Faculty Opinions recommendation of B cell-intrinsic signaling through IL-21 receptor and STAT3 is required for establishing long-lived antibody responses in humans.

Abstract Background Aging is associated with increased intrinsic B cell inflammation, decreased protective antibody responses and increased autoimmune antibody responses. The effects of aging on the metabolic phenotype of B cells and on the metabolic programs that lead to the secretion of protective versus autoimmune antibodies are not known. Methods Splenic B cells and the major splenic B cell subsets, Follicular (FO) and Age-associated B cells (ABCs), were isolated from the spleens of young and old mice and left unstimulated. The RNA was collected to measure the expression of markers associated with intrinsic inflammation and autoimmune antibody production by qPCR. B cells and B cell subsets were also stimulated with CpG and supernatants collected after 7 days to measure autoimmune IgG secretion by ELISA. Metabolic measures (oxygen consumption rate, extracellular acidification rate and glucose uptake) were performed using a Seahorse XFp extracellular flux analyzer. Results Results have identified the subset of ABCs, whose frequencies and numbers increase with age and represent the most pro-inflammatory B cell subset, as the cell type mainly if not exclusively responsible for the expression of inflammatory markers and for the secretion of autoimmune antibodies in the spleen of old mice. Hyper-inflammatory ABCs from old mice are also hyper-metabolic, as compared to those from young mice and to the subset of FO B cells, a feature needed not only to support their higher expression of RNA for inflammatory markers but also their higher autoimmune antibody secretion. Conclusions These results identify a relationship between intrinsic inflammation, metabolism and autoimmune B cells and suggest possible ways to understand cellular mechanisms that lead to the generation of pathogenic B cells, that are hyper-inflammatory and hyper-metabolic, and secrete IgG antibodies with autoimmune specificities.

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Two Cases of Severe Tick-Borne Encephalitis in Rituximab-Treated Patients in Germany: Implications for Diagnosis and Prevention

Open Forum Infectious Diseases ◽

10.1093/ofid/ofx204 ◽

2017 ◽

Vol 4 (4) ◽

Cited By ~ 5

Author(s):

Philipp A Steininger ◽

Tobias Bobinger ◽

Wenke Dietrich ◽

De-Hyung Lee ◽

Michael Knott ◽

...

Keyword(s):

Autoimmune Diseases ◽

B Cell ◽

Standard Therapy ◽

Laboratory Diagnosis ◽

Antibody Responses ◽

B Cell Malignancies ◽

Tick Borne Encephalitis ◽

Preventive Vaccination ◽

Tick Borne Encephalitis Virus ◽

Tbev Infection

Abstract Rituximab (RTX) has become a standard therapy for certain B cell malignancies and autoimmune diseases. We report 2 RTX-treated patients who developed severe tick-borne encephalitis virus (TBEV) infection. The inability to generate new antibody responses renders RTX-treated patients susceptible to TBEV, impedes laboratory diagnosis, and necessitates preventive vaccination in endemic areas.

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Polymorphisms in B Cell Co-Stimulatory Genes Are Associated with IgG Antibody Responses against Blood–Stage Proteins of Plasmodium vivax

PLoS ONE ◽

10.1371/journal.pone.0149581 ◽

2016 ◽

Vol 11 (2) ◽

pp. e0149581 ◽

Cited By ~ 7

Author(s):

Gustavo C. Cassiano ◽

Adriana A. C. Furini ◽

Marcela P. Capobianco ◽

Luciane M. Storti-Melo ◽

Maristela G. Cunha ◽

...

Keyword(s):

B Cell ◽

Plasmodium Vivax ◽

Antibody Responses ◽

Blood Stage ◽

Igg Antibody

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Optimizing oral vaccines: induction of systemic and mucosal B-cell and antibody responses to tetanus toxoid by use of cholera toxin as an adjuvant.

Infection and Immunity ◽

10.1128/iai.61.10.4272-4279.1993 ◽

1993 ◽

Vol 61 (10) ◽

pp. 4272-4279 ◽

Cited By ~ 143

Author(s):

R J Jackson ◽

K Fujihashi ◽

J Xu-Amano ◽

H Kiyono ◽

C O Elson ◽

...

Keyword(s):

B Cell ◽

Cholera Toxin ◽

Tetanus Toxoid ◽

Antibody Responses ◽

Oral Vaccines

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A Systems Biology Approach Identifies B Cell Maturation Antigen (BCMA) as a Biomarker Reflecting Oral Vaccine Induced IgA Antibody Responses in Humans

Frontiers in Immunology ◽

10.3389/fimmu.2021.647873 ◽

2021 ◽

Vol 12 ◽

Author(s):

Lynda Mottram ◽

Anna Lundgren ◽

Ann-Mari Svennerholm ◽

Susannah Leach

Keyword(s):

