Allergy desensitization: what is the mechanism? Could it happen with other immune responses?

Allergy desensitization: what is the mechanism? Could it happen with other immune responses?

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Allergy is a type of immune response against an otherwise harmless substance. If I understand it well, the aim of allergy immunotherapy is not to stimulate an immune response like the immunotherapy for for other diseases, but to progressively reduce it by controlled exposition to the antigen. Is the mechanism understood? Could the repeated long-term exposition to an antigen reduce other types of immune responses (to virus or bacteria for example?)

Allergy desensitization: what is the mechanism? Could it happen with other immune responses? - Biology

Type I (or immediate/anaphylactic) hypersensitivity can be caused by the body’s response to a foreign substance.

Learning Objectives

Describe Type I hypersensitivity reactions

Key Takeaways

Key Points

  • Common triggers for anaphylaxis include venom from insect bites or stings, foods, and medication.
  • People with atopic diseases such as asthma, eczema, or allergic rhinitis have a high risk of anaphylaxis from food, latex, and radiocontrast agents.
  • Anaphylaxis is a severe allergic reaction that starts suddenly and affects many body systems due to the release of inflammatory mediators and cytokines from mast cells and basophils.

Key Terms

  • anaphylaxis: A severe and rapid systemic allergic reaction to an allergen, causing a constriction of the trachea, preventing breathing anaphylactic shock.
  • hives: Itchy, swollen, red areas of the skin which can appear quickly in response to an allergen or due to other conditions.
  • mast cells: A mast cell is a resident cell of several types of tissues and contains many granules rich in histamine and heparin. Mat cells play a role in allergy, anaphylaxis, wound healing and defense against pathogens.

Type I hypersensitivity is also known as immediate or anaphylactic hypersensitivity. Anaphylaxis typically produces many different symptoms over minutes or hours. Symptoms typically include raised bumps on the skin ( hives), itchiness, red face or skin (flushing), or swollen lips.

Hives and flushing on the back of a person with anaphylaxis: Hives and flushing on the back of a person with anaphylaxis

Anaphylaxis: A representation of the signs and symptoms of anaphylaxis that result from an allergic reaction.

Anaphylaxis can be caused by the body’s response to almost any foreign substance. Common triggers include venom from insect bites or stings, foods, and medication. Foods are the most common trigger in children and young adults. Medications and insect bites and stings are more common triggers in older adults. Less common causes include physical factors, biological agents (such as semen), latex, hormonal changes, food additives (e.g. monosodium glutamate (MSG) and food coloring), and medications that are applied to the skin (topical medications). Exercise or temperature (either hot or cold) may also trigger anaphylaxis by causing tissue cells known as mast cells to release chemicals that start the allergic reaction.

Anaphylaxis caused by exercise is often also linked to eating certain foods. If anaphylaxis occurs while a person is receiving anesthesia, the most common causes are certain medications that are given to produce paralysis (neuromuscular blocking agents), antibiotics, and latex. Many foods can trigger anaphylaxis, even when the food is eaten for the first time. In Western cultures, the most common causes are eating or being in contact with peanuts, wheat, tree nuts, shellfish, fish, milk, and eggs.

People with atopic diseases such as asthma, eczema, or allergic rhinitis have a high risk of anaphylaxis from food, latex, and radiocontrast agents. These people do not have a higher risk from injectable medications or stings. People who have disorders caused by too many mast cells in their tissues (mastocytosis) or who are wealthier are at increased risk. The longer the time since the last exposure to an agent that caused anaphylaxis, the lower the risk of a new reaction.

Anaphylaxis is a severe allergic reaction that starts suddenly and affects many body systems. It results from the release of inflammatory mediators and cytokines from mast cells and basophils. This release is typically associated with an immune system reaction, but may also be caused by damage to cells that are not related to an immune reaction. When anaphylaxis is caused by an immune response, immunoglobulin E (IgE) binds to the foreign material that starts the allergic reaction (the antigen ). The combination of IgE bound to the antigen activates FcεRI receptors on mast cells and basophils. The mast cells and basophils react by releasing inflammatory mediators such as histamine. These mediators increase the contraction of bronchial smooth muscles, cause blood vessels to widen (vasodilation), increase the leakage of fluid from blood vessels, and depress the actions of the heart muscle. There is also an immunologic mechanism that does not rely on IgE, but it is not known if this occurs in humans. When anaphylaxis is not caused by in immune response, the reaction is due to an agent that directly damages mast cells and basophils, causing them to release histamine and other substances that are usually associated with an allergic reaction (degranulation). Agents that can damage these cells include contrast medium for X-rays, opioids, temperature (hot or cold), and vibration.

