Allergies! Type I Hypersensitivity: When More Isn’t Better

Our last article discussed various hay fever inducing allergens encountered throughout the year. We learned that even for some of the most allergenic pollens, like birch and ragweed, only certain antigens derived from the pollen actually induce an allergic response. While the differences in the structure of these primary antigens can partially explain why some are allergenic and others are not, it really boils down to how the antigen interacts with an individual’s immune system. Some molecules make better allergens than others because they interact with the major player in Type I hypersensitivity, immunoglobulin E (IgE).

Interestingly, IgE earned its name based on the fact that it reacted with the ragweed pollen antigen E, now known as the primary ragweed antigen “Amb a 1”. In 1921, scientists K. Prausnitz and H. Kustner identified a serum component that was responsible for allergic reaction. It wasn’t until 1966 that T. and K. Ishikawa identified IgE as the serum component. Everyone has a small amount of this potent antibody circulating the blood; IgE accounts for less than 0.05-0.2% (0.1-0.4 μg/mL) of the circulating antibodies in non-atopic individuals. Some, but not all, atopic individuals have higher levels of circulating IgE, up to 0.79%.

Even Sabrina Fairchild knew that “More isn’t always better…sometimes it’s just more.”

In individuals without allergies, an IgE-mediated immune response occurs as a defense against parasitic infections. In this case, the resulting physiological changes clear the parasite and protect the body against further damage caused by the parasite. However, in individuals with allergies, the IgE-mediated response is classified as a Type I hypersensitivity.

Let’s follow a pollen grain on its first journey in an allergic individual. The first encounter of an allergen sensitizes the individual to that specific allergen, but symptoms are not experienced. Initially, the pollen particle encounters the peripheral defenses, nasal hairs, eyelids, and beating cilia in the throat. These hairs prevent most particles from entering the airway or sinuses. Pollen particles must be extremely tiny (about 1x10^-6 meters) to pass through this initial barrier. Upon reaching the nasal mucosa, enzymes in mucous secretions break down the tough outer shell of the pollen (the exine), releasing the allergenic substance.

 

Antigen presenting cells engulf the allergenic substance, process it with enzymes, and display the antigen on the cell surface within a cradle-like protein called the class II major histocompatibility complex (MHC). Another type of immune cell, called T-helper, or Th, cells bind the presented antigen. Th2 cells release molecules called cytokines, which communicate to naive B cells to begin dividing and maturing. Some B cells differentiate into plasma cells, which produce and secrete a specific class of antibodies, or immunoglobulin (Ig). Humans produce 5 circulating antibody isotypes:  IgG, IgM, IgA, IgD and IgE. Particularly, Th2 cells produce the cytokines interleukin (IL)-4 and IL-13, which stimulate B cells to produce IgE. The allergic response appears to be localized, as plasma cells secreting IgE are 1000 times greater in nasal mucosa than in circulation.

In addition to producing the correct isotype, the plasma cells also produce highly specific antibodies that will bind the antigen tightly. Through the process of clonal selection and clonal expansion, a specific IgE molecule with high affinity for the antigen is produced en masse, creating an army like the clone troopers.

Although the army of IgE clones may not be as large as the clone troopers, it's every bit as powerful in wreaking immune havoc.

The circulating IgE has a specific receptor that allows it to bind tissue mast cells and blood basophils. At this point, the body is considered “sensitized” to the allergen. Additionally, memory B cells are formed in preparation for the second encounter of the antigen.

Nothing happens yet, but the body essentially lays in wait to encounter the allergen again. Upon second exposure, the allergenic antigen binds two IgE molecules that are already situated on the mast cells and basophils. These crosslinked IgE molecules are much more stable and can continue sending signal for weeks. The signal, as allergy sufferers know all too well, is a massive inflammatory response mediated by various pharmacologically active molecules contained within and produced by mast cells and basophils. These cells store the inflammatory molecules, like histamine, in granules or inner pockets. When the antigen binds IgE, mast cells and basophils undergo degranulation, releasing large amounts of chemical mediators like the histamine targeted by most antihistamine allergy medications.

