What Is Allergy? — A False Alarm, and Why It Rings More Often

Sneezing That Starts on the Same Day Every Spring

Every year around the time cherry blossoms bloom, some people find themselves hit with sneezing fits and a blocked nose every morning. The person walking right next to them on the same path is completely fine. Both breathed in the exact same pollen, but only one person suffers.

In some households, a baby's cheeks turn red and raw as the child scratches all night long. A few years later, that same child develops a wheezing cough, and by school age, they are sniffling every spring. Parents naturally wonder if these events are connected.

This article compares allergies to a false alarm. It is an event where something harmless enters, yet the alarm goes off as if a fire has broken out. We will follow what this alarm prepares during a first encounter, where it sounds during the next encounter, and what life-threatening alarms look like, while looking at how far explanations have come for why this alarm has started ringing more often over the past few decades.

An Alarm Blaring for Something Harmless

It is estimated that between one-fifth and nearly one-third of the global population experiences allergies (PMID 40320144, PMID 36219943).

An allergy is an overreaction of the immune system to substances that are harmless to most people. The immune system is a network of cells and substances that recognizes and blocks invaders like bacteria and viruses that enter the body. In an allergy, this network mistakes a non-invader for an invader. It is an instance where the alarm described in "How Does the Immune System Tell 'Self' from 'Other'? — Guards at the Gate, and a Patrol That Remembers Faces" goes off for something harmless.

An allergen is a substance that triggers an allergic reaction, such as pollen, house dust mites, or food proteins. For most people, these are just passing substances.

Then why does such an alarm system exist in the body? Type 2 immunity is a branch of immunity that evolved to fight parasites and toxins. Type 2 immunity pushes out parasites and larvae that have entered body tissues, and defends the barriers of the skin and internal body walls where many microbes live (PMID 39962262). The same apparatus that triggers allergic reactions is reported to be useful in blocking parasites, animal venoms, and various toxins (PMID 36219943).

Allergies are reactions where this pathway has been set to the wrong target (PMID 36219943). The alarm system chooses the wrong thing to sound for, and overreacts to something harmless. Unlike a real alarm system, however, the immune system has no headquarters directing the alarm from a single place. The alarm is sounded individually by cells throughout the body.

An allergy is an alarm triggered when a branch of immunity meant to block parasites and poisons mistakenly identifies a harmless substance as an enemy.

The First Meeting Is Quiet

Someone who has no reaction the year they first breathe in pollen may start sneezing every spring a few years later. In between, the immune system has prepared to fight back against the pollen.

What is used for this preparation is the antibody. B cells are white blood cells that make antibodies, and a single cell makes antibodies for only one target. An antibody is a Y-shaped protein produced by B cells that sticks precisely to a specific target. How antibodies acquire so many shapes, and how the body remembers a partner it met once for a long time, is traced in "What Is an Antibody? — Millions of Keys Cut in Advance, and the Ones That Fit".

IgE is a type of antibody mainly involved in allergic reactions. Sensitization is the process where the immune system meets a substance for the first time and makes IgE tailored to it, and at this stage, there are usually no symptoms. People with an allergic constitution make IgE even when they encounter a very small amount of an allergen, and this sensitization mostly happens in childhood (PMID 33999439).

Where does the made IgE go? Mast cells are immune cells located at the borders of the body, such as the skin, airways, and gut, that wait with IgE attached to their surfaces and pour out substances like histamine when they encounter an allergen. Despite the name, it has nothing to do with getting fat; the name comes from looking like a cell that has eaten its fill because the inside of the cell is full of granules. Histamine is one of the substances poured out by mast cells, which widens blood vessels and causes water to leak out between the blood vessel walls.

IgE attaches to a snugly fitting spot on the surface of mast cells and similar white blood cells circulating in the blood. IgE attached in that way prepares those cells to burst open the next time they encounter the same allergen (PMID 36219943). It is similar to registering in advance on an alarm, telling it, "Sound the alarm when this smell appears."

