In this episode, the body is invaded by cedar pollen which harmlessly and mindlessly wander around, scaring the cells. While Memory Cell recalls a legend describing how the Meteors of Disaster (i.e., pollen) will devastate the human body, Plasma Cell eliminates the pollen with IgE antibody. The increased IgE concentrations prompt Mast Cell to release a huge amount of histamine which drowns the cells and devastates the human body. While Plasma Cell and Mast Cell butt heads, Red Blood Cell rolls an unknown package. Inside the package is a robot which proceeds to blast the cells away and destroy the surrounding environment to suppress the allergic response. After the robot runs out of power, the cells emerge out of the wreckage and forgive Plasma Cell and Mast Cell.

How would an allergy happen in real life? Read on as we look at how allergies develop and how they can be suppressed.

What are allergies?

Allergies arise from an excessive immune response to “harmless” environmental substances. These substances, called allergens, come from many different sources in the environment, including:

• Aeroallergens (allergens that are found in the air) such as pollen (featured in the episode) and dust mites;
• Food such as nuts, eggs and shellfish;
• Venom from insects such as wasps, bees and ants; and
• Occupational materials such as latex and nickel.

Schematic	Microscopic	Anime

An environmental substance that a lot of people are allergic to is pollen. Pollen are the sperm of plants; they contain a single cell that eventually develops into a male sperm cell. Inside the cell are enzymes and structural proteins that make up the allergens of pollen. The sperm is protected by an inner wall made of plant materials cellulose and pectin and an outer wall that is tough and resistant to disintegration. This outer wall is similar to the surface of the meteor that crashed into the lake at the beginning of the episode.

Did you know? The pollen in the anime episode come from Japanese cedar trees (Cryptomeria japonica). Its allergens (Cry j 1 and Cry j 2) are enzymes that break down carbohydrates so that a pollen tube is elongated to allow the sperm to travel to the egg in the flower.

Allergy responses are mediated by IgE and histamine from plasma and mast cells respectively. The severity of allergies can vary depending on the allergen and route of exposure. These can range from hay fever (aka allergic rhinitis) which are associated with stuffy noses to anaphylaxis which is a life-threatening allergic reaction. Despite what the cells experienced in the episode, allergies to pollen usually elicit mild reactions that cause hay fever. Hence, I will not be explaining anaphylaxis in this blog post. 

In the episode, the release of IgE and mast cells occurred over a short-period of time. In real-life, allergy responses develop over two distinct stages. The naïve human body must first be sensitised to an allergen which occurs in the priming stage. The actual allergic response occurs on subsequent exposures to the allergen which is encompassed in the re-exposure stage.

The priming stage

The epithelial barrier of the respiratory tract is exposed to aeroallergens such as pollen. Some allergens, particularly pollen, contain enzymes that break down the epithelial barrier while other allergens promote inflammatory responses. These events lead to the breakdown of the epithelial barrier which allow allergens to enter the body and be taken up by dendritic cells (DCs). DCs are activated, enabling their migration to the draining lymph nodes. Along the way, they process the allergen so that they can present epitopes of the allergen to naïve CD4⁺ T cells, stimulating their differentiation to helper T cells. Helper T cells interact with B cells that are binding to the allergen. Here, helper T cells secrete various cytokines such as IL-4 and IL-5 which enables B cells to switch antibody production to IgE. As B cells differentiate into plasma cells, they produce and release IgE which quickly bind to IgE receptors (FcεRI) on mast cells and basophils, the main producers of histamine. These cells do not usually degranulate during the priming stage because it takes time to develop IgE antibodies to the allergen. By the time IgE antibodies bind to cells, the allergen has disappeared.

