Allergies: A Simplified Primer

‘Tis the season for allergies.   You’ve probably wondered why certain folks have allergies and others don’t.  What is an allergy anyway and why are there are so many different forms of treatment?

Allergy is a response from the immune system to substances that are normally found in the environment and harmless to most people.  The immune system is the body’s defense to foreign invaders.  When exposed to an abnormal foreign substance, such as a virus, bacteria, fungus, bug or parasite, the immune system kicks into action to fight off the invader.   Those foreign substances are called antigens.  There are several immunologic pathways the body uses to fight off antigens.  One of these is the allergy pathway, which is mediated by a particular immunoglobin called IgE.  Immunoglobulins are also called antibodies, proteins made by plasma cells, a type of white blood cell in the body.  An allergen is a type of antigen that specifically triggers the IgE pathway. 

There are numerous potential allergens in the environment, often dependent on location (such as pollens), certain foods, and the dander (sloughed-off skin cells) of furry animals such as cats.  I’ll use a cat as an example since they are notoriously allergenic and besides, I don’t like cats.  Not everyone reacts to an allergen, which is to say not everyone has an IgE trigger when exposed to one.  This is the reason some people have no allergies while others can have many.  It's the reason not everyone is allergic to cats, despite their like or dislike of them.  Allergens are harmless to folks not prone to allergies, as opposed to other antigens such as harmful bacteria and viruses which are harmful to everyone. 

The Allergy Pathway

Here’s the process in simple terms, and you can use the nifty diagram below to follow along (which, by the way, is a slide from a lecture I give to medical students and residents on this very topic).

 

Exposure to an antigen (such as cat dander) triggers plasma cells to create IgE.  This occurs on first exposure to the allergen in those susceptible.  Not everyone forms IgE to a given allergen however.  Those who are nonallergic simply do not form IgE and life goes on merrily.  Thus, those who don’t create IgE against cat dander will never experience an allergic reaction to cats.  This is great for cat lovers. 

However, in those who are allergic, IgE is formed on first exposure to the allergen.  Yet, there is not a reaction immediately.  The IgE circulates in the blood stream and then attaches to mast cells, another type of white blood cell.  It is upon the second exposure to the allergen (e.g., cat dander) that triggers the process.  The allergen binds to the IgE already attached to the mast cells, causing those cells to degranulate.  The mast cells carry numerous substances called mediators, stored within small granules floating in its cytoplasm.  These granules travel to the periphery of the cell, merge with the cell membrane and then open up, releasing these mediators out from the mast cell and into circulation.

Some of those mediators are pre-formed and stored in the granule.  One such mediator is histamine.  Histamine acts in multiple areas in the body, including the mucosa that lines the nose, sinuses, throat, upper airway and lungs.  Histamine has a variety of effects.  It causes blood vessels to vasodilate (open up to become wider), making them permeable and leaky, such that serum from the blood stream leaks into surrounding tissue—the reason for the runny nose and postnasal drip with allergies.  This also causes swelling of soft tissue, increasing tissue volume and the reason for nasal stuffiness and congestion.  Histamine also causes bronchoconstriction--narrowing of the small airways to the lungs.  These leads to wheezing and asthma and dyspnea (difficulty breathing).  Gland cells called goblet cells are also stimulated, causing them to secrete more mucous.  Other symptoms include itching and sneezing and coughing (a neural response to clear antigens out of the nose and lungs).

Other mediators trigger chemotaxis or cell migration.  Amongst these are eosinophil and neutrophil chemotactic factors (ECF and NCF) which cause the migration of those respective cells (more members of the white blood cell group).  These along with additional mast cells are recruited to the site and release a bunch of additional mediators including more histamine.  Among other mediators are interleukins (abbreviated IL).  By the way, white blood cells are also called leukocytes.  Interleukin, as its name implies, is produced from one leukocyte to affect another.  The various interleukins are numbered due to their varying effects.  In the allergic process, IL-4 and IL-5 are two of the most important. 

Eosinophils, mast cells, basophils, T-helper cells (all leukocytes) produce and secrete IL-4.  IL-4 attracts B-cells (another type of leukocyte) which then transform to plasma cells which create more antibodies.  Within the plasma cell a process called class switching occurs, by which IgG is converted to IgE.  Hence, more IgE is produced, exacerbating the entire allergic process, creating a never-ending vicious cycle.

IL-5 stimulates the migration of more eosinophils, which release their mediators (including IL-4) and adding to the awful problem.

The granules also release mediators that cause formation of other substances.  One of these is an enzyme called phospholipase, which converts phospholipids (found in cell membranes) into arachidonic acid, which in turn triggers the creation of prostaglandins (PG) and leukotrienes (LT), substances that further exacerbate inflammation in the body and adding to allergic symptoms. 

Wow.  The complexity of disease continues to be discovered, but humankind has craftily created cures.  The treatments have varying results, which is the reason there are numerous forms of therapy.  So keep in mind, what works well for one allergic person may not be effective in another.  We’re all different, including our like or dislike of cats.   