Even if IgE tailored to a substance is caught in a blood test or skin test, that only means sensitization has occurred, not immediately that it is an allergy. Whether symptoms actually arise when you encounter that substance is a separate question to check.

At the first meeting, the immune system makes IgE tailored to a harmless substance and attaches it to mast cells, and at this stage, there is usually no symptom.

An Alarm Ringing on the Second Meeting

A few years later in the spring, the same pollen enters the nose again. This time, the IgE waiting on the surface of the mast cell catches the pollen protein. Then the mast cell immediately pours out the substances it had stored inside (PMID 36219943, PMID 33999439).

The various substances poured out by the mast cell make the blood vessel walls leaky, and histamine also triggers signals that widen the blood vessels (PMID 34360549). These symptoms that appear immediately are caused together by histamine and various other substances (PMID 36219943).

Inflammation is a response where the body gathers immune cells and swells the site to counter stimuli such as damage, infection, or substances entering from outside the body. Because the spot where IgE binds is a very picky spot that only accepts IgE, even a very small amount of allergen can trigger large inflammation (PMID 33999439).

Symptoms similar to allergies can also arise through pathways that do not go through IgE. Different types of antibodies can be involved, and there are also pathways that directly touch the mast cells (PMID 36219943). Still, the majority of allergies start from this immediate reaction going through IgE (PMID 36219943).

When IgE on the mast cell catches the allergen on the second meeting, the mast cell pours out substances like histamine and symptoms begin immediately.

The Places Where the Alarms Sound

Depending on where in the body the same alarm sounds, it can show up as different diseases.

Atopic dermatitis is a disease deeply intertwined with alarms sounding in the skin. Atopic dermatitis is a skin disease where the skin becomes dry and extremely itchy, with inflammation that repeats for a long time, often commonly called eczema. Atopic dermatitis occurs across all ages and races, and accounts for the largest share of the burden caused by skin diseases worldwide (PMID 32738956). It frequently develops on the cheeks and head in infants, and in skin folds like the inside of the elbows and behind the knees in older children and adults (PMID 31690388).

Atopic dermatitis is intertwined with a strong genetic predisposition, a failure of the outer skin layer to do its job properly, and immune-driven inflammation. Type 2 immunity is central, but several other immune pathways are also involved (PMID 32738956). If there is an abnormality in the gene for a protein that builds the skin barrier, atopic dermatitis is more likely to develop (PMID 31690388).

When the alarm sounds in the nose, it is allergic rhinitis. Allergic rhinitis is a disease where the inside of the nose reacts to allergens such as pollen and house dust mites, leading to repeated sneezing, runny nose, and nasal congestion. Allergic rhinitis that comes every season because of pollen is commonly called hay fever.

When it sounds in the airways, it can become asthma. Asthma is a disease with long-standing inflammation in the airways, where the airways repeatedly narrow easily in response to triggers and then widen again. How asthma is intertwined with allergies, and the fact that there is also asthma without allergies, is covered in "What Is Asthma? — An Airway That Too Easily Narrows, and the Inflammation That Keeps It Swollen".

There are also alarms that sound from food. Food allergies are developing in an increasing number of people worldwide, especially in high-income, industrialized regions. Food allergies that do not go through IgE may also be more common than previously known (PMID 38214821). How food allergies are diagnosed, and how they relate to a baby's weaning diet, is followed in "What Is Food Allergy? — Which Door Came First".

These diseases are all grouped together as allergic diseases in which type 2 immunity is involved (PMID 39962262).

The same alarm can appear as atopic dermatitis if it sounds in the skin, allergic rhinitis if it sounds in the nose, and asthma if it sounds in the airways. However, multiple paths besides allergies are intertwined in both atopic dermatitis and asthma.

The March That Starts on a Baby's Cheek

Let us picture the child from the beginning once more. It is the child whose cheeks flared red as an infant, who wheezed a few years later, and who sniffled every spring by the time they started school.