The antigen acts like Wile E. Coyote, detonating the IgE fuse, causing the mast cell bomb to explode and release clouds of histamine. Histamine, in turn, damages only our tissues, never touching the elusive (and harmless) Roadrunner allergen.

Mast cells quickly synthesize additional mediators, including leukotriene and prostaglandin. These mediators signal certain physiological changes, including vasodilation (nasal blockage), smooth muscle contraction (coughing), increased mucus secretion (runny nose), and increased vascular permeability (inflammation). Sensory nerves are stimulated, resulting in sneezing and itching. This early phase, or immediate hypersensitivity reaction, happens so rapidly that symptoms are noticed within minutes of exposure to the allergen.

Although histamine is probably the most well-known pharmacologically active molecule, it is actually not the most potent or the longest acting player. Rather, it is the first molecule released in the allergic reaction. Following degranulation, mast cells and basophils produce and release other mediators called prostaglandins and leukotrienes. Initially, contraction of bronchial and tracheal muscles is mediated by histamine, but shortly after, further contraction occurs as a result of prostaglandin and leukotrienes. Leukotrienes are 10 times more potent than histamine at causing bronchoconstriction than histamine.

How an antigen, say pollen, triggers an allergic response.

About 50% of the time, 4 to 8 hours after the early phase reaction, the late phase begins. Other cytokines, particularly IL-5, attract other inflammatory cells, including eosinophils. The symptoms of the late phase reaction resemble those of the early phase, but tend to be characterized by less sneezing and itching and more congestion and mucus production. The inflammatory response from the late phase can damage tissues and last for days.

So why do some people endure the suffering of hay fever and others do not? Tune in next time to find out the genetic and environmental factors that contribute to allergic rhinitis.

 

 

Contributed by Julia van Rensburg, PhD
Follow Julia on Twitter.

Ishizaka K, Ishizaka T, & Hornbrook MM (1966). Physico-chemical properties of human reaginic antibody. IV. Presence of a unique immunoglobulin as a carrier of reaginic activity. Journal of immunology (Baltimore, Md. : 1950), 97 (1), 75-85 PMID: 4162440

Kasaian MT, Meyer CH, Nault AK, & Bond JF (1995). An increased frequency of IgE-producing B cell precursors contributes to the elevated levels of plasma IgE in atopic subjects. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology, 25 (8), 749-55 PMID: 7584687

Verstraelen, S., Bloemen, K., Nelissen, I., Witters, H., Schoeters, G., & Heuvel, R. (2008). Cell types involved in allergic asthma and their use in in vitro models to assess respiratory sensitization Toxicology in Vitro, 22 (6), 1419-1431 DOI: 10.1016/j.tiv.2008.05.008

Takhar P, Smurthwaite L, Coker HA, Fear DJ, Banfield GK, Carr VA, Durham SR, & Gould HJ (2005). Allergen drives class switching to IgE in the nasal mucosa in allergic rhinitis. Journal of immunology (Baltimore, Md. : 1950), 174 (8), 5024-32 PMID: 15814733

Hay Fever: Maladies, Melodies And Remedies

In addition to kicking off the barbeque, swimming and vacation seasons, spring also marks the beginning of that pesky and sometimes debilitating seasonal woe, hay fever. Much like Noel Coward’s 1924 play Hay Fever, the colloquial designation has really nothing to do with hay or fever. Clinically known as allergic rhinitis, hay fever describes the hypersensitivity to airborne allergens and the onslaught of bothersome symptoms they provoke. Approximately 20% of the world’s population suffers from seasonal or perennial hay fever. Even Paul Simon wasn’t spared from the suffocating spiral that is allergies.