Research Focus - Allergy & Asthma

The ITN’s portfolio has focused on modifying validated desensitization protocols to induce durable tolerance. These studies were designed to test whether allergens could induce tolerance by altering the allergen structure, the timing of administration or the route of administration, and whether early allergen introduction in at-risk children could prevent future allergies. The ITN is currently developing novel trials to advance desensitization to true tolerance by focusing on combination therapies that administer allergen in the context of an immune modifying therapy (called “allergen plus”). The goal is to target known allergic pathways in a manner that will facilitate non-inflammatory recognition and processing of antigens to enhance the efficacy and safety of immunotherapy. The ITN will also continue to explore new allergen preparations and routes of administration to maximize the effectiveness of true tolerogenic protocols.

The ITN is also pioneering the in vitro definition of allergen-specific tolerance. As part of this effort the ITN has initiated a set of pilot studies to map detailed, time-dependent immune responses to allergen immunotherapy, as well as to refine methodologies for optimal specimen collection and processing. The goal is to use this information to design treatment regimens and clinical studies that better target allergic pathways and promote tolerance.

Mechanisms of Allergic Rhinitis


The primary step in the cascade of allergic inflammation is orchestrated by intricate interactions between epithelial (EC) and dendritic cells (DCs) which ultimately lead to the initiation of early and late phase responses. Initially, an inhaled allergen passes through ECs of the nasal mucosa. Once activated, these cells shed a range of chemokines, particularly CCL20, in an ADAM10-mediated manner, which in turn promotes the recruitment of immature DCs [22, 23].

A dysfunctional epithelial barrier can contribute to the pathophysiology of AR. Upregulated activity of histone deacetylase (HDAC) compromises epithelial integrity by impairing tight junction proteins, possibly escalating allergen challenge [24•]. Furthermore, necroptosis-induced release of nuclear IL-33 as well as secretion of TSLP and IL-25 from ECs introduce stimuli required for the development of a pro-allergic dendritic cell of type 2 (DC2) phenotype, defined by the expression of CD141, GATA-3, OX40L, and RIPK4 [25, 26]. A recent study highlighted that epithelium-derived cytokines exert their pro-inflammatory effects in the most severe manner when in combination, suggesting their functions are additive [27]. In addition, these mediators facilitate the development of group 2 innate lymphoid cells (ILC2s), which, together with DC2s, amplify local T helper type 2 (TH2)-mediated allergic inflammation [26, 28]. TSLP and IL-33 can also directly activate TH2 cells, as seen in a murine model of AR [29]. Recently, IL-33 was also established as a key facilitator of mast cell degranulation, resulting from the inhibition of ST2/PI3K/mTOR-mediated autophagy, thereby amplifying early phase responses [30].

After aeroallergen internalization, activated DCs migrate to local lymph nodes. There, major histocompatibility complex (MHC) II-dependent antigen presentation and CD80/CD86-mediated co-stimulation prompt naïve CD4 + T lymphocyte polarization into effector cells [31]. In atopic subjects, presence of IL-4 is key for the development of the TH2 subset [32]. Healthy subjects can also develop an allergen-specific T cell response, though contrastingly, interferon-γ (IFN-γ)-secreting T helper type 1 (TH1) polarization is favored [33]. Furthermore, non-coding RNA GAS5, secreted by the exosomes of the nasal epithelium in AR patients, has been found to downregulate expression of TH1-related transcription factor T bet henceforth suppressing TH1 differentiation [34•].

T follicular helper (TFH) cells are another key subset to arise in the germinal centers (GCs) of lymph nodes in response to DC-mediated antigen presentation. These CD4 + lymphocytes express a surface marker CXCR5 and a transcription factor Bcl6. CXCR5, mutually expressed by B lymphocytes, is crucial for B follicle formation and T and B cell interaction [35]. Besides the lymph nodes, effector TFH cells can also enter the circulation or migrate to the nasal mucosa, where they can acquire TH2-like characteristics and induce local IgE production. Type 2 follicular helper T cells (TFH2) express transcription factor GATA-3 and secrete a TH2 cytokine repertoire [36, 37]. A recent study in mice by Gowthaman et al. showed that IL-13-secreting TFH cells are required to facilitate affinity maturation and differentiation of IgE + B cells [38]. Moreover, AR patients with or without asthma show significant elevation in circulating TFH2 numbers [39].