The allergic march is a tendency for atopic dermatitis and food allergies to begin in infancy, with asthma and allergic rhinitis appearing in turn as the child grows. This sequence is frequently observed in the same children (PMID 38256282), and when viewed in terms of locations in the body, it appears to move from the skin to the gut, and then to the airways (PMID 40320144).

Why this sequence occurs is not yet well understood (PMID 30458183, PMID 32973790). One explanation nominated as a candidate is the skin. The idea is that allergens enter through a damaged skin barrier, making sensitization via the skin easier to occur (PMID 30458183, PMID 34420214).

However, not all children walk this march in the exact same way. At first, the march was considered the only pathway through which allergic diseases develop, but as studies following children over long periods increased, our understanding shifted toward the reality being far more complex (PMID 38256282). One review suggests that this sequence may simply be diseases sharing the same genes and environmental triggers, each revealing itself at the age it is most likely to appear. If so, it is closer to a cluster arriving together than a march (PMID 30458183).

The allergic march is a tendency seen in many children, but the path each child walks is different.

An Alarm That Spreads Rapidly Throughout the Body

Shortly after being stung by a bee or eating something, people sometimes develop hives all over their body and swelling of the lips. This is a case where the alarm does not stay in one place and instead spreads throughout the entire body.

Anaphylaxis is a severe allergic reaction that spreads through the whole body within minutes to hours, and it can become life-threatening due to blocked airways or a drop in blood pressure. A 2024 international consensus defined anaphylaxis as "a severe allergic reaction that can rapidly progress and lead to death" (PMID 39880313).

In anaphylaxis, multiple areas among the skin, airways, stomach and intestines, and [The Heart and the Vessels] can be simultaneously involved (PMID 28800865, PMID 39880313). Substances poured out by mast cells make blood vessels widen and leak, which can swell the airways and cause a shortage of circulating blood that leads to shock (PMID 34360549). It can occur through an allergic reaction mediated by IgE, as well as through pathways that do not involve IgE (PMID 28800865).

The signs can appear like this. Hives and itching suddenly break out, and the lips, tongue, or inside of the throat swells. There is wheezing or a harsh sound when inhaling, and dizziness or fainting and collapse can occur. Vomiting or diarrhea may also happen (PMID 34360549). If signs of shortness of breath or wheezing, swelling of the throat or tongue, or dizziness or fainting appear rapidly after encountering an allergen, it is an emergency that immediately requires an ambulance and an emergency room.

Anaphylaxis is judged by the appearance manifested in the body. Although the levels of substances in the blood or urine are often elevated and used later for confirmation, the results may not come out immediately, so treatment must not be delayed for the sake of tests (PMID 28800865). The foundation of treatment is avoiding the known trigger and an injectable medication called epinephrine, and if anaphylaxis is suspected, this injection must not be delayed (PMID 28800865).

It is reported that anaphylaxis is commonly under-recognized and under-treated compared to reality (PMID 28800865). In babies who cannot speak, it is especially difficult to recognize the early signs (PMID 40380371).

The most common triggers are foods, insect venoms such as bees, and drugs, and which one is most prevalent depends on age (PMID 20519879). In children, food is the most common followed by insect venoms such as bees, while drugs are rarer than in adults (PMID 40380371). Anaphylaxis is a rare illness, but a 2010 review paper compiled data showing that the number of people experiencing it is steadily increasing (PMID 20519879).

Anaphylaxis is a rare but rapidly life-threatening reaction, and it is recognized by the signs that appear in the body.

Children in Houses with Many Siblings

Over the past few decades, asthma and allergic diseases have increased rapidly in Westernized countries. Because human genes do not change that quickly, this rapid increase points to changes in the environment or lifestyle (PMID 34415577).

One clue was the number of siblings. British children who grew up in households with many siblings were less likely to get hay fever (PMID 36506644). The British epidemiologist David Strachan put forward this observation in a short 1989 paper. He suggested that fewer infections caught from older siblings during childhood might be the reason allergies have increased (PMID 16630145). This relationship between the number of siblings and hay fever has been confirmed repeatedly in Britain and other wealthy countries, and even confirmed through objective sensitization measurements like blood tests (PMID 36506644).

