Can Your Cat Cause Demonic Possession?

Cats are routinely associated with malevolent entities in horror stories. They are the favorite pet of witches and villains, a frequent denizen of haunted houses, and the object of several superstitions. Now doctors have linked felines to demonic possession!

Wait, what?

In a new case study published yesterday in the journal Medicine, scientists in China reported that acute infection with the common parasite Toxoplasma gondii triggered the onset of an unusual autoimmune disease called anti-N-methyl-D-aspartate (NMDA) receptor encephalitis. Anti-NMDA receptor encephalitis occurs when the body attacks one of its own brain proteins, leading to bizarre personality changes that mimic the stereotypical behaviors that come to mind when we think about demonic possession.

In this case report, a nine-year-old girl arrived at the hospital with seizures, headache, and vomiting. Then she developed unexplained personality and behavior changes. She tested positive for both anti-NMDA receptor antibodies and recent infection with the Toxoplasma parasite.

Anti-NMDA receptor encephalitis was the subject of the bestselling book, Brain on Fire: My Month of Madness, by Susannah Cahalan. In this memoir, which reads like an episode of Mystery Diagnosis, Cahalan describes her terrifying transformation from a vibrant young journalist to an unrecognizable and violent monster. As her condition progressed, she grew paranoid of others, thought family members were imposters, and lashed out at people. She lost control of her bodily movements, suffered seizures, and spoke in tongues. If you didn’t know better, you’d claim she needed an exorcist. Luckily, a neurologist properly diagnosed her disease and gave her immune suppressant drugs that drove it into remission.

Did Regan have a cat?

It is not clear why some people (mostly women) start making antibodies that attack the NMDA receptors in their brain. Some cases are linked to the development of tumors, especially teratomas in the ovaries. Certain viruses that infect the brain, including herpes simplex virus, have also been linked to anti-NMDA receptor encephalitis. Now it seems Toxoplasma, which also infects the brain, may be a trigger of this haunting disease, too.

Toxoplasma is a devious parasite with a complex life cycle. It is capable of infecting any warm-blooded animal, but can only complete its sexual cycle in the intestines of cats. After infecting a cat, the cat spews billions of infectious parasite oocysts into the litter box (or the environment) for up to two weeks. These oocysts are very sturdy and can last up to two years in the environment, giving them plenty of time to be inhaled or ingested by another animal (including humans). In addition to picking up oocysts from the litter box, garden, or sandbox, we can also acquire the infection by eating undercooked meat or unwashed fruits and vegetables.

Once a person becomes infected, the parasite disseminates throughout bodily tissues, including the brain and heart, and transitions into a latent stage called the tissue cyst. While current treatments can stop the parasite from replicating, no drug exists that can get rid of the tissue cysts. In other words, infection with Toxoplasma is permanent. The thought of having a brain filled with these parasites is disquieting, but most scientists believe the cysts are inert unless the individual becomes immune compromised, in which case the parasites can cause massive tissue damage from unchecked growth.

A growing number of scientists argue, however, that in certain individuals the Toxoplasma tissue cysts are not benign and may cause neurological disorders. One of the better-established correlations is the link between Toxoplasma infection and schizophrenia. Interestingly, up to 10% of schizophrenia patients test positive for anti-NMDA receptor antibodies.

The mechanism explaining how Toxoplasma infection may cause anti-NMDA receptor encephalitis remains to be elucidated. Toxoplasma infection is remarkably common (up to one-third of the global population is believed to carry this parasite), but anti-NMDA receptor encephalitis is rare. For now, the authors of the study advise that clinicians assess the possibility of Toxoplasma infection when evaluating a patient with anti-NMDA receptor encephalitis.

To prevent Toxoplasma infection and minimize your chances of becoming possessed by this parasite, be sure to thoroughly cook meat and wash produce and veggies. Wear gloves and a mask when gardening and keep sandboxes covered when not in use. You cannot catch Toxoplasma by petting your cat, but it is important to clean the litter box promptly and wash your hands with soap and water. Pregnant women, in particular, should heed these warnings as infection during pregnancy can lead to miscarriage or serious congenital birth defects. See the infographic below for more.

UPDATE (7/26/18): A new study was published today by Li et al. that used a mouse model of infection to show that anti-NMDA receptor autoantibodies are induced by the presence of latent Toxoplasma tissue cysts.

