Journal of Autoimmunity 117 (2021) 102576

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Journal of Autoimmunity
journal homepage: www.elsevier.com/locate/jautimm

Mushrooms and immunity

Francesca Motta a, b, M. Eric Gershwin c, Carlo Selmi a, b, *
a
Division of Rheumatology and Clinical Immunology, Humanitas Clinical and Research Center IRCCS, Rozzano, Milan, Italy
b
Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
c
Division of Rheumatology, Department of Medicine, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA

A R T I C L E I N F O A B S T R A C T

Keywords: In the wide field of nutraceuticals, the effects of mushrooms on immunity, cancer and including autoimmunity
Immunity have been proposed for centuries but in recent years a growing interest has led scientists to elucidate which
Leukocytes specific compounds have bioactive properties and through which mechanisms. Glucans and specific proteins are
Cytokines
responsible for most of the biological effects of mushrooms, particularly in terms of immunomodulatory and anti-
Mushrooms
Glucans
tumor results. Proteins with bioactive effects include lectins, fungal immunomodulatory proteins (FIPs), ribo­
Nutraceutical some inactivating proteins (RIPs), ribonucleases, laccases, among others. At the present status of knowledge,
numerous studies have been performed on cell lines and murine models while only a few clinical trials have been
conducted. As in most cases of dietary components, the multitude of variables implicated in the final effect and
an inadequate standardization are expected to affect the observed differences, thus making the available evi­
dence insufficient to justify the treatment of human diseases with mushrooms extracts. We will herein provide a
comprehensive review and critically discussion the biochemical changes induced by different mushroom com­
pounds as observed in in vitro studies, particularly on macrophages, dendritic cells, T cells, and NK cells,
compared to in vivo and human studies. Additional effects are represented by lipids which constitute a minor part
of mushrooms but may have a role in reducing serum cholesterol levels or phenols acting as antioxidant and
reducing agents. Human studies provide a minority of available data, as well illustrated by a placebo-controlled
study of athletes treated with β-glucan from Pleurotus ostreatus. Variables influencing study outcomes include
different mushrooms strains, growing conditions, developmental stage, part of mushroom used, extraction
method, and storage conditions. We foresee that future rigorous research will be needed to determine the po­
tential of mushroom compounds for human health to reproduce the effects of some compounds such as lentinan
which a metaanalysis demonstrated to increase the efficacy of chemotherapy in the treatment of lung cancer and
in the improvement of the patients quality of life.

1. Introduction What we intend for ‘mushroom’ is a ’macrofungus’, i.e. a fungus

visible to human eye. It is usually the fruiting body (basidiocarp), con­
Mushrooms and/or their extracts have been advocated as potential sisting of a stipe and a cap. It produces spores that undergo germination,
immune modulators, including for immunotherapy, treatment of cancer become mycelium and when mating with compatible hyphae form the
and immune regulation in autoimmunity. Fungi and mushrooms are primordia, which will develop into a fruiting body (Fig. 1) [4].
extremely abundant worldwide with great diversity. Their number is Mushrooms have been used for medical purposes since pre-historical
approximately 1.5 million [1] and the number of mushroom species on times [5]. The 3500 year-old mummy discovered in 1991 in an Italian
earth is estimated to be around 150,000–160,000, with only 10% known Alps receded glacier had a mushroom among his possessions, perhaps as
to science. Therefore, we are familiar with 1% of the world fungal biota. a laxative for intestinal parasite disease [6]. Through centuries, mush­
Approximately 2000 species are safe and 700 have pharmacological rooms have had an important part in the culture of the civilizations, such
properties, but not all of these are edible. The majority of mushrooms as ancient Greece, Rome, China and India, for their medical, nutraceu­
belongs to the class of Basidiomycetes, a few are Ascomycetes [2,3]. tical, dietary and psychotropic properties. Oriental medical tradition

* Corresponding author. Division of Rheumatology and Clinical Immunology, Humanitas Clinical and Research Center IRCCS, Via A. Manzoni 56, 20089, Rozzano,
Milan, Italy.
E-mail address: [email protected] (C. Selmi).

https://doi.org/10.1016/j.jaut.2020.102576
Received 20 October 2020; Received in revised form 12 November 2020; Accepted 13 November 2020
Available online 1 December 2020
0896-8411/© 2020 Elsevier Ltd. All rights reserved.
F. Motta et al. Journal of Autoimmunity 117 (2021) 102576

