Biomarkers and Immune Repertoire Metrics Identified by Peripheral Blood Transcriptomic Sequencing Reveal the Pathogenesis of COVID-19

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a global crisis; however, our current understanding of the host immune response to SARS-CoV-2 infection remains limited. Herein, we performed RNA sequencing using peripheral blood from acute and convalescent patients and interrogated the dynamic changes of adaptive immune response to SARS-CoV-2 infection over time. Our results revealed numerous alterations in these cohorts in terms of gene expression profiles and the features of immune repertoire. Moreover, a machine learning method was developed and resulted in the identification of five independent biomarkers and a collection of biomarkers that could accurately differentiate and predict the development of COVID-19. Interestingly, the increased expression of one of these biomarkers, UCHL1, a molecule related to nervous system damage, was associated with the clustering of severe symptoms. Importantly, analyses on immune repertoire metrics revealed the distinct kinetics of T-cell and B-cell responses to SARS-CoV-2 infection, with B-cell response plateaued in the acute phase and declined thereafter, whereas T-cell response can be maintained for up to 6 months post-infection onset and T-cell clonality was positively correlated with the serum level of anti-SARS-CoV-2 IgG. Together, the significantly altered genes or biomarkers, as well as the abnormally high levels of B-cell response in acute infection, may contribute to the pathogenesis of COVID-19 through mediating inflammation and immune responses, whereas prolonged T-cell response in the convalescents might help these patients in preventing reinfection. Thus, our findings could provide insight into the underlying molecular mechanism of host immune response to COVID-19 and facilitate the development of novel therapeutic strategies and effective vaccines.

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Rituximab impairs B‐cell response but not T‐cell response to COVID ‐19 vaccine in auto‐immune diseases

Arthritis & Rheumatology ◽

10.1002/art.42058 ◽

2021 ◽

Author(s):

Samuel Bitoun ◽

Julien Henry ◽

Delphine Desjardins ◽

Christelle Vauloup‐Fellous ◽

Nicolas Dib ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

Cell Response ◽

T Cell Response ◽

B Cell Response

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Rapid T Cell Response to Vaccination Can Occur without Antibody Response in Children Post HSCT.

Blood ◽

10.1182/blood.v104.11.2235.2235 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2235-2235

Author(s):

W. Nicholas Haining ◽

J. Evans ◽

N. Seth ◽

G. Callaway ◽

K. Wucherpfennig ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

Cell Response ◽

Influenza A ◽

T Cell Response ◽

T Cell Memory ◽

Cell Immunity ◽

Before And After ◽

B Cell Response

Abstract Vaccination is widely used to improve pathogen-specific immunity in patients post HSCT, but it is not known whether patients can mount an effective T cell response to vaccine antigens (vAg). Moreover the relationship between T and B cell response to vAg has not been studied. We hypothesized that a sufficiently sensitive assay of T cell response to vAg would allow vaccination to be used as a tool to measure immune recovery post HSCT and improve vaccine design. We therefore: (1) developed a flow-cytometry-based approach to quantify and characterize T cells specific for vAg; (2) validated it by measuring T cell immunity to influenza A in normal donors; and (3) characterized the T and B cell response to influenza vaccination in pediatric HSCT patients. PBMC were labeled with CFSE and stimulated in vitro with whole influenza Ag. Ag-specific T cells were sensitively detected by their proliferation (loss of CFSE fluorescence) and simultaneous expression of the activation marker HLA-DR. Proliferating/active T cells could be readily detected after stimulation with influenza A Ag in healthy adult (n=4) and pediatric (n=19) donors but were absent in control conditions. Both CD4+ and CD8+ T cell proliferation was detected in all donors but one, and in children as young as 6mo. Staining with MHC I- and MHC II-tetramers confirmed that the proliferating/active population contained T cells specific for immunodominant CD8+ and CD4+ epitopes, demonstrating that vAg were processed and presented to epitope-specific T cells. To characterize the phenotype of influenza-specific T cell memory, we separated memory and naive CD4+ cells prior to antigen-stimulation. Antigen-experienced (CD45RA−/CCR7−) but not naive (CD45RA+/CCR7+) T cells proliferated to vAg confirming that the assay detected pre-existing influenza-A-specific T cell memory. We next assessed Influenza-A-specific T cell immunity before and after influenza vaccination in five pediatric HSCT recipients (mean age 10.6y, range 5–15y; mean time from transplant 13m, range 3–21m). Prior to vaccination the CD4 proliferation to influenza-A was a mean of 3.3% (range 0.04–11%). Following vaccination CD4 proliferation increased significantly in all patients (mean 19.0%, range 6.9%–31.8%, p=0.02). This increase was specific as proliferation to control Ag was unchanged. Influenza-A CD8+ proliferation also increased in 3 of 5 patients but was not statistically significant for the group consistent with the limited efficacy of soluble vAg in inducing CD8+ T cell response. All patients had detectable influenza-A-specific IgG levels prior to vaccination but despite a T cell response to vaccination in all patients, none had a significant increase in IgG level following vaccination. Only one patient had an IgM response; this patient also had the highest influenza-A-specific CD4 proliferation before and after immunization suggesting that there may be a threshold of T cell response required for a B cell response. Using a novel assay we demonstrate that a T cell response to vaccination can occur without an accompanying B cell response. This assay provides a more sensitive measure of immunity to vaccination and allows vaccine response to be used as a benchmark of strategies to accelerate post-HSCT T cell reconstitution.

