B cells and the antibodies they produce have a deeply penetrating influence on human physiology. Here, we review current understanding of how B cell responses are initiated; the different paths to ...generate short- and long-lived plasma cells, germinal center cells, and memory cells; and how each path impacts antibody diversity, selectivity, and affinity. We discuss how basic research is informing efforts to generate vaccines that induce broadly neutralizing antibodies against viral pathogens, revealing the special features associated with allergen-reactive IgE responses and uncovering the antibody-independent mechanisms by which B cells contribute to health and disease.
This Review provides a comprehensive overview of our current understanding of B cells and the antibodies they produce, at the cellular and molecular level, and their roles in protective immunity and disease.
Germinal center (GC) B cells cycle between the dark zone (DZ) and light zone (LZ) during antibody affinity maturation. Whether this movement is necessary for GC function has not been tested. Here we ...show that CXCR4-deficient GC B cells, which are restricted to the LZ, are gradually outcompeted by WT cells indicating an essential role for DZ access. Remarkably, the transition between DZ centroblast and LZ centrocyte phenotypes occurred independently of positioning. However, CXCR4-deficient cells carried fewer mutations and were overrepresented in the CD73+ memory compartment. These findings are consistent with a model where GC B cells change from DZ to LZ phenotype according to a timed cellular program but suggest that spatial separation of DZ cells facilitates more effective rounds of mutation and selection. Finally, we identify a network of DZ CXCL12-expressing reticular cells that likely support DZ functions.
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•CXCR4-deficient B cells are gradually outcompeted of influenza-induced GCs•GC B cells transition from the DZ to LZ state according to a cellular program•DZ access is required for normal somatic hypermutation rates•The DZ contains a dense network of CXCL12-expressing reticular cells
The germinal center (GC) is an important site for the generation and selection of B cells bearing high-affinity antibodies, yet GC cell migration and interaction dynamics have not been directly ...observed. Using two-photon microscopy of mouse lymph nodes, we revealed that GC B cells are highly motile and extend long cell processes. They transited between GC dark and light zones and divided in both regions, although these B cells resided for only several hours in the light zone where antigen is displayed. GC B cells formed few stable contacts with GC T cells despite frequent encounters, and T cells were seen to carry dead B cell blebs. On the basis of these observations, we propose a model in which competition for T cell help plays a more dominant role in the selection of GC B cells than previously appreciated.
Chiral amines are valuable building blocks for the pharmaceutical industry. ω-TAms have emerged as an exciting option for their synthesis, offering a potential "green alternative" to overcome the ...drawbacks associated with conventional chemical methods. In this review, we explore the application of ω-TAms for pharmaceutical production. We discuss the diverse array of reactions available involving ω-TAms and process considerations of their use in both kinetic resolution and asymmetric synthesis. With the aid of specific drug intermediates and APIs, we chart the development of ω-TAms using protein engineering and their contribution to elegant one-pot cascades with other enzymes, including carbonyl reductases (CREDs), hydrolases and monoamine oxidases (MAOs), providing a comprehensive overview of their uses, beginning with initial applications through to the present day.
IgE antibodies may be protective in parasite immunity, but their aberrant production can lead to allergic disease and life-threatening anaphylaxis. Despite the importance of IgE regulation, few ...studies have directly examined the B cells that express IgE, because these cells are rare and difficult to detect. Here, we describe fluorescent IgE reporter mice and validate a flow cytometry procedure to allow sensitive and specific identification of IgE-expressing B cells in vivo. Similar to IgG1+ cells, IgE+ B cells differentiated into germinal center (GC) B cells and plasma cells (PCs) during primary immune responses to a T cell-dependent hapten-protein conjugate and the helminth Nippostrongylus brasiliensis. However, the participation of IgE+ B cells in GCs was transient. IgE+ B cells had an atypical propensity to upregulate the transcription factor Blimp-1 and undergo PC differentiation. Most IgE+ PCs were short lived and showed reduced affinity maturation, revealing intrinsic mechanisms that restrict the IgE antibody response.