still relies on the use of mushroom for remedies preparation [7]. Sci­ on hundreds of different species. Glucans are the main polysaccharides
entific studies on the mechanisms underlying their medical properties found in mushrooms, as they constitute the fungal cell wall, and are
were lacking until the last decades, when progresses have been made excreted into the cell growth medium, therefore their recovery, purifi­
and molecular studies, clinical trials, papers, journals and congresses cation and characterization is generally feasible [7,10]. As glucans are
have been dedicated to mushrooms [2]. recognized by different immune cells, their effects are pleiotropic and
several experiments have tried to elucidate them. Different methods are
2. Mushroom type and composition available to extract and purify glucans, potentially affecting their ac­
tivities [11]. The most common type of glucan and the most important
The gross composition of mushrooms is water (90%), and the for biological activities consists of a backbone of D-glucose-linked β-(1
remaining 10% consists of protein and amino acids (10%–40%) → 3) frequently branched at O-6 by β-D-glucose residues as side chains
including primarily leucine, valine, glutamine, glutamic and aspartic (hereafter referred to as β-glucan) [10]. A large variability can be
acids, fats (2%–8%), mainly linoleic, oleic and palmitic fatty acid, car­ observed in mushroom species and its concentrations range from 0.21 to
bohydrates (3%–28%) such as chitin, glycogen, trehalose and mannitol, 0.53 g/100 g dry weight [12]. In addition, α- and mixed D-glucans can
fibers (3%–32%), and ash (8%–10%), the fraction of dry matter that be found [11], even though the majority are β-glucans, including len­
remains after incineration, mainly composed of salts and metals, such as tinan from Lentinus edodes, schizophyllan from Schizophyllum commune,
potassium, calcium, phosphorus, magnesium, iron, zinc and copper. krestin from Coriolus versicolor, grifolan from Grifola frondosa and scle­
Mushrooms also contain vitamins such as thiamine, riboflavin, niacin, roglucan from Sclerotinia sclerotiorum [13].
tocopherol and vitamin D and antioxydants. Growth features, stage, Glucans cannot be synthesized and their structure includes
harvest and storage condition may influence the chemical composition pathogen-associated molecular patterns (PAMPs), a highly conserved
and the nutritional value of edible mushrooms [7–9]. While in the last pattern able to induce the immune response. Different membrane re­
centuries whole mushrooms were used for treatment and analysed in ceptors, the pattern-recognition receptors (PRRs), can recognize PAMPs,
early studies, it is now ascertained that medical properties are attrib­ such as Dectin-1, complement receptor 3 (CR3), NOD-like (NLR), RIG-I-
utable to polysaccharide fractions, some specific proteins or other like (RLR), and Toll-like receptors (TLR) [14,15]. These are found on
bioactive compounds. They have been identified and purified from fruit macrophages, monocytes, neutrophils, dendritic cells (DCs) and natural
bodies, cultured mycelium and cultured broth and studies now focus on killer (NK) cells [14] and bind with the highest affinity the polymers
their activities [7]. Medicinal mushrooms appear to have several func­ with the greatest molecular weight, such as schizophyllan and scle­
tions, including immunomodulating, antitumor, antioxidant, car­ roglucan [13]. After binding, the signal is transduced through direct
dioprotective, hypocholesterolemic, antiviral, antibiotic, anti-parasitic, receptor activation and/or cellular pathway activation. Studies in ani­
antifungal, hepatoprotective and hypoglycemic effects [2]. In this re­ mal models demonstrate that a possible mechanism could be the
view we will focus on the effects on immunity. Bioactive beneficial glucan-induced clustering of Dectin-1, with subsequent recruitment of
properties have been found in both edible and non-edible mushrooms. downstream proteins activating the nuclear factor
For example, Ganoderma and Coriolus are considered as medicinal but kappa-light-chain-enhancer of activated B cells (NF-κB) and mediating
not edible. The most common medicinal mushrooms are listed in Table 1 the transcription of genes [16]. Dectin-1 is one of the most important
[7]. innate immune receptors for glucans and notably knock out mice for this
receptor show an increased susceptibility to chemically induced colitis,
3. Mushroom bioactive compounds as a consequence of altered responses to fungi. Moreover, in humans, a
polymorphism in the gene for Dectin-1 is linked to a severe form of ul­
3.1. Polysaccharides cerative colitis [17]. Other studies in vitro showed how the macrophage
response to β-glucans could be influenced by the inflammatory milieu. In
Polysaccharides are the mushroom-derived molecules with the most fact, immune cells can be activated by membrane PRRs, by direct
biologically potent effects and numerous studies have been performed membrane binding or by intracellular PRRs, depending on factors as

Fig. 1. Schematic representation of mushrooms life cycle.

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F. Motta et al. Journal of Autoimmunity 117 (2021) 102576

Table 1
Classification of the most common medicinal mushrooms.
Genus Latin name Common name Family Class

Agaricus A. bisporus White mushroom Agaricaceae Basidiomycetes

A. blazei Sun mushroom
A. subrufescens Almond mushroom
Lentinus Lentinula edodes Shiitake Tricholomataceae Basidiomycetes
L. polychrous
Pleurotus P. ostreatus Oyster mushrooms Pleurotaceae Basidiomycetes
P. nebrodensis
P.citrinopileatus
P. sajor-caju
Ganoderma G. lucidum Reishi Ganodermataceae Basidiomycetes
Schizophyllum S. commune Button mushroom Schizophyllaceae Basidiomycetes
Trametes Coriolus (or Trametes) versicolor Turkey tail Polyporaceae Basidiomycetes
Grifola G. frondosa Maitake Polyporaceae Basidiomycetes
Sclerotinia S. sclerotiorum Cottony rot Sclerotiniaceae Ascomycetes

priming with lipopolysaccharide (LPS) and various cytokines and immunomodulatory action involves the activation of NF-κB [23] and
different inflammatory pathways are initiated [18]. stimulates the generation of reactive oxygen species (ROS) and nitric
The route of administration of glucans has been an issue, and the oxide (NO), which contribute to the death of microorganisms. The effect
bioavailability after oral intake remains debated, with only intraperi­ on cytokines has been demonstrated in several studies on different
toneal or intravenous applications being considered adequate. However, mushrooms mostly for β-glucan, in both murine and human macro­
further experiments showed that orally given glucan has similar effects phages, showing increased expression of interleukin (IL)-1, IL-6, tumor
to an injected dose [19] and that the gut-associated lymphoid tissue is necrosis factor (TNF)-α and other pro-inflammatory cytokines and
the principal site of interaction between mushroom extracts and im­ decreased expression or no induction of anti-inflammatory factors, as
mune cells, which have membrane PRRs [20]. IL-10 [24–32]. Table 2 depicts the detailed effects of glucans on mac­
rophages in different studies and Fig. 2 illustrates them.
3.2. Effects of polysaccharides on macrophages Macrophage stimulation by glucans appears to be important in mu­
rine models to mitigate chemotherapy-induced myelosuppression [33,
Macrophages play a role in tissue homeostasis, immune surveillance, 34], to induce wound healing [35], as a defence against viral [36] and
response against pathogens and in the resolution of inflammation. They bacterial infections, i.e. against Salmonella [37] and Cryptococcus [38],
are able to secrete cytokines and mediators and to polarize to M1, as well as against cancer [39,40].
eliciting a cytotoxic immune response, or to M2, with homeostatic and In a few studies α-glucan effect was examined. An α-glucan from
anti-inflammatory effects [21,22]. In macrophages, the β-glucans Grifola frondosa was administered to diabetic mice, leading to reduction