TFH-secreted IL-4, IL-13 and IL-21 together with TH2-derived IL-4 and IL-13 promote B cell ε-germline transcription. Class-switch recombination and B cell activation is finalized by CD40/CD40L interaction between TFH and B cells [40]. The phenomenon of sensitization to allergen occurs when IgE + plasma cells produce sIgE which binds to high affinity FcεRI receptors on the surface of mast cells and basophils. Upon subsequent exposure, the allergen cross-links neighboring IgE molecules and induces degranulation, leading to the early phase responses [38, 41].

Early Phase Responses

The early phase responses (EPR) take place for up to 60 min post-nasal allergen challenge (NAC). During EPR, levels of tryptase in nasal fluid following NAC significantly peak at 5 min post exposure. This elevation is accompanied by severe rhinorrhea, sneezing, itching and nasal obstruction, evident by peaks in total nasal symptom score (TNSS). Moreover, a significant deterioration of peak nasal inspiratory flow (PNIF), a surrogate of nasal congestion, gradually recovers to baseline at 3–4 h post NAC (Fig. 1) [42].

The biphasic response of allergic rhinitis following nasal allergen challenge (NAC). In the early phase, tryptase and total nasal symptom scores (TNSS) peak at 5 min post challenge which is accompanied by deterioration of peak nasal inspiratory flow (PNIF). Eosinophilic cationic protein (ECP), eotaxin, and TH2-related cytokines gradually increase and peak at 8 h during the late phase response which is paralleled by ongoing nasal congestion. Created with

A key mechanistic feature of the early phase reactions is IgE-dependent mast cell and basophil degranulation [43]. High affinity IgE receptors preferentially bind free IgE molecules, whereas IgE-allergen immune complexes are cleared upon binding to low-affinity receptor CD23 on B cells [44]. FcεRI are expressed not only on basophils and mast cells, but DCs as well. The expression of high-affinity receptors can be elevated in response to increasing serum IgE. Irrespective of allergic status, IgE primarily binds to basophil rather than DC receptors [45]. Just recently, it was demonstrated that upon allergen exposure, increases in serum IgE are accompanied by expansion of IgE + plasmablasts. Moreover, IgE-related memory cells were found to reside in the allergen-specific IgG + B cell fraction [46•].

Following the allergen cross-linking of adjacent IgE molecules, the mediator release from intracytoplasmic granules in the airway is orchestrated by phosphodiesterase 3 which mediates intracellular signaling of cGMP and cAMP [47]. The contents released include histamine, tryptase, cysteinyl leukotrienes and prostaglandin D2 [43, 47]. Notably, overexpression of CD300c, which acts in a co-stimulatory manner for IgE-dependent basophil activation, is seen in patients with AR [48].

Stimulation of histamine receptors H1 and H2 located on sensory neurons causes itching and sneezing, whereas stimulation of these receptors on ECs results in downregulation of tight junctions, thus increasing vascular permeability. Locally produced histamine in nasal secretions of AR patients is sufficient to compromise epithelial integrity in vitro, which is essentially a mechanism of continuous exacerbation of the allergic cascade [49]. This, together with cysteinyl leukotriene and prostaglandin D2-mediated chemoattraction, promotes immune cell influx to the nasal mucosa [50].

Although basophils and mast cells share numerous functional similarities, recent findings have elucidated regulatory differences of the effector functions. Several studies suggest that basophils and mast cells have different thresholds of stimulation to achieve FcεRI-dependent activation [51,52,53]. Moreover, studies show that mast cell survival is actively promoted by monomeric IgE binding to FcεRI which in turn induces an autocrine secretion of IL-3. While basophils similarly respond to IL-3, the induction of the cytokine is not subjected to monomeric IgE [54]. Besides promoting basophil survival, pre-exposure to IL-3 can also enhance histamine and pro-TH2 cytokine production upon IgE-allergen cross-linking [55]. Recent in vitro studies have demonstrated that peripheral basophils can be activated in an allergen-independent manner by cell-cell contact with ECs [56] or by high concentrations of serum IgE [57].

