Working Paper Review Version 2 This version is not peer-reviewed

Memory Generation and Re-Activation in Food Allergy

Version 1 : Received: 2 March 2021 / Approved: 3 March 2021 / Online: 3 March 2021 (11:36:33 CET)
Version 2 : Received: 1 May 2021 / Approved: 5 May 2021 / Online: 5 May 2021 (12:38:46 CEST)

A peer-reviewed article of this Preprint also exists.

Journal reference: Immunotargets and Therapy 2021, 10, 171-184
DOI: 10.2147/ITT.S284823

Abstract

Recent evidence has highlighted the critical role of memory cells in maintaining lifelong food allergies, thereby identifying these cells as therapeutic targets. IgG+ memory B cells replenish pools of IgE-secreting cells upon allergen exposure, which contract thereafter due to the short lifespan of tightly regulated IgE-expressing cells. Advances in the detection and highly dimensional analysis of allergen-specific B and T cells from allergic patients have provided insight on their phenotype and function. The newly identified Th2A and Tfh13 populations represent a leap in our understanding of allergen-specific T cell phenotypes, though how these populations contribute to IgE memory responses remains poorly understood. Within, we discuss the mechanisms by which memory B and T cells are activated, integrating knowledge from human systems and fundamental research. We then focus on memory reactivation; specifically, on the pathways of secondary IgE responses. Throughout, we identify areas of future research which will help identify immunotargets for a transformative therapy for food allergy.

Subject Areas

food allergy; IgE; memory responses; anaphylaxis; B cells; T cells;

Comments (1)

Comment 1
Received: 5 May 2021
Commenter: RODRIGO JIMENEZ-SAIZ
Commenter's Conflict of Interests: Author
Comment: The manuscript was submitted to Immunotargets and Therapy and this is the first revision. Please see below our reply to the editor, which includes the changes made.

To the Editor:
We thank the reviewers for their kind words about the manuscript and their rigorous review and insightful suggestions to improve it. We have prepared a revised manuscript which we hope addresses the reviewers’ comments and is suitable for publication in Immunotargets and Therapy. Below, we have provided a point-by-point reply to the reviewers’ comments. 

Reviewer 1 Line 176: It is known from inhibition experiments that low-affinity IgE exists. Which cells may regulate this IgE production? Can these memory B cells exhibit long-lasting memory as well? If not, which apoptotic mechanisms may contribute to this?
Response:We thank the reviewer for highlighting an area where we could expand our discourse. To our knowledge, the mechanisms which maintain the memory of low affinity IgE have not yet been thoroughly investigated. However, Mesin et al. (doi:10.1016/j.cell.2019.11.032) demonstrated that mutated (presumably high affinity) B cells are selected during a recall response, and that low affinity cells do not appear to efficiently participate in secondary responses.None-the-less, we acknowledge the work done by He et al. (doi: 10.1038/s41467-017-00723-0), which demonstrated using transfer systems that lowly mature memory B cells yield low affinity IgE and have updated the manuscript at lines 124-128 to read:“In mice, a population of mature CD80+CD73+PDL2+IgG1+ MBCs yields the majority of secondary IgE-secreting cells, especially those with high affinity for allergen. Less mature MBC populations (CD80-CD73+/-) yield low affinity IgE or re-enter the germinal center (GC) to affinity mature, but ultimately were found to contribute sparingly to secondary IgE production.”Further, we have added the hypothesis made by Gowthaman et al. (doi: 10.1126/science.aaw6433) regarding Tfh2 cells being sufficient for low affinity IgE production at lines 191-192:“Genetic deletion of Tfh13 cells did not abrogate IgE production, suggesting that Th2-biased Tfh2 cells may be sufficient for low affinity IgE production.

“  The IgE-mediated FcεRI up-regulation and stabilization and the slow kinetics of IgE dissociation from FcεRI appear to essential for establishing long-lasting memory of mast cells and basophils. This mechanism of memory formation and maintenance is totally different from the immunological memory of B and T cells.
 Response:We thank the reviewer for this insightful comment. We have inserted the following at line 74 in the revised manuscript: “In the absence of IgE production, IgE that remained bound to the surface of mast cells was capable of inducing anaphylaxis for an additional 100 days.” The ability of surface-bound IgE to mediate anaphylaxis remains only transiently once circulating IgE disappears. We contend that this does not classify as “memory” as this mechanism alone could not regenerate allergen-specific IgE production and maintain persistent food allergies.