The hygiene hypothesis is the idea that a reduction in childhood infections or encounters with microbes may be the reason allergies have increased.

The idea was refined after that. The old friends hypothesis is the idea that modern life has reduced encounters with living things like microbes and parasites that humans have lived with for a long time, leading to underdeveloped devices that regulate immune responses. A 2006 review noted that as lifestyles changed fundamentally, a consensus began to gather around the idea that encounters with living things like microbes and parasites, which are important for the development of immune-regulating devices, have decreased (PMID 16630145).

The same review separated household hygiene habits from this hypothesis. It stated that the trend of increasing allergies matches neither the trend of decreasing disease-causing infections nor the trend of changing household hygiene habits. At the same time, it strongly supported efforts to maintain better hygiene habits and suggested changing the name to something like the "microbial exposure hypothesis" so that the word "hygiene" would not discourage good hygiene habits (PMID 16630145). As of a 2001 review, evidence that hidden infections prevent allergic asthma was still lacking (PMID 11964721).

What the hygiene hypothesis points to is the decreased encounters with various microbes due to changing lifestyles, which is distinct from hygiene habits like handwashing.

Children Raised on Farms

There are two agricultural communities in the United States whose ancestors and lifestyles are very similar in many ways, but who farm using different methods. The Amish farm using traditional methods, and the Hutterites use industrialized methods (PMID 27518660). When comparing 60 children from both communities, asthma in Amish children was one-fourth the level, and allergy sensitization was one-sixth the level. Bacterial components in Amish house dust were 6.8 times higher, and the composition of microorganisms in the house dust was also different (PMID 27518660).

Innate immunity is an immune system we are born with, which responds within minutes to hours even to intruders it is seeing for the first time. The innate immune cells of children in the two communities differed significantly in proportion, appearance, and function. When an extract brewed from Amish house dust was put into the noses of mice, the allergic asthma response of the mice was suppressed, whereas Hutterite house dust did not do so (PMID 27518660). The researchers concluded that the Amish environment moves and refines the innate immune response to prevent asthma (PMID 27518660). There were 60 humans, and the experiments confirming the pathway of protection were done in mice.

The farm effect is the phenomenon where children raised on traditional farms develop less asthma and allergies. In various rural areas of Europe as well, children raised on farms consistently had fewer hay fever and sensitizations, and less consistently, fewer cases of asthma (PMID 17607001). One of the exposures most strongly linked to protection by epidemiological studies is early-life contact with livestock and their feed (PMID 21060319). In an analysis combining multiple studies, farm contact before the first birthday was linked to less sensitization, while the results for farm contact during adulthood were mixed (PMID 25270644).

What explains the link between farms and less asthma is also being narrowed down. In a study examining the mattress dust of 1,018 German students, among various bacteria in the farm environment, nine specific bacterial groups explained two-thirds of the link between farm exposure and less asthma. This was a study surveyed at a single point in time, and the same results appeared in other groups (PMID 42517701).

Microbes inside the body may also be involved. Gut microbes are small living things, including bacteria, that gather and live inside the human gut, particularly the large intestine. In a study following children from rural environments from birth, babies whose gut microbes were more mature around their first birthday had less asthma by school age. This maturation explained 19% of the farm effect (PMID 33139948).

However, most of these studies are observational studies. Observational studies are research where people's lives are not interfered with, leaving them to live as they normally do and watching what happens afterwards. There is still no definitive evidence showing how encountering microbes prevents allergies in humans, and animal experiments are at the stage of showing a plausible mechanism. A review paper notes that translating this knowledge into ways to protect children requires confirmation in humans first (PMID 34415577).

That children raised on traditional farms have fewer allergies is a consistently observed link, and microbes explain part of it, but the mechanism in humans has not been confirmed yet.

