Allergens are widely prevalent environmental antigens such as plant pollen, cat dander, house dust mite proteins, specific food proteins, and the like. Allergens are present all around us so potentially everyone is equally exposed to them. However, the allergen-specific immune responses in the allergic are excessive and cause collateral damage while those in the non-allergic don’t. Thus, dysregulation of allergen-specific immune responses is the basis for allergic reactions.
Problem is that a unifying hypothesis to explain allergy has to contend with the fact that allergy rates have dramatically increased in affluent countries in just the past few decades, too short a time period to be explained by changes at the genetic level alone since those would take several generations to manifest their effects throughout the population.
Clearly something has changed in the human-environment interface but what?
Research in recent years suggests that this “something”may be Microbiota – Wikipedia, which are now increasingly recognized as important if not essential to human health.
- Back in the 1980s, the British epidemiologist, David Strachan, noticed that younger siblings in large families had lower risks for common allergies such as eczema and hay fever. Younger siblings also dealt with higher frequencies of common childhood infections (1).
- Strachan conceptualized this inverse relation between childhood infections and allergy risks as the Hygiene hypothesis – Wikipedia, that excessive hygiene dramatically reduces exposure to infectious stimuli necessary to protect against allergies.
- As the importance of microbiota became clearer, the “Hygiene hypothesis” morphed into the idea that exposure to not just pathogens but to all types of microbes, especially early in life, is necessary to properly “train” the immune system to make well-balanced and effective responses.
The expanded version of the “Hygiene hypothesis” thus holds that disruptions in such proper “training” lead to allergies, autoimmune diseases and other chronic inflammatory disorders.
Currently the most fashionable interpretations (2) contend that microbial metabolites and the innate immune system mediate such immune system “training”, and that disturbances in microbiota composition lead to innate immune system dysfunction, which in turn leads to chronic inflammation.
However, such interpretations fail to provide an accurate mechanistic basis for how each of these disorders actually manifests itself. After all an allergic individual isn’t allergic to every allergen but only to specific allergen(s) even though the nature of allergens is such that some of them are practically all around us all the time.
The specificity about the target(s) of dysregulated immune responses in each chronic inflammatory disorder such as an allergy cannot be explained by non-specific attributes such as microbial metabolites and innate immune system function.
A newer approach* put forward by myself and my colleague contends that allergy is a two-step process (3), wherein
- Some individuals are already predisposed either genetically or epigenetically to make highly skewed (and consequentially excessive) types of immune responses to allergens,
- That normally such propensity remains unexpressed or silent,
- That a specific allergy manifests when in the 2nd step such individuals also develop, during the course of their life, a specific immune system deficit, a “hole”, in a subset of their T cell population called FoxP3+ Regulatory T cell – Wikipedia, an antigen-specific and -dependent deficit driven by loss of specific commensal microbiota species in their body.
This approach could explain not just how allergy actually manifests itself but also how rates of specific allergies increased so dramatically in mere decades as hygiene practices dramatically altered microbiota diversity in affluent countries.
* We are co-founders of the company Tregeutix Inc. that focuses on developing microbiota guided antigen-specific immunotherapies based on this idea that we have dubbed SPIRAL (Specific ImmunoRegulatory Algorithm).
Bibliography
1. Strachan, David P. “Hay fever, hygiene, and household size.” BMJ: British Medical Journal 299.6710 (1989): 1259. https://www.ncbi.nlm.nih.gov/pmc…
2. Reynolds, Lisa A., and B. Brett Finlay. “Early life factors that affect allergy development.” Nature Reviews Immunology 17.8 (2017): 518. http://users.unimi.it/minucci/Mo…
3. Usharauli, David, and Tirumalai Kamala. “Concurrent cross‐reactivity of microbiota‐derived epitopes to both self and pathogens may underlie the ‘Hygiene hypothesis’.” Scandinavian Journal of Immunology: e12708. Concurrent cross‐reactivity of microbiota‐derived epitopes to both self and pathogens may underlie the “Hygiene hypothesis”
https://www.quora.com/What-is-the-root-cause-of-any-allergic-reaction/answer/Tirumalai-Kamala