 

With the blooming of spring flowers and sprouting of fresh green leaves and grasses, we are reminded that life is all around us. Quite literally, too, as windborne plant pollen is small enough to enter our eyes, nose, and mouth. Pollen, the primary cause of seasonal allergies, contains the male gametophytes of seed-bearing grasses and trees. Each pollen grain contains a generative cell, or sperm, which fertilizes the egg of the female plant, and a vegetative cell, which develops into a pollen tube and delivers the sperm to the ovule. Many trees and grasses rely on wind to spread their pollen and fertilize the female plant. So although your college roommate may have been discrete while attempting to procreate, wind-pollinated plants uphold no such personal boundaries.



Next time you smell a flower, realize you are sniffing a plant’s “naughty bits”.

So which plants are responsible for producing the powdered cheese-like substance that coats our houses, bicycles, and cars? Although thousands of plant species produce pollen that makes the Holderness family cough and gag, only a handful are responsible for their allergic wheezing and sneezing.

The exact timing of seasonal allergies can vary depending on region and climate. You can blame your early spring allergies on tree pollen, particularly that from birch trees. From March to May, many other trees including beech, ash, pine, box elder, cottonwood, oak, mulberry, elm, alder, cedar, hazel, willow, poplar, linden, olive, hornbeam, and plane contribute to early spring allergies. By June, grass pollen becomes predominant, especially timothy and ryegrass. Other grasses such as Bermuda, Johnson, Kentucky bluegrass, orchard, redtop, sweet vernal, and rye contribute to allergies. As the heat and humidity rises during July and August, your hair and electricity bill aren’t the only things that grow. Molds can thrive in grass, grains and leaves; airborne spores can cause hay fever.

The warm days and cool nights of late summer and autumn are perfect conditions for weeds, particularly ragweed, which is the primary cause of autumn-onset seasonal allergies. Ragweed can produce metric tons of pollen per square mile of plant. Other weeds that produce allergenic pollen are cocklebur, burning bush, lamb’s quarters, pigweed, plaintain, Russian thistle, sagebrush, mugwort, and sheep sorrel.

The heavy vegetation towards the end of the growing season provides a perfect breeding ground for additional outdoor mold. Mold grows in fallen autumn leaves, hay, and straw, and can be stirred up during raking or baling. In general, mold spores are considered perennial allergens because mold has the potential to grow outdoors and indoors, especially in kitchens, bathrooms, and basements throughout the entire year. However, growth conditions are optimal during different seasons, potentially resulting in a seasonal effect with mold allergies.

Even in winter, mold spores on indoor live pine trees can cause an allergic reaction. So even though the pine tree isn’t releasing pollen, it can still aggravate hay fever symptoms.

Other perennial allergens besides mold spores include dust mites, pet hair dander, and cockroach droppings. Dust mites are always present, but have been shown to increase with installation and use of central heating and insulated windows in apartment buildings. And although we may not even know cockroaches are present, the proteins in their droppings can cause hay fever. Cat dander is the most common cause of pet allergies, but thankfully The Big Bang Theory writers conveniently overlooked Sheldon’s alleged cat dander allergy so he could adopt this zazzy guy.

What is it about allergens that trigger the allergic response? Although scientists have worked to understand the molecular details of allergens and how they interact with components of our immune system, there is no clear answer as to what specifically makes something allergenic. However, within many of the most common allergens, the primary antigen has been identified. The antigen is the specific molecule that is recognized by our immune system. Antigens can be different components of a bacterial cell or viral particle; in the case of allergens, it is a protein derived from pollen, dander, mold, etc.

Pollen from birch trees is one of the largest contributors to hay fever in spring and early summer in North America The primary antigen from birch tree pollen, Betula verrucosa is called Bet v 1. The Bet v 1 antigen exists as a mixture of 14 isoforms that share ≥ 96.5% sequence identity; these isoforms possess different binding capabilities for the antibody immunoglobulin E (IgE). In fact, only 1 of the 14 isoforms, Bet v 1.0101, induces an immune response in an individual with birch tree allergy, and the two other isoforms tested, Bet v 1.0401 and Bet v 1.1001 induced no response (PMID:  20005001). Immune cells isolated from patients with no birch tree allergy did not react to any of the isoforms. The difference in the antigens is their affinity for the IgE, but precisely what makes one antigen more reactive than the other is unclear. On a basic level, the protein sequence and structure influence the binding to antibodies.