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Germ line tumor-associated immunoglobulin VH region peptides provoke a tumor-specific immune response without altering the response potential of normal B cells

Blood ◽

10.1182/blood-2004-01-0105 ◽

2004 ◽

Vol 104 (3) ◽

pp. 752-759 ◽

Cited By ~ 9

Author(s):

Qiang Lou ◽

Raymond J. Kelleher ◽

Alessandro Sette ◽

Jenni Loyall ◽

Scott Southwood ◽

...

Keyword(s):

Immune Response ◽

B Cells ◽

B Cell ◽

Cell Response ◽

Germ Line ◽

T Cell Response ◽

Binding Potential ◽

Variable Regions ◽

B Cell Response

AbstractPrevious studies have suggested that murine T cells are tolerant to epitopes derived from germ line variable regions of immunoglobulin (Ig) heavy (VH) or light chains. This has lead to the prediction that germ line VH-region epitopes found in neoplastic B cells cannot be used to provoke an antitumor immune response. To test these assumptions and address the question of how such a vaccine may alter the normal B-cell response, an antibody-forming B-cell hybridoma (1H6) expressing a conserved germ line VH gene with specificity for dextran was generated and used as a tumor model. Using algorithms for predicting major histocompatibility complex (MHC) binding, potential MHC class I and II binding peptides were identified within the 1H6 VH region, synthesized, and tested for MHC binding and immunogenicity. We show that germ line VH peptides, when presented by dendritic cells, are immunogenic in vitro and provoke a tumor-specific protective immune response in vivo. We conclude that (1) it is possible to induce a T-cell response to germ line VH peptides; (2) such peptides can be used to generate a B-cell tumor-specific vaccine; and (3) a vaccine targeting VH peptides expressed by the dominant dextran-specific B-cell clonotype had no effect upon the magnitude of the normal B-cell response to dextran.

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The mycobacterial glycolipid glucose monomycolate induces a memory T cell response comparable to a model protein antigen and no B cell response upon experimental vaccination of cattle

Vaccine ◽

10.1016/j.vaccine.2009.05.078 ◽

2009 ◽

Vol 27 (35) ◽

pp. 4818-4825 ◽

Cited By ~ 21

Author(s):

Thi Kim Anh Nguyen ◽

Ad P. Koets ◽

Wiebren J. Santema ◽

Willem van Eden ◽

Victor P.M.G. Rutten ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

Cell Response ◽

T Cell Response ◽

Protein Antigen ◽

Memory T Cell ◽

Model Protein ◽

B Cell Response

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REGULATION OF THE IMMUNE RESPONSE

Journal of Experimental Medicine ◽

10.1084/jem.137.6.1325 ◽

1973 ◽

Vol 137 (6) ◽

pp. 1325-1337 ◽

Cited By ~ 11

Author(s):

John W. Kappler ◽

Michael Hoffmann

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

Cell Response ◽

Cellular Proliferation ◽

Plaque Assay ◽

Cell Activity ◽

T Cell Response ◽

Vitro Assay ◽

B Cell Response

The kinetics of the in vivo response to SRBC was studied in mouse spleen at both the B cell and T cell levels. The B cell response was assayed by following the appearance of antibody-secreting cells in the spleen using the hemolytic plaque assay. The T cell response was monitored by following the increase in or "priming" of helper activity in the spleen using a quantitative in vitro assay. The role of cellular proliferation in both responses was established with the inhibitor of mitosis, vinblastine. The results show that, although the development of T cell activity precedes that of anti-SRBC PFC by as much as 1 day, T cells lag at least 1 day behind B cells in the onset of cellular proliferation. The evidence suggests either that the helper T cell which proliferates in response to SRBC does so after helping in the initiation of the primary B cell response or that the proliferative T cell response and the initiation of the primary B cell response involve two different subpopulations of T cells.

