Mucosal Mast Cells in Food Allergies

Mucosal Mast Cells in Food Allergies: History

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Subjects: Allergy

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Mucosal mast cells (MMCs) localized in the intestinal mucosa play a key role in the development of IgE-mediated food allergies. Recent advances have revealed that MMCs are a distinctly different population from connective tissue mast cells localized in skin and other connective tissues. MMCs are inducible and transient cells that arise from bone marrow-derived mast cell progenitors, and their numbers increase rapidly during mucosal allergic inflammation. However, the mechanism of the dramatic expansion of MMCs and their cell functions are not well understood.

mucosal mast cells
notch signaling
TGF-β
food allergy
oral immunotherapy

1. Introduction

Humans have long suffered from food allergies. Hippocrates (460-377 BC), an ancient Greek physician, wrote about a suspected case of allergy to cheese [1]. The principal treatment for food allergies is the identification and avoidance of the causative food, which has remained largely unchanged from ancient times to the present. However, these approaches create a serious problem with food energy intake [2]. Therefore, the development of therapeutic agents and treatments for food allergies is in high demand, but to achieve this, we need to understand the underlying mechanisms.

Food allergies are classified into three groups according to the immunological mechanism: IgE-mediated, non-IgE-mediated, and mixed. Typical food allergies are IgE-mediated, and thus the main symptoms are caused by immediate hypersensitivity reactions in which food allergen-specific IgE and mast cells play a central role. In some non-IgE-mediated allergies, such as pseudo-allergies, mast cell activation also plays an important role in the onset of allergic symptoms [3,4,5]. In developed countries, the prevalence of food allergies is 6% to 10% in infants and 2% to 5% in adults [6,7,8,9], indicating that they are more common in children. However, it has recently been demonstrated that some patients with irritable bowel syndrome (IBS) have abdominal pain caused by local IgE-mediated food allergy reactions [10]. The prevalence of IBS in developed countries is approximately 10% to 15% and is more common in adults. More than 50% of patients with IBS have symptoms triggered by a meal, despite negative results of serum food allergen-specific IgE antibodies and skin prick tests [11,12]. Recent studies have shown that many of these patients are negative for food allergen-specific IgE in serum but positive for the intestinal mucosa, which leads to a local IgE-mediated food allergy reaction [10,12]. Based on these findings, Aguilera-Lizarraga et al. [10] proposed a new disease concept called “food-induced disorders mediated by mast cell activation”. IBS, in which foods are involved in the onset of symptoms, is part of a spectrum of food-induced disorders, and systemic food allergy is at extreme end of the spectrum.

Many studies using animal models have shown that mast cells in the intestinal mucosa are the major effector cells in IgE-mediated food-induced disorders, including food allergies [10,13,14,15,16]. Therefore, intestinal mucosal mast cells are an attractive target for therapeutic intervention in those diseases.

2. MMCs as a Potential Therapeutic Target for the Treatment of Food Allergies

2.1. Blockade of Notch Signaling

Notch signaling is a potent inducer of MMC differentiation. To investigate whether the symptoms of food allergies are attenuated by the inhibition of Notch signaling, we administered the Notch signaling inhibitor DAPT, also known as a γ-secretase inhibitor, to a mouse model of IgE-meditated food allergy sensitized with ovalbumin (OVA). The expansion of MMCs in the small intestine and colon was significantly suppressed in mice treated with DAPT during the effector phase. Predictably, the severity of allergic diarrhea and the degree of hypothermia induced by oral administration of OVA were lower in mice treated with DAPT than in the control mice. The concentration of serum OVA-specific IgE in DAPT-treated mice was the same level as in the control mice, indicating that the reduction in MMC numbers contributed to the attenuation of symptoms [63]. Since Notch signaling is not only involved in MMC differentiation but also in the differentiation of various immune cells, long-term administration of a Notch signaling inhibitor may lead to undesirable side effects in food-allergic patients. Therefore, the idea of administering a Notch signaling inhibitor to patients with food allergies is not very promising. However, these results suggest that the inhibition of MMC differentiation and the suppression of Notch target gene expression in mast cells can be effective in the treatment of IgE-mediated food allergies.

