scholarly journals Defective Toll-Like Receptors Driven B Cell Response in Hyper IgE Syndrome Patients With STAT3 Mutations

2021 ◽  
Vol 9 ◽  
Author(s):  
Ruolan Gong ◽  
Jing Wu ◽  
Yingying Jin ◽  
Tongxin Chen
Keyword(s):  
B Cell ◽  
Cell Response ◽  
Gene Mutations ◽  
Toll Like Receptor ◽  
Cell Responses ◽  
Hyper Ige Syndrome ◽  
Class Switch ◽  
Cell Class ◽  
Stat3 Mutations ◽  
B Cell Response

Autosomal dominant hyper-IgE syndrome (AD-HIES) is a rare inherited primary immunodeficient disease (PIDs), which is caused by STAT3 gene mutations. Previous studies indicated a defective Toll-like receptor (TLR) 9-induced B cell response in AD-HIES patients, including proliferation, and IgG production. However, the other TLRs-mediated B cell responses in AD-HIES patients were not fully elucidated. In this study, we systematically studied the B cell response to TLRs signaling pathways in AD-HIES patients, including proliferation, activation, apoptosis, cytokine, and immunoglobulin production. Our results showed that the TLRs-induced B cell proliferation and activation was significantly impaired in AD-HIES patients. Besides, AD-HIES patients had defects in TLRs-induced B cell class switch, as well as IgG/IgM secretion and IL-10 production in B cells. Taken together, we first systematically reported the deficiency of TLRs driven B cell response in AD-HIES patients, which help to have a better understanding of the pathology of AD-HIES.

scholarly journals Insights into the regulatory mechanism controlling the inhibition of vaccine-induced seroconversion by maternal antibodies

Blood ◽  
2011 ◽  
Vol 117 (23) ◽  
pp. 6143-6151 ◽  
Author(s):  
Dhohyung Kim ◽  
Devra Huey ◽  
Michael Oglesbee ◽  
Stefan Niewiesk
Keyword(s):  
B Cell ◽  
Cell Response ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Maternal Antibodies ◽  
Cross Linking ◽  
Complement Protein ◽  
Cell Responses ◽  
B Cell Responses ◽  
B Cell Response

AbstractThe inhibition of vaccination by maternal antibodies is a widely observed phenomenon in human and veterinary medicine. Maternal antibodies are known to suppress the B-cell response. This is similar to antibody feedback mechanism studies where passively transferred antibody inhibits the B-cell response against particulate antigens because of epitope masking. In the absence of experimental data addressing the mechanism underlying inhibition by maternal antibodies, it has been suggested that epitope masking explains the inhibition by maternal antibodies, too. Here we report that in the cotton rat model of measles virus (MV) vaccination passively transferred MV-specific immunoglobulin G inhibit B-cell responses through cross-linking of the B-cell receptor with FcγRIIB. The extent of inhibition increases with the number of antibodies engaging FcγRIIB and depends on the Fc region of antibody and its isotype. This inhibition can be partially overcome by injection of MV-specific monoclonal IgM antibody. IgM stimulates the B-cell directly through cross-linking the B-cell receptor via complement protein 3d and antigen to the complement receptor 2 signaling complex. These data demonstrate that maternal antibodies inhibit B-cell responses by interaction with the inhibitory/regulatory FcγRIIB receptor and not through epitope masking.

scholarly journals Longitudinal dynamics of the human B cell response to the yellow fever 17D vaccine

2020 ◽  
Vol 117 (12) ◽  
pp. 6675-6685 ◽  
Author(s):  
Anna Z. Wec ◽  
Denise Haslwanter ◽  
Yasmina N. Abdiche ◽  
Laila Shehata ◽  
Nuria Pedreño-Lopez ◽  
...  
Keyword(s):  
B Cell ◽  
Yellow Fever ◽  
Cell Response ◽  
Affinity Maturation ◽  
Immunoglobulin M ◽  
Viral Envelope ◽  
Cell Responses ◽  
B Cell Responses ◽  
Human B Cell ◽  
B Cell Response

A comprehensive understanding of the development and evolution of human B cell responses induced by pathogen exposure will facilitate the design of next-generation vaccines. Here, we utilized a high-throughput single B cell cloning technology to longitudinally track the human B cell response to the yellow fever virus 17D (YFV-17D) vaccine. The early memory B cell (MBC) response was mediated by both classical immunoglobulin M (IgM) (IgM+CD27+) and switched immunoglobulin (swIg+) MBC populations; however, classical IgM MBCs waned rapidly, whereas swIg+and atypical IgM+and IgD+MBCs were stable over time. Affinity maturation continued for 6 to 9 mo following vaccination, providing evidence for the persistence of germinal center activity long after the period of active viral replication in peripheral blood. Finally, a substantial fraction of the neutralizing antibody response was mediated by public clones that recognize a fusion loop-proximal antigenic site within domain II of the viral envelope glycoprotein. Overall, our findings provide a framework for understanding the dynamics and complexity of human B cell responses elicited by infection and vaccination.