Systems Biology ◽

Immune Responses ◽

B Cell ◽

Vaccine Development ◽

Oral Vaccine ◽

Antibody Responses ◽

Cell Maturation ◽

Antigen Specificity ◽

B Cell Maturation ◽

B Cell Maturation Antigen

Vaccines against enteric diseases could improve global health. Despite this, only a few oral vaccines are currently available for human use. One way to facilitate such vaccine development could be to identify a practical and relatively low cost biomarker assay to assess oral vaccine induced primary and memory IgA immune responses in humans. Such an IgA biomarker assay could complement antigen-specific immune response measurements, enabling more oral vaccine candidates to be tested, whilst also reducing the work and costs associated with early oral vaccine development. With this in mind, we take a holistic systems biology approach to compare the transcriptional signatures of peripheral blood mononuclear cells isolated from volunteers, who following two oral priming doses with the oral cholera vaccine Dukoral®, had either strong or no vaccine specific IgA responses. Using this bioinformatical method, we identify TNFRSF17, a gene encoding the B cell maturation antigen (BCMA), as a candidate biomarker of oral vaccine induced IgA immune responses. We then assess the ability of BCMA to reflect oral vaccine induced primary and memory IgA responses using an ELISA BCMA assay on a larger number of samples collected in clinical trials with Dukoral® and the oral enterotoxigenic Escherichia coli vaccine candidate ETVAX. We find significant correlations between levels of BCMA and vaccine antigen-specific IgA in antibodies in lymphocyte secretion (ALS) specimens, as well as with proportions of circulating plasmablasts detected by flow cytometry. Importantly, our results suggest that levels of BCMA detected early after primary mucosal vaccination may be a biomarker for induction of long-lived vaccine specific memory B cell responses, which are otherwise difficult to measure in clinical vaccine trials. In addition, we find that ALS-BCMA responses in individuals vaccinated with ETVAX plus the adjuvant double mutant heat-labile toxin (dmLT) are significantly higher than in subjects given ETVAX only. We therefore propose that as ALS-BCMA responses may reflect the total vaccine induced IgA responses to oral vaccination, this BCMA ELISA assay could also be used to estimate the total adjuvant effect on vaccine induced-antibody responses, independently of antigen specificity, further supporting the usefulness of the assay.

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Impact on antibody responses of B-cell-restricted transgenic expression of a viral gene inhibiting activation of NF-κB and NFAT

Archives of Virology ◽

10.1007/s00705-015-2419-x ◽

2015 ◽

Vol 160 (6) ◽

pp. 1477-1488

Author(s):

Sílvia Cristina de Paiva e Almeida ◽

Vivian Leite de Oliveira ◽

Robert Michael Evans Parkhouse

Keyword(s):

B Cell ◽

Antibody Responses ◽

Viral Gene ◽

Transgenic Expression

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Antiviral Protection and Germinal Center Formation, But Impaired B Cell Memory in the Absence of CD19

Journal of Experimental Medicine ◽

10.1084/jem.188.1.145 ◽

1998 ◽

Vol 188 (1) ◽

pp. 145-155 ◽

Cited By ~ 49

Author(s):

Thomas Fehr ◽

Robert C. Rickert ◽

Bernhard Odermatt ◽

Jürgen Roes ◽

Klaus Rajewsky ◽

...

Keyword(s):

T Cell ◽

B Cells ◽

B Cell ◽

Cell Activation ◽

Antibody Responses ◽

B Cell Activation ◽

Protein Antigens ◽

Cell Memory ◽

B Cell Memory

Coligation of CD19, a molecule expressed during all stages of B cell development except plasmacytes, lowers the threshold for B cell activation with anti-IgM by a factor of 100. The cytoplasmic tail of CD19 contains nine tyrosine residues as possible phosphorylation sites and is postulated to function as the signal transducing element for complement receptor (CR)2. Generation and analysis of CD19 gene–targeted mice revealed that T cell–dependent (TD) antibody responses to proteinaceous antigens were impaired, whereas those to T cell–independent (TI) type 2 antigens were normal or even augmented. These results are compatible with earlier complement depletion studies and the postulated function of CD19. To analyze the role of CD19 in antiviral antibody responses, we immunized CD19−/− mice with viral antigens of TI-1, TI-2, and TD type. The effect of CD19 on TI responses was more dependent on antigen dose and replicative capacity than on antigen type. CR blocking experiments confirmed the role of CD19 as B cell signal transducer for complement. In contrast to immunization with protein antigens, infection of CD19−/− mice with replicating virus led to generation of specific germinal centers, which persisted for >100 d, whereas maintenance of memory antibody titers as well as circulating memory B cells was fully dependent on CD19. Thus, our study confirms a costimulatory role of CD19 on B cells under limiting antigen conditions and indicates an important role for B cell memory.

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B cell-intrinsic epigenetic modulation of antibody responses by dietary fiber-derived short-chain fatty acids

Nature Communications ◽

10.1038/s41467-019-13603-6 ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 24

Author(s):

Helia N. Sanchez ◽

Justin B. Moroney ◽

Huoqun Gan ◽

Tian Shen ◽

John L. Im ◽

...

Keyword(s):

Fatty Acids ◽

B Cells ◽

B Cell ◽

Dna Recombination ◽

Short Chain Fatty Acids ◽

Histone Deacetylation ◽

Antibody Responses ◽

Short Chain ◽

Autoantibody Production ◽

Chain Fatty Acids

AbstractShort-chain fatty acids (SCFAs) butyrate and propionate are metabolites from dietary fiber's fermentation by gut microbiota that can affect differentiation or functions of T cells, macrophages and dendritic cells. We show here that at low doses these SCFAs directly impact B cell intrinsic functions to moderately enhance class-switch DNA recombination (CSR), while decreasing at higher doses over a broad physiological range, AID and Blimp1 expression, CSR, somatic hypermutation and plasma cell differentiation. In human and mouse B cells, butyrate and propionate decrease B cell Aicda and Prdm1 by upregulating select miRNAs that target Aicda and Prdm1 mRNA-3′UTRs through inhibition of histone deacetylation (HDAC) of those miRNA host genes. By acting as HDAC inhibitors, not as energy substrates or through GPR-engagement signaling in these B cell-intrinsic processes, these SCFAs impair intestinal and systemic T-dependent and T-independent antibody responses. Their epigenetic impact on B cells extends to inhibition of autoantibody production and autoimmunity in mouse lupus models.

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