Allergy

• 1. Introduction

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  An allergy is the immune system getting an enemy badly wrong. The body meets an ordinarily harmless substance, decides it is a threat, and mounts an exaggerated defense against it. The result can be a runny nose and itchy eyes, or it can be a collapse of blood pressure that ends in death. The substance behind the trouble is called an allergen, and the list of usual suspects is mundane. Pollen, certain foods, metals, insect stings, medications, and materials such as latex all appear on it. How does a grain of pollen come to be treated like an invading pathogen? Why do roughly 20% of people in the developed world react to it while their neighbors do not? And why do the rates of these diseases appear to be climbing? The word itself is barely more than a century old. A Viennese pediatrician named Clemens von Pirquet first used "allergy" in 1906, after watching patients react faster and harder to a second injection than to the first.

• 2. The Mistaken Defense

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  Immunoglobulin E, an antibody known as IgE, sits at the center of the misfire. The first time the body meets an allergen, a professional antigen-presenting cell shows it to a TH2 lymphocyte, a T cell that makes a signaling chemical called interleukin-4. That signal pushes B cells to manufacture large amounts of IgE. Secreted IgE then circulates in the blood and clips onto receptors on the surface of mast cells and basophils. At that point the cells are sensitized, primed and waiting. On a later encounter, the allergen binds to the IgE held on those cells. When more than one IgE-receptor complex grips the same allergenic molecule, the cell is triggered. Mast cells and basophils undergo degranulation, spilling histamine and other inflammatory chemicals such as leukotrienes and prostaglandins into the surrounding tissue. The effects ripple outward as vasodilation, mucous secretion, nerve stimulation, and smooth muscle contraction. Whether the storm stays local or goes system-wide depends on the person, the allergen, and how it entered. Asthma confines the reaction to the respiratory system; eczema confines it to the dermis. The drama is not over when the histamine fades. Two to twenty-four hours later, a late-phase response can arrive, as neutrophils, eosinophils, and macrophages migrate to the original site and keep the inflammation burning.

• 3. Where The Body Reacts

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  Airborne particles strike wherever air reaches the body, so dust and pollen hit the eyes, nose, and lungs. Allergic rhinitis, the condition most people call hay fever, brings sneezing, nasal congestion, a runny nose, and itching of the nose and eyes. Inhaled allergens can also drive up mucus in the lungs and bring on coughing and wheezing. The common triggers in the air include pollen, house dust mites, animal dander, and mold spores. The gut runs its own surveillance operation through the gut-associated lymphoid tissue, which must tell a dangerous organism apart from a harmless food protein. CD103+ dendritic cells sample antigens across the intestinal lining and travel to mesenteric lymph nodes, where they promote regulatory T cells that return to the gut and keep the peace with chemicals such as interleukin-10. When that regulatory machinery breaks down, the immune response can swing toward IgE-mediated hypersensitivity and food allergy. The intestinal microbiome shapes this balance, and early-life loss of microbial diversity has been tied to greater risk of food allergy and atopic disease. A reaction need not begin in the mouth at all. Allergens can slip in through damaged skin, and in people with impaired skin barriers, such as those with atopic dermatitis, that route may set up a food allergy before oral tolerance is ever established. With an insect sting, the skin barrier is breached directly, and a large local reaction can spread redness greater than 10 cm across that lasts one to two days.

• 4. The Usual Allergens

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  Ninety percent of allergic responses to food trace back to just eight sources: cow's milk, soy, eggs, wheat, peanuts, tree nuts, fish, and shellfish. In the United States population, the most common food allergy is a sensitivity to crustacea, and despite their fearsome reputation, peanuts are not the most common food allergy in adults or children. Egg allergy affects one to two percent of children, but about two-thirds of them outgrow it by the age of 5, and the sensitivity is usually to proteins in the white rather than the yolk. Milk-protein allergy, which is not the same thing as lactose intolerance, is most common in children, and roughly 10% of children with a milk allergy will also react to beef. Latex tells a different story, one shaped by occupation. Latex allergy is believed to affect less than one percent of the general population, but among healthcare workers the rate runs between seven and ten percent, blamed on inhaled allergenic proteins in operating rooms, intensive-care units, and dental suites. The strangest twist is in the fruit bowl. People allergic to latex may also react to banana, avocado, kiwifruit, and chestnut, because latex proteins are structurally homologous with some plant proteins. Penicillin breeds a different kind of confusion. About 10% of people report a penicillin allergy, yet 90% of that group turn out not to have one, and serious allergies occur in only about 0.03%. Poison ivy works by a mechanism all its own. Urushiol, the culprit oil, is not a protein but a hapten that binds to and reshapes proteins on skin cells, so the immune system stops recognizing those cells as its own. About 25% of the population mounts a strong response to urushiol, and 80 to 90% of adults will develop a rash after exposure to 0.0050 mg of the purified compound.