Table 2
Effects of mushroom glucans on macrophages.
Mushroom Type of glucan Type of Pro- or anti-inflammatory Other effect Ref
macrophages effects

Ganoderma australe β-glucan Murine Pro-inflammatory [25]

Polyporus rhinocerus β-glucan (PRA-1p) Murine Pro-inflammatory [26]
Pleurotus sajor-caju β-glucan Murine Pro-inflammatory [27]
Amillariella mellea β-glucan Murine Pro-inflammatory [28]
Volvariella volvacea α-glucan Murine Pro-inflammatory [30]
Macrocybe lobayensis Crude polysaccharide Murine Pro-inflammatory [31]
Russula senecis Crude polysaccharide Murine Pro-inflammatory [32]
Grifola frondosa MT-α-glucan (400,000–450,000Da) Murine Anti-inflammatory Improvement of glucose, triglycerides, [41]
cholesterol and free fatty acid levels.
Amelioration of ultrastructural changes of
pancreatic β-cells
Lentinus edodes β-glucan (LeP-N2) Murine Pro-inflammatory [42]
Grifola frondosa β-glucan Murine Anti-inflammatory [50]
Pleurotus ostreatus Mushroom concentrate Murine Anti-inflammatory [52]
Lentinula edodes β-glucan (lentinan) Murine Anti-inflammatory [53]
Xylaria nigripes Polysaccharides Murine Anti-inflammatory [54]
Agrocybe chaxingu β-glucan Murine Anti-inflammatory Topical application reduced ear-induced [55]
edema in mice
Grifola frondosa β-glucan Murine Anti-inflammatory [56]
Lentinula edodes β-glucan (lentinan) Human Anti-inflammatory [29]
Ganoderma lucidum, Three extracts from nine commercial Human Pro-inflammatory [43]
Lentinula edodes and preparation, with high β-glucan-
Grifola frondosa α-glucan ratio
Pleurotus citrinopileatus Polysaccharide fraction (450 kDa) Human Anti-inflammatory [44]
Agaricus subrufescens (syn. Zymosan, curdlan and polysaccharide Human Pro-inflammatory [45]
Agaricus blazei Murill) extract
and Coprinus comatus
Cordyceps militaris Aqueous extract, alkaline extract, Human Pro or anti-inflammatory [46]
β-(1 → 3)-D-glucan effects, depending on aqueous
or alkaline extraction
Lentinus edodes ‘in house’ lentinan and commercial Human Anti-inflammatory [51]
extract

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F. Motta et al. Journal of Autoimmunity 117 (2021) 102576

Fig. 2. Effects of mushroom polysaccharides on monocytes and macrophages. Mushroom polysaccharides seem to have a pro-inflammatory activity, inducing M1
macrophages. On the other hand, if monocytes are stimulated with glucans as PCPS at early stages, the differentiation in M2 anti-inflammatory macrophages
is promoted.

of NO and IL-1 macrophages production, improvement of glucose, tri­ militaris have different effects depending on the type of extraction. The
glycerides, cholesterol and free fatty acid levels and amelioration of aqueous extract, which is more rich of mannose and galactose and poor
ultrastructural changes of pancreatic β-cells, suggesting a protective role of glucose, stimulates a pro-inflammatory response, while the alkaline
on pancreatic islets [41]. extract, with a higher amount of glucose and a lower content of the two
Of note, in a recent study Li and Colleague obtained a β-glucan (LeP- other monosaccharides, show the inhibition of inflammatory genes, as
N2) from Lentinus edodes and showed its ability to activate macrophages observed for the purified β-(1 → 3)-D-glucan [46]. Moreover, when
with ROS and NO production in a dose-dependent manner, with no analysed in detail, the effect of glucans might be dual with
cytotoxicity until the dose of 100 μg/mL [42]. pro-inflammatory properties in some pathways and inhibitory in others.
In a study on human macrophages, nine commercially available In this regards, Ahn and Colleagues described that lentinan had an effect
preparations from three mushroom species, Ganoderma lucidum, Lenti­ on inflammasome activation and cytokine maturation in murine bone
nula edodes, and Grifola frondosa, were analysed for β- and α-glucan marrow-derived macrophages. Lentinan up-regulated pro-inflammatory
contents and three extracts were selected based on the highest β-glucan cytokines and the expression of the inflammasome components NLRP3
contents. These extracts led to a dose-dependent increase in cytokine and pro-IL-1β. However, lentinan also selectively inhibited the IL-1β
expression in both non-LPS and LPS stimulated macrophages, with a maturation in response to AIM2 inflammasome activation, ameliorated
synergistic effect on the expression of IL-1α, IL-6 and TNF-α and an LPS-induced lethality and reduced IL-1β secretion induced by Listeria
antagonistic effect on the expression of IL-10. A combined mushroom monocytogenes-mediated AIM2 inflammasome activation. Therefore,
formula had EC50 values lower than 100 μg/mL and even lower in TNF-α while stimulating the expression of pro-inflammatory cytokines, it
expression from LPS treated macrophages compared to the individual selectively attenuates the cytokine maturation in response to AIM2
extracts, suggesting a potential synergistic effect of the mushroom for­ inflammasome activation. The Authors suggest lentinan as an anti-in­
mulas [43]. flammasome agent, especially for AIM2 inflammasome [47]. On the
As already mentioned, the capability of mushrooms to stimulate the contrary, in previous studies, other glucans as paramylon and zymosan
production of pro-inflammatory cytokines is likely dependent on com­ failed to modulate IL-1β secretion [48,49]. It could be possible that
plex factors, among which an important variable is the stage of matu­ polysaccharides have different effect depending on the type of glucans,
ration of immune cell precursors. In fact, a polysaccharide derived from their chemical structures, the method for extraction, the cells and the
Pleurotus citrinopileatus (PCPS) showed anti-inflammatory effect on setting used to study their effects and a multitude of variables not yet
macrophages, modulating the monocyte-to-macrophage differentiation completely understood. For example, a high molecular weight fraction
early, at the monocyte stage, promoting the development of alternative from Grifola frondosa inhibits TNF-α, IL-6 and NF-κB activation in
activated macrophages with anti-inflammatory properties. The response LPS-induced macrophages. On the base of chemical and enzymatic an­
of PCPS-treated monocytes to interferon (IFN)-γ + LPS led to reduced alyses, a glucan with a β-(1 → 4)-linked backbone and β-(1 → 6)-linked
levels of TNF, IL-6 and CCR2 and a tendency to increase IL-10, CCL2 and branches has been identified and may contribute to the
CCL8, with anti-inflammatory effect. Therefore, an early stimulation of anti-inflammatory activity, interacting with TLR2 rather than Dectin-1
macrophage precursor with mushroom glucans might induce a long- or CR3 receptors [50]. Murphy and Colleagues compared an ‘in house’
lasting anti-inflammatory effect [44]. Zymosan and mushroom poly­ lentinan and a commercial extract and reported that the latter has higher
saccharide extracts led to a different response of THP-1 monocytes amounts of α-glucans and less β-glucans while both reduce
compared to macrophages, the latter producing higher levels of cyto­ cytokine-induced NF-κB activation in human alveolar epithelial A549
kines upon stimulation [45]. cells, with the ‘in house’ extract being more potent. However, in acti­
Other factors implicated in the bioactivity of mushroom poly­ vated THP-1 derived macrophages, the commercial extract is more
saccharides are their composition and structure. It has been demon­ effective in attenuating pro-inflammatory cytokine production (TNF-α,
strated that polysaccharides derived from the Ascomycete Cordyceps IL-8, IL-2, IL-6, IL-22), transforming growth factor (TGF)-β and IL-10.