Birch pollen primary antigen Bet v 1 (wikipedia.org)

One complication with diagnosing and treating allergies is the potential for cross-reactivity between different antigens. In some parts of the world, allergic patients are double-sensitized to ragweed and mugwort, Artemisia vulgaris. The flowering season of these two plants overlaps, making it difficult to diagnose the primary sensitizer. In addition to increasing the number of allergies a patient may have, cross-reactivity also complicates prescription of the correct immunotherapy to combat the primary allergy. The primary antigen of mugwort is Art v 1 and up to 95% of people are sensitized to Art v 1. However, a minor mugwort antigen, Art v 6 shares high homology with and commonly cross-reacts with the primary ragweed antigen, Amb a 1. At least 90% of ragweed-allergen sufferers are sensitized to Amb a 1. This means that patients who are allergic to ragweed may be sensitive to mugwort and vice versa. New proteomic technologies allow for more accurate diagnoses of the primary sensitizer so that the proper immunotherapy can be prescribed. Treatment of allergies will be discussed in article 4 of this series.

With so many potential allergens bombarding us more or less year-round, it’s almost surprising that more of us don’t suffer from hay fever. As mentioned above, 1 in 5 people are afflicted and, unfortunately, that number is increasing, particularly in suburban areas of North America. Perhaps the reason allergies are not more common is because they are not hardwired into us, as is the immune response to infectious agents such as bacteria, viruses, and parasites. Hay fever is considered an atopy, a genetic predisposition to mount inappropriate immune responses to harmless environmental allergens. The immune response mounted against allergens will be described in detail in article 2 of this series.

The tendency to have seasonal allergies is hereditary, but does not follow Mendelian principles, like inheritance of eye or hair color. In addition to genes, the environment contributes to allergy susceptibility. Understanding the genetic and environmental factors involved in allergy development is complex and requires sound knowledge of the actual allergic response. A more complete discussion of genetic and environmental factors that influence allergy susceptibility will be presented in the third article of this series. We hope you’ll tune in for the remaining articles in this ongoing series.

Contributed by:  Julia van Rensburg
Follow Julia on Twitter.
 

Hirsch T, Hering M, Bürkner K, Hirsch D, Leupold W, Kerkmann ML, Kuhlisch E, & Jatzwauk L (2000). House-dust-mite allergen concentrations (Der f 1) and mold spores in apartment bedrooms before and after installation of insulated windows and central heating systems. Allergy, 55 (1), 79-83 PMID: 10696861

Leb VM, Jahn-Schmid B, Schmetterer KG, Kueng HJ, Haiderer D, Neunkirchner A, Fischer GF, Nissler K, Hartl A, Thalhamer J, Bohle B, Seed B, & Pickl WF (2008). Molecular and functional analysis of the antigen receptor of Art v 1-specific helper T lymphocytes. The Journal of allergy and clinical immunology, 121 (1), 64-71 PMID: 18037161

Jahn-Schmid B, Hauser M, Wopfner N, Briza P, Berger UE, Asero R, Ebner C, Ferreira F, & Bohle B (2012). Humoral and cellular cross-reactivity between Amb a 1, the major ragweed pollen allergen, and its mugwort homolog Art v 6. Journal of immunology (Baltimore, Md. : 1950), 188 (3), 1559-67 PMID: 22205029

Wopfner N, Bauer R, Thalhamer J, Ferreira F, & Chapman M (2008). Immunologic analysis of monoclonal and immunoglobulin E antibody epitopes on natural and recombinant Amb a 1. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology, 38 (1), 219-26 PMID: 18028463

Asero R, Bellotto E, Ghiani A, Aina R, Villalta D, & Citterio S (2014). Concomitant sensitization to ragweed and mugwort pollen: who is who in clinical allergy? Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology, 113 (3), 307-13 PMID: 25053399

8 Cuddly Creatures and the Dark, Deadly Diseases They Carry

This is the winning entry submitted for the "Buzzfeed Research Contest" organized by Melanie Fox at BORN TO SCIENCE at the Indiana University School of Medicine.

