Germinal Center B Cells Replace Their Antigen Receptors in Dark Zones and Fail Light Zone Entry when Immunoglobulin Gene Mutations are Damaging

Stewart, Isabelle; Radtke, Daniel; Phillips, Bethan; McGowan, Simon J.; Bannard, Oliver

doi:10.1016/j.immuni.2018.08.025

Cited by 78 publications

(96 citation statements)

References 54 publications

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“…This was the first recurring chromosome abnormality ever reported in lymphoproliferative disorders. C-MYC in place next to immunoglobulin heavy locus (IGH) results in the expression of c-Myc protein, which is a key transcriptional factor that promotes cell cycle and B Cell Lymphomagenesis DOI: http://dx.doi.org /10.5772/intechopen.87241 B-cell receptors (BCRs) on their cell membrane, and BCRs allow the cell to bind to a specific antigen and initiate an antibody response [18,23,25]. Despite these common features, differences in routes of antigen transport, lymphocyte trafficking, and unique cell populations determine the role of a specific secondary lymphoid tissue in immune responses to various foreign antigens.…”

Section: Germinal Center B-cell Dynamicsmentioning

confidence: 99%

“…The dark zone contains large centroblasts that are rapidly proliferating and undergoing somatic mutation. These cells grow to small nonproliferating centrocytes in the light zone, and binding antigen on follicular dendritic cells (FDCs) and development further depend on receiving signals from helper T cells [18,22,23,28].…”

Section: Germinal Center B-cell Dynamicsmentioning

confidence: 99%

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B Cell Lymphomagenesis

Škunca¹

2020

Normal and Malignant B-Cell

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Lymphoid neoplasms are a heterogeneous group of malignancies whose diagnosis depends on a very good analysis of hematopathology and morphology, immunophenotype, cytogenetic, molecular, and clinical characteristics. B-cell lymphomas begin from different developmental stages of B cells in germinal centers of secondary lymphoid tissue. The evolution of B-cell lymphomagenesis depends on different numbers of signal pathways. Proteins that play key point of signaling networks are changed by aberrant chromosomal expression, translocation, and/or accumulation, and those events determine the fate of the affected B cells. Many chemokines and cytokines have been implicated in providing the line for the cellular surviving and interaction in lymphoid organogenesis. Specific chromosomal alterations were associated with significant changes in gene-expression signatures that reflect various aspects of lymphoma cell biology as well as the host response to the lymphoma. The goal of this study was to find out a correlation between tumor markers and survival in patients with subgroups of DLBCL. The goal is to find out chronic autoimmune or pathogen-induced immune reactions resulting in lymphoid neogenesis. So we address (i) chemokines and adhesion molecules involved in lymphoid neogenesis, (ii) the autoimmune diseases and pathogens which are associated with the development of B-cell lymphomas, and (iii) the molecular mechanisms involved in the initiation and progression of DLBCL.

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Section: Germinal Center B-cell Dynamicsmentioning

confidence: 99%

Section: Germinal Center B-cell Dynamicsmentioning

confidence: 99%

B Cell Lymphomagenesis

Škunca¹

2020

Normal and Malignant B-Cell

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“…It remained unclear where chronic infection caused diversion in the stepwise, cyclic scheme of GC B cell differentiation. A typical progression through the GC involves rapid proliferation and somatic hypermutation in the DZ, exit from cell cycle and testing of BCR, and then key decision points in the LZ to initiate either DZ re-entry or begin a PC or MBC differentiation path (Mesin et al, 2016;Shlomchik et al, 2019;Stewart et al, 2018). To understand how chronic infection altered these biological decision points in the GC, we next applied pseudotime analysis to the single-cell data to infer differentiation trajectories and cluster relationships (Qiu et al, 2017b(Qiu et al, , 2017a.…”

Section: Chronic Infection Promotes Terminal B Cell Differentiation Amentioning

confidence: 99%

Chronic viral infection promotes early germinal center exit of B cells and impaired antibody development