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F. Motta et al. Journal of Autoimmunity 117 (2021) 102576

Moreover, it reduces the oxidative stress-induced early apoptosis, while administered orally to tumor-bearing mice is captured by macro­
the ‘in house’ extract attenuated late apoptosis [51]. Other studies phages and DCs in the Peyer’s patches, transported to the spleen
support the observation of anti-inflammatory properties of glucans on significantly changing the cellular composition, increasing the number
macrophages, thus reducing the production of NO and cytokines even of CD4, CD8, B, NK cells and DCs, while decreasing the number of
after stimulation [52–56]. Of note, an Agaricus blazei Murill extract, splenic myeloid-derived suppressor cells. It also induces the immune
known to be pro-inflammatory in vitro, showed reduction of cytokines response against cancer by increasing the IFN-γ expression in Peyer’s
levels in human whole blood of healthy volunteers after oral intake of patches, spleen tumor and mesenteric lymph nodes. Moreover, the
the extract for several days [57]. proliferation of T lymphocytes induced by MD/tumor lysate DCs was
Taken altogether, the unconclusive and in some cases conflicting higher than that induced by tumor lysate alone-stimulated DCs [63].
results account for the great heterogeneity of mushrooms, derived A similar effect can be obtained with schizophyllan [64] and with
polysaccharides, extraction techniques, biological pathways involved sparan derived from Sparassis crispa, which increased maturation and
and underline the importance of rigorous studies and trials to settle the cytokine production in murine DCs and promote T lymphocyte prolif­
issue. eration and activation with release of IFN-γ [60]. A Ganoderma lucidum
extract activates DCs, induces secretion of IL-23 but not IL-12 and pro­
3.3. Effects of polysaccharides on dendritic (DCs) and T cells motes the differentiation of Th17 cells. T cells produce large amounts of
IL-17 but not of IFN-γ, different from cells cultured with LPS-stimulated
DCs have an important role in immune defence, contributing to an­ DCs [61]. An extract from Agaricus brasiliensis induces the production
tigen presentation to cluster of differentiation (CD)4+ and CD8+ T cells, IL-6 and TNF-α from bone marrow derived DCs in a dose dependent
thus stimulating acquired immune response against pathogens and manner, in the presence of exogenous granulocyte macrophage-colony
tumor cells [58]. The immunomodulatory effects of glucans on DCs are stimulating factor (GM-CSF). In addition, DCs have a crucial role in
mediated by Dectin-1 for some compounds [59], by TLR4 for others [60] stimulating IFN-γ production by splenocytes [65].
and the intracellular signaling appears to be transduced through the The DCs and T cells-mediated immunomodulating potential of
MEK-ERK cascade [61]. The effects of glucans on DCs and T cells in vitro mushrooms is effective in murine models of colitis, where Grifola fron­
are reported in Table 3 and illustrated in Fig. 3. dosa and Agaricus bisporus extracts stimulate IL-23 [66], malaria parasite
The α-glucan YM-2A, isolated from Grifola frondosa, was shown to infection, with lentinan-induced DCs maturation and Th1 immune
have an impact on maturation and function of DCs, increasing the response [67], allergy, with Th1 polarization and reduced IgE produc­
expression of maturation markers, as major histocompatibility complex tion elicited by Agaricus blazei Murill extract [68]. In addition, para­
(MHC) class II molecules, CD80 and CD86, in dose-dependent manner, mylon, a β-1,3-D-glucan isolated from Euglena gracilis Z, has been shown
increasing IL-12p40, TNF-α, and IL-6 production by DCs, but not IL-10 to inhibit the development of atopic dermatitis in mice models [69].
and promoting CD4 and CD8 lymphocytes proliferation and produc­ Through activation of DCs in the Peyer’s patches and induction of T-cell
tion of IFN-γ. In addition, it had an adjuvant effect on a vaccine against response, the oral administration of glucan fractions inhibits tumor
murine tumors, increasing IFN-γ producing T cells thus reducing tumor growth and improves survival rate in murine models of colon carcinoma
growth and improving survival in murine models [59]. and melanoma [70].
A soluble β-glucan D-fraction extracted from Grifola frondosa, in In human DCs a mushroom extract leads to significant dose-
combination with a TLR9 agonist, synergistically increases the surface dependent elevation of IL-8, CCL4, granulocyte-colony stimulating fac­
expression of CD80, CD86 and MHC class II and cytokine production in tor (G-CSF), TNF-α, IL-1β and IL-6. The increase of G-CSF, TNF-α and IL-
DCs, but not IL-10, generating a polarized type 1 T cell response. As for 1β is greater than those induced by LPS, whereas IL-2, IL-8 and IFN-γ
α-glucan, it acts as an anti-tumor, increasing DCs in the tumor site and levels are similar after extract and LPS stimulation. IL-5, IL-10, IL-12 and
inducing activation of CD4 and CD8 T lymphocytes [62]. A different IL-13 are not increased by the same mushroom extracts [71]. In a
study on Grifola frondosa demonstrated that labelled MD-extract different study, human DCs analysed in vitro show no cytokine

