The enigma of IgE+ B-cell memory in human subjects

doi:10.1016/j.jaci.2012.12.1569

Journal of Allergy and Clinical Immunology

Volume 131, Issue 4, April 2013, Pages 972-976

https://doi.org/10.1016/j.jaci.2012.12.1569 Get rights and content

Our understanding of the origin and fate of the IgE-switched B cell has been markedly improved by studies in mouse models. The immediate precursor of the IgE-switched B cell is either a relatively naive nonswitched B cell or a mature IgG-switched B cell. These 2 routes are referred to as the direct and indirect pathways, respectively. IgE responses derived from each pathway differ significantly, largely reflecting the difference in time spent in a germinal center and thus time for clonal expansion, somatic hypermutation, affinity maturation, and acquisition of a memory phenotype. The clinical and therapeutic implications for IgE responses in human subjects are still a matter of debate, largely because the immunization procedures used in the animal models are significantly different from classical atopic sensitization to allergens from pollen and mites. On the basis of the limited information available, it seems likely that these atopic IgE responses are characterized by a relatively low IgG/IgE ratio, low B-cell memory, and modest affinity maturation, which fits well with the direct switching pathway. It is still unresolved how the IgE response evolves to cover a wide epitope repertoire involving many epitopes per allergen, as well as many different allergens from a single allergen source.

Section snippets

The elusive IgE-switched B cell

Circulating IgE⁺ B cells are extremely rare in human subjects.4, 5, 6, 7 Analysis of IgE cDNA transcripts from cells in human blood indicates that most circulating IgE-producing cells are more related to PCs than to B cells (see below). The scarcity of IgE-committed memory B cells is supported by the plasma IgE antibody response on allergen injection during allergen-specific immunotherapy (SIT), which is very modest (typically 2-fold) for IgE, compared with 10- to 100-fold for IgG.⁸ A lack of

Tracking IgE-switched B cells by using mice with transgenically tagged IgE

IgE reporter mice with an increased power to detect IgE⁺ B cells have recently been generated. Talay et al¹³ challenged the current thinking that IgE⁺ memory B cells do not participate in GC reactions. The authors cleverly engineered mice to express green florescence protein in tandem with the membrane form of IgE under the control of the IgE promotor. With these mice, they were able to identify in 2 models (Nippostrongylus brasiliensis infection and a hapten-protein conjugate) IgE-switched GC

Transcriptome analysis of the IgE heavy chain variable domain CDR3

The case for high-affinity allergen-driven IgE in patients with allergic disease includes observations that IgE transcripts of 3 patients with grass pollen allergy showed IgE with related CDR3 and high levels of somatic mutations within the CDR, which is consistent with oligoclonal expansion of B cells.¹⁶ On analysis of 1366 IgE transcripts from 13 children, it was noted that the patients with asthma showed evidence of more clonal diversity and higher SHM in their IgE repertoires than patients

Affinity of IgE to protein allergens and its relation to the effector function of IgE

Xiong et al²² argue that the indirect, high-affinity route to IgE is most relevant in relation to atopic allergy. Their main argument is that the affinity of IgE produced through the direct route is too low to be pathogenic. We want to argue that IgE produced through the direct route is the most relevant in the setting of atopic allergy. The 2 antigens used for the affinity discussion by Xiong et al²² were both haptens: a 13-mer peptide and nitrophenyl. It is difficult to extrapolate these data

Potential role of IgE in expanding the IgE repertoire according to the “initiator allergen” hypothesis

The atopic IgE response to mites and pollen is unusual in at least 3 ways. First, the isotype-committed B memory component is almost absent. Second, the IgG/IgE ratio is generally less than 3 (ie, much lower than in the animal models),26, 27 which suggests that this atopic immune response might lack mature GCs altogether. Third, the repertoire involves many epitopes on many allergens. This is surprising because allergens are supposed to belong to a very special subset of antigens. If so, one

Direct and indirect switching pathways in relation to therapy

The comment by Xiong et al²² that low-affinity IgE might be protective against allergic disease is presumably based on the idea that high levels of “irrelevant” IgE could saturate IgE receptors. This idea ignores the potent effect of IgE in increasing the number of IgE receptors on mast cells and basophils.³⁶ Attempts to use deliberate parasite infection have not supported the concept that low-affinity IgE is protective against allergy.³⁷ Although the anti-inflammatory activities of some

Summary and conclusions

1.
Some SHM and affinity maturation occurs even in the direct pathway of B-cell isotype switching to IgE.
2.
IgE⁺ B cells can be present in GCs but not in close proximity with T cells.
3.
IgE-switched B cells show a predisposition for premature differentiation into PCs, and IgE⁺ B memory cells are rare in the circulation.
4.
The affinity requirements for IgE-mediated activation of mast cells and basophils by protein allergens are modest and likely to be met by IgE produced through the direct pathway.
5.

