scholarly journals Follicular Helper T (TFH) Cell Targeting by TLR8 Signaling For Improving HBsAg-Specific B Cell Response In Chronic Hepatitis B Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Natarajan Ayithan ◽  
Lydia Tang ◽  
Susanna K. Tan ◽  
Diana Chen ◽  
Jeffrey J. Wallin ◽  
...  
Keyword(s):  
Chronic Hepatitis ◽  
B Cells ◽  
Hepatitis B ◽  
B Cell ◽  
Cell Response ◽  
Functional Cure ◽  
Cell Responses ◽  
Follicular Helper ◽  
B Cell Response

Identifying signaling pathways that induce B cell response can aid functional cure strategies for chronic hepatitis B infection (CHB). TLR8 activation with ssRNA was shown to enhance follicular helper T cell (TFH) function leading to improved B cell responses in vitro. We investigated whether this mechanism can rescue an exhausted immune response in CHB infection. Effect of TLR8 agonism on supporting cytokines and TFH and B cells were evaluated using ex vivo and in vitro assays. The ability of an oral TLR8 agonist to promote TFH and B cell response was tested in samples from phase 1b clinical trial. TLR8 agonism induced TFH polarizing cytokine IL-12 in monocytes. Treatment of peripheral blood mononuclear cells (PBMCs) from CHB patients with TLR8 agonists induced cytokine IL-21 by TFH cells with enhanced IL-21+BCL-6+ and ICOS+BCL-6+ co-expression. Mechanistically, incubation of isolated naïve CD4+ T cells with TLR8 triggered monocytes resulted in their differentiation into IL-21+ICOS+BCL-6+ TFH in an IL-12 dependent manner. Furthermore, co-culture of these IL-21 producing TFH with autologous naïve B cells led to enhanced memory (CD19+CD27+) and plasma B cell generation (CD19+CD27++CD38+) and IgG production. Importantly, in TFH from CHB patients treated with an oral TLR8 agonist, HBsAg-specific BCL-6, ICOS, IL-21 and CD40L expression and rescue of defective activation induced marker (AIM) response along with partial restoration of HBsAg-specific B cell ELISPOT response was evident. TLR8 agonism can thus enhance HBV-specific B cell responses in CHB patients by improving monocyte-mediated TFH function and may play a role in achieving HBV functional cure.

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

Blood ◽  
2004 ◽  
Vol 104 (3) ◽  
pp. 752-759 ◽  
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.

scholarly journals Rapid isolation and immune profiling of SARS-CoV-2 specific memory B cell in convalescent COVID-19 patients via LIBRA-seq

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Bing He ◽  
Shuning Liu ◽  
Yuanyuan Wang ◽  
Mengxin Xu ◽  
Wei Cai ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Single Cell ◽  
Cell Response ◽  
Critical Role ◽  
Antigen Specificity ◽  
Memory B Cell ◽  
Specific Memory ◽  
B Cell Response

AbstractB cell response plays a critical role against SARS-CoV-2 infection. However, little is known about the diversity and frequency of the paired SARS-CoV-2 antigen-specific BCR repertoire after SARS-CoV-2 infection. Here, we performed single-cell RNA sequencing and VDJ sequencing using the memory and plasma B cells isolated from five convalescent COVID-19 patients, and analyzed the spectrum and transcriptional heterogeneity of antibody immune responses. Via linking BCR to antigen specificity through sequencing (LIBRA-seq), we identified a distinct activated memory B cell subgroup (CD11chighCD95high) had a higher proportion of SARS-CoV-2 antigen-labeled cells compared with memory B cells. Our results revealed the diversity of paired BCR repertoire and the non-stochastic pairing of SARS-CoV-2 antigen-specific immunoglobulin heavy and light chains after SARS-CoV-2 infection. The public antibody clonotypes were shared by distinct convalescent individuals. Moreover, several antibodies isolated by LIBRA-seq showed high binding affinity against SARS-CoV-2 receptor-binding domain (RBD) or nucleoprotein (NP) via ELISA assay. Two RBD-reactive antibodies C14646P3S and C2767P3S isolated by LIBRA-seq exhibited high neutralizing activities against both pseudotyped and authentic SARS-CoV-2 viruses in vitro. Our study provides fundamental insights into B cell response following SARS-CoV-2 infection at the single-cell level.

scholarly journals Stereotyped B-cell responses are linked to IgG constant region polymorphisms in multiple sclerosis