Table 3
Effects of mushroom glucans on dendritic cells and lymphocytes.
Mushroom Type of glucan Type of Effects on DC and Other effects Ref
DCs lymphocytes

Grifola frondosa α-glucan YM-2A Murine DC maturation, CD4 and Enhanced DCs vaccine [59]
CD8 lymphocytes as an adjuvant
stimulation
Grifola frondosa Soluble β-glucan D-fraction Murine DC maturation, CD4 and Enhanced DCs anti- [62]
CD8 lymphocytes tumor effect
stimulation
Grifola frondosa MD-fraction Murine DC maturation, CD4 and Reduction of tumor [63]
CD8 lymphocytes volume
stimulation
Schizophyllum commune Schizophyllan K3-SPG Murine CD8 lymphocyte [64]
stimulation
Sparassis crispa Sparan (1,3-β-D-glucan) Murine DC maturation, T [60]
lymphocyte stimulation
Ganoderma lucidum Water soluble extract Murine DC maturation, CD4 [61]
lymphocyte stimulation
Agaricus brasiliensis 1,6-β-glucan with a small amount of 1,3- Murine Splenocyte stimulation [65]
β-glucan extract
AndoSan™ extract (82.4% from Agaricus blazei Moisture 5.8 g, protein 2.6 g, fat 0.3 g, Human Pro-inflammatory [71]
Murill, 14.7% from Hericium erinaceum and carbohydrates 89.4 g (of which β-glucan cytokine release
2.9% from G. frondosa) constitutes 2.8 g) and ash 1.9 g
Pleurotus sajor-caju β-glucan extract Human CD4 and CD8 lymphocytes IgG neutralizing [72]
stimulation antibodies to HPV (in
mice)

Legend. DCs: dendritic cells. CD: cluster of differentiation. IgG: immunoglobulin G. HPV: human papilloma virus.

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F. Motta et al. Journal of Autoimmunity 117 (2021) 102576

Fig. 3. Effects of mushroom glucans on dendritic

cells and lymphocytes. Glucans activate dendritic
cells and T lymphocyte proliferation and polarization
towards a type 1 immune response. B cells are also
activated and Ig production is increased after glucans
stimulation. Legend. MHC II: major histocompatibil­
ity complex class II. CD: cluster of differentiation. IL:
interleukin. TNF: tumor necrosis factor. IFN: inter­
feron. Ig: immunoglobulin. Red arrows indicate pro-
inflammatory stimuli. . (For interpretation of the
references to color in this figure legend, the reader is
referred to the Web version of this article.)

production and no increase of maturation markers, albeit T cells stim­ [76]. The glucan-induced maturation of DCs into more immunostimu­
ulated by glucans and immunoglobulin against viral antigens are latory cells is a promising tool for a more efficient immunotherapy
significantly elevated [72]. against cancer.
The molecular structure of glucans and their ability to stimulate DCs
to activate acquired immune response led to test their potential role in
enhancing vaccine delivery and efficacy. Glucans are good antigen 3.4. Effects of polysaccharides on NK cells
carriers and can be used for nasal delivery of vaccines, as they are up-
taken in the nasal-associated lymphoid tissue [73,74]. Moreover, it NK cells are part of the innate immune system and play a role in
has been shown that carbon nanotubes binding lentinan are able to in­ response against pathogens, in viral infected and cancer cells through
crease antigen accumulation in cells and potentiate cellular and humoral recognition and lysis of target cells and induction of cytokines able to
immunity [75]. It has also been demonstrated that the intravenous in­ stimulate innate and adaptive immune response [77]. Table 4 summa­
jection of K3-fraction from schizophyllan, but not a TLR9 agonist alone, rizes the effect of mushroom polysaccharides on NK cells.
is accumulated in the tumor microenvironment and stimulates immu­ In vitro studies on murine cells show that the oral intake of an extract
nogenic cell death of malignant cells through IFN and IL-12 production combination of Grifola frondosa and Lentinula edodes is the most active in
stimulating both the cellular and humoral branch of immune reactions,

Table 4
Effects of mushroom glucans on NK cells.
Mushroom Type of glucan Type of Effects on NK cells Other effects Ref
NK