Staupe

Vella

Manne

et al. 2019

Preprint

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Chronic viral infections disrupt B cell responses leading to impaired affinity maturation and delayed control of viremia. Previous studies have identified early pre-germinal center (GC) B cell attrition but the impact of chronic infections on B cell fate decisions in the GC remains poorly understood. To address this question, we used single-cell transcriptional profiling of virus-specific GC B cells to test the hypothesis that chronic viral infection disrupted GC B cell fate decisions leading to suboptimal humoral immunity. These studies revealed a critical GC differentiation checkpoint that is disrupted by chronic infection, specifically at the point of dark zone re-entry. During chronic viral infection, virusspecific GC B cells were shunted towards terminal plasma cell (PC) or memory B cell (MBC) fates at the expense of continued participation in the GC. Early GC exit was associated with decreased B cell mutational burden and antibody quality. Persisting antigen and inflammation independently drove facets of dysregulation, with a key role for inflammation in directing premature terminal GC B cell differentiation and GC exit. Thus, these studies define GC defects during chronic viral infection and identify a critical GC checkpoint that is short-circuited, preventing optimal maturation of humoral immunity.

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“…Studying how BCR expression boosts the competitive fitness of MYC‐expressing lymphoma B cells may help to unveil whether similar strategies operate in normal mature B cells, especially when recruited in the highly competitive GC environment during an immune response. For instance, the rapid disappearance of continuously arising Ig‐negative B cells in the dark zone could reflect a competitive disadvantage of these cells at the expense of Ig‐positive cells, rather than a cell‐intrinsic defect in cell survival . BCR loss may also prevent the exit of Ig‐defective B cells from the dark zone due to a sustained response to the chemokine CXCL12 .…”

Section: Future Directionsmentioning

confidence: 99%

“…For instance, the rapid disappearance of continuously arising Ig‐negative B cells in the dark zone could reflect a competitive disadvantage of these cells at the expense of Ig‐positive cells, rather than a cell‐intrinsic defect in cell survival . BCR loss may also prevent the exit of Ig‐defective B cells from the dark zone due to a sustained response to the chemokine CXCL12 . Centrocytes expressing higher levels of c‐MYC possibly resulting from stronger/longer interactions with TF H cells may outcompete those with lower MYC levels, limiting the possibility of the latter cells to recirculate to the dark zone .…”

Section: Future Directionsmentioning

confidence: 99%

The B‐cell receptor in control of tumor B‐cell fitness: Biology and clinical relevance

Perucho

Tripodo

Sindaco

et al. 2019

Immunological Reviews

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Summary Surface expression of a functional B cell antigen receptor (BCR) is essential for the survival and proliferation of mature B cells. Most types of B‐cell lymphoproliferative disorders retain surface BCR expression, including B‐cell non‐Hodgkin lymphomas (B‐NHL) and chronic lymphocytic leukemia (CLL). Targeting BCR effectors in B‐NHL cell lines in vitro has indicated that this signaling axis is crucial for malignant B cell growth. This has led to the development of inhibitors of BCR signaling, which are currently used for the treatment of CLL and several B‐NHL subtypes. Recent studies based on conditional BCR inactivation in a MYC‐driven mouse B‐cell lymphoma model have revisited the role of the BCR in MYC‐expressing tumor B cells. Indeed, lymphoma cells losing BCR expression continue to grow unless subjected to competition with their BCR‐expressing counterparts, which causes their elimination. Here, we discuss the molecular nature of the fitness signal delivered by the BCR to MYC‐expressing malignant B cells, ensuring their preferential persistence within a rapidly expanding tumor population. We also review growing evidence of Ig‐negative cases belonging to several B‐NHL subtypes and CLL, and discuss the clinical implications of these findings in relation to an emerging picture of clinical resistances to anti‐BCR therapies.

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Germinal Center B Cells Replace Their Antigen Receptors in Dark Zones and Fail Light Zone Entry when Immunoglobulin Gene Mutations are Damaging

Cited by 78 publications

References 54 publications

B Cell Lymphomagenesis

B Cell Lymphomagenesis

Chronic viral infection promotes early germinal center exit of B cells and impaired antibody development

The B‐cell receptor in control of tumor B‐cell fitness: Biology and clinical relevance

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