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Nano-Microparticle Platforms in Developing Next-Generation Vaccines

Vaccines ◽

10.3390/vaccines9060606 ◽

2021 ◽

Vol 9 (6) ◽

pp. 606

Author(s):

Giuseppe Cappellano ◽

Hugo Abreu ◽

Chiara Casale ◽

Umberto Dianzani ◽

Annalisa Chiocchetti

Keyword(s):

Immune Response ◽

T Cell ◽

Cell Response ◽

Humoral Response ◽

Cd8 T Cell ◽

T Cell Response ◽

Next Generation ◽

Emerging Viruses ◽

Whole Cells ◽

Effector Functions

The first vaccines ever made were based on live-attenuated or inactivated pathogens, either whole cells or fragments. Although these vaccines required the co-administration of antigens with adjuvants to induce a strong humoral response, they could only elicit a poor CD8+ T-cell response. In contrast, next-generation nano/microparticle-based vaccines offer several advantages over traditional ones because they can induce a more potent CD8+ T-cell response and, at the same time, are ideal carriers for proteins, adjuvants, and nucleic acids. The fact that these nanocarriers can be loaded with molecules able to modulate the immune response by inducing different effector functions and regulatory activities makes them ideal tools for inverse vaccination, whose goal is to shut down the immune response in autoimmune diseases. Poly (lactic-co-glycolic acid) (PLGA) and liposomes are biocompatible materials approved by the Food and Drug Administration (FDA) for clinical use and are, therefore, suitable for nanoparticle-based vaccines. Recently, another candidate platform for innovative vaccines based on extracellular vesicles (EVs) has been shown to efficiently co-deliver antigens and adjuvants. This review will discuss the potential use of PLGA-NPs, liposomes, and EVs as carriers of peptides, adjuvants, mRNA, and DNA for the development of next-generation vaccines against endemic and emerging viruses in light of the recent COVID-19 pandemic.

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The immune response against myelin basic protein in two strains of rat with different genetic capacity to develop experimental allergic encephalomyelitis.

Journal of Experimental Medicine ◽

10.1084/jem.141.1.72 ◽

1975 ◽

Vol 141 (1) ◽

pp. 72-81 ◽

Cited By ~ 61

Author(s):

D E McFarlin ◽

S C Hsu ◽

S B Slemenda ◽

F C Chou ◽

R F Kibler

Keyword(s):

Immune Response ◽

T Cell ◽

Experimental Allergic Encephalomyelitis ◽

Cell Response ◽

Basic Protein ◽

T Cell Response ◽

Skin Tests ◽

Allergic Encephalomyelitis ◽

Experimental Allergic

After challenge with guiena pig basic protein (GPBP) Lewis (Le) rats, which are homozygous for the immune response experimental allergic encephalomyelitis (Ir-EAE) gene, developed positive delayed skin tests against GPBP and the 43 residue encephalitogenic fragment (EF); in addition, Le rat lymph node cells (LNC) were stimulated and produced migration inhibitory factor (MIF) when incubated in vitro with these antigens. In contrast Brown Norway (BN) rats, which lack the Ir-EAE gene, did not develop delayed skin tests to EF and their LNC were not stimulated and did not produce MIF when incubated in vitro with EF. These observations indicate that the Ir-EAE gene controls a T-cell response against the EF. Le rats produced measurable anti-BP antibody by radioimmunoassay after primary challenge. Although no antibody was detectable in BN rats by radioimmunoassay, radioimmunoelectrophoresis indicated that a small amount of antibody was formed after primary immunization. After boosting intraperitoneally, both strains of rat exhibited a rise in anti-BP antibody; which was greater in Le rats. In both strains of rat the anti-BP antibody reacted with a portion of the molecule other than the EF. Since EF primarily evokes a T cell response, it is suggested that the EF portion of the BP molecule may contain a helper determinant in antibody production.

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B cell activation by cytomegalovirus.

Journal of Experimental Medicine ◽

10.1084/jem.158.6.2171 ◽

1983 ◽

Vol 158 (6) ◽

pp. 2171-2176 ◽

Cited By ~ 39

Author(s):

L M Hutt-Fletcher ◽

N Balachandran ◽

M H Elkins

Keyword(s):

T Cell ◽

B Cell ◽

Virus Replication ◽

Human Cytomegalovirus ◽

Cell Response ◽

Cell Activation ◽

B Cell Activation ◽

T Cell Help ◽

Cell Activator ◽

B Cell Response

Human cytomegalovirus is shown to be a nonspecific polyclonal B cell activator. The B cell response is independent of virus replication and requires little, if any, T cell help.

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