Grifola frondosa - MaitakeGold 404 (MTG404) extract Murine MTG404-Shiitake combination and MTG Increased phagocytosis (highest for [78]
and Lentinula - an α-glucan-rich whole Shiitake 404 alone activated NK. AHCC activated combination of MTG404 and Shiitake)
edodes mushroom powder from Gourmet NK only in the highest NK cells to target
Mushrooms, Inc. (Sebastopol, CA, cells ratio.
USA)
- AHCC (Amino-Up Chemical
Company, Sapporo, Japan)
- an α-glucan-rich nutraceutical
ingredient prepared by culturing
Shiitake and other Basidiomycetes
Pleurotus ostreatus Polysaccharide or glucans from Murine Increased NK cytotoxicity Decrease in malignanant cell volume and [79]
mycelia and fruit body number
Astraeus AE2 heteroglucan Murine NK activation Macrophages activation Tumor regression. [80]
hygrometricus Increased survival.
Grifola frondosa MD-fraction Murine NK activation Enhanced cisplatin antitumor and [81]
antimetastatic activity compared to cisplatin
alone. Reduced cisplatin-induced
nephrotoxicity and myelotoxicity
Trametes versicolor Mycelium and fermented substrate Human NK activation Activation of monocytes and lymphocytes [82]
Pleurotus ostreatus Extract rich in carbohydrate Human NK activation Anti-tumor activity against breast and lung cell [83]
lines
Pleurotus ostreatus Pleuran Human Increased NK cell number Reduction of upper respiratory infection [84]
symptoms. No reduction of phagocytosis in
glucan-treated group

Legend. NK: natural killer cells.

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F. Motta et al. Journal of Autoimmunity 117 (2021) 102576

compared to the compounds alone. The combination and Grifola extract production of antibodies [92]. The immunization with a Reishi poly­
alone are able to activate NK cells [78]. Glucans isolated from the saccharide fraction induces the production of antibodies against murine
mycelia and fruit body of Pleurotus ostreatus can induce lymphocyte Lewis lung carcinoma cells, with increased antibody-mediated cyto­
proliferation, macrophage activation, macrophage and NK cell mediated toxicity and reduced production of tumor-associated inflammatory
cytotoxicity. A study on Dalton’s lymphoma mice tumor model showed mediators, in particular CCL2 [93].
the ability of mycelia and fruit body glucan supplementation to inhibit
tumor growth, with increased survival, and this effect is associated with 3.6. Proteins
an enhanced immune response and apoptosis of malignant cells [79].
Similar results were obtained with a heteroglucan isolated from Astraeus As previously mentioned, mushrooms consist of polysaccharides and
hygrometricus [80]. of a proportion of proteins that are receiving a growing focus due to the
A MD-fraction from Grifola frondosa also exhibits antitumor and bioactive properties, including lectins, fungal immunomodulatory pro­
antimetastatic activities. In tumor-bearing mice it effectively enhances teins (FIPs), ribosome inactivating proteins (RIPs), ribonucleases, lac­
cisplatin antitumor activity compared to cisplatin alone. The fraction cases, and other proteins. These are usually isolated through a protocol
also induces IL-12 production, leading to increased NK cells activity in including different step as extraction, ammonium sulfate precipitation,
cisplatin-treated mice and mRNA expression of GM-CSF, G-CSF, chromatography and filtration [94].
macrophage-colony stimulating factor (M-CSF) and IFN-γ in spleno­ Lectins are non-immunoglobulin proteins or glycoproteins able to
cytes, thus reducing myelotoxicity. Of clinical relevance, it is able to specifically bind to cell surface carbohydrates, inducing cell agglutina­
reduce cisplatin-induced nephrotoxicity [81]. tion. Their molecular masses, subunit number and carbohydrate speci­
A study on human peripheral blood cells in vitro showed that the ficity vary among species and from different parts of the mushroom and
mycelium of Trametes versicolor and its fermented substrate activate NK the expression levels may change depending on fruit-body age, season,
cells as well as lymphocytes and monocytes [82]. An extract from location and year [95]. Lectins have antiproliferative, antitumor, anti­
Pleurotus ostreatus is effective in activating human NK cells in vitro and to viral and immune stimulating properties; proteins from different
stimulate their cytotoxic activity with induction of IFN-γ against lung mushrooms have shown antitumor activity, probably by cross-linking
and breast cancer cells, with the largest effect against breast cancer cells, the altered cancer cell glycoproteins. A ricin B-like lectin from Clito­
enhanced in the presence of IL-2. It also causes the up-regulation of cybe nebularis is able to induce hemoagglutination by binding to blood
KIR2DL gene expression, which stimulates cytokine and chemokine group A carbohydrates and has antiproliferative activity specific to
secretion and of NKG2D receptors on NK cells, which increased the human leukemic T cells [96]. Lectins from Pholiota adiposa have mito­
production of IFN-γ [83]. genic activity toward mouse splenocytes, inhibitory effect on human
