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The Great Immunomodulators
Unveiling the intricacies of the immune system and the potential of medicinal mushrooms to modulate individual immune responses.
In the realm of health and medicine, the humble mushroom takes centre stage as a potent immunomodulator. These versatile organisms have a rich history in both culinary traditions and Eastern medicinal practices, with varieties like reishi, turkey tail, shiitake, and maitake dating back centuries in traditional Chinese medicine. Now science in the West is opening its eyes to the historic uses of medicinal mushrooms, on a mission to understand the power of mushrooms from a molecular perspective. While mushrooms might not be the first thing that comes to mind in the context of health, we don’t have to look far to notice its presence. The biggest breakthrough of modern medicine was penicillin as the first antibiotic, which is of course a fungus! But to understand how mushrooms can help us, let’s first take a look at how the immune system actually works.
The Immune System Unveiled
The immune system serves as a sophisticated defence mechanism for the body, comprising a intricate network of cells, organs, proteins, and tissues. Its primary function is to safeguard the body against external threats by identifying unfamiliar substances and launching a defence against them. What we call the immune system is made up of two parts, the innate immune system which acts as the initial line of defence, employing barriers like the skin, mucus membranes, and stomach acid to prevent the entry of unwanted substances. In the event of a breach, it deploys rapid, broad-scale measures to neutralise and eliminate invaders, reacting to anything not recognised as “self”.
And then we have the adaptive immune system which is more precise and targeted. It learns to recognise specific foreign materials, responding to particular molecules and launching a targeted attack before pathogens can cause widespread damage. Vaccination is a prime example of leveraging the adaptive immune system, as it enables the body to recognise and combat a virus more effectively if exposed later.
White blood cells are the pivotal players in the immune response. They circulate the body through the blood and lymphatic vessels looking for any substances they don’t recognise as self, classing them as antigens. But how do these white blood cells know what’s self and what’s not? Well, they use special detectors called receptors to find pathogen-associated molecular patterns. When they detect a pathogen, it’s like an alarm goes off, and the white blood cells start multiplying and signalling to other cell types to do the same. Phagocytes, belonging to the innate immune system, engulf and break down pathogens (think Pac-Man style), while lymphocytes, part of the adaptive immune system, create a record of encountered pathogens in the form of antibodies. These antibodies serve as a memory, allowing for swift recognition and response upon future encounters with the same pathogens.
But sometimes immune systems don’t work the way they should – this could mean they are either not able to do enough or are trying to do too much. For example, immunocompromised people are unable to raise an immune response and are not capable of fighting pathogens effectively. On the other hand, immune systems that go into overdrive can end up attacking non-pathogenic cells, including your own, as in the case of autoimmune disorders.
Now we understand how the immune system works and how it can falter, let’s take a look at immunomodulation and how science is working towards ways to help it. Immunomodulation is simply the immune system’s ability to up- or down-regulate as required and immunomodulators can help make this process more effective (we’re looking at you mushrooms). In medical terms, immunomodulators are treatments that increase or decrease immune responses depending on the requirement for the specific conditions. For instance, an avenue being explored to treat various cancers is to increase the immune response, to help it seek out and kill cancer cells, while in autoimmune diseases immunomodulators would aim to suppress the immune response because it is unnecessarily attacking the body’s own healthy cells.
Momentum is gathering in biotechnological and pharmacological developments, to try and implement functional modulation of the various immune system components. Because of the intricate and complex nature of the immune system there are understandably many potential targets. While conventional molecular screening for potential synthetic compounds is always ongoing, scientists are also turning their attention to Mother Nature in the form of plants and mushrooms – the original medicines. Many plants and mushrooms have been used medicinally for thousands of years, but now new research is exploring what in mushrooms is actually doing the trick. The benefit of identifying and exploring such compounds from sources already used as foods means there’s no need for the lengthy testing routine like with synthetic medications.
Why and how are fungi so adept at stimulating and modulating the human immune system?