Brain on Fire has also been made into a movie that can be seen now on Netflix.

Contributed by: Bill Sullivan

Follow Bill on Twitter.

Sneezin' All Season

Notice that not one person is covering their mouth 
and nose here. Makes for better video, 
but still…..gross.

The spring allergy season is back with a vengeance. Many of your friends and loved ones are sneezing, looking as if someone killed their dog, and stuffing facial tissues in their pockets and purses like they were fifty dollar bills. Despite the TV commercials that suggest otherwise, people don’t get that upset with other people’s sneezing, unless they neglect to cover their nose and mouth, in which case they deserve all the ridicule that can be heaped upon them. However, it makes one wonder what exactly is going on inside them that causes them to sneeze, and how does that sneeze play out biologically? Now there’s an interesting story.

A sneeze is the body’s way of trying to expel foreign material that is irritating the respiratory system, most likely the very upper respiratory system – the nasal passages. In the case of spring allergies, the offender is most likely to be grains of pollen. The rhinitis (rhino = nose, and -itis = inflammation) caused by seasonal allergens (hay fever to you and me) are small particles that stimulate an immune response for some reason. In almost all cases they are not harmful particles, as is the case with pollen grains, except that some can induce very strong allergic responses. So why do some people’s bodies try so hard to expel them?

An allergen is nothing more than a protein or carbohydrate, some sort of biomolecule, that your body recognizes as foreign and against which it mounts a specific immune response. For most people, any one specific particle may be seen as foreign, but your body doesn’t go crazy over it; it has been tolerized (learned not to respond), or the response is held in check by other parts of the immune system. But for those unlucky few (or many), pollen grains are a type of allergen that stimulates a large IgE (one type of antibody) response, along with chemicals like histamine and leukotrienes.

The reasons that some people develop an allergic rhinitis to one or more materials aren’t completely known. There is some evidence that if you are fighting off a viral infection and at the same time are first exposed to the allergen, then the heightened activity of the immune system will stimulate a response to the innocuous material. And once that happens, you’re sunk. The body has an immune memory; it builds a small army of cells that then recognize that particular allergen, and if it enters the body again, a strong response will follow and an additional memory response will be built.

Goldenrod has a bad reputation as an autumn allergen. In

truth, it is an insect pollinated plant, so it is not carried by

the wind and snorted as an allergen. Look, she’s not

sneezing. The problem is all the ragweed that grows near

the goldenrod – it’s wind-pollinated.

Therefore, some people believe that too much exposure to viruses and bacteria and other foreign materials when very young will lead to more allergies (there is a genetic component that makes some people more susceptible, but that is too big a topic for us here). On the other hand, many scientists believe that the opposite situation is just as bad or worse for developing allergies. If an environment is too clean, then children are very likely to develop food, seasonal, and perennial allergies. This is called the hygiene hypothesis, and most researchers accept it as true, even if we aren't quite sure of its mechanisms yet.

It may be that too little exposure to bacteria and viruses (which stimulate more a type of immune response called Th1) actually makes the body more likely to go overboard when an antigen stimulates a Th2 response (the type of response induced by allergens). There needs to be a balance between Th1 and Th2 that helps keep them both from over-reacting. It is also possible that when babies are very young, before they have had time to develop their own adaptive immune system (build on their own by being exposed), it is important to stimulate their innate immune system (always on guard and doesn’t require learning to react). The innate response helps build the adaptive system and works to balance the adaptive Th1 and Th2 responses.

It is no coincidence that farmers’ kids have fewer food and

environmental allergies. They are exposed to more

arabinogalactan, which scientists think this is one of the

antigens that teaches the Th1 and Th2 systems to balance

and dampens their response so body doesn’t over react to

foreign molecules and develop allergic responses

and memory response.

Finally, the hygiene hypothesis of allergy development may be mediated by a lack of early childhood allergen and germ exposure which prevents the development of a regulatory immune response. Regulatory immune cells are stimulated each time an immune response is generated; they work to tone down the response and finally turn it off. If not exposed often enough to foreign materials when young, many kids these days don’t develop the regulatory system that would keep the Th2 response to allergens in check. Think about it, hyper-clean environments with HEPA filtered air conditioners and vacuum cleaners, antibacterial soaps, surface and toys, the fact that kids just don’t play outside much anymore. These could all lead to more allergies just because their bodies haven’t learned to handle foreign molecules well.