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 POS0001 PHENOTYPE AND FUNCTIONAL CHARACTERISTICS OF ANTIGEN-SPECIFIC, AUTO-REACTIVE B CELL RESPONSES REVEAL DIFFERENTIAL IMMUNOLOGICAL ACTIVITY IN PATIENTS WITH SYSTEMIC SCLEROSIS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 203.3-203
Author(s):  
C. Wortel ◽  
N. Van Leeuwen ◽  
S. Liem ◽  
M. Boonstra ◽  
C. Fehres ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
B Cell ◽  
Cell Response ◽  
Functional Characteristics ◽  
Targeted Interventions ◽  
Cell Responses ◽  
B Cell Responses ◽  
Spontaneous Secretion ◽  
Igg Secretion ◽  
B Cell Response

Background:Systemic Sclerosis (SSc) is a systemic autoimmune disease that carries the highest mortality burden among the rheumatic diseases. Disease risk and course are difficult to predict in individual patients, and anti-inflammatory and B-cell depleting therapies show varying results. >95% of SSc patients harbor autoantibodies. Among those, anti-topoisomerase antibodies (ATA) and anti-centromere antibodies (ACA) are most prevalent, mutually exclusive in individual patients and associate with distinct disease phenotypes. Despite these associations, the clinical value of both ATA and ACA for patient stratification within these phenotypes is limited. Here, we hypothesized that phenotypic and functional characteristics of the underlying autoreactive B cell responses could allow insights in differential ‘immunological disease activity’ in individual patients, thereby providing indications as to potential drivers of these responses as well as granularity as to which patients may benefit from targeted interventions.Objectives:To assess phenotypic and functional characteristics of anti-topoisomerase and anticentromere specific B cell responses in individual patients with SSc.Methods:Peripheral blood mononuclear cells (PBMC) from ATA- and ACA-positive SSc patients were cultured without stimulation or in the presence of CD40L-expressing fibroblasts, IL-21 and BAFF. Following culture, ATA- and ACA-IgG and -IgA were measured in culture supernatants by ELISA. In addition, PBMC were depleted of circulating plasmablasts by fluorescence activated cell sorting (FACS), and isolated plasmablasts were cultured separately. Furthermore, the presence of antigen-specific plasmablasts was confirmed by ELISPOT. Finally, the degree of spontaneous ATA secretion was correlated to the presence or absence of interstitial lung disease (ILD; based on high-resolution computed tomography). Healthy donors and patients with rheumatoid arthritis served as controls.Results:We observed that individual ATA- and ACA-positive SSc patients harbored 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, while spontaneous ACA-IgA secretion was undetectable in patients harboring ACA. FACS experiments and ELISPOT showed that the spontaneous ATA-IgA and -IgG secretion was attributable to circulating plasmablasts. Of note, the degree of spontaneous ATA-IgG secretion was remarkably higher in patients with ILD than in those without.Conclusion:Our findings demonstrate that individual ATA-positive SSc patients harbor activated ATA-IgG and ATA-IgA B cell responses, as indicated by the spontaneous secretion of both ATA isotypes by circulating plasmablasts. Importantly, by taking the presence of plasmablasts as a proxy for recent B cell activation, our data suggest a link between the activity of the antigen-specific B cell response and the presence of ILD. In contrast, 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. In fact, the remarkable ATA-IgA secretion points towards a potential mucosal trigger of the ATA response, which may be continuously active in individual patients.Disclosure of Interests:None declared.

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 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 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.

scholarly journals CD72 negatively regulates B lymphocyte responses to the lupus-related endogenous toll-like receptor 7 ligand Sm/RNP

2016 ◽  
Vol 213 (12) ◽  
pp. 2691-2706 ◽  
Author(s):  
Chizuru Akatsu ◽  
Kenro Shinagawa ◽  
Nobutaka Numoto ◽  
Zhihong Liu ◽  
Ayse Konuskan Ucar ◽  
...  
Keyword(s):  
B Cell ◽  
Lupus Erythematosus ◽  
Cell Response ◽  
B Lymphocyte ◽  
Crystallographic Analysis ◽  
Autoimmune Response ◽  
Toll Like Receptor ◽  
Lymphocyte Responses ◽  
Tlr7 Ligand ◽  
B Cell Response

Toll-like receptor 7 (TLR7) plays an essential role in development of systemic lupus erythematosus by co-stimulating B cells reactive to the endogenous TLR7 ligand Sm/ribonucleoprotein (RNP), a crucial lupus self-antigen. However, how the TLR7-mediated autoimmune response is regulated is not yet known. In this study, we demonstrate that CD72, an inhibitory B cell co-receptor known to prevent development of lupus, recognizes Sm/RNP at the extracellular C-type lectin-like domain (CTLD) and specifically inhibits B cell response to Sm/RNP. Moreover, the CTLD of CD72c, a lupus-susceptible allele, binds to Sm/RNP less strongly than that of lupus-resistant CD72a. Reduced binding of CD72c is supported by x-ray crystallographic analysis that reveals a considerable alteration in charge at the putative ligand-binding site. Thus, CD72 appears to specifically inhibit B cell response to the endogenous TLR7 ligand Sm/RNP through CTLD-mediated recognition of Sm/RNP, thereby preventing production of anti-Sm/RNP antibody crucial for development of lupus.

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