B cell receptor ligation induces IgE plasma cell elimination

Abstract

The proper regulation of IgE production safeguards against allergic disease, highlighting the importance of mechanisms that restrict IgE plasma cell (PC) survival. IgE PCs have unusually high surface B cell receptor (BCR) expression, yet the functional consequences of ligating this receptor are unknown. Here, we found that BCR ligation induced BCR signaling in IgE PCs followed by their elimination. In cell culture, exposure of IgE PCs to cognate antigen or anti-BCR antibodies induced apoptosis. IgE PC depletion correlated with the affinity, avidity, amount, and duration of antigen exposure and required the BCR signalosome components Syk, BLNK, and PLCγ2. In mice with a PC-specific impairment of BCR signaling, the abundance of IgE PCs was selectively increased. Conversely, BCR ligation by injection of cognate antigen or anti-IgE depleted IgE PCs. These findings establish a mechanism for the elimination of IgE PCs through BCR ligation. This has important implications for allergen tolerance and immunotherapy as well as anti-IgE monoclonal antibody treatments.

The origins and longevity of IgE responses as indicated by serological and cellular studies in mice and humans

“…Two studies suggest limited antigen‐specific IgE titer change in pollen allergic individuals over a four‐month period with dupilumab alone, which would instead indicate persistent IgE + ASC cause pollen allergy 179,180 . Intriguingly, in one of those studies, patients concomitantly undergoing subcutaneous immunotherapy had IgE titres that dropped 50%–60%, 179 arguing putatively persistent IgE + ASC were being killed by exposure to cognate antigen, as would be predicted from a recent mouse study where IgE BCR ligation was shown to cause IgE + ASC apoptosis 181 . Additional human studies point to a long‐lived IgE + ASC population by showing IgE titer maintenance in periods of allergen avoidance, 182 but it is possible that without IL‐4R blockade IgE + ASC production occurs constantly from GC or mBC.…”

“…179,180 Intriguingly, in one of those studies, patients concomitantly undergoing subcutaneous immunotherapy had IgE titres that dropped 50%-60%, 179 arguing putatively persistent IgE + ASC were being killed by exposure to cognate antigen, as would be predicted from a recent mouse study where IgE BCR ligation was shown to cause IgE + ASC apoptosis. 181 Additional human studies point to a long-lived IgE + ASC population by showing IgE titer maintenance in periods of allergen avoidance, 182 but it is possible that without F I G U R E 4 Potential pathways to IgE production in mice and humans. IgE class-switch recombination (CSR) may occur during (1) the preGC phase of a B cell response, to give rise to IgE + preGC B cells, which go on to become short-lived extrafollicular IgE + ASC.…”

“…126 In contrast, IgE + B cells exhibit strong autonomous BCR signaling, which is associated with a predisposition to differentiation into ASC. 149,151,152 Whether IgE + ASC can transition to maturity and remain as long-lived in bone marrow is unclear; however, antigen ligation of the IgE BCR on ASC promotes SYK-and BCL2L11-dependent apoptosis, 181,192 limiting the life span of most IgE + ASC. other vaccines such as influenza split-virus vaccines fail to generate populations of ASC that survive for even that length of time.…”

“… 179 , 180 Intriguingly, in one of those studies, patients concomitantly undergoing subcutaneous immunotherapy had IgE titres that dropped 50%–60%, 179 arguing putatively persistent IgE + ASC were being killed by exposure to cognate antigen, as would be predicted from a recent mouse study where IgE BCR ligation was shown to cause IgE + ASC apoptosis. 181 Additional human studies point to a long‐lived IgE + ASC population by showing IgE titer maintenance in periods of allergen avoidance, 182 but it is possible that without IL‐4R blockade IgE + ASC production occurs constantly from GC or mBC. A study of dupilumab treatment in atopic dermatitis patients argues that the rare patients whose IgE levels are unchanged might be those in which IL‐4R signaling is not completely blocked.…”

Sequential Switching Through IgG1 is Redundant for Allergic Reactivity and Memory to Allergens

“…However, we have since learned more about mechanisms which uniquely restrict IgE and not IgG1 responses (e.g. IL-21) 7,32,33 , exposing that IgE and IgG1 may be less tightly linked than once thought. Furthermore, it is generally assumed that the rate at which switch remnants are identified represents the minimal possible contribution of IgG1 intermediaries given that only a portion of switching events leave these remnants 31 .…”