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Unlike in the human, in most mouse models, the sIgG levels are much higher than those found in untreated patients with atopy. These high sIgG levels in experimental animals (often >10,000 ng/mL) point to an immune response with active GCs.11,18 This is markedly different from what has been found in humans regarding specific IgG (sIgG) and sIgE levels to airborne allergens.
To review the literature and discuss a hypothesis as to why most people do not have allergy. This hypothesis is dependent on the following 3 main components: (1) airborne allergens (eg, from pollen or mites) are weak antigens that induce a B-cell response only in immunologically most reactive subjects (ie, with atopy); (2) a roadblock to production of immunoglobulin E (IgE) is the T helper 2/interleukin 4 requirement for class switch to IgE; (3) activated germinal centers prevent the formation of mature IgE-switched B-cells, creating a second roadblock to IgE production.
Transgenic reporter mice and a cross-sectional human cohort.
From the mouse studies, we selected the data on histology and tissue-derived cell suspensions published by several groups in 2011 to 2014. From the human cohort, we selected our published microarray data on the levels of allergen-specific IgE and IgG in serum.
The immune response to airborne atopic allergens entails both IgE and IgG antibodies rather than just an IgG or IgE response. However, as expected for an immune response without mature germinal centers, the specific IgG levels will be very low, typically in the ng/ml range.
Control of IgE production is not just through the T helper 2/interleukin 4–mediated class switch. Recent studies suggest that mature germinal centers are likely to provide protection against the development of allergy to airborne allergens, as well. This may explain why allergen exposure does not induce allergen-specific IgE in everyone.
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Drug-induced anaphylaxis is a hyperacute reaction affecting multiple organs that can be of fatal consequence. Its incidence is increasing, consistent with a global increased sensitization to various allergens and drugs in the population. Few risk factors and mechanisms have been identified from human studies due to the rarity of anaphylactic events and their unpredictability. This systemic reaction is caused by the rapid release of a large range of functionally diverse mediators, including histamine and platelet-activating factor as the main drivers identified. Mechanisms defined from models of experimental anaphylaxis identify drug-specific antibodies of the IgE and IgG class that link the drug to antibody receptors on multiple cell types, causing their activation and mediator release. In the case of drugs with peculiar chemical structures, antibodies may not be necessary because drug-binding receptors, such as Mas-related G protein–coupled receptor member X2, have been identified. This review describes the complex reaction leading to drug-induced anaphylaxis that can involve various antibody classes, various cell types—including mast cells, neutrophils, platelets, basophils, macrophages, and monocytes—and their mediators and receptors that, importantly, can be activated alone or in association to participate in the severity of the reaction.
Food allergy and omics
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Food allergy (FA) prevalence has been increasing over the last few decades and is now a global health concern. Current diagnostic methods for FA result in a high number of false-positive results, and the standard of care is either allergen avoidance or use of epinephrine on accidental exposure, although currently with no other approved treatments. The increasing prevalence of FA, lack of robust biomarkers, and inadequate treatments warrants further research into the mechanism underlying food allergies. Recent technological advances have made it possible to move beyond traditional biological techniques to more sophisticated high-throughput approaches. These technologies have created the burgeoning field of omics sciences, which permit a more systematic investigation of biological problems. Omics sciences, such as genomics, epigenomics, transcriptomics, proteomics, metabolomics, microbiomics, and exposomics, have enabled the construction of regulatory networks and biological pathway models. Parallel advances in bioinformatics and computational techniques have enabled the integration, analysis, and interpretation of these exponentially growing data sets and opens the possibility of personalized or precision medicine for FA.
Lifelong memory responses perpetuate humoral T <inf>H</inf> 2 immunity and anaphylaxis in food allergy
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Citation Excerpt :
The expansion of IgG1+ memory B cells was accompanied by BM reconstitution with antigen-specific IgE+ PCs, whereas the population of IgG1+ PCs of the same specificity remained unchanged; this implies that the recall response was driven by IgG1+ memory B cells that class-switched and differentiated into IgE+ PCs. Although sequential class-switching from an intermediate IgG-expressing B cell to IgE has been reported in patients with atopic dermatitis50 and ex vivo tonsil B-cell cultures,51 the relevance of both direct and sequential class-switching to IgE in patients with food allergy remains to be elucidated.52,53 Even though GC activity was induced during the primary immune response (sensitization), it was absent during recall responses.
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.
We sought to evaluate mechanisms underlying persistent IgE and allergic responses to food allergens.
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).
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).
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.
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A substantial subgroup of asthmatic patients have “nonallergic” or idiopathic asthma, which often takes a severe course and is difficult to treat. The cause might be allergic reactions to the gram-positive pathogen Staphylococcus aureus, a frequent colonizer of the upper airways. However, the driving allergens of S aureus have remained elusive.
We sought to search for potentially allergenic S aureus proteins and characterize the immune response directed against them.
S aureus extracellular proteins targeted by human serum IgG₄ were identified by means of immunoblotting to screen for potential bacterial allergens. Candidate antigens were expressed as recombinant proteins and used to analyze the established cellular and humoral immune responses in healthy adults and asthmatic patients. The ability to induce a type 2 immune response in vivo was tested in a mouse asthma model.
We identified staphylococcal serine protease–like proteins (Spls) as dominant IgG₄-binding S aureus proteins. SplA through SplF are extracellular proteases of unknown function expressed by S aureus in vivo. Spls elicited IgE antibody responses in most asthmatic patients. In healthy S aureus carriers and noncarriers, peripheral blood T cells elaborated T_H2 cytokines after stimulation with Spls, as is typical for allergens. In contrast, T_H1/T_H17 cytokines, which dominated the response to S aureus α-hemolysin, were of low concentration or absent. In mice inhalation of SplD without adjuvant induced lung inflammation characterized by T_H2 cytokines and eosinophil infiltration.
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: J.M.D. has received honoraria payments for education presentations and contracted research funds from Stallergenes Pty Ltd and is supported by funds from the Australian National Health and Medical Research Council, the Asthma Foundation of Queensland, and the University of Queensland.