Late Phase Responses

Late phase responses (LPR) occur at 4 to 12 h post allergen challenge and are generally characterized by tissue recruitment of eosinophil, TH2 cells, and ILC2s [43, 58]. Significant increases in nasal eotaxin, eosinophil cationic protein (ECP), and TH2-related cytokines IL-4, IL-5, IL-9, and IL-13 are detected within 8 h of NAC. Elevation of IL-5 and IL-13 inversely correlates with PNIF, making nasal obstruction the clinical hallmark of late phase reactions (Fig. 1) [42].

A wide repertoire of TH2-derived cytokines (IL-4, IL-5, IL-9, IL-13) orchestrates a variety of critical allergic reactions. Although TH2 phenotype develops in response to basophil-derived IL-4, subsequently differentiated TH2 cells secrete IL-4 in an autocrine manner to maintain their identity [32, 59]. A study in a mouse model of HDM-allergic airway inflammation showed that TH2-derived IL-4, similarl to histamine, can contribute to the disruption of mucosal barrier by tight junction downregulation [43, 49]. IL-4 and IL-13 upregulate endothelial adhesion molecules, such as ICAM-1 and VCAM-1, to facilitate migration of effector cells to the nasal mucosa [60]. IL-5 is critical for tissue eosinophilia, as it not only promotes their release from bone marrow but also inhibits their apoptosis [61, 62]. A similar cell survival-promoting effect of this cytokine was recently observed in CD4 + T cells of AR patients [63]. Locally recruited eosinophils secrete toxic mediators which damage the nasal epithelium [64, 65]. Finally, TH2-derived IL-9 promotes mast cell differentiation and maturation [66].

TH2 cells express CRTH2 which is a receptor for prostaglandin D2 secreted during the EPR. The expression of this receptor on TH2 cells is regulated by tyrosine kinase and was found to be elevated 6 h post NAC suggesting it is the peak of TH2 migration [67]. Furthermore, a study exploring the spectrum of AR has identified TH2 cells highly expressing ST2, a receptor for IL-33, as the most pathological subset, which is not present in asymptomatic sensitized patients. The evolvement of this phenotype could be the immunological shift required for the clinical manifestation of AR [68•]. A relatively novel subset of allergen-specific TH2 cells (TH2A), virtually absent in non-atopic subjects, was found to be key in promoting a swift response to an allergen [69•]. Furthermore, TH17-derived IL-17 was found to be elevated in the serum of AR patients. This cytokine can potentially contribute to the pathology of AR by promoting sIgE synthesis in B cells [70, 71].

Accumulating evidence suggests that type 2 inflammation is not the sole driver of the LPR. A study involving nasal mucosa of grass pollen (GP) allergic patients showed that late phase responses also involve upregulation of genes related to alternative complement pathway (factor P and C5AR1) and the inflammasome components (IL-1α and IL-1β), the latter being shown to promote neutrophil recruitment [72]. Moreover, a study on birch pollen-allergic peripheral blood neutrophils demonstrated their capability to fully process and present the allergen subsequently promoting Bet v 1-specific T cell proliferation and cytokine production [73•]. In a HDM-sensitized murine asthma model, inhibition of the complement component C5a was shown to reduce TH2 infiltration and IL-4 concentration in the lung tissue without affecting their counterparts ILC2s, suggesting it has a role in amplifying type 2 inflammation [74].

Recent studies in the context of AR have highlighted the emerging role of PD-1/PD-L1 axis among its immune checkpoint counterparts. Soluble PD-L1, significantly more abundant in the circulation of healthy subjects compared to AR, was shown to negatively correlate with IL-4 as opposed to being positively associated with IFN-γ which suggests that T cell exhaustion is a potential protective mechanism against the disorder [75]. The blockade of this co-inhibitory axis can indeed promote allergen-specific CD4 + T responses in cases of both PAR and SAR. However, given that it affects both TH1 and TH2 cells in vitro, the contributions of this mechanism could be studied further considering possible local or cell-cell interactions [76].