Pleuran, an insoluble β-(1,3/1,6) glucan from Pleurotus ostreatus, is immunodeficiency virus (HIV)-1 reverse transcriptase and anti­
effective in reducing upper respiratory tract infections risk in athletes, as proliferative activity toward hepatoma Hep G2 cells and breast cancer
illustrated in two human studies. In a randomized trial, a group of MCF7 cells [97]. Analogous antiviral and antitumor effects have been
athletes supplemented with pleuran for 3 months have a significantly demonstrated for lectins from Russula mushroom [98,99], Lactarius
lower number of respiratory infection symptoms and increased number flavidulus [100] and Hericium erinaceum [97]. A lectin from Pleurotus
of circulating NK cells compared with a placebo-treated control group ostreatus activated TLR6 signaling pathway in DCs and increased hepa­
[84]. Similarly, in a double-blind trial, twenty athletes were randomized titis B virus (HBV) specific antibody levels and T helper response,
to dietary supplementation with 100 mg of a β-glucan from Pleurotus overcoming HBV tolerance in transgenic mice [101]. A
ostreatus or placebo, once a day for 2 months. A significant reduction in mannose-binding lectin from Narcissus tazetta showed in vitro antiviral
NK cell activity is observed in the placebo group after intensive exercise, activity against several viruses in a dose-dependent manner, including
whereas no significant reduction in number and activity ensues in the influenza A (H1N1, H3N2, H5N1), influenza B viruses and human res­
β-glucan group, suggesting a protective role of this mushroom extract in piratory syncytial virus [102]. Lectins can also stimulate mitosis in
modulating exercise-induced changes in NK cells in athletes [85]. lymphocytes and splenocytes, by binding to T-cell receptors, triggering
the signaling cascade and IL-2 gene expression [95].
3.5. Effects of polysaccharides on B cells While lectins do no possess enzymatic activity, FIPs are a family of
enzymes (named LZ-8, gts, jap, fve, vvo, gsi, among others), purified
Limited data are available on the effects of mushroom poly­ from different edible mushrooms, with a molecular weight around 13
saccharides on B lymphocytes. While no significant effect has been re­ kDa and including 110–114 amino acids. These share common
ported in some studies [86], some lines of evidence showed conserved motifs, essential for their functions and are studied predom­
immunomodulatory properties on B cells but the net effects remain inantly for their antitumor activities, based on in vitro or murine models
unclear (Fig. 3). Zhuling polysaccharide, from the fruit bodies of Poly­ effects showing capability to elicit the immune response toward cancer
porus umbellatus, is constituted by a (1 → 6, 1 → 4)-linked β-D-gluco­ cells. Possible mechanisms of action involve T cell receptor binding,
pyranosyl backbone, substituted at O-3 position of (1 → 6)-linked activation and signal transduction with production of cytokines as IFN-γ
β-D-glucopyranosyl by (1 → 3)-linked β-D-glucopyranosyl branches and or IL-2 with consequent cytotoxic response, inhibition of telomerase
is a potent activator of B cells, macrophages and DCs in a murine model. activity and cell apoptosis [103]. FIPs are in fact able to suppress telo­
The B cell stimulating properties appear to be determined by its merase, inducing premature senescence, for example in human bladder
branches, as their depletion causes a reduction of the activating effect. cancer cells [104], even in those resistant to cisplatin [105] and human
The polysaccharide also elicits a specific IgM production in mice. lung adenocarcinoma cells [106]. Another type of programmed cell
Human subjects have circulating antibodies against Zhuling backbone, death is autophagy, induced by FIPs in non-small cell lung cancer [107,
suggesting that its epitope is shared by environmental antigens, as 108]. Furthermore, the potential application of FIPs as adjuvants for
β-glucans constitute the cell wall of saprophytic bacteria and fungi, and cancer immunotherapy has been analysed, with results revealing
is able to induce an adaptive humoral responses [87]. significantly stronger adjuvant effect with enhancement of type 1 im­
Other β-glucans are known to induce B cell activation, as Ganoderma mune response when administered in association with tumor antigen,
lucidum’s [88]. Moreover, crude polysaccharides from Pleurotus nebro­ compared to the antigen alone. Tumor-bearing mice co-immunized with
densis extracted in hot water enhances the activity of B lymphocytes an oncoprotein and a FIP had a significantly longer tumor-free survival.
[89], polysaccharides extracted from Flammulina velutipes increases FIPs can induce DCs maturation and Th1 polarization and the IFN-γ
the production of IgM and IgG [90], from Cantharellus cibarius Fr have a response elicited by CD4+ and CD8+ T lymphocytes had a crucial role in
proliferative effect on B cells [91], from Coriolus versicolor induces the the antitumor effect. In addition, the production of specific antibodies

