scholarly journals Excessive CD11c+Tbet+B cells promote aberrant TFHdifferentiation and affinity-based germinal center selection in lupus

2019 ◽  
Vol 116 (37) ◽  
pp. 18550-18560 ◽  
Author(s):  
Wenqian Zhang ◽  
Huihui Zhang ◽  
Shujun Liu ◽  
Fucan Xia ◽  
Zijian Kang ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Molecular Mechanisms ◽  
Affinity Maturation ◽  
Antibody Affinity ◽  
Autoantibody Production ◽  
Cell Responses ◽  
Antigen Presenting

Excessive self-reactive and inadequate affinity-matured antigen-specific antibody responses have been reported to coexist in lupus, with elusive cellular and molecular mechanisms. Here, we report that the antigen-specific germinal center (GC) response―a process critical for antibody affinity maturation―is compromised in murine lupus models. Importantly, this defect can be triggered by excessive autoimmunity-relevant CD11c+Tbet+age-associated B cells (ABCs). In B cell-intrinsic Ship-deficient (ShipΔB) lupus mice, excessive CD11c+Tbet+ABCs induce deregulated follicular T-helper (TFH) cell differentiation through their potent antigen-presenting function and consequently compromise affinity-based GC selection. Excessive CD11c+Tbet+ABCs and deregulated TFHcell are also present in other lupus models and patients. Further, over-activated Toll-like receptor signaling in Ship-deficient B cells is critical for CD11c+Tbet+ABC differentiation, and blocking CD11c+Tbet+ABC differentiation in ShipΔB mice by ablating MyD88 normalizes TFHcell differentiation and rescues antigen-specific GC responses, as well as prevents autoantibody production. Our study suggests that excessive CD11c+Tbet+ABCs not only contribute significantly to autoantibody production but also compromise antigen-specific GC B-cell responses and antibody-affinity maturation, providing a cellular link between the coexisting autoantibodies and inadequate affinity-matured antigen-specific antibodies in lupus models and a potential target for treating lupus.

scholarly journals Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses

2018 ◽  
Vol 215 (6) ◽  
pp. 1571-1588 ◽  
Author(s):  
Norbert Pardi ◽  
Michael J. Hogan ◽  
Martin S. Naradikian ◽  
Kaela Parkhouse ◽  
Derek W. Cain ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Neutralizing Antibodies ◽  
Affinity Maturation ◽  
Modified Nucleosides ◽  
Vaccine Platform ◽  
Intradermal Vaccination ◽  
Cell Responses ◽  
Follicular Helper

T follicular helper (Tfh) cells are required to develop germinal center (GC) responses and drive immunoglobulin class switch, affinity maturation, and long-term B cell memory. In this study, we characterize a recently developed vaccine platform, nucleoside-modified, purified mRNA encapsulated in lipid nanoparticles (mRNA-LNPs), that induces high levels of Tfh and GC B cells. Intradermal vaccination with nucleoside-modified mRNA-LNPs encoding various viral surface antigens elicited polyfunctional, antigen-specific, CD4+ T cell responses and potent neutralizing antibody responses in mice and nonhuman primates. Importantly, the strong antigen-specific Tfh cell response and high numbers of GC B cells and plasma cells were associated with long-lived and high-affinity neutralizing antibodies and durable protection. Comparative studies demonstrated that nucleoside-modified mRNA-LNP vaccines outperformed adjuvanted protein and inactivated virus vaccines and pathogen infection. The incorporation of noninflammatory, modified nucleosides in the mRNA is required for the production of large amounts of antigen and for robust immune responses.

scholarly journals Peripheral tolerance checkpoints imposed by ubiquitous antigen expression limit antigen-specific B-cell responses under strongly immunogenic conditions

2020 ◽  
Author(s):  
Jeremy F. Brooks ◽  
Peter R. Murphy ◽  
James E.M. Barber ◽  
James W. Wells ◽  
Raymond J. Steptoe
Keyword(s):  
B Cells ◽  
B Cell ◽  
Plasma Cells ◽  
Affinity Maturation ◽  
Peripheral Tolerance ◽  
Cell Detection ◽  
Autoantibody Production ◽  
Cell Responses ◽  
Counter Selection ◽  
B Cell Responses

