B Cell Intrinsic Mechanisms Constraining IgE Memory

Laffleur, Brice; Debeaupuis, Orianne; Dalloul, Zeinab; Cogné, Michel

doi:10.3389/fimmu.2017.01277

Cited by 19 publications

(17 citation statements)

References 105 publications

(136 reference statements)

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“…Our data suggest two mechanisms underlying IgE regulation in humans: a relative deficiency of membrane immunoglobulin expression and an immature IgE PB gene expression program suggestive of weakened activation, proliferation, and survival capacity. These results are largely consistent with extensive studies of mIgE signaling and IgE memory in murine models of allergy (57–61), and provide evidence supporting the use of animal models for this disease. Furthermore, the ability to capture GLT splice variant, polarization, and biallelic expression information within single B cells presents an exciting application of scRNA-seq for future mechanistic studies of GLT production and CSR.…”

Section: Resultssupporting

confidence: 85%

Human IgE producing B cells have a unique transcriptional program and generate high affinity, allergen-specific antibodies

Croote

Darmanis

Nadeau

et al. 2018

Preprint

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IgE antibodies provide defense against helminth infections, but can also cause life-threatening allergic reactions. Despite their importance to human health, these antibodies and the cells that produce them remain enigmatic due to their scarcity in humans; much of our knowledge of their properties is derived from model organisms. Here we describe the isolation of IgE producing B cells from the blood of individuals with food allergies, followed by a detailed study of their properties by single cell RNA sequencing (scRNA-seq). We discovered that IgE B cells are deficient in membrane immunoglobulin expression and that the IgE plasmablast state is more immature than that of other antibody producing cells. Through recombinant expression of monoclonal antibodies derived from single cells, we identified IgE antibodies which had unexpected cross-reactive specificity for major peanut allergens Ara h 2 and Ara h 3; not only are these among the highest affinity native human antibodies discovered to date, they represent a surprising example of convergent evolution in unrelated individuals who independently evolved nearly identical antibodies. Finally, we discovered that splicing within B cells of all isotypes reveals polarized germline transcription of the IgE, but not IgG4, isotype as well as several examples of biallelic expression of germline transcripts. Our results offer insights into IgE B cell transcriptomics, clonality and regulation, provide a striking example of adaptive immune convergence, and offer an approach for accelerating mechanistic disease understanding by characterizing a rare B cell population underlying IgE-mediated disease at single cell resolution.

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Section: Resultssupporting

confidence: 85%

Human IgE producing B cells have a unique transcriptional program and generate high affinity, allergen-specific antibodies

Croote

Darmanis

Nadeau

et al. 2018

Preprint

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“…Recently, B and T cell interactions outside lymphoid tissues, such as in the lung, have been observed; however, these interactions do not appear dependent on classical T FH cells [ 152 ]. Given the potency of IgE, some studies suggest that IgE-producing B cells may be generated de novo from IgG + memory B cells upon appropriate stimulation and context [ 153 ]. Interestingly, IL-21 appears to induce apoptosis in IgE-producing B cells [ 154 ], possibly providing a regulatory mechanism ensuring transient IgE responses in most individuals.…”

Section: Respiratory Allergic Sensitisation: the Mechanisms In Rodmentioning

confidence: 99%

Immunological Processes Driving IgE Sensitisation and Disease Development in Males and Females

Leffler

Stumbles

Strickland

2018

IJMS

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IgE sensitisation has increased significantly over the last decades and is a crucial factor in the development of allergic diseases. IgE antibodies are produced by B cells through the process of antigen presentation by dendritic cells, subsequent differentiation of CD4+ Th2 cells, and class switching in B cells. However, many of the factors regulating these processes remain unclear. These processes affect males and females differently, resulting in a significantly higher prevalence of IgE sensitisation in males compared to females from an early age. Before the onset of puberty, this increased prevalence of IgE sensitisation is also associated with a higher prevalence of clinical symptoms in males; however, after puberty, females experience a surge in the incidence of allergic symptoms. This is particularly apparent in allergic asthma, but also in other allergic diseases such as food and contact allergies. This has been partly attributed to the pro- versus anti-allergic effects of female versus male sex hormones; however, it remains unclear how the expression of sex hormones translates IgE sensitisation into clinical symptoms. In this review, we describe the recent epidemiological findings on IgE sensitisation in male and females and discuss recent mechanistic studies casting further light on how the expression of sex hormones may influence the innate and adaptive immune system at mucosal surfaces and how sex hormones may be involved in translating IgE sensitisation into clinical manifestations.

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“…This combination of circumstances has severely complicated the analysis of mIgE‐expressing B cells in the past. Fortunately, the situation has changed with the recent development and analysis of several mouse model systems that allow straightforward tracking of (m)IgE‐switched B cells by flow cytometry (reviewed in). Several different approaches aimed at either co‐expressing fluorescent proteins specifically with the membrane‐bound splice variant of IgE or at improving staining protocols of mIgE‐expressing cells .…”

Section: The Enigma Of Mige‐expressing B Cellsmentioning

confidence: 99%

Memory control by the B cell antigen receptor

Engels

Wienands

2018

Immunological Reviews

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The generation of memory B cells (MBCs) that have undergone immunoglobulin class switching from IgM, which dominates primary antibody responses, to other immunoglobulin isoforms is a hallmark of immune memory. Hence, humoral immunological memory is characterized by the presence of serum immunoglobulins of IgG subtypes known as the γ-globulin fraction of blood plasma proteins. These antibodies reflect the antigen experience of B lymphocytes and their repeated triggering. In fact, efficient protection against a previously encountered pathogen is critically linked to the production of pathogen-specific IgG molecules even in those cases where the primary immune response required cellular immunity, for example, T cell-mediated clearance of intracellular pathogens such as viruses. Besides IgG, also IgA and IgE can provide humoral immunity depending on the microbe's nature and infection route. The molecular mechanisms underlying the preponderance of switched immunoglobulin isotypes during memory antibody responses are a matter of active and controversial debate. Here, we summarize the phenotypic characteristics of distinct MBC subpopulations and discuss the decisive roles of different B cell antigen receptor isotypes for the functional traits of class-switched B cell populations.

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B Cell Intrinsic Mechanisms Constraining IgE Memory

Cited by 19 publications

References 105 publications

Human IgE producing B cells have a unique transcriptional program and generate high affinity, allergen-specific antibodies

Human IgE producing B cells have a unique transcriptional program and generate high affinity, allergen-specific antibodies

Immunological Processes Driving IgE Sensitisation and Disease Development in Males and Females

Memory control by the B cell antigen receptor

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