In a recent article published in Science Translational Medicine, researchers reviewed the cause and the underlying pathophysiology of allergic diseases. They also pursued evidence of the role of genetics, the epithelial barrier, the immune system, environmental changes, and pollutants, biological and chemical, in allergy pathogenesis.

Additionally, the researchers reviewed the treatments under development for allergy and the future challenges and needs of allergy research.

Background

In recent decades, numerous studies have reported the increased prevalence of allergic diseases worldwide, especially serum immunoglobulin E (IgE) levels-associated allergic disorders. Atopic diseases, in part, are mediated by IgE and are the most studied allergic diseases. They share underlying pathophysiological mechanisms, and their examples include allergic rhinitis, asthma, atopic dermatitis, and food allergies.

Metaexposome, the cumulative environmental exposures affecting all living organisms and their genomes, has been altered by climate changes and global warming.

Thus, cases of de novo allergy and immunological disorders are increasing in severity in those with comorbidities.

Allergic diseases vary in complexity and dynamics between people and regions, as assessed by multi-omics and systems biology studies. Likewise, precision medicine, a personalized allergen-specific management system, has introduced biomarkers, geno- and pheno-, endo-, regio- and thera-types of allergic diseases.

Allergy development and its underlying etiology

Due to epithelial defects, some people develop allergies due to enhanced permeability to antigens from infectious microbes and other stressors into the skin, digestive tract, and lungs. Epithelium-derived cytokines favor the switching of the B cell isotype class to IgE. Then, IgE binds to the effector cells' surface, such as basophils and mast cells, via Fc epsilon (Fcε) R1, high-affinity IgE receptors, causing sensitization.

In sensitized individuals, ensuing exposure to allergens leads to the release of de novo–synthesized histamine, prostaglandins, etc. These manifest as bronchoconstriction, eosinophilic infiltration, and muscle contraction.

Up to 95% of asthma cases are acquired genetically; similarly, up to 91%, 71%, and 82% of cases of allergic rhinitis, atopic dermatitis, and food allergy, respectively, have roots in genetics. Some genes associated with allergic diseases are filaggrin, ovo-like transcriptional repressor 1 (OVOL1), and interleukin 33 (IL-33), involved in skin barrier function, epidermal differentiation, epithelia-derived alarmins, respectively. Other examples include antigen presentation gene, human leukocyte antigen(HLA)-DQ; T helper cells, TH1, TH2, and regulatory T cells (Treg) gene regulation IL-4 and forkhead box P3 (Foxp3).

A loss of function mutation of the filaggrin gene damages the epithelial layer exacerbating many allergic diseases. Two chemical pollutants, sodium dodecyl sulfate (SDS) and sodium dodecyl benzene, present in laundry and dishwasher detergents, shampoos, et cetera., damage the lung and skin epithelium, even at 1:100,000 dilution.

However, heritable genetics alone cannot explain the surge in many allergic diseases. Several studies have shown increased allergies among migrants who moved from a region with a low prevalence to an area with a higher prevalence of atopic diseases, suggesting the role of the earth’s climate changes in allergic diseases.

It gave rise to the “old friends hypothesis,” suggesting that increases in allergy represent a lack of exposure to commensal microbes that evolved concurrently with humans inhabiting their skin, gut, and respiratory tract. Examples include helminths, Helicobacter pylori, and the hepatitis A virus, for which humans had natural immune tolerance.

Role of climate change in surging allergic diseases

The current research also highlighted the role of changes in the environmental conditions or climate in altering the metaexposome, leading to more allergic diseases. Indeed, human exposure to anthropogenic pollutants in soil, air, and water increased in the past few decades, and so did their exposure to antibiotics and processed foods. Concomitantly, their exposure to beneficial microbes decreased.

Humans have triggered around 1°C temperature increase since preindustrial times leading to global warming increasing more over time, with unprecedented consequences. Allergy and immunology science lies at an intersection where it is crucial to protect planetary biodiversity while protecting human health, especially of high-risk populations, children, pregnant women, and aboriginal peoples. Few buildings in poor areas have air conditioning or adequate ventilation to reduce smoke and pollution exposure. Many children play in schoolyards for most of the day, exposing themselves to dust and pollen, increasing the odds of developing allergic rhinitis.

