Biology subjects

Waserman, S.

Publications and source records attributed to Waserman, S..

5 recordsLinked to original sources

bioRxiv2023

Pathogenic IgE-fated B cell memory retains functional plasticity

Long-lived immunoglobulin (Ig) E responses against innocuous environmental and dietary antigens (Ags) are maintained by an IgG1-dominant memory B cell (MBC) compartment primed for IL-4 responsiveness. The plasticity of the MBC compartment destined for IgE class switch recombination (CSR), however, remains poorly understood. In this work, we report a critical IL-4/IL-13 dependency for the pathogenic IgE fate of type 2-polarized MBCs. Initiating a recall response in the absence of IL-4/IL-13 signaling diminished the type 2 MBC phenotype in mice and humans and, in mice, permitted the emergence of long-lived Ag-specific IgG2c+ MBCs. The divergence to a type 1-like response was dependent on IFN-{gamma} signaling and arose from both unswitched and class-switched Ag-specific B cells in vivo. This reprogrammed fate was sustained even beyond therapeutic intervention, revealing fundamental insight into the plasticity of the allergen-specific MBC response. One Sentence SummaryB cell responses to allergens can be reprogrammed away from a pathogenic fate through IL-4/IL-13 signaling blockade.

immunology↗

bioRxiv2023

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

Allergic reactions to foods are driven by allergen-binding immunoglobulin (Ig)E antibodies. IgE- expressing cells can be generated through a sequential class switching pathway where activated B cells first switch to an intermediary isotype, most frequently IgG1, and then to IgE. It has been proposed that sequential class switch recombination is important in generating high affinity IgE, augmenting anaphylactic reactions, and in holding the memory of IgE responses. Here, we observed surprising redundancy of sequential switching through IgG1 for the functional affinity of the IgE repertoire against multiple food allergens as well as for the ability of IgE to elicit anaphylaxis. We further found that sequential switching via IgG1 was irrelevant for allergic memory. These results indicate that allergen-specific IgG1 B cells are redundant in sensitization, anaphylaxis, and food allergy persistence, thereby implicating other switching pathways as important considerations in the development of therapeutics for allergic diseases.

immunology↗

bioRxiv2023

A Distinct Phenotype of Polarized Memory B cell holds IgE Memory

Allergen-specific IgE antibodies mediate allergic pathology in diseases such as allergic rhinitis and food allergy. Memory B cells (MBCs) contribute to circulating IgE by regenerating IgE-producing plasma cells upon allergen encounter. We report a population of type 2 polarized MBCs defined as CD23hi, IL-4Rhi, CD32low at the transcriptional and surface protein levels. These "MBC2s" are enriched in IgG1 and IgG4-expressing cells, while constitutively expressing germline transcripts for IgE. Allergen-specific B cells from patients with allergic rhinitis and food allergy were enriched in MBC2s. MBC2s generated allergen specific-IgE during sublingual immunotherapy, thereby identifying these cells as the primary reservoir of IgE. The identification of MBC2s provides insights into the maintenance of IgE memory, which is detrimental in allergic diseases, but which could be beneficial in protection against venoms and helminths. One-Sentence SummaryIdentification of a novel memory B cell subset which holds allergen specific IgE memory.

immunology↗

bioRxiv2020

Interrupting reactivation of immunological memory reprograms allergy and averts anaphylaxis

IgE production against innocuous antigens can lead to life-threatening reactions such as anaphylaxis. While IgE levels drastically decline with strict allergen avoidance, the ability to regenerate IgE can persist for a lifetime, as is the case for peanut allergy. The mechanism by which IgE regenerates remains unresolved. A novel culture system and application of single-cell RNA-sequencing, elucidated the transcriptomic signature of human peanut-reactive B and T cells and revealed IL-4/IL-13 as a signaling pathway critical for the IgE recall response. Indeed, interruption of this pathway not only prevented IgE production and anaphylaxis, but also reprogrammed the pathogenic response against peanut. This investigation advances our understanding of the mechanism that regenerates IgE in food allergy and spotlights IL-4/IL-13 blockade as a therapeutic with disease-transforming potential. One Sentence SummarySingle-cell transcriptomics of allergic memory responses reveals how to teach the immune system to forget.

immunology↗

bioRxiv2019

BCR analysis of single-sorted, putative IgE+ memory B cells in food allergy: an ephemeral existence?

Immunoglobulin (Ig) E is the critical effector molecule in allergic reactions. Consequently, research efforts to understand the biology of IgE-expressing cells is of paramount importance. In particular, the role of IgE+ memory B cells (MBCs) in the perpetuation of allergic reactivity has been the subject of intense research. Studies in mice have convincingly established that IgE+ B cells are rare and transient and, therefore, an unlikely candidate to maintain allergic disease. In contrast, IgE+ MBCs have been detected by flow cytometry in the sputum and peripheral blood of humans and have been proposed as a clinical marker of allergic disease. We established a method to genetically validate, at the single-cell level, the putative IgE+ MBCs identified by flow cytometry from humans. We, then used this information to develop an enhanced flow cytometry protocol that more accurately identifies bona fide IgE+ MBCs. We found that IgE+ MBCs were detected in some patients with atopic dermatitis, but at a frequency that was ~100 times lower than previously reported. We also found that IgE+ MBCs were undetectable in PBMCs from peanut allergic patients. These findings provide tools to identify bona fide IgE+ MBCs, demonstrate their extreme rarity in circulation and are consistent with the lack of a central role for IgE+ MBCs in the maintenance of allergic sensitivity.\n\nOne Sentence SummaryThe frequency of IgE+ MBCs in the peripheral circulation of humans is orders of magnitude lower than previously reported and comparable between allergic and healthy donors, which cautions about the clinical utility of their assessment.

immunology↗