2021 ◽  
Author(s):  
Ida Lindeman ◽  
Justyna Polak ◽  
Shuo-Wang Qiao ◽  
Trygve Holmøy ◽  
Rune A. Høglund ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
B Cells ◽  
Gene Family ◽  
B Cell ◽  
Cell Response ◽  
Memory B Cells ◽  
Constant Region ◽  
Cell Responses ◽  
B Cell Responses ◽  
B Cell Response

AbstractClonally related B cells infiltrate the brain, meninges and cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients, but the mechanisms driving the B-cell response and shaping the immunoglobulin repertoires remain unclear. Here, we used single-cell full-length RNA-seq and B-cell receptor reconstruction to simultaneously assess the phenotypes, isotypes, constant region polymorphisms, and the paired heavy- and light-chain repertoires in intrathecal B-lineage cells. We detected extensive clonal connections between the memory B cell and antibody-secreting cell (ASC) compartments and observed clonally related cells of different isotypes, including IgM/IgG1, IgG1/IgA1, IgG1/IgG2, and IgM/IgA1. There was a strong dominance of the G1m1 allotype constant region polymorphisms in ASCs, but not in memory B cells. Tightly linked to the G1m1 allotype, we found a preferential pairing of the IGHV4 gene family with the κ variable (IGKV)1 gene family. These results link IgG constant region polymorphisms to stereotyped B-cell responses in MS, indicating that the intrathecal B-cell response in these patients could be directed against structurally similar epitopes. The data also suggest that the dominance of the G1m1 allotype in ASCs may occur as a result of biased differentiation of intrathecal memory B cells.

scholarly journals BNT162b2 Vaccine Induces Divergent B cell responses to SARS-CoV-2 S1 and S2

2021 ◽  
Author(s):  
R Camille Brewer ◽  
Nitya S Ramadoss ◽  
Lauren J Lahey ◽  
William H Robinson ◽  
Tobias V Lanz
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Response ◽  
Messenger Rna ◽  
Vaccine Dose ◽  
S Protein ◽  
Cell Responses ◽  
Novel Variants ◽  
B Cell Responses ◽  
B Cell Response

The first ever messenger RNA (mRNA) vaccines received emergency approvals in December 2020 and are highly protective against SARS-CoV-2. However, the contribution of each dose to the generation of antibodies against SARS-CoV-2 spike (S) protein and the degree of protection against novel variants, including delta, warrant further study. Here, we investigated the B cell response to the BNT162b2 vaccine by integrating repertoire analysis with single-cell transcriptomics of B cells from serial blood collections pre- and post-vaccination. The first vaccine dose elicits highly mutated IgA+ plasmablasts against the S protein subunit S2 at day 7, suggestive of recall of a memory B cell response generated by prior infections with heterologous coronaviruses. On day 21, we observed minimally-mutated IgG+ activated switched memory B cells targeting the receptor binding domain (RBD) of the S protein, likely representing a primary response derived from naive B cells. The B cell response against RBD is specifically boosted by the second vaccine dose, and encodes antibodies that potently neutralize SARS-CoV-2 pseudovirus and partially neutralize novel variants, including delta. These results demonstrate that the first vaccine dose activates a non-neutralizing recall response predominantly targeting S2, while the second vaccine dose is vital to boosting neutralizing anti-S1 RBD B cell responses.

scholarly journals SAT0297 DIFFERENTIAL PHENOTYPES OF DISEASE-SPECIFIC AUTO-REACTIVE B CELL RESPONSES IN PATIENTS WITH SYSTEMIC SCLEROSIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1093.2-1094
Author(s):  
C. Wortel ◽  
N. Van Leeuwen ◽  
M. Boonstra ◽  
R. Toes ◽  
T. Huizinga ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
B Cells ◽  
B Cell ◽  
Cell Response ◽  
Mononuclear Cells ◽  
Research Support ◽  
Cell Responses ◽  
B Cell Responses ◽  
Spontaneous Secretion ◽  
B Cell Response