ILC2s are innate counterparts of TH2 cells. They share the expression of CRTH2 but are lineage negative and act in an antigen-independent manner [28]. It was shown that upon stimulation with epithelial cell-derived TSLP and IL-33, ILC2s actively reset their miRNA repertoire, similar to the behavior of T cells after antigen stimulation. miR-19a in particular is crucial for the regulation of IL-13 production [77]. A study by Miao et al. demonstrated an increase in circulating IL-13 + ILC2s together with a greater capacity of this subset to produce IL-13 in response to IL-33 and IL-25 which was observed during natural pollen season in mug-worth sensitized asthmatics [78]. Similarly, SAR patients were shown to have elevated frequencies of total ILC2 and IL-13 + ILC2 during grass pollen season, compared to out-of-season which correlated with seasonal symptom severity [79]. To support that, an in-season study involving grass pollen-sensitized patients of allergic rhinoconjunctivitis showed a significant increase in circulating ILC2 numbers. Here, ILC2s did not demonstrate an enhanced ability to produce IL-4 and IL-13 after in vitro stimulation with phorbol 12-myristate 13-acetate and ionomycin. In the allergic group, the functional impairment was rather observed in ILC1s, the counterparts of the TH1 subset, as evidenced by reduced IFN-γ production [80].

Mechanisms of AIT in Allergic Rhinitis

AIT is a standard therapeutic approach that is indicated for those AR patients whose symptoms persist in spite of consumption of conventional anti-allergic medication. Numerous double-blind, placebo-controlled clinical studies have demonstrated that both SCIT and SLIT are effective options for managing seasonal and perennial allergies. Critically, on-going treatment-induced desensitization can translate into long-term allergen-specific tolerance and clinical benefit, lasting for 2 to 3 years after its cessation [19,20,21]. Accumulating evidence fuels a more comprehensive understanding of AIT-related mechanisms of tolerance (Fig. 2 Table 1).

Mechanisms of allergic sensitization and allergen immunotherapy (AIT). (A) Upon inhalation of the allergen, ECs recruit DCs and polarize them to a pro-allergic DC2 phenotype. These cells uptake the allergen and migrate to lymph nodes, where they present it to naïve T cells and promote the development of TH2 and TFH subsets. TFH and TH2 cells collectively facilitate B cell maturation and class-switch recombination which leads to allergen-specific IgE production. These IgE molecules bind to high-affinity receptors on basophil and mast cell surfaces this way sensitizing the patient. The early phase reactions are triggered when a sensitized individual is subsequently exposed to the allergen, which in turn cross-links neighboring IgE molecules on basophil and mast cell surfaces and prompts the release of vasodilatory and chemoattractive mediators. This facilitates the recruitment of late phase effector T cells and eosinophils. (B) AIT suppresses the development of DC2 phenotype and promotes naïve T cell differentiation to regulatory phenotypes (iTregs, FOXP3 + Tregs, TFR cells). These subsets in turn suppress TH2, TH2A and TFH responses and favor the differentiation of TH1. Inhibition of TH2 responses results in reduced local eosinophilia and prevents the development of IgE + plasma cells. AIT also induces Bregs and IgG + /IgA + plasma cells which produce blocking antibodies that compete with IgE for binding to the allergen, preventing the cross-linking of high-affinity receptors on mast cell and basophil surfaces and inhibiting their degranulation. Red arrows represent inhibition of effector cells green arrows represent AIT-induced regulatory phenotypes and their effects black arrows represent increases or decreases of the population frequencies. EC, epithelial cells DC, dendritic cells TH2, T helper type 2 cell TFH, T follicular helper cell Treg, T regulatory cell Breg, B regulatory cell. Created with

Effect of AIT on Innate Immune Responses

Innate responses are triggered by initial allergen interactions with the physical barrier—the nasal epithelium. To date, no studies in humans have demonstrated a reduction of epithelium-derived pro-inflammatory cytokines following AIT. However, a recent study of SCIT in a murine Der f-sensitized model demonstrated a reduced IL-25 secretion and restoration of epithelial integrity by ameliorating said cytokine-related endoplasmic reticulum stress and EC apoptosis [99]. However, such findings remain to be replicated in human models. The subsequent allergen presentation by DCs bridges the innate and adaptive immunity. Historically, AIT-induced elevation of complement component 1Q (C1Q)-expressing DCreg phenotype has been associated with the response to treatment. This DC subset favors the development of regulatory T cell phenotype [26, 81]. More recently, HDM-SCIT was shown to induce a temporary increase in FcεRI expression on DCs, suggesting that IgE/FcεRI signaling in this subset can contribute to the development of tolerance [45].

