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J Allergy Clin Immunol. 2017 Dec;140(6):1604-1615.e5. doi: 10.1016/j.jaci.2017.01.018. Epub 2017 Feb 16.

Lifelong memory responses perpetuate humoral TH2 immunity and anaphylaxis in food allergy.

Author information

1
McMaster Immunology Research Centre (MIRC), Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
2
Departments of Immunology and Medicine, Roswell Park Cancer Institute, Buffalo, NY.
3
Department of Microbiology & Immunology, McGill University, Montreal, Quebec, Canada.
4
Department of Respiratory, Inflammation & Autoimmunity, MedImmune, Gaithersburg, Md.
5
Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
6
McMaster Immunology Research Centre (MIRC), Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada. Electronic address: jordanam@mcmaster.ca.

Abstract

BACKGROUND:

A number of food allergies (eg, fish, shellfish, and nuts) are lifelong, without any disease-transforming therapies, and unclear in their underlying immunology. Clinical manifestations of food allergy are largely mediated by IgE. Although persistent IgE titers have been attributed conventionally to long-lived IgE+ plasma cells (PCs), this has not been directly and comprehensively tested.

OBJECTIVE:

We sought to evaluate mechanisms underlying persistent IgE and allergic responses to food allergens.

METHODS:

We used a model of peanut allergy and anaphylaxis, various knockout mice, adoptive transfer experiments, and in vitro assays to identify mechanisms underlying persistent IgE humoral immunity over almost the entire lifespan of the mouse (18-20 months).

RESULTS:

Contrary to conventional paradigms, our data show that clinically relevant lifelong IgE titers are not sustained by long-lived IgE+ PCs. Instead, lifelong reactivity is conferred by allergen-specific long-lived memory B cells that replenish the IgE+ PC compartment. B-cell reactivation requires allergen re-exposure and IL-4 production by CD4 T cells. We define the half-lives of antigen-specific germinal centers (23.3 days), IgE+ and IgG1+ PCs (60 and 234.4 days, respectively), and clinically relevant cell-bound IgE (67.3 days).

CONCLUSIONS:

These findings can explain lifelong food allergies observed in human subjects as the consequence of allergen exposures that recurrently activate memory B cells and identify these as a therapeutic target with disease-transforming potential.

KEYWORDS:

IgE; IgG(1); T(H)2; anaphylaxis; food allergy; germinal centers; mast cells; memory B cells; peanut allergy; plasma cells

PMID:
28216433
PMCID:
PMC6298600
DOI:
10.1016/j.jaci.2017.01.018
[Indexed for MEDLINE]
Free PMC Article

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