: Disclosure of potential conflict of interest: J. M. Davies has consultancy arrangements with Stallergenes Pty Ltd, France; is employed by the University of Queensland; has received one or more grants from or has one or more grants pending with the National Health Medical Research Council of Australia, the Asthma Foundation of Queensland, the University of Queensland, and the Australian Society for Clinical Immunology and Allergy; has received one or more payments for lecturing from or is on the speakers' bureau for Stallergenes Pty Ltd; and has received one or more payments for travel/accommodations/meeting expenses from Stallergenes for delivery of research presentations. T. A. Platts-Mills has received one or more grants from or has one or more grants pending with the National Institutes of Health/National Institute of Allergy and Infectious Diseases. R. C. Aalberse declares that he has no relevant conflicts of interest.

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Reviews and feature articleThe enigma of IgE+ B-cell memory in human subjects

Section snippets

The elusive IgE-switched B cell

Tracking IgE-switched B cells by using mice with transgenically tagged IgE

Transcriptome analysis of the IgE heavy chain variable domain CDR3

Affinity of IgE to protein allergens and its relation to the effector function of IgE

Potential role of IgE in expanding the IgE repertoire according to the “initiator allergen” hypothesis

Direct and indirect switching pathways in relation to therapy

Summary and conclusions

J Allergy Clin Immunol

Mol Immunol

Immunotechnology

Immunity

Adv Immunol

Immunity

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Chest

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

On the differentiation of mouse IgE(+) cells

Nat Immunol

Frequency analysis of IgE-secreting B lymphocytes in persons with normal or elevated serum IgE levels

J Immunol

Inefficient processing of mRNA for the membrane form of IgE is a genetic mechanism to limit recruitment of IgE-secreting cells

Eur J Immunol

Saturation of immunoglobulin E (IgE) binding sites by polyclonal IgE does not explain the protective effect of helminth infections against atopy

Infect Immun

Grass pollen immunotherapy induces mucosal and peripheral IL-10 responses and blocking IgG activity

J Immunol

The development of IgE+ memory B cells following primary IgE immune responses

Eur J Immunol

Antigen-specific immunoglobulin E+ B cells are preferentially localized within germinal centres

Immunology

IgE(+) memory B cells and plasma cells generated through a germinal-center pathway

Nat Immunol

The origin of IgE memory and plasma cells

Cell Mol Immunol

VH gene usage in immunoglobulin E responses of seasonal rhinitis patients allergic to grass pollen is oligoclonal and antigen driven

Clin Exp Allergy

Reviews and feature article
The enigma of IgE⁺ B-cell memory in human subjects