Role of the microbiome in allergy

Next comes the role of the microbiome in disrupting the epidermal barrier. For instance, Staphylococcus aureus secretes proteases and toxins in some areas of the skin of diseased individuals, stimulating TH2 cytokines, such as IL-4. Other bacteria associated with the allergic disease are Clostridium difficile, Escherichia coli, Haemophilus, and Streptococcus species.

Studies have also shown that cutaneous microbial composition shapes adaptive immunity to commensals in neonates. These gut bacteria activate intestinal IL-10–secreting B cells for immune tolerance and mucosal homeostasis, and any disruptions to them have health implications.

Furthermore, infections from respiratory viruses [e.g., respiratory syncytial virus (RSV)] in younger infants whose lungs are under development could lead to an increased risk of asthma. There is enough data evidence that a third of infants hospitalized for bronchiolitis develop asthma later.

Prevention and treatment of allergies

Exposure to allergens and repairing epithelial barriers early in life could prevent allergies. In addition, avoiding air pollutants (e.g., pollen) could prevent exacerbations of allergies. However, introducing a diverse diet during infancy decreases the risk of allergies by activating tolerogenic pathways by Treg cells. The Learning Early About Peanut (LEAP) allergy first evidenced that early introduction of peanuts into the infant diet prevented allergy later, thus, informing food introduction guidelines globally. Likewise, researchers are exploring moisturizers mimicking the skin’s physiological pH and lipid composition as a potential method of preventing the incidence of allergy caused due to damaged skin.

Other prevention strategies could be decreasing emanations from fossil fuels to a minimum and using filters to prevent pollen exposure. In this regard, monitoring applications that provide real-time pollutant information and making high-efficiency particulate air (HEPA) filters available for poor populations in developing nations could help reduce indoor air pollution.

An arsenal of anti-allergy drugs and allergen-specific immunotherapy is available for treatment. These include antihistamines and Janus kinase (JAK) inhibitors. The United States Food and Drug Administration (FDA) approved Omalizumab, a monoclonal antibody, for asthma treatment in 2003. After 12 years, they also approved another biologic, Mepolizumab, for asthma treatment. By 2022, many more biologics targeting cytokines involved in the allergic pathway became available for clinical use, e.g., Dupilumab, an IL-4R inhibitor. An antibody cocktail of two human monoclonal IgG antibodies is also in phase III clinical trial.

Specifically for allergic rhinitis, sublingual immunotherapy (SLIT) has emerged as a better substitute in recent years. Likewise, oral immunotherapy (OIT) has shown promise as food allergies treatments. In 2021, Palforzia, a peanut allergy drug, received approval. Other drugs that have shown promise against allergies and other immune disorders are Bruton’s tyrosine kinase (BTK) and JAK inhibitors that simultaneously target multiple JAK members and are under evaluation in clinical trials. Similarly, oral formulations, Abrocitinib & Upadacitinib, and one topical JAK inhibitor, Ruxolitinib, have received FDA approval. Another atopic dermatitis drug, Baricitinib, approved by the European Medicines Agency (EMA), is undergoing clinical trials in the US.

Conclusions

The study provided enough evidence that due to cumulative effects of climate change on the severity and incidence of allergies would increase their prevalence and clinical impact despite advances in their diagnosis, prevention, and treatment. Early identification of skin barrier defects in neonates could prove beneficial. Researchers developed a method for detecting skin barrier early by electric impedance spectroscopy, under investigation for clinical use. The limited availability of basophil activation tests as routine clinical tests is a challenge that needs to be addressed.

In this regard, the point-of-care microbasophil activation test,  i-BID, seems promising. Likewise, mast cell assays could greatly help with an allergy diagnosis. Most importantly, there should be tools to detect exposure to chemicals; as since the 1960s, human exposome has encountered over 200,000 new chemicals. Future studies should also evaluate allergic diseases and asthma morbidities for precision medicine and validate new predictive biomarkers. Improved systems biology tools, e.g., humanized animal disease models, could aid in safely analyzing allergic reactivity. This could reverse the current trend of increasing allergies with higher severity.