AbstractA series of layered peripheral checkpoints maintain self-reactive B cells in an unresponsive state. Autoantibody production occurs when these checkpoints are breached, however, when and how this occurs is largely unknown. In particular, how self-reactive B cells are restrained during bystander inflammation in otherwise healthy individuals is poorly understood. A weakness has been the unavailability of methods capable of dissecting physiologically-relevant B-cell responses, without the use of an engineered B-cell receptor. Resolving this will provide insights that decipher how this process goes awry during autoimmunity or could be exploited for therapy. Here we use a strong adjuvant to provide bystander innate and adaptive signals that promote B-cell responsiveness, in conjunction with newly developed B cell detection tools to study in detail the ways that peripheral tolerance mechanisms limit the expansion and function of self-reactive B cells activated under these conditions. We show that although autoreactive B cells are recruited into the germinal centre, their development does not proceed, possibly through rapid counter-selection. Consequently, differentiation of plasma cells is blunted, and autoantibody responses are transient and devoid of affinity maturation. We propose this approach and these tools can be more widely applied to track antigen-specific B cell responses to more disease relevant antigens, without the need for BCR transgenic mice, in settings where tolerance pathways are compromised or have been genetically manipulated to drive stronger insights into the biology underlying B cell-mediated autoimmunity.

scholarly journals Conserved Gammaherpesvirus Protein Kinase Selectively Promotes Irrelevant B Cell Responses

2019 ◽  
Vol 93 (8) ◽  
Author(s):  
Eric J. Darrah ◽  
Christopher N. Jondle ◽  
Kaitlin E. Johnson ◽  
Gang Xin ◽  
Philip T. Lange ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
Protein Kinase ◽  
B Cell ◽  
Germinal Center ◽  
Unique Feature ◽  
Latent Infection ◽  
B Cell Differentiation ◽  
Cell Responses ◽  
B Cell Responses

ABSTRACTGammaherpesviruses are ubiquitous pathogens that are associated with B cell lymphomas. In the early stages of chronic infection, these viruses infect naive B cells and subsequently usurp the B cell differentiation process through the germinal center response to ensure latent infection of long-lived memory B cells. A unique feature of early gammaherpesvirus chronic infection is a robust differentiation of irrelevant, virus-nonspecific B cells with reactivities against self-antigens and antigens of other species. In contrast, protective, virus-specific humoral responses do not reach peak levels until a much later time. While several host factors are known to either promote or selectively restrict gammaherpesvirus-driven germinal center response, viral mechanisms that contribute to the irrelevant B cell response have not been defined. In this report we show that the expression and the enzymatic activity of the gammaherpesvirus-encoded conserved protein kinase selectively facilitates the irrelevant, but not virus-specific, B cell responses. Further, we show that lack of interleukin-1 (IL-1) receptor attenuates gammaherpesvirus-driven B cell differentiation and viral reactivation. Because germinal center B cells are thought to be the target of malignant transformation during gammaherpesvirus-driven lymphomagenesis, identification of host and viral factors that promote germinal center responses during gammaherpesvirus infection may offer an insight into the mechanism of gammaherpesvirus pathogenesis.IMPORTANCEGammaherpesviruses are ubiquitous cancer-associated pathogens that usurp the B cell differentiation process to establish life-long latent infection in memory B cells. A unique feature of early gammaherpesvirus infection is the robust increase in differentiation of B cells that are not specific for viral antigens and instead encode antibodies that react with self-antigens and antigens of other species. Viral mechanisms that are involved in driving such irrelevant B cell differentiation are not known. Here, we show that gammaherpesvirus-encoded conserved protein kinase and host IL-1 signaling promote irrelevant B cell responses and gammaherpesvirus-driven germinal center responses, with the latter thought to be the target of viral transformation.

scholarly journals Germinal Center B Cells Regulate Their Capability to Present Antigen by Modulation of HLA-DO

2002 ◽  
Vol 195 (8) ◽  
pp. 1063-1069 ◽  
Author(s):  
Kim S. Glazier ◽  
Sandra B. Hake ◽  
Helen M. Tobin ◽  
Amy Chadburn ◽  
Elaine J. Schattner ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Antigen Presentation ◽  
Mhc Class Ii ◽  
Germinal Center ◽  
B Cell Differentiation ◽  
Protein Levels ◽  
Peptide Exchange ◽  
Antigen Presenting

Peptide acquisition by MHC class II molecules is catalyzed by HLA-DM (DM). In B cells, HLA-DO (DO) inhibits or modifies the peptide exchange activity of DM. We show here that DO protein levels are modulated during B cell differentiation. Remarkably, germinal center (GC) B cells, which have low levels of DO relative to naive and memory B cells, are shown to have enhanced antigen presentation capabilities. DM protein levels also were somewhat reduced in GC B cells; however, the ratio of DM to DO in GC B cells was substantially increased, resulting in more free DM in GC B cells. We conclude that modulation of DM and DO in distinct stages of B cell differentiation represents a mechanism by which B cells regulate their capacity to function as antigen-presenting cells. Efficient antigen presentation in GC B cells would promote GC B cell–T cell interactions that are essential for B cells to survive positive selection in the GC.

scholarly journals Transcription factors IRF8 and PU.1 are required for follicular B cell development and BCL6-driven germinal center responses