In terms of seasonal allergic rhinitis, the allergens we are talking about most often are pollen grains. Many plants are fertilized by insects; the insect comes to a flower to drink nectar, the pollen sticks to them, and when they get to the next flower, the pollen is transferred to the stigma and the male gamete cells grow out of the pollen grain via the pollen tubules, down to the ova and fertilized the egg. However, that isn’t the only way pollen grains can be dispersed to other plants; the wind often plays a role. Wind-pollinated plants have small pollen grains, light enough that they will be spread far and wide by a gentle breeze. Unfortunately, this is rather hit or miss; they aren't going to be blown directly to another plant of the same species (as a bee would carry them to the next flower). Since the chances of a single pollen grain finding a flower are low, the plant has to make millions of times more pollen grains. That is a problem for people who suffer seasonal allergies.

Iguanas, especially marine iguanas, sneeze more than any

other animal. The sneezing is a way for the to expel certain

salts that are a byproduct of their digestive process.

There is just so much pollen in the air, the chances of coming across some each day of the season are so high as to be inevitable. Many plants take advantage of the spring increases in temperature, sunlight, and water to do their reproduction, so there is a lot of pollen around in the springtime. Other plants reproduce in the fall, so seasonal allergies come back then, although the offending pollen types will be different from spring to fall. The pollen is in the air, you breathe in the pollen, and it gets stuck in the mucus of your nasal passages. This prevents it from getting to your lungs, but your body still wants to get rid of it. So how does your body know it is there and then trigger a sneeze?

Immune cells are always on the prowl for foreign invaders, especially in/on parts of the body that contact the outside world. Your nose qualifies as such, so there are many immune cells  patrolling your nasal passages that recognize specific antigens. When an immune cell meets that one antigen (or maybe two if there is a cross reaction) that it is built to recognize, it triggers a response. In the case of allergic rhinitis, the responses are to release an antibody type called IgE. The IgE then binds to other immune cells, like eosinophils and mast cells, and then release histamine and leukotrienes, amongst other things. The histamine makes your nose and eyes itch. The chemicals make the small blood vessels leaky, so fluid comes out making your eyes water and your nose run. They stimulate more mucus production, so you get congested. Blech! In addition, the histmaine and leukotrienes do one more thing, they stimulate nerve endings in your nose to trigger a sneeze. The sneeze is meant to get those allergens out of your system as quickly and forcefully as possible.

Contrary to popular belief, your eyes won’t pop out if you

sneeze with while they are open. The blood pressure does

tend to rise fractionally behind your eyes when sneezing,

but it isn’t enough to make them bulge, let alone pop out.

The reasons that the reflex closes your eyes is to avoid

having infected mucus or saliva fly into them and to protect

them during your wild head movement when sneezing.

The nerve impulse travels to your brain, a part called the medulla, and this triggers a constriction of your intercostal chest muscles, your diaphragm, and your abdominals. You inhale, and the constriction of the palate and larynx then holds the air in your lungs as your chest and abdominal muscles start to contract. This builds up pressure, until the throat opens and the air comes rushing out at 70-100 mph. A sneeze can travel 12-20 feet and can carry 40,000 droplets of saliva and mucus. This is: 1) very good for expelling allergenic particles in the nose and throat, and 2) not something anyone wants to share with you, so cover your mouth and nose – preferably in the crook of your elbow in case you plan on opening any doors or shaking hands soon.

There is another reason why a sneeze might be in order during allergy time. A 2012 study showed that the mechanism to get rid of mucus (called the muciliary elevator) sometimes get stalled when mucus is overproduced and full of particles. The clearance mechanism uses the rhythmic beating of cilia on the nasal cells to brush the mucus toward the mouth to be coughed out or swallowed. The researchers used some nasal tissue and sent a pressure wave over the cells to mimic a sneeze. The pressure wave stimulated the cells to start clearing mucus by beating their cilia, so the scientists describe a sneeze as a rebooting of the mucus clearing mechanism. Unfortunately, people with chronic sinusitis and chronic allergies have nasal passage tissues that don’t reboot, so they just keep sneezing and sneezing without any relief. In the case of people with allergies, antihistamines and decongestants are a savior. For everyone else, just sneeze and be done with it – don’t self-medicate at the drop of a hat, people take too many drugs.