2.2. Blockade of IL-4 Signaling

In allergic inflammation in both human and mouse mucosa, IL-4 is a key cytokine for inducing MMC expansion and conferring inflammatory phenotypes to MMCs. Thus, the blockade of IL-4 signaling may prevent MMC expansion in IgE-mediated food allergies. Dupilumab, a fully human monoclonal antibody against the IL-4 receptor α chain (IL-4Rα), has already been used to treat patients with severe atopic dermatitis (AD), asthma, and chronic rhinosinusitis with nasal polyposis (CRSwNP) [81]. IL-4Rα is shared with IL-4 receptor and IL-13 receptor, and thus dupilumab blocks both IL-4 and IL-13 signaling. IL-4 and IL-13 are signature type 2 cytokines and exert diverse effects on multiple cells. IL-4 plays a critical role in Th2 differentiation in T cells and IgE class switching in B cells. IL-13 induces goblet cell hyperplasia and smooth muscle cell proliferation [82]. In addition, both IL-4 and IL-13 act on mast cells, basophils, eosinophils, macrophages, fibroblasts, epithelial cells, and keratinocytes [83]. Dwyer et al. [77] performed data analysis of single-cell RNA sequencing from a patient with CRSwNP evaluated before and after six weeks of treatment with dupilumab and found markedly reduced expression of IL17RB (encoding IL-25 receptor), a newly identified marker of human MC_Ts. This indicates that dupilumab also targets MMCs and may be effective in suppressing mucosal allergy inflammation caused by MMCs. At this time, there are only a few reports of food-allergic patients treated with dupilumab. Rial et al. [84] have recently reported that a 30-year-old woman with severe AD who had newly developed a food allergy to corn and nuts acquired a tolerance to these foods by treatment with dupilumab. This case report suggests that the blockade of IL-4 signaling may be effective in the treatment of food allergies, although it is unclear whether MMCs are the primary target.

IL-33 and IL-25 secreted by various cell types activate Th2-type cytokine production and exacerbate allergic diseases. The neutralization of these cytokines by specific antibodies has been shown to be effective in suppressing the Th2 immune responses [85]. Therefore, these cytokines, which enhance the production of IL-4 and IL-13, may also be potent therapeutic targets.

2.3. Activation of an Inhibitory Receptor

Mast cells express the inhibitory receptor CD300f, also known as leukocyte mono-immunoglobulin-like receptor 3 (LMIR3), on the cell surface. CD300f has two immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and an immunoreceptor tyrosine-based switch motif (ITSM) in its intracellular region, which are phosphorylated upon binding to its ligand ceramide [86]. Src homology 2 domain-containing protein phosphatase (SHP)-1 and -2, which are recruited to the phosphorylated ITIMs and ITSM, negatively regulate high-affinity IgE receptor FcεRI-mediated signaling, resulting in the suppression of IgE-mediated mast cell activation. Uchida et al. [87] have shown that CD300f is also expressed on the cell surface of MMCs, MMC9, and β7 integrin⁺ MCp in the small intestinal lamina propria in mice. In a mouse model of IgE-mediated food allergy, the serum level of mMCP-1, a marker of MMC activation, was higher in CD300f-deficient mice than in wild-type mice after oral allergen challenge. Moreover, food allergy responses, such as allergic diarrhea and the transient drop in body temperature induced by allergen challenge, were exacerbated in CD300f-deficient mice compared to wild-type mice. These results suggest that IgE/MMC-mediated food allergy reactions may be attenuated by the activation of CD300f. Based on this hypothesis, ceramide-containing vesicles were administrated to the mouse model of IgE-mediated food allergy. As expected, the food allergy responses were attenuated in mice pretreated with the vesicles. Therefore, CD300f is a potential therapeutic target for the treatment of IgE-mediated food allergies.

In addition to the inhibitory receptor, inhibitory cytokines, such as IL-37, may also function to suppress excessive activation of mast cells [88]. Thus, these natural inhibitors of immune responses could also be used as therapeutic agents.

3. Roles of MMCs in Oral Immunotherapy

Oral immunotherapy (OIT) is a promising treatment for patients with food allergies to induce desensitization and eventually sustain unresponsiveness to food allergens. In general, the process of OIT is composed of an initial build-up in which the allergen is administered repeatedly with a gradual increase followed by a maintenance phase. The first goal of OIT is desensitization, which is defined as a lack of clinical reactivity to allergens and is maintained by regular allergen exposure. The efficacy of OIT for egg, milk, and peanuts has been demonstrated by many randomized placebo-controlled trials [89]. However, OIT also has the risks of adverse reactions, such as oral itching, eosinophilic gastrointestinal disorders, and anaphylaxis [89,90]. To mitigate the risks of OIT, there is great interest in developing approaches to effectively and safely induce desensitization.