2019 ◽  
Vol 116 (19) ◽  
pp. 9511-9520 ◽  
Author(s):  
Hongsheng Wang ◽  
Shweta Jain ◽  
Peng Li ◽  
Jian-Xin Lin ◽  
Jangsuk Oh ◽  
...  
Keyword(s):  
Transcription Factors ◽  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Critical Role ◽  
B Cell Lymphoma ◽  
Cell Development ◽  
Affinity Maturation

The IRF and Ets families of transcription factors regulate the expression of a range of genes involved in immune cell development and function. However, the understanding of the molecular mechanisms of each family member has been limited due to their redundancy and broad effects on multiple lineages of cells. Here, we report that double deletion of floxed Irf8 and Spi1 (encoding PU.1) by Mb1-Cre (designated DKO mice) in the B cell lineage resulted in severe defects in the development of follicular and germinal center (GC) B cells. Class-switch recombination and antibody affinity maturation were also compromised in DKO mice. RNA-seq (sequencing) and ChIP-seq analyses revealed distinct IRF8 and PU.1 target genes in follicular and activated B cells. DKO B cells had diminished expression of target genes vital for maintaining follicular B cell identity and GC development. Moreover, our findings reveal that expression of B-cell lymphoma protein 6 (BCL6), which is critical for development of germinal center B cells, is dependent on IRF8 and PU.1 in vivo, providing a mechanism for the critical role for IRF8 and PU.1 in the development of GC B cells.

Interleukin-24 inhibits the plasma cell differentiation program in human germinal center B cells

Blood ◽  
2010 ◽  
Vol 115 (9) ◽  
pp. 1718-1726 ◽  
Author(s):  
Ghyath Maarof ◽  
Laurence Bouchet-Delbos ◽  
Hélène Gary-Gouy ◽  
Ingrid Durand-Gasselin ◽  
Roman Krzysiek ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Cell Fate ◽  
Plasma Cell ◽  
Germinal Center ◽  
Molecular Mechanisms ◽  
Plasma Cells ◽  
Memory B Cells ◽  
Plasma Cell Differentiation

Abstract Complex molecular mechanisms control B-cell fate to become a memory or a plasma cell. Interleukin-24 (IL-24) is a class II family cytokine of poorly understood immune function that regulates the cell cycle. We previously observed that IL-24 is strongly expressed in leukemic memory-type B cells. Here we show that IL-24 is also expressed in human follicular B cells; it is more abundant in CD27+ memory B cells and CD5-expressing B cells, whereas it is low to undetectable in centroblasts and plasma cells. Addition of IL-24 to B cells, cultured in conditions shown to promote plasma cell differentiation, strongly inhibited plasma cell generation and immunoglobulin G (IgG) production. By contrast, IL-24 siRNA increased terminal differentiation of B cells into plasma cells. IL-24 is optimally induced by BCR triggering and CD40 engagement; IL-24 increased CD40-induced B-cell proliferation and modulated the transcription of key factors involved in plasma cell differentiation. It also inhibited activation-induced tyrosine phosphorylation of signal transducer and activator of transcription-3 (STAT-3), and inhibited the transcription of IL-10. Taken together, our results indicate that IL-24 is a novel cytokine involved in T-dependent antigen (Ag)–driven B-cell differentiation and suggest its physiologic role in favoring germinal center B-cell maturation in memory B cells at the expense of plasma cells.

scholarly journals Antigen recognition strength regulates the choice between extrafollicular plasma cell and germinal center B cell differentiation

2006 ◽  
Vol 203 (4) ◽  
pp. 1081-1091 ◽  
Author(s):  
Didrik Paus ◽  
Tri Giang Phan ◽  
Tyani D. Chan ◽  
Sandra Gardam ◽  
Antony Basten ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Plasma Cell ◽  
Germinal Center ◽  
Germinal Centers ◽  
Affinity Maturation ◽  
B Cell Differentiation ◽  
High Affinity ◽  
Germinal Center B Cell

B cells responding to T-dependent antigen either differentiate rapidly into extrafollicular plasma cells or enter germinal centers and undergo somatic hypermutation and affinity maturation. However, the physiological cues that direct B cell differentiation down one pathway versus the other are unknown. Here we show that the strength of the initial interaction between B cell receptor (BCR) and antigen is a primary determinant of this decision. B cells expressing a defined BCR specificity for hen egg lysozyme (HEL) were challenged with sheep red blood cell conjugates of a series of recombinant mutant HEL proteins engineered to bind this BCR over a 10,000-fold affinity range. Decreasing either initial BCR affinity or antigen density was found to selectively remove the extrafollicular plasma cell response but leave the germinal center response intact. Moreover, analysis of competing B cells revealed that high affinity specificities are more prevalent in the extrafollicular plasma cell versus the germinal center B cell response. Thus, the effectiveness of early T-dependent antibody responses is optimized by preferentially steering B cells reactive against either high affinity or abundant epitopes toward extrafollicular plasma cell differentiation. Conversely, responding clones with weaker antigen reactivity are primarily directed to germinal centers where they undergo affinity maturation.