Dogfish Head 90 Minute Imperial IPA is one of the beers

that is famous for making people, those who are susceptible,

sneeze. Fermented beverages are high in histamine, and this

may be a reason for the sneezing. Or perhaps it could be an

allergy to the boiled form of alpha acids from hops;

iso-alpha acids like humulone.

More interestingly, people can sneeze for non-allergic reasons. The immune response to a cold virus produces the same chemicals and sneeze response, while pulling at your eyebrows or tweezing them stimulates the same nerve that innervates your nasal passages so you might sneeze then as well. But there are weirder reasons. Some people, called photics, sneeze in response to sudden onset of a bright light. This is a genetic trait and involves higher brain centers, like the visual cortex. Therefore, it is a reflex that extends beyond the brainstem or spinal cord – very weird. It is called, for obvious reasons, ACHOOs (Autosomal Dominant Compelling Helio-Opththalmic Outburst syndrome). Other people suffer from snatiation –sneezing when their bellies are full. This is also genetic and is inherited as an autosomal dominant trait. And some people have a tendency to sneeze after being intimate. The weirdest? Sneezing with hoppy beers – but that’s another story.

Contributed by
Mark E. Lasbury, MS, MSEd, PhD
As Many Exceptions As Rules

Zhao, K., Cowan, A., Lee, R., Goldstein, N., Droguett, K., Chen, B., Zheng, C., Villalon, M., Palmer, J., Kreindler, J., & Cohen, N. (2012). Molecular modulation of airway epithelial ciliary response to sneezing The FASEB Journal, 26 (8), 3178-3187 DOI: 10.1096/fj.11-202184

Teebi AS, & al-Saleh QA (1989). Autosomal dominant sneezing disorder provoked by fullness of stomach. Journal of medical genetics, 26 (8), 539-40 PMID: 2769729

Takubo M, Inoue T, Jiang S, Tsumuro T, Ueda Y, Yatsuzuka R, Segawa S, Watari J, & Kamei C (2006). Effects of hop extracts on nasal rubbing and sneezing in BALB/c mice. Biological & pharmaceutical bulletin, 29 (4), 689-92 PMID: 16595900

Langer, N., Beeli, G., & Jäncke, L. (2010). When the Sun Prickles Your Nose: An EEG Study Identifying Neural Bases of Photic Sneezing PLoS ONE, 5 (2) DOI: 10.1371/journal.pone.0009208

Allergy Medications Are Nothing to Sneeze At

If you were a kid or a parent in the last 4 decades, you may remember the likes of Mr. Tickle, Mr. Greedy, or Little Miss Bossy. These stumpy characters, created by Roger Hargreaves, were intended to teach children lessons by acting according to their namesakes throughout various challenging situations.

So when Mr. Sneeze, with the help of Little Miss Sunshine, discovered that he had allergies, it appeared that educating children about hay fever was the primary goal of this 2003 children’s book. But it didn’t stop there. British pharmaceutical company GlaxoSmithKline, who commissioned the book, took it one step too far and slipped in a couple pages promoting their allergy medications, Piriton and Piriteze.

In the story told by GSK, Mr. Sneeze may be better known as Mr. Sneak.

 Although never available in stores, the book was sold at GSK roadshows and to Tesco (similar to Costco) Clubcard holders and was available through Allergy UK, a charity that collaborated on the book. How it was approved in the first place remains a mystery, as it violated a law prohibiting the direct advertising of any drug to children. Not surprisingly, GSK came under fire as the British government initiated an investigation and GSK eventually withdrew the book. The story made a splash, with many scientific journals and leading news sources, including Nature, the British Medical Journal, BBC news, and the Guardian covering it.

The BMJ article commented that adding to the controversy, the drugs GSK promoted were no longer the first choice of pediatric antihistamines. As if the real travesty was marketing an outdated product to unsuspecting children and their parents. Nevertheless, the comment highlights a key point:  allergy medications have improved drastically over the years, primarily increasing in safety, efficacy, and ease of use.

