Self-control for IgE production

Immunoglobulin E (IgE) was the last discovered immunoglobulin class (in 1966). Having evolved from the same ancestral " IgY " gene duplicated in mammals 300 million years ago, IgG and IgE indeed followed very different careers with IgG now being the predominant serum Ig while IgE reaches levels 100,000-fold lower. In contrast, IgE became the most potent Ig, notably active against parasites, toxins and venoms, with ability to trigger vigorous or even violent immune reactions against antigens at nanomolar concentrations. Throughout evolution, it has clearly been an important issue for the immune system to maintain the production of such a powerful but dangerous weapon, which is responsible for severe anaphylaxis, under tight control [1]. Although class switch recombination (CSR) to Cε initiating IgE production is quite active in vitro, it is only weakly present in vivo due to various limitations (including inhibitory cytokines from the cell microenvironment, Cε gene-specific features with tightly regulated germline transcription and a poorly efficient acceptor switch region). For previously unknown reasons, IgE-switched lymphocytes additionally seem predisposed to a special fate, with boosted differentiation into short-lived plasma cells [2] and rapid in vivo apoptosis in germinal centers [3]. Previous studies of the elusive IgE + B-cells in vivo thus relied on mice with helminth infections or transgenic models coupling IgE production to expression of a fluorescent marker. This notably demonstrated that Cε CSR can occur either directly from Cµ and then yield low affinity IgE antibodies, or from sequential CSR with a Cγ1/IgG1 intermediate, permitting somatic hypermutation and production of high affinity IgE. Whatever the pathway, IgE-switched B-cells further rapidly disappear for reasons that might relate to stimulation conditions (cytokines, T-cell help) or be B-cell intrinsic. B-cell receptors (BCR), i.e. membrane anchored Ig (mIg), are major regulators of multiple aspects of cell physiology, such as cell survival, activation, proliferation, differentiation, and eventually activation-induced cell death [4]. There are clear indications that mIgM, mIgG and mIgA differentially support B cell survival and fate after activation, with mIgG and mIgA specially boosting plasma cell differentiation [5]. The IgE-class BCR has multiple peculiarities, including its transcription from a gene lacking a conventional polyadenylation site, the specific intracellular interactions of the mIgE tail, and its low expression level with alternatively spliced isoforms. We recently demonstrated that by itself, mIgE BCR directly restrains IgE production independently of the stimulation conditions and microenvironment [6]. This BCR-supported autonomous control of IgE + lymphocytes …