You can pause for a bit, take a 10-minute coffee or vodka break, and then move on to…

 

Treatment

Here’s the same diagram, marked with the site-of-action for each of the various therapies we’ll cover:

1.   Avoidance.  Get rid of the darn cat.  Eliminating the source of the allergen is the simplest treatment, though understandably many find it difficult get rid of a beloved pet.  In case you’re wondering, you can shave all the fur off a cat and it still will produce allergy-inducing dander.  And a thorough cleaning of carpet, furnishings, clothes etc is also needed since dander can be anywhere.  This holds true for other allergens such as dust mites, which are also anywhere.  Avoiding foods you already know will trigger an allergic response is a no-brainer.  Moving to a different environment often helps.  The tropics are a great place with low allergen levels.  Patients have jokingly asked that I write a prescription for a trip to Hawaii, paid by their medical insurance.  One can only dream…

2.  Block the allergen from entering the body, such as HEPA filters or frequently washing bedding and clothes. 

3.  Block the ability of an allergen to bind to IgE.  This is accomplished by allergy immunotherapy or desensitization, known as “allergy shots.”  This treatment is allergen-specific and requires injecting small doses of the allergen(s) on a regular basis for a number of years.  The goal is to build a tolerance when exposed to the allergens and preventing activation of the whole allergic cascade.  In essence, this is a way to boost your immune system to counteract another part of your immune system.  With this type of therapy, the immune system creates another class of antibody called IgG, which binds to the IgE on the mast cells but does not trigger degranulation.  IgG normally binds to other antigens, but in this particular case, it is directed to block IgE, to act as an anti-IgE immunoglobulin, or anti-IgE IgG, which is a mouthful but heck, that’s science for you.  Once there is enough anti-IgE IgG bound to all the IgE, any allergen entering the system is blocked from binding to the occupied IgE.  Thus no mast cell degranulation occurs and the patient lives allergy free, even in a cat-infested environment.

4.  Cromolyn sodium.  This older remedy comes in the form of a nasal spray.  It’s been around for ages and is over-the-counter (OTC).  It prevents the mast cell from degranulating.

5.  Antihistamines.  These block histamine receptors found on many cells.  They prevent the histamine effects on target tissue and help reduce nasal drainage, sneezing, itching and mucosal congestion.  These can be found OTC as loratadine (Claritin), cetirizine (Zyrtec) or fexofenadine (Allegra).  Diphenhydramine also can be used but has the side effect of drowsiness, so it is best to use this at bedtime.

6.  Decongestants.  These cause vasoconstriction, or narrowing of blood vessels, resulting in decreased blood flow to certain tissues such as the mucosa of the nose and thus reducing tissue congestion and vessel permeability.  They can be taken orally such as pseudoephedrine (Sudafed), or as a nasal spray such as oxymetazaline.  Caution: the latter nasal spray should be used no more than 2-3 days, otherwise you’re at risk for miserable rebound nasal congestion, known as rhinitis medicamentosa.   

7.  Mucolytics mucous thinners).  These reduce the viscosity of mucous or thins it down so that it is easier to clear from sites such as the nose, sinus and lungs.  A common OTC med is Guaifenesin (Robitussin, Mucinex).  Make sure to take it with at least 8 ounces (250 ml) of water to make it effective.

8.  Block leukotriene formation.  Leukotrienes (LT) are inflammatory substances that cause bronchoconstriction and some of the other tissue effects as described above.  They are created from the Arachidonic Acid Cascade.  Montelukast (Singulair) blocks LT formation and initially came out for the treatment of asthma, but later has the indication for seasonal allergies.  It’s available only as a prescription.

9.  Monoclonal antibodies.  This is a relatively newer form of treatment that is very promising and very effective for more severe cases of allergy, particularly those with bad asthma or hard to treat nasal-sinus polyps.  These are specifically designed antibodies that bind to specific interleukin receptors on various leukocytes.

Dupilumab (Dupixent) is a monoclonal antibody that is an IL-4 receptor antagonist.  In other words, it binds to the receptor and blocks its ability to bind to IL-4.

Benralizumab (Fasenra) is binds to the IL-5 receptor on eosinophils.  However, this antibody-receptor complex attracts natural killer cells (NKCs).  The NKC attaches to this complex and does what a NKC is designed to do—destroy and kill the cell.  NKCs typically act on cancer cells, but in this case, you can say this therapy reengineered the NKC to devour normal eosinophils.  This in essence reduces the number of eosinophils in circulation. 

Unlike other forms of immunotherapy such as allergy shots, these two therapies are not allergen-specific; one drug covers it all.  The drawback is they come only in i.m. (intramuscular) form, which means…regular shots in the arm (or other body part of your choosing).

Hope this all makes sense, but the diagrams showing the flow of action hopefully helps you to better understand allergies.  They say a picture is worth a thousand words.  And a cat is still a notorious allergen-producer, no matter how much you shave it.

©Randall S. Fong, M.D.

www.randallfong.com

For more topics on medicine, health and the weirdness of life in general, check out the rest of the blog site at  randallfong.blogspot.com