A recent study led by Harvard scientists and published in the journal Immunity, has found that severe food allergies (anaphylaxis) can be exacerbated by cross-communication between multiple cell types in the skin and the intestine. In short, your skin can tell your gut to prepare for action!

What are allergies/anaphylaxis?

The immune system has the capacity to manufacture billions of different antibodies, each with its own specific molecular target (**see article on somatic recombination). This feat allows for specific defenses against an array of potential pathogens. It sounds great; however, some of these molecules targeted by antibodies may not actually be harmful. Allergies and anaphylaxis are caused by immune over-reactions to harmless substances such as shellfish or pollen. Think angry teen sent to their room only to slam the bedroom door and knock pictures off the wall. No damage would have been done had no tempers flared; however the overreaction caused inadvertent damage. If the immune system remains contained, you can eat all the peanuts, shellfish, etc. that you want, but the second your immune system decides peanut antigens are dangerous, all hell breaks loose. In mild cases, food allergies may lead to swelling of lips and tongue, and hives. More severe cases can lead to anaphylaxis, a more profound milieu of systemic physiologic effects involving the cardiovascular and respiratory systems (e.g. shortness of breath, decrease in blood pressure, and loss of consciousness).

Allergic responses typically revolve around the production of immunoglobulin E (IgE) antibodies targeting the innocuous substance. Upon initial exposure, allergen-specific B cells generate IgE antibodies against the innocuous substance, and upon subsequent exposures these antibodies can bind to the substance and cause a cascade of immunological events eventually leading to allergy symptoms. The anaphylactic response results from increased permeability of the gastrointestinal tract that leads to the entry of food antigens into the blood resulting in a more robust “emergency” response.

Why do we get allergies? In short, we don’t know. Like many human ailments, genetic predisposition combined with environmental triggers appear to play a role. Many allergens are also associated with enzymes that cleave proteins (proteases) that can aberrantly activate components of the immune system (e.g. IL-33 discussed in this paper and complement components), while other allergens contain pathogen associated molecular patterns (PAMPS) that can trigger inflammatory responses. However they are triggered, the immune system activates to clear the insult from the body; it just so happens that the insult, in this case, does not warrant such a response.

Interestingly, the immune response to allergies is similar to the immune response of helminth infections (e.g. pinworms, hookworms, tapeworms). Furthermore, the hygiene hypothesis, based upon epidemiological studies, suggests that the increasing incidence of allergies and autoimmunity in developed countries is, at least in part, driven by a decrease in infections, notably parasitic infections. The premise of the hygiene hypothesis is that the prevalence of infections promotes a healthy balance in the immune system, while eliminating these infections predisposes an individual to aberrant inflammation. Although this is a source of constant debate, it does pose an interesting connection between helminth infections and allergies.

What’s the connection between the skin and food allergies?

The amount anti-allergen IgE an individual makes to a food allergen is a poor prognostic indicator of the severity of an allergic response. In other words, just because you have a large amount of anti-peanut IgE, it does not mean that you will experience an anaphylactic response following peanut butter consumption. However, the number of mast cells in the intestine does associate with allergy severity, suggesting they are the gatekeepers of food-induced anaphylaxis. Interestingly, there is also a strong connection between food allergen-specific IgE and anaphylaxis among individuals with atopic dermatitis (AD), a condition characterized by chronic skin inflammation. Until the publication of this manuscript by Leyva-Castillo and colleagues, the mechanism linking dermatitis and oral anaphylaxis was unknown.

The authors sought to decipher a mechanism by which skin injury predisposes the gut for an inflammatory response to food allergens. They accomplished this by utilizing a tape stripping strategy on mice to initiate skin injury. Following tape stripping of otherwise unmanipulated mice, they observed an expanded population of mast cells within the intestine, an accompanied by signs of mast cell activation. These results show a clear alteration in intestinal mast cells following skin irritation. They subsequently examined the effect of tape stripping on oral anaphylaxis to OVA. The studies found that while both tape stripped and unmanipulated animals displayed a strong allergic response to orally ingested OVA, the response was exacerbated in the tape stripped mice. Furthermore, this response does not occur in the absence of intestinal mast cells further supporting the hypothesis that skin injury facilitates oral anaphylaxis through priming intestinal mast cells.

Skin injury potentiates mast cell response via IL-33 and IL-25

So there is a connection between skin injury, mast cell accumulation in the intestine, and anaphylactic response to orally ingested antigen, but how does this crosstalk occur? Previous publications have shown that keratinocytes (cells in the skin) release signals (IL-33 and IL-25) in response to injury and that these signals are capable of activating mast cells. In this model, tape stripping led to elevated keratinocyte-derived IL-33 and mast cell expansion. Furthermore, the authors went on to show that the IL-33 responsible for mast cell expansion must come from keratinocytes and IL-25, specifically from intestinal tuft cells, can contribute to this expansion as well.

Innate lymphoid cells represent intermediate between keratinocytes and intestinal mast cells

Interestingly, the authors approached an additional cellular explanation by conducting the tape stripping experiments in mice lacking innate lymphoid cells (ILCs) which contribute to intestinal homeostasis. The mast cell expansion previously observed in the tape stripping model was eliminated in mice lacking a specific group of ILCs called ILC2s. Furthermore, tape stripping induced an expanded population of ILC2s in intestine that was dependent upon keratinocyte produced IL-33. In addition, by impairing the function of the ILC2s, they impeded the mast cell expansion, suggesting that the ILC2s play middleman between the keratinocytes and the intestinal mast cells.

To bring these findings into the realm of human disease, the authors examined intestinal biopsies of individuals with atopic dermatitis (AD). The study found that patients with AD accumulated mast cells in their intestines suggesting the link between skin injury, characteristic of AD, and mast cell expansion. Though the data presented in this article are inconclusive as to the definitive relation of skin injury and anaphylaxis in humans, it does seem to suggest a potential mechanism that could predispose AD patients to anaphylactic responses to oral antigens.

To briefly summarize, the authors demonstrate that skin injury induces IL-33 release from keratinocytes. This IL-33 (along with IL-25 from tuft cells) stimulates the proliferation of ILC2s in the intestine that induce intestinal mast cell expansion. The large population of mast cells in the intestine leads to a greater susceptibility to oral anaphylaxis, likely through the increase vascular and intestinal permeability resulting from their activation.

Tissue crosstalk

Not only does this study provide pivotal information regarding anaphylaxis, but it also discusses an often-overlooked aspect of our physiology – different tissues communicate and coordinate with each other. In this particular case, the skin cells can warn the intestinal cells of an upcoming insult leading to immune preparedness. Other studies have examined crosstalk between the gut and brain. For example, studies have found an association with particular intestinal microbes (Akkermansia muciniphila and Acinetobacter calcoaceticus) and multiple sclerosis (Cekanaviciute et. al. 2017). Similar findings have been made in connection with intestinal microbes and Parkinson’s disease (Sampson et. al. 2016). Based upon these studies and others, it appears as though altering the intestinal microbiome modifies the immune response, which induces changes in the physiology of distal sites.

We can no longer look to a single site of inflammation for the answers to disease-related questions. Though symptoms of a disease may manifest predominantly in a single tissue, the deeper immunologic underpinnings may arise from a completely different location.

Image credit: Creative Commons (https://search.creativecommons.org/photos/bfc26daa-353b-4425-bfb8-d1f6888be2bc)

Christopher Horton earned a Ph.D. in Immunology from the University of Oklahoma Health Sciences Center and is currently an Assistant Professor of Biology at Southwestern Oklahoma State University. Follow on twitter @cghorton_PhD