scholarly journals Stochasticity enables BCR-independent germinal center initiation and antibody affinity maturation

2017 ◽  
Vol 215 (1) ◽  
pp. 77-90 ◽  
Author(s):  
Jared Silver ◽  
Teng Zuo ◽  
Neha Chaudhary ◽  
Rupa Kumari ◽  
Pei Tong ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
De Novo ◽  
Somatic Hypermutation ◽  
Affinity Maturation ◽  
B Cell Receptors ◽  
Antibody Affinity ◽  
V Region ◽  
Combinatorial Assembly

Two immunoglobulin (Ig) diversification mechanisms collaborate to provide protective humoral immunity. Combinatorial assembly of IgH and IgL V region exons from gene segments generates preimmune Ig repertoires, expressed as B cell receptors (BCRs). Secondary diversification occurs when Ig V regions undergo somatic hypermutation (SHM) and affinity-based selection toward antigen in activated germinal center (GC) B cells. Secondary diversification is thought to only ripen the antigen-binding affinity of Igs that already exist (i.e., cognate Igs) because of chance generation during preimmune Ig diversification. However, whether stochastic activation of noncognate B cells can generate new affinity to antigen in GCs is unclear. Using a mouse model whose knock-in BCR does not functionally engage with immunizing antigen, we found that chronic immunization induced antigen-specific serological responses with diverse SHM-mediated antibody affinity maturation pathways and divergent epitope targeting. Thus, intrinsic GC B cell flexibility allows for somatic, noncognate B cell evolution, permitting de novo antigen recognition and subsequent antibody affinity maturation without initial preimmune BCR engagement.

scholarly journals Antigen affinity discrimination is an intrinsic function of the B cell receptor

2010 ◽  
Vol 207 (5) ◽  
pp. 1095-1111 ◽  
Author(s):  
Wanli Liu ◽  
Tobias Meckel ◽  
Pavel Tolar ◽  
Hae Won Sohn ◽  
Susan K. Pierce
Keyword(s):  
B Cells ◽  
Immune Responses ◽  
B Cell ◽  
Molecular Mechanisms ◽  
Cell Receptor ◽  
Selective Advantage ◽  
Affinity Maturation ◽  
Cell Responses ◽  
Highly Sensitive

Antibody affinity maturation, a hallmark of adaptive immune responses, results from the selection of B cells expressing somatically hypermutated B cell receptors (BCRs) with increased affinity for antigens. Despite the central role of affinity maturation in antibody responses, the molecular mechanisms by which the increased affinity of a B cell for antigen is translated into a selective advantage for that B cell in immune responses is incompletely understood. We use high resolution live-cell imaging to provide evidence that the earliest BCR-intrinsic events that follow within seconds of BCR–antigen binding are highly sensitive to the affinity of the BCR for antigen. High affinity BCRs readily form oligomers and the resulting microclusters grow rapidly, resulting in enhanced recruitment of Syk kinase and calcium fluxes. Thus, B cells are able to read the affinity of antigen by BCR-intrinsic mechanisms during the earliest phases of BCR clustering, leading to the initiation of B cell responses.

scholarly journals Modulation of Igβ is essential for the B cell selection in germinal center

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Kagefumi Todo ◽  
Orie Koga ◽  
Miwako Nishikawa ◽  
Masaki Hikida
Keyword(s):  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Molecular Mechanisms ◽  
Antigen Receptor ◽  
Affinity Maturation ◽  
Down Regulation ◽  
Antigen Receptor Signaling ◽  
Essential Components ◽  
Selection Of

Abstract The positive and negative selection of antigen-reactive B cells take place in the germinal center (GC) during an immune responses. However, the precise molecular mechanisms underlying these selection machineries, including the involvement of antigen receptor signaling molecules, remain to be elucidated. We found that expression levels of Igα and Igβ, which are the essential components of B cell antigen-receptor complex, were differentially regulated in GC B cells and that the expression of Igβ was more prominently down-regulated in a portion of GC B cells. The suppression of Igβ down-regulation reduced the number of GL7+GC B cells and the affinity maturation in T-dependent responses was markedly impaired. In addition, the disease phenotypes in autoimmune-prone mice were ameliorated by blocking of Igβ down-regulation. These results suggest that Igβ down-regulation is involved in the normal positive selection in GC and the accumulation of autoreactive B cells in autoimmune-prone mice.

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