The EPR are mediated by mast cells and basophils which act in an antigen-independent manner. AIT reduces the infiltration of these effector cells which is followed by decreases of histamine and tryptase in the nasal mucosa of AR patients [82, 91,92,93]. A recent study involving SCIT for GP allergy demonstrated a 447-fold decrease in basophil sensitivity to the allergen 1 year into the treatment. The trend remained similar a year following treatment cessation. Remarkably, long-term clinical efficacy correlated with the reduction of basophil sensitivity 3 weeks into the treatment suggesting this could be a potential predictive biomarker [94]. A strong correlation between CD203c expression and clinical efficacy of SLIT for Parietaria was documented in a randomized 12-month trial. Interestingly, the reference group treated with conventional medication exhibited slightly reduced threshold of basophil activation, which highlights that AIT can serve to not only treat the disease but also prevent its progression [95]. Recently, an alternative to surface marker expression for evaluating basophil function has been described. Principally, the histamine amount released from the cell inversely correlates with intracellular fluorochrome-labeled diamine oxidase (DAO). Upon ex vivo basophil stimulation with GP allergen, the frequency of DAO + basophils was significantly higher in SCIT and SLIT-treated compared to the untreated group. Critically, this suppression of histamine release correlated with the alleviation of clinical symptoms [96••]. A proteomics approach has been implemented in a study investigating cedar pollen (CP)-SLIT effects on mast cell degranulation, as responder and non-responder groups were not distinguishable by serum IgE, IgG or relevant cytokines. Thrombospondin 1 (THRS-1) was identified as a significant suppressant of mast cell degranulation elevated in the responder group compared to non-responders [97].

In the following LPR, the main innate cell populations are eosinophils and ILCs. Reduced local eosinophil infiltration is a characteristic feature resulting from AIT-induced dampening of upstream TH2 responses together with reduced eotaxin concentrations in nasal fluids [91, 98, 104, 114, 115]. ILCs are the sole innate immunity component of the lymphoid lineage. A murine airway inflammation model demonstrated a reduced proportion of IL5 + ILC2s in the circulation without affecting innate ILC-activating cytokines IL-33 and IL-25 after a 2-month birch pollen-SCIT [107]. In contrast, a 4-month GP-SCIT in humans failed to induce alterations of ILC2 frequencies in the periphery [80]. The first evidence of the effects of AIT on circulating ILC2s in humans was reported by Lao-Araya et al. Here, GP-SCIT for 8 months and more reduced circulating total and IL-13 + ILC2 frequencies in SAR patients during the pollen season which was accompanied by reduced seasonal symptoms [79]. In the context or PAR, responders to a 2-year HDM-SCIT exhibited a significant decrease in circulating ILC2 and elevation of ILC1 frequencies compared to non-responders and the untreated group, ultimately achieving a similar ILC2/ILC1 proportion as seen in healthy subjects. Moreover, ex vivo ILC2 stimulation with Der p1, IL-33 and IL-2 showed that ILC2s in AIT-treated group exhibit a reduced expression of activation marker CD69, however, without any impairment of cytokine secretion [116]. Very recently, a novel regulatory ILC (ILCreg) subset has been described. ILCregs were demonstrated to suppress lung [113•] and intestinal [117] inflammation by secreting IL-10. Following this, Morita et al. were able to demonstrate an in vitro induction of ILCreg subset derived from ILC2s upon exposure to retinoic acid (RA) and the presence of IL-2 and IL-33. ILCregs demonstrated a dose-dependent IL-10 production in response to RA, while IL-5 and IL-13 were not elevated. Transcriptome profiling of sorted IL-10 + ILCs revealed a downregulation of ILC2-related genes, such as CRTH2 and CD127 with conversely elevated Treg-related CD25 and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) expression. However, IL-10 production rather than CTLA-4 activity was critical for ILCreg-dependent anti-proliferative activity toward CD4 + T cells and ILC2s. Concordantly, in human nasal tissue, epithelial cell-derived RA was also shown to promote ILCreg development from ILC2s. Conclusively, this novel subset dampens excessive inflammation [118]. The potential role of ILCregs in AIT-induced tolerance remains to be investigated in future studies.

Testing and diagnosis of IgE-mediated food allergies

Diagnosing food allergies can happen a few ways:

  • Your child may have had a reaction to a food which led to an evaluation by an allergist
  • Your child may have had a flare of eczema, which led to concerns about a food allergy
  • You may have discussed concerns about your child with her pediatrician, who recommended consultation with a specialist

When you meet with allergy specialists at The Children’s Hospital of Philadelphia, we will discuss your child’s food reaction history, as well as get a detailed medical and family history. Based on your child’s history and findings, our allergy specialists may recommend testing.