Mysteries Still Unsolved

More than 30 years have passed since the hygiene hypothesis was proposed, and in the 21st century, the microbes, environments, and lifestyle factors that explain sibling count and farm effects have been examined one by one. However, none of them has remained a definitive explanation (PMID 36506644). A 2022 review article borrowed a phrase from British Prime Minister Winston Churchill to call the mechanism by which allergies vary according to family size "a riddle wrapped in a mystery inside an enigma" (PMID 36506644).

Candidate factors continue to grow, with things like the disappearance of parasitic infections, indoor heating and ventilation, house dust mites, diet, parental smoking, and air pollution being discussed. However, our understanding so far has mostly come from observational studies, and further research is needed to determine what the actual causes are (PMID 28207081).

There are also observations that do not fit. A 2013 review noted that asthma has begun to decrease in some Western countries with little evidence that those countries have become less clean, and pointed out that asthma is prevalent in Latin American countries where infections are frequent (PMID 23103806). The same review wrote that there is substantial evidence to question the hygiene hypothesis. However, it concluded that these counterexamples contradict only the narrow version—that "microbes in early childhood suppress specific immune responses to prevent allergic asthma"—while the broader version may still be correct, though its mechanism is not yet clear (PMID 23103806).

Other explanations have also emerged. A hypothesis was proposed in 2021 suggesting that substances that have increased along with industrialization, urbanization, and modern life damage the outer cell layers of the skin, airways, and gut, and that this serves as the foundation for the increase in allergies and various other diseases (PMID 33846604).

The hygiene hypothesis is not yet an answer, but it has left a legacy. The same 2022 review summarized that this hypothesis fundamentally changed how we view the relationship between humans and their microbial environment, and gave rise to the idea that meeting early rather than avoiding is beneficial for healthy immune development (PMID 36506644). The encounters discussed in this article refer to encounters with environments where diverse microbes live, which is a different story from disease-carrying infections or handwashing as seen earlier. This is still a direction of thought, and as the review mentioned earlier states, verifying it in humans comes first (PMID 34415577).

While the explanation that a reduced encounter with diverse microbes is the reason for the increase in allergies has been discussed for a long time, no single factor has remained a definitive explanation, and its mechanism has not yet been elucidated.

Where to Look Next

The basic way the immune system recognizes and remembers intruders can be seen in How Does the Immune System Tell 'Self' from 'Other'? — Guards at the Gate, and a Patrol That Remembers Faces. How B cells prepare countless shapes of antibodies in advance is continued in What Is an Antibody? — Millions of Keys Cut in Advance, and the Ones That Fit, and the brakes applied to keep the immune system from attacking its own body are covered in Why Doesn't the Immune System Attack Us? — The Brakes on the Patrol. Whether it is encountered first through the skin or the mouth, the story of solid foods and food allergies is followed by What Is Food Allergy? — Which Door Came First.

The alarm sounding in the airway continues in What Is Asthma? — An Airway That Tightens Too Easily, and the Inflammation That Keeps It Swollen. What gut-dwelling microbes do can be seen in What Do Gut Microbes Do? — Guests Who Eat the Leftovers, Guests Who Hold the Room. What a positive result on a blood test or skin test does and does not mean can be explored in What a Test Actually Tells You — An Introduction to Sensitivity, Specificity, and Pretest Probability.