Background:Systemic Sclerosis (SSc) carries the highest mortality burden among the rheumatic diseases. >95% of SSc patients harbor autoantibodies. Anti-topoisomerase antibodies (ATA) and anti-centromere antibodies (ACA) are most prevalent, mutually exclusive in individual patients, associate with distinct disease phenotypes and predict disease. Whether and how these auto-reactive B cell responses contribute to disease, however, is currently unclear.Objectives:To delineate phenotypic and functional characteristics of anti-topoisomerase and anti-centromere specific B cell responses in individual patients with SSc.Methods:Peripheral blood mononuclear cells (PBMC) obtained from ATA- and ACA-positive SSc patients were cultured without stimulation or in the presence of CD40L-expressing fibroblasts, IL-21 and BAFF. In addition, PBMC were depleted of circulating plasmablasts (CD19+CD20-CD27++) by fluorescence activated cell sorting (FACS), and isolated plasmablasts were cultured separately. ATA- and ACA-IgG and -IgA were measured in culture supernatants by ELISA. B cell subsets were defined by flow cytometry. Healthy donors and patients with rheumatoid arthritis served as controls.Results:We observed that ATA- and ACA-positive SSc patients harbour circulating B cells that secrete either ATA-IgG or ACA-IgG upon stimulation, depending on their serotype. In addition, we noted spontaneous secretion of ATA-IgG and, more remarkably, extensive secretion of ATA-IgA in ATA-positive patients. This degree of spontaneous, antigen-specific IgA secretion was specific for the ATA response in ATA-positive patients, while spontaneous ACA-IgA secretion was undetectable in the ACA-positive patient group. FACS experiments showed that spontaneously ATA-IgA secreting B cells were primarily present in the plasmablast compartment.Conclusion:Our findings demonstrate that ATA-positive SSc patients harbour an activated ATA-IgG and ATA-IgA B cell response, as indicated by the spontaneous secretion of both ATA isotypes by circulating plasmablasts. Remarkably, the ACA B cell response was far less active and lacked the active IgA component which suggests a difference in the triggers driving these autoreactive B cell responses in patients. Moreover, the remarkable ATA-IgA secretion points towards a potential mucosal origin of the ATA response.Disclosure of Interests:Corrie Wortel: None declared, Nina van Leeuwen: None declared, Maaike Boonstra: None declared, Rene Toes: None declared, Thomas Huizinga Grant/research support from: Ablynx, Bristol-Myers Squibb, Roche, Sanofi, Consultant of: Ablynx, Bristol-Myers Squibb, Roche, Sanofi, Jeska de Vries-Bouwstra: None declared, Hans Ulrich Scherer Grant/research support from: Bristol Myers Squibb, Sanofi, Pfizer, Speakers bureau: Pfizer, Lilly, Roche, Abbvie

scholarly journals Lethal Coinfection of Influenza Virus and Streptococcus pneumoniae Lowers Antibody Response to Influenza Virus in Lung and Reduces Numbers of Germinal Center B Cells, T Follicular Helper Cells, and Plasma Cells in Mediastinal Lymph Node

2014 ◽  
Vol 89 (4) ◽  
pp. 2013-2023 ◽  
Author(s):  
Yuet Wu ◽  
Wenwei Tu ◽  
Kwok-Tai Lam ◽  
Kin-Hung Chow ◽  
Pak-Leung Ho ◽  
...  
Keyword(s):  
Influenza Virus ◽  
B Cells ◽  
Virus Infection ◽  
B Cell ◽  
Cell Response ◽  
Plasma Cells ◽  
Pneumococcal Infection ◽  
Influenza Virus Infection ◽  
Follicular Helper ◽  
B Cell Response

ABSTRACTSecondaryStreptococcus pneumoniaeinfection after influenza is a significant clinical complication resulting in morbidity and sometimes mortality. Prior influenza virus infection has been demonstrated to impair the macrophage and neutrophil response to the subsequent pneumococcal infection. In contrast, how a secondary pneumococcal infection after influenza can affect the adaptive immune response to the initial influenza virus infection is less well understood. Therefore, this study focuses on how secondary pneumococcal infection after influenza may impact the humoral immune response to the initial influenza virus infection in a lethal coinfection mouse model. Compared to mice infected with influenza virus alone, mice coinfected with influenza virus followed by pneumococcus had significant body weight loss and 100% mortality. In the lung, lethal coinfection significantly increased virus titers and bacterial cell counts and decreased the level of virus-specific IgG, IgM, and IgA, as well as the number of B cells, CD4 T cells, and plasma cells. Lethal coinfection significantly reduced the size and weight of spleen, as well as the number of B cells along the follicular developmental lineage. In mediastinal lymph nodes, lethal coinfection significantly decreased germinal center B cells, T follicular helper cells, and plasma cells. Adoptive transfer of influenza virus-specific immune serum to coinfected mice improved survival, suggesting the protective functions of anti-influenza virus antibodies. In conclusion, coinfection reduced the B cell response to influenza virus. This study helps us to understand the modulation of the B cell response to influenza virus during a lethal coinfection.IMPORTANCESecondary pneumococcal infection after influenza virus infection is an important clinical issue that often results in excess mortality. Since antibodies are key mediators of protection, this study aims to examine the antibody response to influenza virus and demonstrates that lethal coinfection reduced the B cell response to influenza virus. This study helps to highlight the complexity of the modulation of the B cell response in the context of coinfection.