 Reviewer 2
Major comment:Line 66-78:I find that the discussion of the persistence of humoral immunity too narrow. I agree with the authors that the most likely cause of life-long serological memory is the memory B cell, but competing hypothesis (and data) do exist and deserves to be discussed. I suggest to discuss the work by Asrat et al. (Sci. Immunol. 2020 vol5) which presents evidence for long-lived plasma cells in allergy and, further, I suggest to discuss the work of Bernasconi et al (Science 2002 298: 2199-2202) whom describes the continuous homeostatic antigen-independent turnover of memory B cells to plasma cells as a mechanism to maintain serological memory.
Response:The reviewer raises good points surrounding alternative hypotheses to the maintenance of allergen-specific IgE and persistent food allergies. We have expanded upon the previous submission to include the following:About homeostatic memory proliferation (Line 79-85 in the revised manuscript):“It is likely that accidental exposures to food allergens drive memory responses that regenerate IgE-secreting cells, thereby maintaining titers of food-specific IgE. As an alternate hypothesis, allergen-specific memory B cells may proliferate homeostatically in response to infections or other inflammatory stimuli and differentiate into antibody-secreting cells. This has been previously observed in the context of vaccination and IgG responses. Although it has not been extensively studied in food allergy, in mice co-sensitized to PN and OVA, sub-clinical exposures to PN alone led to the generation of both PN-specific and OVA-specific GC B-cells.”About long lived IgE PCs (Line 86-92 in the revised manuscript):“One recent publication proposed that mice chronically exposed to house dust mite generate long-lived IgE-secreting cells which home to the bone marrow and maintain titers of allergen-specific IgE. In the same study, IgE+ PCs were detected in the bone marrow of cat allergic patients, but the longevity of these cells is not known. In patients avoiding food allergens, exposures are thought to be rare and therefore do not likely provide the chronic stimulus required for these observations. Additional research is required to understand the importance of this axis in food allergy

.” The statement " (line 68)"..in seasonal allergies, the levels of allergen-specific IgE dramatically decline off season, only to reemerge when allergen returns ." is not completely accurate. What is observed in immunotherapy trials (e.g. Durham et al Allergy Clin Immunol 2012;129:717-25.), is that IgE titers increase slightly after the pollen season only to return to baseline. In fact, IgE baseline titers in immunotherapy pollen trials (evaluated in the placebo group) are very consistent over a five-year period with only minor fluctuation caused by the pollen season. The consistency of IgE titers is also a key element in the diagnosis of allergy, which in many countries rely on specific IgE tests. Large seasonal fluctuations in IgE titers would preclude accurate diagnosis. I suggest remove this statement in line 68, as the maintenance of IgE titers in pollen allergy can be equally explained by long-lived plasma cells or homeostatic turnover of memory B cells. 
Response:We thank the reviewer for his/her expertise in this matter. Upon review of this literature and others, we have removed this line from the manuscript. 

Minor comments:Line 65: The section titles should include "memory B cell" and not just "memory cell" as is done in the T cell sections
Response: The section header now reads: “Memory B Cells Maintain Lifelong Food Allergies”.

Line 93-180: This is a very long section which describes the phenotypic evidence for both B and T memory. I suggest to divide this section into parts, one on B cells and one on T cells to improve readability. A meaningful separation could be done at line 138.
Response: This section has been divided into two at the indicated location. The section headers now read:  “Phenotype of Allergen-Specific Memory B Cells,” and “Phenotype of Allergen-Specific Memory T Cells”.

Line 234 "MBC" abbreviation should be written in full
Response: The section header now reads “Generation of Allergen-Specific Memory B Cells”. 

We hope that these replies address the reviewers’ concerns. 

Sincerely,Joshua F.E. Koenig, Kelly Bruton, Allyssa Phelps, Emily Grydziuszko, Rodrigo Jiménez-Saiz, Manel Jordana 
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