Source Papers

• "Allergy, Anaphylaxis, and Nonallergic Hypersensitivity: IgE, Mast Cells, and Beyond." (2022) — PMID 36219943 — Allergies affect nearly one-third of the global population, and IgE responses are also useful for defense against parasites, venom, and toxins; allergies are a miscalibrated type 2 immune response, where IgE binds to high-affinity receptors on mast cells and basophils to prepare for the next encounter, leading inflammatory mediators like histamine to trigger immediate reaction symptoms, and while pathways bypassing IgE exist, most allergies stem from immediate IgE-mediated reactions.
• "The hygiene hypothesis for allergy - conception and evolution." (2022) — PMID 36506644 — The 1989 paper "Hay fever, hygiene and household size" showed lower hay fever in British children with many siblings (replicated in multiple countries and confirmed by objective sensitization measurements), but the 1989 paper did not use the phrase "hygiene hypothesis," which was followed by "old friends of the immune system" in the early 2000s; no single factor provides a definitive explanation, giving rise to the idea that early encounters are more beneficial than avoidance, though the mechanism remains an enigma in Churchill's words.
• "Type 2 immunity in allergic diseases." (2025) — PMID 39962262 — Type 2 immunity evolved to defend against parasites and toxins, maintaining skin and mucosal barriers rich in parasite expulsion and microbes, and is involved in asthma, allergic rhinitis, atopic dermatitis, and food allergy.
• "The role of allergen-specific IgE, IgG and IgA in allergic disease." (2021) — PMID 33999439 — Atopic constitution leads to IgE production even in response to trace allergens (sensitization, mainly in childhood), and re-exposure increases IgE and causes receptor cross-linking for immediate release, while IgE-mediated antigen presentation sustains T-cell inflammation, and the selective IgE receptor causes massive inflammation even from trace amounts.
• "Mechanisms Governing Anaphylaxis: Inflammatory Cells, Mediators, Endothelial Gap Junctions and Beyond." (2021) — PMID 34360549 — Mast cell mediators (such as histamine) increase vascular permeability, and histamine and PAF signal vasodilation, leading to airway edema, decreased circulatory volume, and distributive shock, with symptoms including hives, itching, swelling of the lips, tongue, and airways, wheezing, inspiratory stridor, vomiting, diarrhea, dizziness, and fainting.
• "Atopic dermatitis." (2020) — PMID 32738956 — Recurrent eczema and severe itching affect all ages and races, representing the highest global burden of skin disease, driven by genetic predisposition, epidermal barrier dysfunction, and T-cell inflammation, with a type 2 dominance alongside multiple pathways.
• "Atopic dermatitis." (2019) — PMID 31690388 — Infants present lesions on the cheeks and scalp, while older children and adults are affected in the skin creases, with filaggrin barrier defects serving as a predisposition.
• "Epidemiology and the Growing Epidemic of Food Allergy in Children and Adults Across the Globe." (2024) — PMID 38214821 — Food allergies are increasing globally, especially in high-income industrialized regions, and the burden of non-IgE food allergies may be larger than expected.
• "Research Progress in Atopic March." (2020) — PMID 32973790 — Allergic diseases appear in a chronological sequence, though some views suggest the sequence is not entirely strict, and the mechanisms remain incompletely understood.
• "The Role of Skin-Gut-Lung Microbiome in Allergic Diseases." (2025) — PMID 40320144 — Allergic diseases affect about 20% of the global population (especially children), and the march follows a spatial sequence of skin → gastrointestinal tract → respiratory tract.
• "The atopic march and atopic multimorbidity: Many trajectories, many pathways." (2019) — PMID 30458183 — Mechanisms are poorly understood, damaged skin barriers facilitate skin sensitization, and shared genetic and environmental triggers may point toward "clustering rather than marching."
• "Dysregulation of the epithelial barrier by environmental and other exogenous factors." (2021) — PMID 34420214 — Epithelial barrier dysfunction contributes to the atopic march via the cutaneous sensitization route.
• "Atopic March or Atopic Multimorbidity-Overview of Current Research." (2023) — PMID 38256282 — These conditions frequently appear sequentially in the same individuals, initially considered the sole pathway, but longitudinal studies have revealed much greater complexity.
• "Anaphylaxis definition, overview, and clinical support tool: 2024 consensus report-a GA2LEN project." (2025) — PMID 39880313 — The first sentence of the definition states, "A serious systemic hypersensitivity reaction that can be rapid in onset and fatal," and the definition also describes the organ systems that may be involved.
