We have learned a lot about allergies and hypersensitivity over the last thirty years. In some cases, an allergy can be a life-threatening challenge (think of peanut or bee sting allergies). But for most of us, sensitivity to pollen, dust, or other common irritants is a source of inconvenience: we experience itchy eyes, runny nose, fatigue and headache, and sometimes even difficulty breathing. Complications from allergy include sinus infections and potentially asthmatic reactions. Why do we experience these symptoms? What mechanisms are involved in our bodies and tissues? The answers to these questions shed new light on the allergic response, and what we can do to address it.
One of the recent ideas is termed the “hygiene hypothesis”.1 The basic concept is that our immune system learns how to behave by testing its response against a variety of microbes, viruses, and infections – particularly during childhood. With the increased prevalence of basic hygiene and antibacterial cleansers, our immune system is left wondering what to do, and may respond with an increase in hypersensitivity: allergy, asthma and autoimmune disease.2
This hypothesis relies on a few basic concepts in immunology: first, our immune systems (responsible for coordinating all inflammation, including the inflammation involved in allergy) are keyed to recognizing a wide range of different molecular “flags” from the outside and inside worlds. These flags are made of sugar, fat and protein chains that are relative unique, and thus recognizable on an individual basis. For example, there are chains on the outer surfaces of viruses and bacteria that are different from microbe to microbe, allowing the immune system to identify each pathogen fairly specifically. These “pathogen-associated molecular patterns” (PAMPs) fit snugly into “pattern-recognition receptors” (PPRs) on immune cells. After this happens, the second piece begins: the immune system initiates a chain of events, coordinated by helper T cells, which can lead to the production of antibodies that activate and enhance the inflammatory response.
In the hygiene hypothesis, a lack of exposure to PAMPs leaves the immune system without a job, and PPRs (which are not 100% specific, and have some degree of flexibility) are left without a target. As a result, the immune system begins to react to our own tissue (autoimmunity) or to other non-disease-causing substances, like common allergens. What is interesting to note is that many of our immune-modulating herbs and mushrooms, like reishi or astragalus, possess PAMP-like constituents such as saponins and polysaccharides that have the ability to interface with PPRs on immune cells. These herbal constituents act both as a “training” system and as a safe area of focus for immune cells, helping to reduce hyper-reactivity to our own tissues or to external allergens.
While there is certainly a lot of value to the hygiene hypothesis, it has always had some gaps that have left me unsatisfied. For instance, we are often allergic to material that (like detergents, solvents, or other chemicals – including bee venom or peanut oil) contains no PAMP-like molecules. Peanut oil has no surface markers, no protein-sugar chains to recognize, so how is the immune system creating this massive allergic reaction against it? Additionally, folks often experience really rapid reactions to allergens, sometimes within minutes of exposure. The classic mechanism relies on multiple relay paths, from white cells to T cells to antibody formation and recruitment, which usually take much longer (think of poison ivy hypersensitivity, effected by T cells, as an example). Finally, why do we have allergies at all? Is there an evolutionary point to this universal annoyance?
Recent developments point us in a new direction that might help answer these questions. As usual, it seems that the allergic response might be more important and useful than we thought, and not just simply a biological curse. Ruslan Medzhitov, a powerhouse researcher in the field of immunology, has been puzzling over the reasons for a long time. He was one of the discoverers of Toll-like receptors, crucial pieces of the immune response that allows for T-cell activation through PPRs, and has continued research into how immunity works since then. And while we generally think of the innate immune system as being controlled by the adaptive (T- and B-cell based), it may actually be more complicated than that. The standard model of allergy and atopy, for example, relies on helper T cells (especially helper-type-2, or Th2 cells) being the main impetus for the production of IgE, which causes histamine reserves to be released and allergies to flare. We use immunomodulating herbs in part to help shift away from this Th2 response, and thereby decrease the intensity of the allergic response – and there is ample evidence to support the fact that this works.3 Medzhitov doesn’t question this fact, but his research is uncovering another, perhaps more important, pathway for allergy and atopy, too.