The re-exposure stage

Upon re-exposure to the allergen, multiple IgE antibodies on mast cells bind to the allergen. This activates mast cells which leads to degranulation and the release of cytokines and mediators. One of the main mediators released from mast cells is histamine which causes immediate hypersensitivity, allergic reactions that arise minutes after the allergen appears. Histamine binds to histamine receptors (named H1R to H4R) in different cells to produce various effects:

• Firstly, histamine acts on blood vessels (via H1R) to dilate them and increase their permeability. This increases plasma leakage from the blood vessel which swells nose tissue, leading to blocked, runny noses.
• Secondly, histamine contracts airway smooth muscle cells (via H1R) in the lungs, constricting airways which can cause breathing difficulties.
• Thirdly, histamine irritates sensory nerve endings in the nose (via H1R) to cause sneezing as well as the skin to produce itching. It also activates sensory nerve endings in the eye to signal the brain that it is (falsely) itchy, causing red, watery eyes. 
• Lastly, histamine engages with white blood cells (via H4R), particularly mast cells and eosinophils, to enhance their recruitment and activity which exacerbates allergic responses.

Did you know? Allergies may also produce a late-phase reaction which occurs 6 to 24 hours after the allergen appears. The reaction involves basophils that release mediators to maintain inflammation, basic proteins that promote further mast cell degranulation and enzymes that damage tissues.

Allergy treatments

Corticosteroids

In the episode, Red Blood Cell rolls an unknown package just as Plasma Cell and Mast Cell were arguing with each other. Inside the package is a robot which proceeds to indiscriminately shoot cells and damage tissues. This robot represents a corticosteroid, steroidal drugs that suppress inflammation. Corticosteroids treat allergies and hay fever by reducing cytokine and mediator release and inhibiting the recruitment of immune cells such as basophils and eosinophils. It does this by entering cells, binding to steroidal receptors inside cells and influencing the expression of genes which leads to reduced inflammation and immune activity. However, if the corticosteroid is taken orally (like what happened in the episode), it can cause a lot of undesirable side-effects and long-lasting damage to the body. That is because corticosteroids can circulate around the body and act on a lot of different cells and tissues to elicit different responses. Hence, oral corticosteroids are not prescribed to treat allergies and hay fever.

Nevertheless, corticosteroids can be taken nasally to reduce the symptoms of allergy while minimising the side-effects. This is because the corticosteroid acts locally in the nose to reduce inflammation without entering and spreading around the body to cause side-effects. Hence, nasal corticosteroids can be used to treat allergy and hay fever. Examples of nasal corticosteroids include budesonide (Rhinocort), fluticasone (Veramyst) and triamcinolone (Nasacort).

Antihistamines

Something that was not discussed in the episode but worth mentioning is antihistamines. Most allergy symptoms are caused by excessive histamine release and action. By blocking histamine receptors on cells to prevent histamine binding to them, the symptoms of allergy can be reduced. This is how oral and nasal antihistamines work to treat allergies. Oral antihistamines such as loratadine (Claratyne) and cetirizine (Zyrtec) can suppress allergic responses. These drugs are not only recommended for treating allergy and hay fever but they are also cheap and available over-the-counter (i.e., you do not need a prescription). Nasal antihistamines such as azelastine hydrochloride (Optivar) and olopatadine hydrochloride (Patanase) are also available which are quicker and more effective in relieving nasal congestion and watery eyes. Typically, they are only available as a prescription.

Did you know? Novel antihistamines are currently being developed and tested as potential new allergy treatments. These novel antihistamines target H4R, commonly found on immune cells, which is associated with worsening allergic responses.

Conclusion

Allergies arise from reactions against many “harmless” environmental agents, including pollen which was showcased in the episode. They involve IgE which are produced during the priming stage and histamine which are released during the re-exposure stage. Histamine has wide-reaching actions, acting on many different cells and tissues to produce symptoms such as blocked, runny noses and sneezing. Thankfully, treatments of allergy are available which act to suppress inflammation or inhibit the actions of histamine. These are widely available over-the-counter and can be used to relieve the symptoms of allergy, particularly when allergens such as pollen and dust mites are ever-present.

In the next episode, we will look at how red and white blood cells develop in the bone marrow. See you then!