• 5. Inherited And Environmental

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  Identical twins share the same allergic diseases about 70% of the time, while non-identical twins match only about 40% of the time. Allergic parents tend to have allergic children, and those children's allergies tend to be more severe. The inheritance is strange, though, because what is passed down is the tendency, not the target. Parents allergic to peanuts may have children allergic to ragweed. Age tilts the odds, with young children most at risk; IgE levels peak in childhood and fall sharply between the ages of 10 and 30. Researchers have mapped a sprawling genetic landscape behind allergic disease, with loci such as ORMDL3 and CHI3L1 tied to susceptibility and genes like FLG governing the mucosal lining. One cytokine stands out in the story of allergic asthma. Interleukin-13, made mostly by activated TH2 cells, aids B-cell switching to IgE, suppresses macrophage function, and acts as the prime mover in allergen-induced asthma through pathways independent of IgE and eosinophils. Genes alone cannot explain the recent rise, because allergic disorders have climbed faster than any genetic change could account for. That gap opened the door to the hygiene hypothesis. It began as an attempt to explain why hay fever and eczema were less common in children from larger families, presumed to trade more infections through their siblings. The idea is that too sterile an environment leaves the TH1 arm of the immune system understimulated, letting an overactive TH2 arm turn benign objects like pollen into targets. Antibiotic use in the first year of life, antibacterial cleaning products, and birth by caesarean section rather than vaginal birth have all been linked to higher rates of allergic disease. Even city trees may play a part. The horticulturist Tom Ogren coined the term "botanical sexism" for the practice of planting predominantly male trees to avoid seed and fruit litter, which raises pollen counts in urban air.

• 6. Finding The Culprit

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  Accurate diagnosis is the foundation of managing allergic disease, and it usually starts with a person's medical history. To detect allergen-specific IgE, two methods carry similar diagnostic value: a skin prick test or an allergy blood test. The skin prick test, also called puncture or prick testing, places tiny amounts of suspected allergens on marked sites, often on the forearm or back, alongside a negative control such as saline and a positive control of histamine. If the patient is allergic, a visible inflammatory reaction usually appears within 30 minutes, ranging from slight reddening to a full wheal and flare like a mosquito bite. Allergists read the result on a severity scale and generally count a wheal at least 3 mm larger than the negative control as positive. Patch testing answers a different question. It identifies the substances behind allergic contact dermatitis, a delayed type IV reaction mediated by T cells rather than the immediate IgE-mediated kind. Patches with standardized allergens are left on the skin, usually the back, for 48 hours, with further readings at 72 to 96 hours because these reactions develop slowly. Blood testing measures specific IgE antibodies and has the advantage of working when skin testing is impractical, such as in people with extensive eczema, in pregnancy, or when antihistamines would interfere. As a rule of thumb, the higher the IgE value, the greater the likelihood of symptoms, though sensitization does not always mean clinical allergy. The history of these blood tests runs through one Swedish company. Pharmacia Diagnostics AB in Uppsala invented and marketed the radioallergosorbent test, or RAST, in 1974, then replaced it in 1989 with the fluorescence-based ImmunoCAP. By 2008 a joint task force of two American allergy organizations declared the term RAST obsolete, urging that it be abandoned as a generic label.

• 7. Avoidance And Relief

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  Avoiding the trigger and taking medications to relieve symptoms remain the core of allergy management. Antihistamines, glucocorticoids, mast cell stabilizers, and antileukotriene agents block the actions of allergic mediators or prevent cells from activating. When a reaction turns to anaphylaxis, injectable adrenaline, also called epinephrine, becomes the rescue, and an epinephrine autoinjector can deliver it where medical care is out of reach. Immunotherapy takes the opposite approach to avoidance. Instead of keeping the allergen away, it exposes the person to larger and larger amounts in an effort to change the immune system's response. Injecting allergens under the skin has proven effective for allergic rhinitis in children and for asthma, with benefits that may last for years after treatment stops. A milder version places the allergen under the tongue, which many people prefer to injections, though for seasonal allergies its benefit is small. The picture for food allergy is unclear, so immunotherapy is not recommended there. Prevention may begin in infancy, and the peanut story is the clearest example. Pediatric guidelines from 2015 and 2017 were revised to encourage introducing peanuts to high-risk infants from the early ages of 4 to 6 months. Researchers examining the data found a 43% drop in the frequency of peanut allergies, which prevented an estimated 40,000 cases and brought a noticeable decline in overall food allergy. Alternative remedies fare poorly by comparison. A review found homeopathic treatments no better than placebo, while the U.S. National Center for Complementary and Integrative Health rates the evidence as relatively strong only for saline nasal irrigation and butterbur among the alternatives it examined.

• 8. Counting The Burden

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  Hay fever and asthma have risen across the Western world over the past two to three decades, with the climb in industrialized nations estimated to have begun in the 1960s and 1970s and accelerated through the 1980s and 1990s. In the United States, allergic rhinitis affects about 35.9 million people, roughly 11% of the population. Asthma prevalence rose 75% from 1980 to 1994 and runs 39% higher in African Americans than in Europeans. Atopic eczema climbed from 3% to 10% in children between 1960 and 1990. The death toll is small but specific. In the United States, insect venom causes at least 40 deaths per year, penicillin anaphylaxis about 400, and latex allergy about 220 cases of anaphylaxis with 3 deaths annually. An estimated 150 people die each year from anaphylaxis due to food allergy. Genetics cannot explain a rise this fast, so attention has turned to the microbial world of the gut. Exposure to food and fecal-oral pathogens such as hepatitis A, Toxoplasma gondii, and Helicobacter pylori, all more common in developing countries, can cut the overall risk of atopy by more than 60%. Some clues to allergy's long human history reach back to ancient Rome. Three members of the Julio-Claudian dynasty, Augustus, Claudius, and Britannicus, are suspected of carrying a family history of atopy, a thread of inherited oversensitivity running through an imperial bloodline.