Allergy: How memory becomes trouble

Much like the brain, the immune system is capable of forming memories. After exposure to a foreign substance, like a bacterium or a virus, the immune system forms cellular memories of their encounter. These encounters are remembered by a group of cells, aptly termed memory cells, that specifically recognize the foreign entity as harmful and in need of eradication. Upon re-exposure, these cells can quickly launch inflammatory attacks against their target, eliminating it before it can harm the body.

Both neurological and immunological memory may slowly decline over time, but they can be restored and strengthened in response to a stimulus. In the case of immunological memory, the cue is repeated exposures to the same intruder. However, memory is a double-edged sword, because undesirable memories may become troublesome — I’m sure we all have some embarrassing memories that we wish to forget. Similarly, the immunological memory may also become debilitating if it causes inflammation against harmless substances like peanuts or pollen, thereby resulting in an allergy. 

With the increasing prevalence of allergic diseases worldwide, it becomes imperative to understand the factors contributing to the immunological memory of allergy. Recently, Asrat and colleagues at Regeneron Pharmaceuticals discovered that, just like neurological memory, immunological memory depends on the duration of the exposure.

IgE: the culprit of allergy

Upon exposure to foreign substances, some immune cells secrete a protein called an antibody to defend against intruders (Figure.1). In the case of allergy, the antibody produced is a specific class known as immunoglobulin E (IgE). Upon binding to allergens, IgE’s can activate immune cells to release inflammatory factors. For example, IgE can induce the release of histamine (the inflammatory factor) upon exposure to pollen (the allergen). Common allergy drugs like Zyrtec and Benadryl alleviate allergy symptoms by blocking the activity of this inflammatory histamine. 

Figure 1: Antibodies. Antibodies are secreted forms of specific proteins immune receptors (B cell receptors) that decorate the surface of B-cells. Figure created with BiorRender.com

As with seasonal allergies, the immune system’s reactivity towards allergens tends to persist after its initial appearance. Interestingly, despite the persistence of most allergies, IgE itself has a short half-life of 2-3 days in the blood. This suggests that there must be immunological memories sustaining the IgE production following the initial allergen exposure; in other words, IgE-secreting memory cells must stick around long after exposure to an allergen, releasing IgE antibodies into the blood in the absence of the instigating allergen. Yet, IgE-producing cells are rarely found in the blood and have not been well characterized by immunologists. 

To understand the role of these persistent IgE-producing cells in allergy, it is essential to understand the cause of their persistence and locate their reservoir in the body. Previously, it has been shown that these cells require multiple stages in their development. Therefore, Asrat and colleagues hypothesized that the immunological memory involved in allergy depends on the duration of allergen exposure. 

Allergen exposure length determines allergy persistence

Asrat and colleagues tested their hypothesis in a mouse allergy model with dust mites being the allergen. The experiment showed that the mice with chronic exposure to the allergen have higher IgE in the blood even 2 months after living in an allergen-free environment (Figure. 2). Since IgE is the mediator for allergic response, the increased IgE in the blood indicates that there is a connection between allergen exposure length and immunological memory.

Figure 2: Allergen exposure time and IgE load. Chronic allergen exposure increases the number of IgE antibodies found in the circulatory system of mice after 2 months resting in the absence of the allergen. Figure created with BiorRender.com

In clinical settings, there have been cases where allergies were inadvertently transferred to a bone marrow recipient from an allergic donor, which suggests that IgE-producing cells may be in the bone marrow. Indeed, the researchers discovered the IgE-producing cells in the bone marrow and characterized them as plasma cells. These plasma cells were shown to persist after living in an allergen-free environment only for the mice that had been chronically exposed to the allergen. This finding highlights the significance of exposure time in consolidating immunological memory. Subsequently, the researchers wondered whether the enhanced immunological memory causes a more severe allergic response. 

A severe allergic reaction may manifest as anaphylaxis, which is characterized by widespread inflammation, and a drop in body temperature. To investigate the effect of exposure duration on allergy severity, the researchers transferred allergen-specific IgE from the allergic mice into non-allergic mice via their blood (Figure. 3). These recipient mice were then challenged with the dust mite allergens via intravenous injection and their temperature was monitored over time as an indicator of anaphylaxis. They found that the IgE from mice with longer allergen exposure time induces a significantly larger temperature drop in recipient mice, even when the amount of IgE transferred is controlled. Therefore, the IgE’s produced during chronic allergen exposure elicit a stronger response against the specific allergen.

Figure 3: Allergen exposure and symptom severity. Recipient mice with IgE from mice chronically exposed to allergens have a greater temperature drop after being challenged with the allergen, indicating that longer allergen exposure leads to more severe allergy symptoms. Figure created with BioRender.com

Relevance to human allergies

Subsequently, the scientists tested the relevance of their findings in humans. The researchers recruited human participants with and without known allergies and isolated plasma cells from their bone marrow. Among these donors, cat allergy was most common and therefore was used as the model in the subsequent experiment. The IgE-containing secretions of their plasma cells were collected and transferred into mice. Upon exposure to cat allergens, only the mice receiving IgE from cat-allergic human donors showed signs of allergic response. Interestingly, the magnitude of allergic response appears to correlate with the total number of allergies that the human donor has! 

Together, these experiments reveal that the immunological memory of allergy is dependent on the duration of allergen exposure. Chronic allergen exposure leads to the generation of bone marrow plasma cells capable of sustaining IgE level in the blood. The valuable insights provided by Asrat and colleagues set a robust foundation for the study of these persistent plasma cells. Further studies of these cells may be valuable in the development of allergy therapy. 


This article summarizes work by Seblewongel Asrat and colleagues:
Asrat, S. et al. Chronic allergen exposure drives accumulation of long-lived IgE plasma cells in the bone marrow, giving rise to serological memory. Sci. Immunol. 5, eaav8402 (2020).

Cover image courtesy of cenczi from Pixabay.

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