The Hygiene Hypothesis -- Redefine, Rename, or Just Clean It Up?

Linda Brookes, MSc; Laurence E. Cheng, MD, PhD

Disclosures

April 06, 2015

In This Article

What Comes First—The Parasite or the Allergy?

When the hygiene hypothesis was first proposed, there was no clear-cut explanation for the observations, which were based on epidemiologic studies. A number of mechanisms underlying the hygiene hypothesis have since been proposed; one of the likely contributors involves suppression of proinflammatory signaling via T-regulatory cells, inducing "anti-inflammatory" effects and control of diseases caused by dysregulated immunity, including allergy. "For the immune response that we see in allergy, the part of the immune system that drives allergic diseases is also seen in parasitic infections. So that begs the question: Did that allergic inflammatory response evolve to deal with parasites? The classic answer would be yes; however, the latest data from animal studies and basic science—though not necessarily proven in humans—suggest that the response to parasites may not be to the parasite itself but to other factors, such as the tissue damage caused by those parasites in our bodies." In a recent review,[17] Dr Cheng and coauthor Richard M. Locksley, MD (Howard Hughes Medical Institute, University of California, San Francisco School of Medicine) proposed that allergic inflammatory responses regulate pathways involved in tissue homeostasis and that parasites feed into these pathways, engaging allergic inflammation to sustain aspects of the parasitic life cycle. In response to parasite infection, an adaptive and regulated immune response is layered on the host effector response. However, in the setting of allergy, the effector response remains unregulated due to a lack of induction of T-regulatory cells, leading to the cardinal features of disease. In their review, Drs Cheng and Locksley suggested that exposure to pathogens during critical developmental periods may train the immune system to focus on exogenous organisms rather than allergens.

"We should think of this immune response as not necessarily being so important for fighting infection but for keeping our barrier surfaces (skin, gut, lungs) intact," Dr Cheng explained. "These barrier surfaces are always being challenged, whether from sun damage, trauma, or an insect bite, and this response is probably always working in the background. What is unique about parasites is that they probably have evolved (and we evolved with them) to have a response that promotes re-establishment of barrier integrity while not damaging or causing problems with the host at uninvolved sites. Without parasites, for whatever reason, this barrier maintenance machinery that is always in the background runs in overdrive, and there is no brake on the system. It is reacting to barrier damage and leading to an overexuberant response to that damage signal."

"What is also interesting about the parasite angle is that people who have parasites don't tend to have allergic diseases," Dr Cheng continued. "They have all of the evidence of allergic diseases—very elevated levels of biomarkers that we would associate with allergy—but no clinical allergy. So the parasites themselves probably invoke an immune response that for lack of a better term you could call 'balanced.' That is to say that the body is capable of localizing the repair machinery to only the anatomic locations that require it and turning it off once the tissue has returned to normal."

"It comes down to this: For whatever reason, the body is responding to a cue in such a way that it thinks that there might be a parasite there," Dr Cheng concluded. "Without that initial parasite infection, there is no balance to ensure that that response is localized. So the question is: What regulates this balance and what initiates that overexuberant response? Does the microbiome help to set this brake to balance the immune response, or perhaps the microbiome directly regulates the allergic immune response? Further research into these questions will go a long way toward helping us understand how this system works. And once we have a better handle on how it works, how it breaks down, we might be able to develop new and more effective treatments."

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