The gold standard for diagnosing a food allergy is to give the child the suspected trigger food in a controlled setting and monitor the results. This is called a food challenge test and it can also help determine if your child has outgrown a food allergy.

Skin test

Your child’s provider may recommend skin testing. Skin-prick testing involves introducing a small quantity of the specific food on your child’s skin, typically on the forearms.

Intradermal testing — injecting a small amount of the suspected allergen under the surface of the skin — is not recommended for foods.

Blood test

Another useful tool in diagnosing and managing food allergies is blood testing, called allergen-specific IgE testing. This test measures the level of antibody produced in the blood in response to a food allergen.

This is a useful tool your allergist may use to measure trends in blood work, in addition to skin testing and reaction history. The blood test should not be done on foods that are currently being consumed.

There is also a newer type of blood test, known as component testing, which may help to identify true allergens compared to false positives.

Latex sensitivity

Latex is a fluid that comes from the rubber tree. It is used to make rubber products, including some rubber gloves, condoms, and medical equipment such as catheters, breathing tubes, enema tips, and dental dams.

Latex can trigger allergic reactions, including hives, rashes, and even severe and potentially life-threatening allergic reactions called anaphylactic reactions. However, the dry, irritated skin that many people develop after wearing latex gloves is usually the result of irritation and not an allergic reaction to latex.

In the 1980s, health care workers were encouraged to use latex gloves whenever touching patients to prevent the spread of infections. Since then, latex sensitivity has become more and more common among health care workers.

Also, people may be at risk of becoming sensitive to latex if they

Have had several surgical procedures

Must use a catheter to help with urination

Work in plants that manufacture or distribute latex products

For unknown reasons, people who are sensitive to latex are often allergic to bananas and sometimes other foods such as kiwi, papaya, avocados, chestnuts, potatoes, tomatoes, and apricots.

Doctors may suspect latex sensitivity based on symptoms and the person's description of when symptoms occur, especially if the person is a health care worker. Blood or skin tests are sometimes done to confirm the diagnosis.

People who are sensitive to latex should avoid it. For example, health care workers can use gloves and other products that are latex-free. Most health care institutions provide them.


The versatile role of mast cells in allergy, in innate immune responses and in the regulation of tissue homeostasis is well recognized. However, it is often not made clear that most mast-cell data derive solely from experiments in mice or rats, species that obviously never suffer from allergic and most other mast-cell-associated human diseases. Data on human mast cells are limited, and the mast-cell source and species from which findings derive are frequently not indicated in the titles and summaries of research publications. This Review summarizes recent data on human mast cells, discusses differences with murine mast cells, and describes new tools to study this increasingly meaningful cell type in humans.


Despite significant progress in identifying risk factors for FA, there is still little that can be recommended to prevent FA. Few of the known risk factors described above are easily modifiable. Furthermore, of the potentially modifiable factors tested in clinical trials to date, most have not been effective in preventing FA. A recent systematic review by the European Academy of Allergy and Clinical Immunology FA and Anaphylaxis Guidelines Group 100 identified 41 randomized controlled trials of potential FA prevention strategies in infancy and childhood. The vast majority of these trials showed little to no effect on preventing FA, including trials of dietary avoidance of food allergens, vitamin supplements (maternal and infant), fish oil, probiotics, prebiotics, symbiotics and hydrolysed formulas. However, the authors also concluded that the evidence around most of these interventions remains very uncertain. Many of the trials were at risk of bias due to lack of robust diagnostic criteria, high loss to follow-up, potential confounding, and lack of blinding, and were underpowered for the outcome of interest.

