environment, but exposed to radically different societal structures and lifestyles. The allergy and asthma epidemic there became apparent in the mid-1960s. The Karelia Allergy Study 2002-2022 9 showed that allergic condiDons became far more common in Finland. The Russian populaDon displayed richer gene-microbe networks with beMer-balanced immune regulatory circuits and lower allergy prevalence. In Finland, a biodiverse natural environment around the home was associated with lower allergy prevalence. AcDng on the theory that lifestyle was causaDve, a naDonwide Finnish Allergy Programme was implemented from 2008-2018, endorsing immune tolerance, nature contacts, and allergy health, with posiDve results 10. Subsequently, a Nature Step to Health 2022-2032 iniDaDve was launched with the aim of prevenDng chronic diseases, nature loss, and climate change as they describe therein. The barriers between self and environment-skin and the respiratory and gastrointesDnal mucosae-have evolved to protect health while allowing exchange of informaDon and resources between the organism and its environment. Barrier funcDon has developed in parallel with the immune system, under condiDons very different from the rapidly changing ones induced by the industrial revoluDon over the last couple of centuries. The "epithelial barrier hypothesis" broadens the scope of substances that may influence immune balance beyond microbes alone. In this Research Topic, Sozener et al. argue that a myriad of potenDally toxic substances is increasingly present in our world, compromising epithelial barriers. As a result, direct exposure of the immune system to exogenous allergens and microbes increases, leading to low-grade persistent inflammaDon (i.e., epitheliiDs), producDon of alarmins, increased permeability, microbial translocaDon, dysbiosis, and consequent chronic type 2 inflammaDon. Beyond these 'wide' hypotheses, addiDonal perspecDves included in this collecDon illuminate aspects that cannot be neglected, along with their specific underlying mechanisms. What might be the effect of highly toxic exposures that occasionally occur on a large scale? This is explored in the report by D. Shusterman and A.G. Simpson, who describe the consequences of accidental exposure of bystander populaDons to highly toxic air pollutants.In two incidents-one in Bhopal, India, and the other in Dunsmuir, California, USAseparated by nearly a decade, exposure to cyanates led not only to acute and deadly toxic effects, but also to respiratory problems that remained chronic in many of those exposed. These events were linked by a common biological pathway involving the irritant ion-channel receptor TRPA1. A less toxic, but much more frequent exposure, is addressed by P. Smith and colleagues. Advanced GlycaDon End Products (AGEs) are compounds formed when sugars bind non-enzymaDcally to proteins, nucleic acids, or lipids. They can form in-vivo but occur at much higher levels in the Western diet due to added sugar, protein dehydraDon, sterilisaDon, and cooking methods. Dietary AGEs (dAGEs) can bind to the Receptor for Advanced GlycaDon End Products (RAGE), part of the endogenous threat-detecDon network. Epidemiological and biochemical data correlate increases in dAGEs with the rise in food allergy seen in several Western countries 11. Shihing the focus from bacteria to arthropods, A. and G. Retzinger put forward a hypothesis suggesDng that allergies have increased due to disrupDon of the ecological balance between primates and acarians (mites and Dcks). The complete "Acari hypothesis" unfolds in six papers, the last three of which are included in this collecDon. It suggests that acarians potenDate, in the human host, the generaDon of IgE against elements of their diet, which includes most human allergens. Referring to the hygiene hypothesis, it argues that a major mechanism for deterring acarians-sweaDng-has been affected by modern hygienic pracDces. Furthermore, it proposes that an acarian paMern-recogniDon receptor, possibly a fibrinogen-related protein, may elicit IgE responses following inoculaDon of the receptor in humans. The final instalment introduces an addiDonal player: the fungus Malassezia, whose feeding requirements are used to explain the increased predisposiDon of children to allergies. These are provocaDve ideas; however, further experimental and observaDonal studies are needed to evaluate the relaDve contribuDon of this pathway to the allergy epidemic. Two arDcles on "pre-asthma," by Scadding et al., nicely show that our definiDons and concepts of disease-and its boundaries-may fundamentally affect epidemiology, as well as our potenDal for intervenDon. PrevenDon can be implemented at the populaDon level, as in the Finnish asthma program, taking advantage of microbial intervenDons such as BCG or RSV vaccinaDon 12,13, early pathway blockade (e.g., through dupilumab) 14, or allergenspecific immunotherapy for allergic rhiniDs 15. For secondary prevenDon, upper airway disease deserves beMer understanding and therapy. InteresDngly, a paper by Lachover-Roth et al. invesDgates acute epidemiological changes induced by the COVID pandemic. No differences in the development of atopic comorbidiDes were found between infants born before and during the pandemic. However, considerably higher airway hyperresponsiveness (AHR) was observed in infants born aher restricDons were eased. It is possible that AHR resulted from the "bounce back" of many common cold viruses that had almost disappeared during lockdowns 16. Whether this will translate into longer-term epidemiological changes remains to be studied. Considering the complete set of hypotheses included in this collecDon, one may observe that they can be complementary, and none excludes any other. Post-industrial revoluDon products-including hygiene-related ones-as well as environmental condiDons may compromise the epithelial barrier, increasing pro-inflammatory signals. Diverse natural metagenomes may include important symbioDc microorganisms that are lost with decreasing biodiversity; both the composiDon and ecology of these communiDes are central drivers of human immunity. Mild respiratory infecDons associated with larger households may drive robust type 1 immunity; such immune responses are closely associated with eubioDc microbiomes 17. Higher-level organisms such as fungi and acarians are integral parts of the microbial environment and may contribute by driving immunity towards hyperreacDve phenotypes. Disease classificaDon and boundaries are also crucial for defining thresholds for intervenDon. In the coming years, major efforts will be needed to translate the above concepts into improved protecDon of human health. SocieDes should be more aware of the exposome, including all the substances used, the food we eat, and the air we breathe. And humanity would greatly gain from intensifying efforts to conserve-and bring closer to us-natural environments.
Papadopoulos et al. (Tue,) studied this question.