The active ingredient in GSK’s Piriton is chlorphenamine, a first generation antihistamine (also found in Advil Allergy and Congestion, for example). Another first-generation antihistamine is the ever-popular diphenhydramine, known by most as Benadryl. These antihistamines are inverse agonists, meaning they work by keeping the H₁ receptor in its inactivated form, precluding the binding of histamine. Although highly effective, first generation antihistamines are plagued with strong sedative effects. This happens because they cross the blood brain barrier (BBB), where they bind 50-90% of H₁ receptors in the central nervous system (CNS) and cause drowsiness. Diphenydramine is such a strong sedative that it is FDA-approved for over-the-counter treatment of insomnia.

Although the drowsiness side effect is undesirable and may impair daily performance, first generation antihistamines are still widely used today, popular because they are fast-acting and relatively safe if used properly. Or, perhaps some people would rather just sleep through allergy season.

The other drug advertised by Mr. Sneeze was Piriteze, which contains cetirizine, a less-drowsy second-generation antihistamine. Second-generation antihistamines, including cetirizine (Zyrtec), fexofenadine (Allegra), and loratidine (Claritin) penetrate the CNS poorly because they are pumped out by P glycoproteins, gatekeepers of the BBB. This greatly reduces the number of CNS H₁ receptors that are occupied, with fexofenadine and loratidine binding negligibly and cetirizine binding up to 30% of the receptors. So, cetirizine may still cause drowsiness at recommended doses, whereas fexofenadine and loratidine should not. Second-generation antihistamines are generally preferred over first-generation for their enhanced safety profile.

P-glycoprotein’s command only works on better-behaved second generation antihistamines; the gatekeeper blind to first-generation antihistamines, which pass through the blood brain barrier.

Antihistamines can also be administered intranasally (azelastine and olopatadine); these medications are as effective as or superior to the second-generation oral antihistamines. However, the most effective treatment for seasonal allergies is actually intranasal corticosteroids. Whereas antihistamines block the early phase allergic response, corticosteroids primarily act during the late phase. These work by inhibiting the recruitment of inflammatory cells, such as eosinophils and basophils, and blocking the secretion of pro-inflammatory mediators such as interleukins, causing a decrease in the levels of circulating leukotriene, histamine, and mast cells. The most potent and effective intranasal corticosteroids are mometasone furoate (Nasonex or Nasacort) and fluticasone propionate (Flonase). The furoate and propionate modifications on the drugs are thought to facilitate their absorption in the nasal mucosa and also reduce their systemic absorption, which means less chance of dangerous side effects.

Glucocorticoids are an anti-inflammatory subclass of corticosteroids that include the natural steroid cortisol. Cortisol, and its synthetic analogues, mometasone and fluticasone, work by activating the glucocorticoid receptor, which down-regulates the production of pro-inflammatory molecules. The furoate and propionate side chains are shown in red and blue, respectively.

Yet another treatment, allergen immunotherapy (allergy shots), may be appropriate for allergy patients who have detectable specific IgE antibodies to relevant trigger allergens. Specific immunotherapy (SIT) involves exposure to increasing doses of specific allergen(s). The dose-increase phase usually lasts 14-28 weeks during which desensitization occurs, meaning cells become less reactive or non-reactive to IgE-mediated immune responses. As discussed previously, Type I hypersensitivity reactions are mediated by T-helper 2 cells and allergy-prone infants have diminished T-helper 1 reactions. Perhaps not surprisingly, successful immunotherapy is associated with a shift towards a Th1-type reaction.

So, whereas antihistamines and glucocorticoids treat allergy symptoms, SIT can actually modify the disease and provide lasting protection against allergies. Furthermore, it has been shown to prevent subsequent sensitization to new allergens. In one study, 3 years of immunotherapy provided protection in some patients for up to 12 years and reduced the occurrence of additional allergies in almost half the patients.

