Tracking Immunoglobulin Repertoire and Transcriptomic Changes in Germinal Center B Cells by Single-Cell Analysis

Corinaldesi, Clarissa; Holmes, Antony B.; Shen, Qiong; Grunstein, Eli; Pasqualucci, Laura; Dalla‐Favera, Riccardo; Basso, Katia

doi:10.3389/fimmu.2021.818758

Cited by 9 publications

(4 citation statements)

References 59 publications

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“…Recent single-cell transcriptome studies provided a more detailed view, segregating the GC into more than the two morphologically distinguishable compartments [ 24 , 25 , 43 , 45 , 46 ]. Of note, two distinct B-cell populations have been described by Kennedy et al [ 25 , 47 ] in the DZ that differ both with respect to function and location: Proliferating DZ (DZp) cells transform into differentiating DZ (DZd) cells before they exit the DZ and re-enter the LZ ( Figure 2 b, [ 25 , 47 ]).…”

Section: Resultsmentioning

confidence: 99%

Classifying Germinal Center Derived Lymphomas—Navigate a Complex Transcriptional Landscape

Loeffler‐Wirth

Kreuz

Schmidt

et al. 2022

Cancers

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Classification of lymphoid neoplasms is based mainly on histologic, immunologic, and (rarer) genetic features. It has been supplemented by gene expression profiling (GEP) in the last decade. Despite the considerable success, particularly in associating lymphoma subtypes with specific transcriptional programs and classifier signatures of up- or downregulated genes, competing molecular classifiers were often proposed in the literature by different groups for the same classification tasks to distinguish, e.g., BL versus DLBCL or different DLBCL subtypes. Moreover, rarer sub-entities such as MYC and BCL2 “double hit lymphomas” (DHL), IRF4-rearranged large cell lymphoma (IRF4-LCL), and Burkitt-like lymphomas with 11q aberration pattern (mnBLL-11q) attracted interest while their relatedness regarding the major classes is still unclear in many respects. We explored the transcriptional landscape of 873 lymphomas referring to a wide spectrum of subtypes by applying self-organizing maps (SOM) machine learning. The landscape reveals a continuum of transcriptional states activated in the different subtypes without clear-cut borderlines between them and preventing their unambiguous classification. These states show striking parallels with single cell gene expression of the active germinal center (GC), which is characterized by the cyclic progression of B-cells. The expression patterns along the GC trajectory are discriminative for distinguishing different lymphoma subtypes. We show that the rare subtypes take intermediate positions between BL, DLBCL, and FL as considered by the 5th edition of the WHO classification of haemato-lymphoid tumors in 2022. Classifier gene signatures extracted from these states as modules of coregulated genes are competitive with literature classifiers. They provide functional-defined classifiers with the option of consenting redundant classifiers from the literature. We discuss alternative classification schemes of different granularity and functional impact as possible avenues toward personalization and improved diagnostics of GC-derived lymphomas.

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Section: Resultsmentioning

confidence: 99%

Classifying Germinal Center Derived Lymphomas—Navigate a Complex Transcriptional Landscape

Loeffler‐Wirth

Kreuz

Schmidt

et al. 2022

Cancers

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“…Nonetheless, some clues pointing to a more heterogeneous nature of a putative COO classification of FLs had been shown by epigenetic data [57]. More recently, this hypothesis was further supported by the characterisation of discrete steps of plasmablastic differentiation as well as the identification of a distinct subpopulation composed of memory B‐cell precursors within the GC (Figure 2) [58,59].…”

Section: Follicular Lymphoma and Its Many Facesmentioning

confidence: 89%

The fifth edition of the WHO classification of mature B‐cell neoplasms: open questions for research

Coupland,

Du,

Ferry

et al. 2024

The Journal of Pathology

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The fifth edition of the World Health Organization Classification of Haematolymphoid Tumours (WHO‐HAEM5) is the product of an evidence‐based evolution of the revised fourth edition with wide multidisciplinary consultation. Nonetheless, while every classification incorporates scientific advances and aims to improve upon the prior version, medical knowledge remains incomplete and individual neoplasms may not be easily subclassified in a given scheme. Thus, optimal classification requires ongoing study, and there are certain aspects of some entities and subtypes that require further refinements. In this review, we highlight a selection of these challenging areas to prompt more research investigations. These include (1) a ‘placeholder term’ of splenic B‐cell lymphoma/leukaemia with prominent nucleoli (SBLPN) to accommodate many of the splenic lymphomas previously classified as hairy cell leukaemia variant and B‐prolymphocytic leukaemia, a clear new start to define their pathobiology; (2) how best to classify BCL2 rearrangement negative follicular lymphoma including those with BCL6 rearrangement, integrating the emerging new knowledge on various germinal centre B‐cell subsets; (3) what is the spectrum of non‐IG gene partners of MYC translocation in diffuse large B‐cell lymphoma/high‐grade B‐cell lymphoma and how they impact MYC expression and clinical outcome; how best to investigate this in a routine clinical setting; and (4) how best to define high‐grade B‐cell lymphoma not otherwise specified and high‐grade B‐cell lymphoma with 11q aberrations to distinguish them from their mimics and characterise their molecular pathogenetic mechanism. Addressing these questions would provide more robust evidence to better define these entities/subtypes, improve their diagnosis and/or prognostic stratification, leading to better patient care. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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“…Those studies lacked other information such as their surface phenotype, function, and in situ localization, making it difficult to compare them directly with our definition of prePC. Recent studies in human tonsils has identified pre-plasmablasts that appeared integrated in the differentiation trajectory from GC to PC 26,27,45 . Indeed, in that study the authors described cells that were intermediate in their transcriptomic profile, and shared clones with both GC B cells and PC.…”

Section: Discussionmentioning

confidence: 99%

Specific pre-plasma cell states and local proliferation at the dark zone - medulla interface characterize germinal center-derived plasma cell differentiation in lymph node

Binet,

Dong,

Attaf

et al. 2024

Preprint

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High affinity antibody-producing plasma cell (PC) production in germinal centers (GC) is crucial for antibody-mediated immune protection after vaccination or infection. The selection of high affinity B cells in the GC light zone instructs PC differentiation in a subset of cells, but the phenotype, differentiation trajectory and spatial localization of those prePC intermediates remain to be characterized. Here, we have used a mouse model to track GC-derived B cells with integrative single-cell and spatial analyses in draining lymph node after immunization. We first identified putative prePC in scRNA-seq datasets, then enriched those cells through their specific surface phenotype for further analysis of their gene expression trajectories and BCR repertoire. We found a continuum of actively proliferating transitional states bridging selected LZ GC B cells and recently exported PCs, with gradually increasing levels of endoplasmic reticulum stress-associated genes and immunoglobulin transcripts. Spatial analyses revealed that recently differentiated PC continued their maturation and proliferation at the interface between the DZ and extensions of the lymph node medulla. Our results provide insights into the intermediate stages and microenvironmental factors involved in the differentiation of GC B cells into PC, with implications for vaccine development and understanding antibody responses.

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Tracking Immunoglobulin Repertoire and Transcriptomic Changes in Germinal Center B Cells by Single-Cell Analysis

Cited by 9 publications

References 59 publications

Classifying Germinal Center Derived Lymphomas—Navigate a Complex Transcriptional Landscape

Classifying Germinal Center Derived Lymphomas—Navigate a Complex Transcriptional Landscape

The fifth edition of the WHO classification of mature B‐cell neoplasms: open questions for research

Specific pre-plasma cell states and local proliferation at the dark zone - medulla interface characterize germinal center-derived plasma cell differentiation in lymph node

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