Study reviews mechanistic data on new methods of allergy prevention and treatment

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

Study: Allergy: Mechanistic insights into new methods of prevention and therapy. Image credit: Buravleva Stock/Shutterstock

In addition, the researchers assessed 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 disease worldwide, especially allergic disease related to serum immunoglobulin E (IgE) levels. Atopic diseases are mediated in part by IgE and are the most studied allergic disease. They share underlying pathophysiological mechanisms, and their examples are allergic rhinitis, asthma, atopic dermatitis and food allergies.

Metaexposome, the cumulative environmental exposure that affects all living organisms and their genomes, has been altered by climate change and global warming.

So cases of the new allergy and immunological disorders are becoming increasingly serious in people with comorbidities.

Allergic diseases vary in complexity and dynamics between people and regions, as assessed by multi-omics and systems biology studies. Similarly, 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 increased permeability to antigens from infectious microbes and other stressors in the skin, digestive tract, and lungs. Epithelial-derived cytokines promote the switch of the B cell isotype class to IgE. Subsequently, IgE binds to the surface of the effector cells, such as basophils and mast cells, via Fc epsilon (Fcε) R1, high-affinity IgE receptors, causing sensitization.

In sensitized individuals, the resulting exposure to allergens leads to the release of the new-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 and epithelial-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 and exacerbates many allergic conditions. Two chemical contaminants, Sodium Dodecyl Sulfate (SDS) and Sodium Dodecyl Benzene, present in laundry and dishwashing detergents, shampoos, and so on., damage the lung and skin epithelium, even at a dilution of 1:100,000.

However, hereditary genetics alone cannot explain the increase 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 global climate changes in allergic disease.

It gave rise to the “old friends hypothesis,” suggesting that an increase in allergy represents a lack of exposure to commensal microbes that co-evolved with humans inhabiting their skin, gut, and airways. Examples are worms, Helicobacter pyloriand the hepatitis A virus, to which humans had a natural immune tolerance.

The role of climate change in increasing allergic disease

The current research also highlighted the role of changes in environmental conditions or climate in altering the metaexposome leading to more allergic conditions. Indeed, human exposure to anthropogenic pollutants in soil, air and water has increased in recent decades, as has their exposure to antibiotics and processed foods. At the same time, their exposure to beneficial microbes decreased.

Humans have caused a temperature rise of about 1°C since pre-industrial times, accelerating global warming over time, with unprecedented consequences. Allergy and immunology science is at a crossroads where it is critical to protect planetary biodiversity while protecting human health, especially of high-risk populations, children, pregnant women and indigenous peoples. Few buildings in poor areas have air conditioning or adequate ventilation to reduce exposure to smoke and pollution. Many children spend most of the day playing in schoolyards, exposing themselves to dust and pollen, increasing the likelihood 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 into 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, Haemophilusand Streptococci types.

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

Furthermore, infections by respiratory viruses [e.g., respiratory syncytial virus (RSV)] in younger babies whose lungs are developing can lead to an increased risk of asthma. There is ample data showing that one third of babies hospitalized for bronchiolitis later develop asthma.

Prevention and treatment of allergies

Exposure to allergens and restoring epithelial barriers at a young age can prevent allergies. In addition, avoiding air pollutants (for example, pollen) can prevent allergies from worsening. However, introducing a varied diet during childhood reduces the risk of allergies by activating tolerogenic pathways by Treg cells. The LEAP (Learning Early About Peanut) Allergy showed for the first time that early introduction of peanuts into the children’s diet prevented later allergy, setting guidelines for food introduction worldwide. Similarly, researchers are investigating moisturizers that mimic the physiological pH and lipid composition of the skin as a possible method of preventing the onset of allergy caused by damaged skin.

Other prevention strategies may include minimizing fossil fuel emissions and using filters to prevent pollen exposure. In this regard, monitoring applications that provide real-time information on pollutants and making high-efficiency particulate air (HEPA) filters available to poor populations in developing countries can help reduce indoor air pollution.

An arsenal of anti-allergy drugs and allergen-specific immunotherapy are available for treatment. These include antihistamines and Janus kinase (JAK) inhibitors. The U.S. Food and Drug Administration (FDA) approved Omalizumab, a monoclonal antibody, in 2003 for the treatment of asthma. After 12 years, they also approved another biologic, Mepolizumab, for the treatment of asthma. By 2022, many more biologics targeting cytokines involved in the allergic pathway became available for clinical use, for example 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 alternative in recent years. Similarly, oral immunotherapy (OIT) has shown promise as treatments for food allergies. In 2021, Palforzia, a peanut allergy drug, received approval. Other drugs that have shown promise against allergies and other immune disorders include Bruton’s tyrosine kinase (BTK) and JAK inhibitors that target multiple JAK members simultaneously and are currently being evaluated in clinical trials. Similarly, oral formulations, Abrocitinib & Upadacitinib, and one topical JAK inhibitor, Ruxolitinib, have received FDA approval. Another drug for atopic dermatitis, Baricitinib, approved by the European Medicines Agency (EMA), is undergoing clinical trials in the US.

Conclusions

The study provided ample evidence that due to the cumulative effects of climate change on the severity and incidence of allergies, their prevalence and clinical impact would increase despite advances in their diagnosis, prevention and treatment. Early identification of skin barrier defects in neonates may be helpful. Researchers have developed a method to detect the skin barrier early through electrical impedance spectroscopy, which is being investigated 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, appears promising. Likewise, mast cell assays can greatly assist in allergy diagnosis. Most importantly, there should be tools to detect chemical exposure; since the 1960s, the human exposome has encountered more than 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, for example humanized animal disease models, could help to safely analyze allergic reactivity. This could reverse the current trend of increasing allergies with higher severity.

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