It turns out that the allergic response, with its histamine release, nerve irritation, swelling and mucus production, can be easily induced by the innate immune system without relying on T cells at all. The white blood cells in our mucous membranes can directly stimulate the interleukins, prostaglandins, and vasoactive cytokines that lead to all the characteristic symptoms of allergy. In fact, Medzhitov’s research goes further: this vary basic response can affect and even control the behavior and differentiation of T cells – meaning that the control is two way, innate and adaptive immunity being intimately interlinked and feeding back on each other.4 This is a clear explanation of how we can show symptoms of allergies to a substance even in the absence of PAMPs: a range of material, from venoms to oils to allergy-producing chemicals can trigger a response by directly engaging innate immunity. Medzhitov speculates that the main reason for this is to provide a quick response to worms and other intestinal parasites that might lack the characteristic surface markers of viruses or bacteria.
But the implications go further: if you rank the different levels of engagement of the immune system, allergy is rapid and relatively mild compared to the full-scale activation of adaptive immunity, plasma cells, and massive antibody cascade. Allergy requires fewer resources (they’re all present in the tissue already, and are mostly chemical in nature), and generally causes less damage to the physiology than a more widespread inflammatory reaction. In the end, it seems that we developed the ability to mount an allergic response as a first-line “expulsion mechanism” for unwanted substances, from toxins to worms, which might be harder to deal with once they permeate the system. It is a relatively low-cost, low-damage approach to just mount an allergic reaction, swell and flush the tissue, and avoid engaging widespread immune response – and most of the time, it works well. If necessary, the immune system can engage more vigorous defenses, but these will drain more resources and cause more damage. They have a higher cost.
The ability of medicinal plants to engage innate immunity is also well-documented. Many polysaccharides enhance the activity of macrophages and other innate-immunity-cells, stimulating their proliferation and activity while also helping to rebalance adaptive Th2 response to prevent long-term hyperreactivity.5 It is interesting to note, however, that this does not lead to increased allergies: in fact, the opposite is true.6 By engaging both innate and adaptive immunity, medicinal plants rich in polysaccharides and saponins are truly rebalancing the immune response by participating in both sides of a very old, and very important, conversation. While they will not cure allergies, they can help reduce symptoms to the point that they become very easy to live with.
And we may not want to “cure” allergies: the last, and perhaps most crucial piece that Medzhitov’s research brings to the fore is that when you suppress or turn off the allergic response, you can have unintended consequences. Once you realize that the innate immune system has the power to control and coordinate all our immunity, and that a short-term, low-cost response might be essential in preventing a more widespread and destructive immune reaction, you begin to see the importance of maintaining a certain healthy degree of sensitivity. This is what Medzhitov discovered: when you remove a mouse’s ability to be allergic, that mouse is more vulnerable to viral and bacterial infection. It gets sicker, more often.
Let’s look at allergy season in a new light. The fact that we over-react to pollen is actually a sign that an ancient and vital part of our immunity is functioning well. It might be over-reacting because of a lack of exposure (hygiene hypothesis), but the solution isn’t to suppress its activity: that will only lead to a less sensitive, more damaging, more resource-draining immune response when we do get exposed to a pathogen. Let’s instead get involved in the conversation between innate and adaptive immunity, by relying on our immunomodulant tonics – astragalus, reishi, maitake, codonopsis and more – to support a more balanced allergic response. And remember that allergies, like almost everything else in human physiology, have a point, have value. As herbalists, we can honor this value ensuring that it gets expressed in a balanced, healthy way.
1. Romagnani, Sergio. "The increased prevalence of allergy and the hygiene hypothesis: missing immune deviation, reduced immune suppression, or both?." Immunology 112.3 (2004): 352-363.
2. Folkerts, Walzl and Openshaw (2000). “Do common childhood infections ‘teach’ the immune system not to be allergic?” Immunology Today 21 (3)
3. Shen H.-H., Wang K., Li W., Ying Y.-H., Gao G.-X., Li X.-B., Huang H.-Q. "Astragalus membranaceus prevents airway hyperreactivity in mice related to Th2 response inhibition." (2008) Journal of Ethnopharmacology, 116 (2), pp. 363-369.
4. Iwasaki, Akiko, and Ruslan Medzhitov. "Control of adaptive immunity by the innate immune system." Nature immunology 16.4 (201)
5. Du, Xiaogang, et al. "Astragalus polysaccharides enhance the humoral and cellular immune responses of hepatitis B surface antigen vaccination through inhibiting the expression of transforming growth factor β and the frequency of regulatory T cells." FEMS Immunology & Medical Microbiology 63.2 (2011): 228-235.
6. Matkovic, Zinka, et al. "Efficacy and safety of Astragalus membranaceus in the treatment of patients with seasonal allergic rhinitis." Phytotherapy research 24.2 (2010): 175-181.