• "Anaphylaxis." (2018) — PMID 28800865 — Allergic (IgE) and nonallergic mechanisms involve the skin, lungs, gastrointestinal tract, and cardiovascular system, and underdiagnosis and undertreatment are common; it is a clinical diagnosis where tests should not delay treatment, and the foundation of treatment is trigger avoidance and epinephrine (without delay).
• "Anaphylaxis in children: Latest insights." (2025) — PMID 40380371 — Pediatric triggers are dominated by food over insect venom, with medications being rarer than in adults, and early recognition is difficult in preverbal infants.
• "Epidemiology of anaphylaxis." (2010) — PMID 20519879 — A rare condition that is steadily increasing, with common triggers including food, venom, and medications, varying by age.
• "Protection against allergies: Microbes, immunity, and the farming effect." (2021) — PMID 34415577 — The rapid increase in Westernized countries over recent decades points to environment and lifestyle rather than genetics, and while definitive mechanistic evidence in humans is still lacking, experimental models suggest plausible mechanisms, making human confirmation important for developing prevention strategies.
• "Too clean, or not too clean: the hygiene hypothesis and home hygiene." (2006) — PMID 16630145 — Strachan's original hypothesis (reduced early infections transmitted via unhygienic contact with older siblings) does not align with the increase in allergies alongside reduced pathogenic infections and changes in home hygiene, leading to a consensus on decreased exposure to microbes and parasites important for immune regulation development, strong support for improved hygiene practices, and a proposal to rename it the "microbial exposure hypothesis."
• "Are infections protecting from atopy?" (2001) — PMID 11964721 — Evidence for protection from respiratory infections and BCG is insufficient, whereas the reduction of sensitization in farm children is consistently replicated.
• "Innate Immunity and Asthma Risk in Amish and Hutterite Farm Children." (2016) — PMID 27518660 — Among 60 children, Amish children showed 4-fold and 6-fold lower rates of asthma and sensitization, respectively, alongside 6.8-fold higher house dust endotoxin levels and differences in innate immune cells, and Amish dust suppressed airway responsiveness in mice, leading to the conclusion of protection via innate immunity.
• "Asthma and allergies in rural areas of Europe." (2007) — PMID 17607001 — Growing up on European farms consistently lowers hay fever and sensitization, while lowering asthma less consistently.
• "Farm living: effects on childhood asthma and allergy." (2010) — PMID 21060319 — Epidemiological studies identify early-life exposure to livestock, feed (and unpasteurized milk) as the most effective protective exposures.
• "Exposure to 'farming' and objective markers of atopy: a systematic review and meta-analysis." (2015) — PMID 25270644 — Farm exposure before the first birthday is associated with reduced sensitization (OR 0.60), whereas adult exposure yields inconsistent results.
• "Gram-Positive Bacteria and the Inverse Association between Farm Exposure and Childhood Asthma." (2026) — PMID 42517701 — In 1,018 German schoolchildren, mattress dust scores for nine genera of Gram-positive bacteria mediated two-thirds of the inverse farm-asthma association, observed in a cross-sectional study and replicated in an independent cohort.
• "Maturation of the gut microbiome during the first year of life contributes to the protective farm effect on childhood asthma." (2020) — PMID 33139948 — Gut microbiome maturation at 12 months is associated with farm exposure and reduced school-age asthma, mediating 19% of the farm effect.
• "Can We Be Too Clean for Our Own Good? The Hygiene Hypothesis Reviewed." (2017) — PMID 28207081 — Expanded to include parasite eradication, heating, ventilation, dust mites, diet, smoking, and pollution, but mostly observational and epidemiological studies warrant further research to establish causality.
• "The hygiene hypothesis in allergy and asthma: an update." (2013) — PMID 23103806 — Counterexamples include a decrease in asthma in some Western countries (with no evidence of becoming less clean) and high asthma rates in Latin America despite high infection burdens; the narrow version conflicts with these, but the broad version may remain valid despite unclear mechanisms.
• "Does the epithelial barrier hypothesis explain the increase in allergy, autoimmunity and other chronic conditions?" (2021) — PMID 33846604 — Proposes an expanded epithelial barrier hypothesis suggesting that an increase in epithelial barrier-damaging agents linked to industrialization, urbanization, and modern lifestyles underlies the rise in allergies and autoimmunity.