized during combination antiretroviral therapy: a longitudinal study, APMIS, 126, 10.1111/apm.12795

Wang, 2019, High TLR7 Expression Drives the Expansion of CD19(+)CD24(hi)CD38(hi) Transitional B Cells and Autoantibody Production in SLE Patients, Front Immunol, 10, 10.3389/fimmu.2019.01243

Giltiay, 2019, The Plasticity of Newly Formed B Cells, J Immunol, 203, 10.4049/jimmunol.1900928

Oliviero, 2020, Expansion of atypical memory B cells is a prominent feature of COVID-19, Cell Mol Immunol, 17, 10.1038/s41423-020-00542-2

Kaneko, 2020, Loss of Bcl-6-Expressing T Follicular Helper Cells and Germinal Centers in COVID-19, Cell, 183, 143, 10.1016/j.cell.2020.08.025

Wang, 2020, Characteristics of Peripheral Lymphocyte Subset Alteration in COVID-19 Pneumonia, J Infect Dis, 221, 10.1093/infdis/jiaa150

Garcia-Bates, 2013, Association between magnitude of the virus-specific plasmablast response and disease severity in dengue patients, J Immunol, 190, 10.4049/jimmunol.1103350

Varnaite, 2020, Expansion of SARS-CoV-2-Specific Antibody-Secreting Cells and Generation of Neutralizing Antibodies in Hospitalized COVID-19 Patients, J Immunol, 205, 10.4049/jimmunol.2000717

De Biasi, 2020, Expansion of plasmablasts and loss of memory B cells in peripheral blood from COVID-19 patients with pneumonia, Eur J Immunol, 50, 10.1002/eji.202048838

Mathew, 2020, Deep immune profiling of COVID-19 patients reveals distinct immunotypes with therapeutic implications, Science, 369, 1, 10.1126/science.abc8511

Winslow, 2017, CD11c+ T-bet+ memory B cells: Immune maintenance during chronic infection and inflammation, Cell Immunol, 321, 8, 10.1016/j.cellimm.2017.07.006

Jenks, 2018, Distinct Effector B Cells Induced by Unregulated Toll-like Receptor 7 Contribute to Pathogenic Responses in Systemic Lupus Erythematosus, Immunity, 49, 725, 10.1016/j.immuni.2018.08.015

Aravena, 2017, TIM-1 defines a human regulatory B cell population that is altered in frequency and function in systemic sclerosis patients, Arthritis Res Ther, 19, 8, 10.1186/s13075-016-1213-9

Caldwell, 2001, Differential effects of physiologically relevant hypoxic conditions on T lymphocyte development and effector functions, J Immunol, 167, 10.4049/jimmunol.167.11.6140

Kojima, 2010, Differentiation stage-specific requirement in hypoxia-inducible factor-1alpha-regulated glycolytic pathway during murine B cell development in bone marrow, J Immunol, 184, 10.4049/jimmunol.0800167

Juno, 2020, Humoral and circulating follicular helper T cell responses in recovered patients with COVID-19, Nat Med, 26, 10.1038/s41591-020-0995-0

Huang, 2020, C-reactive protein, procalcitonin, D-dimer, and ferritin in severe coronavirus disease-2019: a meta-analysis, Ther Adv Respir Dis, 14, 10.1177/1753466620937175

Pan, 2020, Factors associated with death outcome in patients with severe coronavirus disease-19 (COVID-19): a case-control study, Int J Med Sci, 17, 10.7150/ijms.46614

Ye, 2020, Dynamic changes of D-dimer and neutrophil-lymphocyte count ratio as prognostic biomarkers in COVID-19, Respir Res, 21, 169, 10.1186/s12931-020-01428-7

Woodruff, 2020, Extrafollicular B cell responses correlate with neutralizing antibodies and morbidity in COVID-19, Nat Immunol, 21, 10.1038/s41590-020-00814-z