Research into the ability of both extracts and isolated metabolites from mushrooms to modulate the immune system is a thriving area and these metabolites could provide avenues of treatments for cancer, immunodeficiency diseases, teaming up with antibiotics, and even boosting vaccine effects. The main players seem to be polysaccharides, which are found in many foods, but mushrooms have a particularly high content. These are molecules with a high molecular weight and are found in the cell walls both of fruiting bodies and the mycelium. So far, more than 35 different polysaccharide groups have been extracted, with betaglucans being the most prevalent compound family.
In contrast to betaglucans from other sources, ones from mushrooms are characterised by β-1,3-glucans with short β-1,6-side chains. Mushroom betaglucans also owe their properties to the triple helix formation, which is one of the key factors influencing the bioactivity of mushroom betaglucans. This unique molecular structure is what allows them to be recognised by receptors located on the surface of human immune cells. Our immune system recognises these betaglucans as foreign invaders (non-self), and this recognition is like pressing the “go” button for our immune system. It triggers a response, revving up our immune system and making it more effective. Several receptors on immune cells have been identified, with the most extensively studied being dectin-1, which mediates betaglucan activation of phagocytosis (remember phagocytes are the Pac-Man like white blood cells of our innate immune system). Other white blood cells, like neutrophils, macrophages, and dendritic cells, also have receptors that recognise these betaglucans. The good thing about betaglucans is that they are resistant to gastric juice, so can safely be consumed and pass through the digestive tract to the small intestine where they bind to macrophage receptors (dectin-1) and from there get transported around the lymphatic system. When dectin-1 gets activated, it sets off a chain reaction – stimulating phagocytosis (the immune cells munching on invaders), endocytosis (cells taking in substances), and the production of ‘reactive oxygen species’ that target and destroy harmful microorganisms.
Betaglucans also stimulate the production of cytokines. Cytokines are small soluble proteins that act as intracellular mediators in an immune response via many different pathways – effectively a messaging system that allows swifter destruction responses by the appropriate white blood cells. Cytokine expression is an important part of the immune system response – increasing inflammatory cytokines at the start of an infection will help kill off invaders quickly for example. Studies have shown that oyster, reishi, shiitake and maitake extracts can impact specific cytokine expression in human macrophage cells, acting as highly potent immunostimulators. Additionally, it appeared as though the active compounds in the extracts had a synergistic effect, where they work better together than in isolation.
Cytokines also play a key role in cancer research: a study into reishi, cordyceps, turkey tail and maitake explored how these mushroom metabolites modify cytokines within specific cancer models, as well as the direct impact of the mushrooms on the cancer. In vitro evidence was produced showing the mushrooms elucidating an anticancer immunological response. Research over the last several decades shows that mushrooms have properties that slow tumour growth, regulate tumour genes, as well as increase malignant cell phagocytosis (i.e. the phagocytes eat and destroy cancer cells in the body)3. The immunomodulating action of mushroom metabolites is especially valuable as a protective or preventive treatment and as a co-treatment with chemotherapy. Mushroom polysaccharides seem to be able to prevent the complex, multi-step process by which normal cells turn into cancerous cells, and they show direct anti-tumor activity against various synergetic tumours and prevent tumour metastasis (the process by which cancer cells spread to other parts of the body). Their activity is especially beneficial when used in conjunction with chemotherapy.
Phew! A lot of information to digest! But hopefully information that goes some way towards aiding a deeper understanding of the beautiful complexity that is our immune system and how mushrooms may interact and help its functioning. We’re only just beginning to scratch the surface of the potent potential of medicinal mushrooms as immunomodulators, and while we are still some steps away from devising full cancer treatments, the interest and effort going into researching the “how” and “why” may open up whole new worlds of medical benefits. Research so far is showing plenty of positive effects of mushroom metabolites in extract form when it comes to kickstarting immune responses, so as we head into cold and flu season it won’t hurt to boost your white blood cells’ response time with some mushroom love!
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