3.1. Harmful Effects of MMCs

Undesirable allergic reactions during OIT are triggered by the IgE-mast cell axis. One approach to prevent these reactions is to use an anti-IgE antibody. Omalizumab is a humanized IgG1κ monoclonal antibody that binds to the Fc region of human IgE and is currently applied for the treatment of severe uncontrolled asthma, allergic rhinitis, and chronic spontaneous urticaria [91,92,93]. This antibody blocks the interaction between IgE and FcεRI and reduces the level of free IgE in circulation, preventing the development of IgE-mediated allergic reactions. The use of omalizumab with OIT has been investigated in several small trials for the treatment of milk, egg, and peanut allergies [94]. Notably, these trials have shown that the combination of omalizumab and OIT can not only reduce adverse events but also the time to acquisition of desensitization. These reports support the idea that the activation of mast cells, including MMCs, impairs the acquisition of desensitization to allergens. Therefore, blockade of the IgE-mast cell axis will improve the safety and efficacy of OIT.

3.2. Helpful Effects of MMCs

There are several reports on the mechanisms by which the early initiation phase of OIT induces desensitization. Displacement of the actin cytoskeleton in desensitized mast cells inhibits IgE-dependent calcium influx and thus suppresses mast cell degranulation [95]. Another report demonstrates that OIT-induced mast cell hyporesponsiveness is induced by enhanced internalization of IgE bound to the cell surface [96]. These studies indicate that mast cells become unresponsive to allergens, resulting in the suppression of the induction of allergic symptoms. In addition, it is believed that the expansion of the Treg population is involved in the acquisition of desensitization and/or sustained unresponsiveness to allergens in the late initiation phase of OIT [97,98]. The mechanism by which Treg expansion is induced in cases of successful OIT is poorly understood. Previous studies have shown that, under certain conditions, mast cells play a role in immunosuppression by producing cytokines, such as IL-2 and IL-10 [99,100]. IL-2 is essential for the proliferation, survival, maintenance, and functional capacity of Tregs, which constitutively express IL-2 receptor α chain (CD25) [101]. Although IL-10 is a well-known immunosuppressive cytokine produced by Tregs, it also plays an important role in the differentiation and functional capacity of Tregs themselves [102,103]. Takasato et al. [104,105] have demonstrated a helpful effect of MMCs in OIT using a mouse model of OIT. OIT shifted MMCs from pathogenic (or pro-allergic) status to regulatory (desensitization) status. OIT-induced desensitized MMCs contributed to the expansion of Tregs by releasing immunosuppressive cytokines, such as IL-2 and IL-10, in addition to reduced reactivity to allergens and the suppressed release of the Th2 cytokine, IL-4. These results provide new insights into the role of MMCs in the mucosal immune system.

The second goal of OIT is the acquisition of sustained unresponsiveness to allergens, which is the long-term loss of reactivity to allergens independent of continued exposure to them. However, current OIT therapy has not been able to efficiently induce sustained unresponsiveness for specific allergens to food-allergic patients [89,106]. A major problem is that the mechanism by which sustained unresponsiveness is induced by OIT remains unknown. We have recently shown that the expansion of immunosuppressive cells, including Tregs, IL-10-expressing Th2, and myeloid-derived suppressor cells (MDSCs), contributes to the establishment of sustained unresponsiveness by OIT, and that Notch signaling is involved in these expansion processes [107]. However, the roles of MMCs were not analyzed in this study, and thus further research is needed.

4. Concluding Remarks

In summary, intestinal MMCs play a central role in the development of food-induced disorders mediated by mast cell activation, including systemic food allergies. Mouse MMCs are induced to differentiate mainly by TGF-β and Notch ligands, stimulated to proliferate rapidly by IL-4 and IL-9, and converted to an inflammatory phenotype by IL-4. Although there are still many unanswered questions about human mast cells, transcriptome and proteome analyses suggest that they are not so different from mouse mast cells [36]. Thus, these cytokines and ligands are potential therapeutic targets for food-induced disorders.

Recent advances have revealed that MMCs (MC_T in humans) are a distinctly different population from CTMCs (MC_TC in humans). However, the functions of MMCs are still poorly understood. The number of MMCs increases dramatically during mucosal allergic inflammation. However, are β7 integrin⁺ MCp the only source of MMCs? What happens to the expanded MMCs after the inflammation has ended? Food allergies in humans are often accompanied by cutaneous symptoms in addition to mucosal symptoms. Are MMCs involved in the induction of cutaneous symptoms such as erythema and urticaria? Food-induced disorders, including systemic food allergy, cause abdominal pain. How do MMCs and sensory nerves interact? Do MMCs contribute to the establishment of oral tolerance? MMCs may have as-yet-unidentified functions and roles that are unique to the mucosal immune system. Therefore, research focusing on MMCs will further advance the treatment of food-induced disorders.

This entry is adapted from the peer-reviewed paper 10.3390/cells11030329

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