scholarly journals IL-21–Deficient T Follicular Helper Cells Support B Cell Responses Through IL-27 in Patients With Chronic Hepatitis B

2021 ◽  
Vol 11 ◽  
Author(s):  
Arshi Khanam ◽  
Natarajan Ayithan ◽  
Lydia Tang ◽  
Bhawna Poonia ◽  
Shyam Kottilil
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis B ◽  
B Cell ◽  
Chronic Hepatitis B ◽  
Neutralizing Antibodies ◽  
Cell Function ◽  
Viral Clearance ◽  
Cell Responses ◽  
Follicular Helper ◽  
B Cell Responses

Chronic Hepatitis B (CHB) affects over 350 million people worldwide. Current treatment does result in reduced complications; however, a cure (development of antibodies to the S antigen) is not achieved, requiring life-long therapy. Humoral responses contribute to viral elimination by secreting neutralizing antibodies; though, effective induction of humoral immunity require CD4T cell differentiation into T follicular helper (TFH) cells that support B cell response through interleukin-21 (IL-21). In CHB, mechanism of TFH-B interactions is seldom described. During CHB, TFH cells are defective in producing IL-21 in response to hepatitis B surface antigen (HBsAg). However, regardless of low IL-21, TFH cells efficiently support B cell responses by producing interleukin-27 (IL-27), which directs the formation of plasmablasts and plasma cells from memory and naïve B cells by enhancing B lymphocyte-induced maturation protein-1. IL-27 not only improved total antibody production but HBsAg-specific IgG and IgM secretion that are essential for viral clearance. Importantly, IL-27+TFH cells were significantly associated with HBV DNA reduction. Therefore, these findings imply a novel mechanism of TFH mediated B cell help in CHB and suggest that IL-27 effectively compensate the function of IL-21 by supporting TFH-B cell function, required for protective antibody response and may contribute to viral clearance by providing potential target for achieving a functional cure.

scholarly journals Hemolysis Inhibits Humoral B Cell Responses and Modulates Alloimmunization Risk in Patients with Sickle Cell Disease

Blood ◽  
2020 ◽  
Author(s):  
Mouli Pal ◽  
Weili Bao ◽  
Rikang Wang ◽  
Yunfeng Liu ◽  
Xiuli An ◽  
...  
Keyword(s):  
B Cells ◽  
Sickle Cell Disease ◽  
B Cell ◽  
Sickle Cell ◽  
Cell Response ◽  
Cell Activity ◽  
Immunomodulatory Activity ◽  
Heme Oxygenase 1 ◽  
Cell Disease ◽  
B Cell Response

Red blood cell alloimmunization remains a barrier for safe and effective transfusions in sickle cell disease (SCD), but the associated risk factors remain largely unknown. Intravascular hemolysis, a hallmark of SCD, results in the release of heme with potent immunomodulatory activity, although its effect on SCD humoral response, specifically alloimmunization, remains unclear. Here, we found that cell-free heme suppresses human B cell plasmablast/plasma cell differentiation by inhibiting the DOCK8/STAT3 signaling pathway, which is critical for B cell activation, as well as by upregulating heme oxygenase 1 (HO-1) through its enzymatic byproducts, carbon monoxide and biliverdin. Whereas non-alloimmunized SCD B cells were inhibited by exogenous heme, B cells from the alloimmunized group were non-responsive to heme inhibition and readily differentiated into plasma cells. Consistent with a differential B cell response to hemolysis, we found elevated B cell basal levels of DOCK8 and higher HO-1-mediated inhibition of activated B cells in non-alloimmunized compared to alloimmunized SCD patients. To overcome the alloimmunized B cell heme insensitivity, we screened several heme-binding molecules and identified quinine as a potent inhibitor of B cell activity, reversing the resistance to heme suppression in alloimmunized patients. B cell inhibition by quinine only occurred in the presence of heme and through HO-1 induction. Altogether, these data suggest that hemolysis can dampen the humoral B cell response and that B cell heme responsiveness maybe a determinant of alloimmunization risk in SCD. Quinine by restoring B cell heme sensitivity may have therapeutic potential to prevent and inhibit alloimmunization in SCD patients.

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