Traditionally, SIT is administered subcutaneously (under the skin) by injection. However, last year three sublingual (under the tongue) allergen immunotherapy drugs were approved by the FDA in rapid succession. Oralair, which contains 5 grass pollen extracts (timothy, Kentucky blue, perennial rye, orchard and sweet vernal), became the first FDA-approved sublingual allergen extract. Eight days later, the FDA announced approval of Grastek, which contains only timothy grass extracts. Another 6 days later, Ragwitek was approved for the treatment of short ragweed pollen allergies. Whereas Oralair and Grastek are approved for pediatric use (10+ and 5+ years, respectively), Ragwitek is for adults (18+) only. All drugs showed moderate efficacy in clinical trials, with approximately 20-25% reduction in symptoms and need for symptom-management medication during one allergy season, compared to patients in the placebo group.

If needles aren’t your cup of tea, sublingual immunotherapy may provide a more palatable option.

Interestingly, the allergen extracts given by injection are not tested in clinical trials, but are FDA-approved based on purity, safety, and potency. Nonetheless, subcutaneous immunotherapy (SCIT) has been used safely and successfully worldwide for decades. And although it is new in the US, sublingual immunotherapy (SLIT) has been used successfully in Europe for years. From a cost perspective, immunotherapies compare favorably to pharmacotherapies (drugs like antihistamines and glucocorticoids).

Some people want a spoonful of sugar to help the medicine go down…or perhaps a spoonful of honey in place of medication entirely. Anecdotal evidence suggests that eating local, unfiltered raw honey can have similar effects to SIT by desensitizing the immune system. The idea is logical:  bees incorporate pollen into honey; therefore, eating local, unprocessed honey will expose you to the pollen prevalent in your area. Only a few studies have addressed the efficacy of honey for allergy treatments; one lasted only 10 days (no reduction in allergies observed) or used birch pollen-spiked honey for 5 months (effective at reducing allergies). Unfortunately, neither of these studies properly evaluated honey as an allergy treatment. The first had the right idea, but desensitization requires months (not days) to be effective, and while the second study demonstrates the feasibility of the idea, artificially-spiked honey does not address the real question.

Despite the shortcomings of these studies, the reason honey will never be recommended for allergy treatment is also logical:  the types of pollen bees primarily use are from fragrant flowers, not the wind-carried pollen from grasses like timothy and ragweed or trees like birch, which are responsible for the majority of allergies. Furthermore, the dose of any allergenic pollen in honey is very low and not controlled, making it virtually impossible to achieve desensitization analogous to that observed with SIT.

Searching for an allergy cure in a “hunny” jar will only get you sticky…you’d be better off sticking your head in it to reduce your exposure to wind-carried pollen.

While honey may help clear the bitter aftertaste from intranasal or sublingual medications, it will do little to alleviate your allergies. Better to stick to the tried-and-true methods for real allergy relief - while we may not yet know how best to prevent allergies, certainly many effective options exist to treat them.

Contributed by: Julia van Rensburg, PhD

Follow Julia on Twitter.

Ariano R, Berto P, Tracci D, Incorvaia C, & Frati F (2006). Pharmacoeconomics of allergen immunotherapy compared with symptomatic drug treatment in patients with allergic rhinitis and asthma. Allergy and asthma proceedings : the official journal of regional and state allergy societies, 27 (2), 159-63 PMID: 16724637

Nasser S, Vestenbaek U, Beriot-Mathiot A, & Poulsen PB (2008). Cost-effectiveness of specific immunotherapy with Grazax in allergic rhinitis co-existing with asthma. Allergy, 63 (12), 1624-9 PMID: 19032235

Wallace DV, Dykewicz MS, Bernstein DI, Blessing-Moore J, Cox L, Khan DA, Lang DM, Nicklas RA, Oppenheimer J, Portnoy JM, Randolph CC, Schuller D, Spector SL, Tilles SA, Joint Task Force on Practice, American Academy of Allergy, Asthma & Immunology, American College of Allergy, Asthma and Immunology, & Joint Council of Allergy, Asthma and Immunology (2008). The diagnosis and management of rhinitis: an updated practice parameter. The Journal of allergy and clinical immunology, 122 (2 Suppl) PMID: 18662584

Derendorf H, & Meltzer EO (2008). Molecular and clinical pharmacology of intranasal corticosteroids: clinical and therapeutic implications. Allergy, 63 (10), 1292-300 PMID: 18782107

Sur DK, & Scandale S (2010). Treatment of allergic rhinitis. American family physician, 81 (12), 1440-6 PMID: 20540482

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
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