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► Reporter mice and intracellular staining can reliably detect IgE+ B cells in vivo ► IgE+ B cells can differentiate into GC B cells, but participation in GCs is limited ► IgE+ B cells exhibit elevated Blimp-1 expression and PC differentiation ► IgE+ B cells tend to become short-lived PCs, thus restraining cell numbers
Germinal centers (GCs) are important sites of antibody affinity maturation. In the classical model, the GC dark zone contains large centroblasts that are rapidly proliferating and undergoing somatic ...hypermutation of their antibody variable-region genes. Centroblasts give rise to smaller nonproliferating centrocytes in the light zone that compete for binding antigen on follicular dendritic cells. Recently, the approach of real-time imaging of GCs by two-photon microscopy of intact lymph nodes has provided new insights into GC dynamics that both support and challenge fundamental aspects of this model. Here we review recent and older findings on cell migration, proliferation, and interaction dynamics in the GC and discuss a model in which dark- and light-zone cells are morphologically similar, proliferation occurs in both zones, and GC B cells compete for T cell help as well as antigen.
Identification of germinal center (GC) B cells is typically reliant on the use of surface activation markers that exhibit a wide range of expression. Here, we identify Ephrin-B1, a ligand for ...Eph-related receptor tyrosine kinases, as a specific marker of mature GC B cells. The number of Ephrin-B1
GC B cells increases during the course of an immune response with Ephrin-B1
GC B cells displaying elevated levels of Bcl6,
, and
relative to their Ephrin-B1
counterparts. We further identified a small proportion of recently dividing, somatically mutated Ephrin-B1
GC B cells that have begun to down-regulate Bcl6 and
and express markers associated with memory B cells, such as CD38 and EBI2. Transcriptional analysis indicates that these cells are developmentally related to memory B cells, and likely represent a population of GC memory precursor (PreMem) B cells. GC PreMem cells display enhanced survival relative to bulk GC B cells, localize near the edge of the GC, and are predominantly found within the light zone. These findings offer insight into the significant heterogeneity that exists within the GC B cell population and provide tools to further dissect signals regulating the differentiation of GC B cells.
IgE antibodies may elicit potent allergic reactions, and their production is tightly controlled. The tendency to generate IgE has been thought to reflect the balance between type 1 and type 2 ...cytokines, with the latter promoting IgE. Here, we reevaluated this paradigm by a direct cellular analysis, demonstrating that IgE production was not limited to type 2 immune responses yet was generally constrained in vivo. IL-21 was a critical negative regulator of IgE responses, whereas IFN-γ, IL-6, and IL-10 were dispensable. Follicular helper T cells were the primary source of IL-21 that inhibited IgE responses by directly engaging the IL-21 receptor on B cells and triggering STAT3-dependent signaling. We reconciled previous discordant results between mouse and human B cells and revealed that the inhibition of IgE class switch recombination by IL-21 was attenuated by CD40 signaling, whereas IgG1 class switch recombination was potentiated by IL-21 in the context of limited IL-4. These findings establish key features of the extrinsic regulation of IgE production by cytokines.
Lough Neagh is the largest and the most economically important lake in Ireland. It is also one of the most nutrient rich amongst the world's major lakes. In this study, 16S rRNA analysis of total ...metagenomic DNA from the water column of Lough Neagh has revealed a high proportion of Cyanobacteria and low levels of Actinobacteria, Acidobacteria, Chloroflexi, and Firmicutes. The planktonic virome of Lough Neagh has been sequenced and 2,298,791 2×300 bp Illumina reads analysed. Comparison with previously characterised lakes demonstrates that the Lough Neagh viral community has the highest level of sequence diversity. Only about 15% of reads had homologs in the RefSeq database and tailed bacteriophages (Caudovirales) were identified as a major grouping. Within the Caudovirales, the Podoviridae and Siphoviridae were the two most dominant families (34.3% and 32.8% of the reads with sequence homology to the RefSeq database), while ssDNA bacteriophages constituted less than 1% of the virome. Putative cyanophages were found to be abundant. 66,450 viral contigs were assembled with the largest one being 58,805 bp; its existence, and that of another 34,467 bp contig, in the water column was confirmed. Analysis of the contigs confirmed the high abundance of cyanophages in the water column.
This Brief Review delves into B cell responses in the context of allergy. The primary contribution of B cells to allergy is the production of IgE, the Ab isotype that triggers immediate ...hypersensitivity reactions through the release of mediators from mast cells and basophils. B cells may also have protective roles in allergy, such as through the production of IgG or as regulatory B cells. In this review, I focus on the basic principles of B cell differentiation and discuss features relevant to allergic immune responses. In particular, I discuss: (1) class-switch recombination; (2) plasma cell differentiation; (3) germinal centers and affinity maturation; and (4) memory B cells and recall responses, with an emphasis on IgE, IgG1, and IgG4. I also consider how B cells may contribute to allergic responses independent of Ab production-for example, by serving as APCs.
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