1. With their fluffy fur coats and fun personalities, some say cats make the best pets. Others say cats are evil.



Cats are the definitive hosts for the parasite Toxoplasma gondii. Pregnant women are asked not to change their cat litter boxes because these parasites can be transmitted through feline waste. If a mother becomes infected during pregnancy, the parasite can cross the placenta and infect the fetus, causing catastrophic effects including brain damage, blindness and even death.

2. Sometimes the dog’s bite is indeed worse than its bark!

Rabies can be spread through a dog’s bite. This clever virus is able to travel along nerves all the way to the brain, where it wreaks havoc on the nervous system. Animals infected with rabies show erratic physical movements and can develop paralysis. Other symptoms include having difficulty swallowing, leading to a fear of water (“hydrophobia”) and subsequent drooling. So to keep Fido (and yourself) from foaming at the mouth, make sure to get your puppy pals vaccinated!

3. From the Easter Bunny to Peter Rabbit, rabbits have had their place in our childhood stories. But beware the nightmare: those cute bunnies may carry a bacterium called Francisella tularensis.

Depending on where the bacterium first contacts its host, Francisella can cause a variety of symptoms in a disease called tularemia. Symptoms of tularemia include ulcers in the skin, pneumonia, vomiting and more rarely, liver and spleen problems.

4. Slow and steady, those long-living turtles seem to represent all that is patient and wise.

They also carry Salmonella, a bacterium that when ingested can cause a potential life-threatening disease whose symptoms include vomiting, diarrhea, and headaches. RecentSalmonella outbreaks have been attributed to contaminated produce (and to pet bearded dragons in 2014), and the CDC estimates that nearly 1.2 million individuals become infected each year, leading to approximately 450 deaths.

5. These cute armored creatures can swim, run, climb, and roll into balls.

The nine-banded armadillo is a reservoir for the bacterium Mycobacterium leprae. Mycobacterium leprae causes leprosy, a devastating disease that causes nerve damage and horrific skin lesions.

6. The child’s favorite pet, hamsters are mostly harmless, except when they carry the LCM virus.

LCM, or lymphocytic choriomeningitus, causes inflammation of the wrappings of the brain and spinal cord. This virus can be acquired by individuals who come in to contact with fresh urine, droppings or dirty bedding from infected rodents, so avoid touching your eyes, nose and mouth while handling your furry friend or cleaning their cage.

7. Is that a bird? Is that a plane? No, it’s a flying squirrel!

And its cargo just might be Rickettsia prowazekii, a bacterium that causes the infamous typhus fever. Infection initially presents with a rash followed by muscle pain and fever which usually last 7-10 days.

8. It’s fun to say ‘chinchillas’ and it’s fun to play with a chinchilla.

But it’s not fun to get Giardia from these little furballs! Giardia is a parasite with a whiplike tail or “flagella” that is commonly found in bodies of water. Interestingly, a study done in Belgium in 2010 found that 66% of pet Chinchillas tested were infected with Giardia. Infection with Giardia, the most frequently diagnosed intestinal parasitic disease in the US, causes an uncomfortable diarrheal disease that can last for multiple weeks and cause severe dehydration.

Take-Home

Your cuddly furry friends can still be your best friends. Just be observant of strange behaviors and signs, get your pets vaccinated if possible, wash your hands after playing with them, and if Junior dares his brother to lick the pet turtle, tell him that is a very bad idea.

Contributed by: Dr. William Sullivan Jr.’s Laboratory, Department of Pharmacology & Toxicology, Microbiology & Immunology at IUSM: Sherri Huang, Imaan Benmerzouga, Joe Varberg, Michael Harris, Leah Padgett, Victoria Jeffers, William Sullivan Jr.