Although some of the risk of FA is likely to be already established at birth, to date there are no known effective preventative strategies that can be applied during pregnancy. The only intervention that is currently widely recommended to reduce the risk of FA is timely introduction of peanut into the infant's diet. This recommendation is primarily based on the results of a large, high-quality randomized controlled trial in high-risk infants conducted in the United Kingdom 9 —a country with a relatively high prevalence of FA. The relevance of these findings to countries with a low peanut allergy prevalence is less clear. 101 There is also evidence from meta-analyses of multiple trials that early introduction of egg into the infant diet reduces the risk of egg allergy, although the extent of the reduction in risk appears lower than for peanut. 44


Besides their involvement in generating allergen-specific IgE antibodies that contribute to the pathogenesis of food allergy, B cells can also produce allergen-specific antibodies of other isotypes that may rather protect against food allergies. In mice, mucosal IgA was found to inhibit the uptake of antigens by epithelium and may protect against food allergy. 65 Other mouse studies suggest that allergen-specific IgG antibodies may offer protection against allergic reactions by means of allergen interception, as well as by signaling through the inhibitory IgG receptor FcγRIIb on mast cells and basophils. 66 Allergen-specific IgG antibodies can also mediate feedback inhibition on allergen-specific IgE production by B cells through simultaneous engagement of FcγRIIb and BCR leading to a reduction of antibody production by B cells. 67, 68 In line with this protective response, administration of allergen-specific IgG antibodies during experimental sensitization to food allergens in a mouse model could prevent development of allergic responses and also enhanced tolerance induction in a desensitization model. 69 It was demonstrated that, while sera obtained from peanut sensitized but tolerant children did not cause peanut-induced mast cell activation, depletion of IgG4 from these sera resulted in peanut-induced mast cell activation. This suggests that IgG4 blocking antibodies may contribute to absence of clinical reactivity in peanut sensitized individuals. 70

In particular, allergen-specific antibodies of the IgG4 isotype have been associated with immune tolerance to allergens, as it has several non-inflammatory properties. IgG4 can form bi-specific functionally monovalent antibodies through a process called Fab-arm exchange. 71 These bi-specific IgG4 antibodies are impaired in their capacity to form immune complexes and may interfere with immune complex formation by other allergen-specific antibody isotypes. IgG4 antibodies also have a disrupted C1q binding site, leading to their inability to fix complement. Increases in serum allergen-specific IgG4 have been observed in response to allergen immunotherapy (AIT) and have also been reported in healthy subjects exposed to relatively high doses of allergens, such as non-allergic beekeepers and cat owners. 36, 72

While IgE and IgG4 have long been recognized as key players in the regulation of allergic responses, 36 it was recently reported that IgD may have both enhancing and protective roles in IgE-mediated allergic responses. 73 A small subset of human B cells expresses IgD in absence of IgM. This has been attributed to transcriptional inactivation of the IgM locus and not to classical CSR. 74 IgD has a short serum half-life and constitutes less than 0.5% of the total serum immunoglobulins. It was demonstrated that certain antigens including cow's milk allergens and bee venom allergens can induce specific IgD production by B cells. Secreted IgD can bind to basophils through galectin-9, which interacts with CD44, leading to production of type 2 cytokines by basophils and promotion of Th2-mediated responses. 73 It was also found that IgD-activated mast cells can facilitate IgE production in chronic rhinosinusitis patients with nasal polyps, supporting this potential enhancing effect of IgD on allergic inflammation. 75 On the other hand, IgD may function as a protective mediator against type I hypersensitivity reactions as it was found to constrain IgE-mediated basophil and mast cell degranulation. 73 Interestingly, serum IgD antibodies against milk-derived allergens alpha s1-casein, beta-lactoglobulin were increased in cow's milk allergic children after oral immunotherapy. 73 Similarly, in a cohort of HDM AIT-treated patients, allergen-specific IgD was significantly increased after 2 years of treatment. 76 Although the exact contribution of allergen-specific IgD antibodies in the context of IgE-mediated allergic inflammation remains incompletely understood, the currently available data suggest that IgD contributes to allergic sensitization through enhancing IgE production. On the other hand, IgD may also play a role in the induction of allergen tolerance by suppressing IgE-mediated basophil (and potentially also mast cell) degranulation. 75

WAO Meetings

WAO Webinar Series
&ldquoNew insights for the Optimal Management of Allergic Diseases&rdquo
Thursday, 23 September 2021

&ldquoPrecision allergy molecular diagnostic applications ([email protected])&rdquo
Friday, 22 October 2021

WAO-BSACI 2022 UK Conference
25-27 April 2022
Edinburgh, Scotland, United Kingdom
In collaboration with the British Society of Allergy and Clinical Immunology (BSACI)

WAC 2022
Istanbul, Turkey
In collaboration with the Turkish National Society of Allergy and Clinical Immunology (TNSACI)

2023 Hawai'i Symposium: Food & Respiratory Allergies
Kona, Hawai'i, United States
18-20 May 2023


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