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F. Motta et al. Journal of Autoimmunity 117 (2021) 102576

directed towards the oncoprotein is enhanced, thereby indicating that Table 5

antitumor effect involves both cellular and humoral immune response Effects of mushroom extracts on the development of autoimmunity in murine
[109]. A FIP derived from Antrodia camphorata elicits murine macro­ models.
phage activation with cytokines, chemokines and NF-kB-related gene Mushroom Disease Effect Ref
expression, including TNF-α, IL-1β, IL-6, and IL-12, CCL3, CCL4, CCL5 extract
and CCL10, but not IL-10, CCL17, CCL22 and CCL24, thus inducing a M1 Zymosan Diabetes mellitus Delay in the development of [118]
polarization [110]. On the other hand, RIPs inactivate ribosomes by diabetes
eliminating one or more adenosine residues from ribosomal RNA. They Zymosan Autoimmune Improvement of [119]
encephalomyelitis manifestations in chronic and
induce HIV-1 reverse transcriptase inhibition, have antifungal and
relapsing disease
antiproliferative activities towards different cancer cells [94,111]. Phellinus Autoimmune Prevention of the disease, [120]
Similar to RIPs, mushroom ribonucleases exert HIV reverse transcriptase igniarius encephalomyelitis suppression of the
inhibition and antiproliferative effects on tumors, by catalyzing the extract demyelination and the
degradation of RNA into smaller parts. The antitumor activity was infiltration of immune cells in
the spinal cord
demonstrated in different tumor cells, as leukemia, hepatoma, breast Curdlan Autoimmune Increase of the incidence of the [121]
cancer and rhabdomyosarcoma cells [112]. encephalomyelitis disease
Laccases are multicopper oxidases, implicated in immunogenesis and Zymosan, Autoimmune Induction of the disease in [122]
in the metabolic turnover of complex organic substances. Their inhibi­ curdlan and arthritis genetically susceptible mice
laminarin
tory activity on HIV-1 reverse transcriptase, hepatitis C virus replication,
Zymosan Autoimmune Induction of the disease in [123]
proliferation of hepatoma HepG2 cells and breast cancer MCF7 cells has arthritis genetically susceptible mice
been demonstrated [94,113]. It is worthy to note that although some Curdlan Spondyloarthritis Induction of the disease in [124]
proteins appear to maintain their bioactivity after different processes of genetically susceptible mice;
purification, sterilization and heating, others do not keep stability [94]. IL-23 inhibitors prevented the
disease.
Therefore, attention has to be paid to standardize trials on human pa­
tients, in order to obtain efficacious compounds and comparable results.
Phellinus igniarius significantly decreased the daily incidence rate of
3.7. Lipids autoimmune encephalomyelitis in a mouse model of multiple sclerosis,
improved the clinical score, suppressed the demyelination and the
Fats constitute a minor part of mushrooms and may have a role in the infiltration of immune cells in the spinal cord [120]. On the contrary,
modulation of lipid levels. In facts, polyunsaturated fatty acids may studies on curdlan showed that it can increase the incidence or the
reduce serum cholesterol [114]. Ergosterol and tocopherol have anti­ severity of autoimmune encephalomyelitis [121]. In mice genetically
oxidant properties able to protect from cancer, cardiovascular and susceptible to the development of autoimmune arthritis, the injection of
degenerative diseases. Linoleic acid reduces cardiovascular diseases, zymosan, curdlan and laminarin can trigger chronic arthritis, while only
triglyceride levels and blood pressure [7] and can also have transient arthritis developed in normal mice [122]. Moreover, when
anti-inflammatory activity [115]. Lipids contained in mushrooms can germ-free arthritis-prone mice harbored intestinal microbiota from pa­
have anti-inflammatory properties, due to their high content of unsat­ tients affected by rheumatoid arthritis and were then treated with
urated fatty acids, which are precursors of eicosanoids, implicated in the zymosan, they developed severe autoimmune arthritis [123]. In another
balance between inflammatory and anti-inflammatory processes. An study, curdlan induced spondyloarthritis manifestations in
anti-inflammatory effect was shown on murine macrophages treated autoimmune-prone mice, with development of enthesitis, peripheral
with Imleria badia biomass extracts, due at least partly to the high pro­ and sacroiliac joint arthritis, dactylitis, uveitis and Crohn-like ileitis.
portion of fatty acids present in the mushroom extract [116]. IL-23 inhibitors prevented the development of peripheral arthritis and
the disease was transferable with CD4+ cells to severe combined
3.8. Phenols immunodeficient mice. Moreover, curdlan-treated mice developed
anti-proteoglycan and anti-type II collagen autoantibodies [124].
Phenols present an aromatic ring with one or more hydroxyl groups The dichotomous results obtained on the role of mushrooms in
and have an antioxidant activity as reducing agents, free radical scav­ autoimmunity account for the multitude of factors involved in the
engers, or chelators of metal ions (e.g., Fe, Cu), which can generate ROS. etiopathogenesis of autoimmune diseases and the numerous mushroom
Phenols are able to inhibit cyclooxygenase, lipoxygenase, microsomal extracts that can exert different immunomodulatory effects. In fact, even
monooxygenase, NADH oxygenase, C protein kinase or S-glutathione in a murine models where host genetic background and environmental
transferase, preventing the formation of free radicals and acting as factors are well-known, the variability of the clinical phenotype can
antiallergenic, antiatherogenic, anti-inflammatory, antimicrobial, depend on the type, concentration, administration route, timing and
antithrombotic, cardioprotective and vasodilators. In vitro experiments several other variables of the mushroom compound considered.
show how phenols reduce monocyte adhesion to cells and inhibited the This imply that we are still far from a comprehensive understanding
expression of cytokines [117]. of the roles of mushrooms in autoimmunity and further research is
needed.
4. Mushrooms and autoimmunity
5. Human studies
The potential role of mushroom compounds in the protection against
autoimmunity has been investigated with in vitro studies and experi­ Considering the multitude of potential beneficial effects of mush­
mental murine models (Table 5). Zymosan injection can delay the rooms on health, relatively few clinical studies and trials have been
development of diabetes in non-obese diabetic (NOD) mice, inducing the performed and in particular, given the anti-tumor and immunomodu­
production of TGF-β by modifying the phenotype of pancreas infiltrating latory properties showed in vitro and in murine models, the anti-cancer
macrophages and promoting regulatory T cell response [118]. In addi­ and the anti-inflammatory activities of mushrooms in vivo have been
tion, zymosan can improve chronic and relapsing experimental auto­ evaluated. As the bioactive effects have been mainly evaluated in cells
immune encephalomyelitis, regulating co-stimulation of lines or in animal models and it can be difficult to identify the specific
antigen-presenting cells, MHC class II expression and promoting the molecule responsible for the outcome and the best dosage and treatment
differentiation of regulatory T cells [119]. A mushroom extract from

8
F. Motta et al. Journal of Autoimmunity 117 (2021) 102576

period, a poor standardization of mushroom compounds used, their Table 6

posology and timing can be noticed in clinical trials. Nonetheless, some Effects of mushroom extracts on autoimmune diseases.
favourable outcome has been achieved, although some trial has failed. Mushroom extract Disease Effect Ref
In a revision of randomized clinical trials published from 2004 to 2016
AndoSan™ extract Inflammatory Anti-inflammatory [131]
in China, including 3117 patients, lentinan plus chemotherapy was (82.4% from Agaricus bowel diseases
found to be more effective than chemotherapy alone in the treatment of blazei Murill, 14.7%
lung cancer and in the improvement of quality of life. In 18 cases from Hericium
lentinan-associated adverse reactions occurred, the most serious being erinaceum and 2.9%
from G. frondosa)
allergic shock [125]. The effect of Ganoderma lucidum in cancer has been AndoSan™ extract Inflammatory Anti-inflammatory, [132]
evaluated in a meta-analysis and which underlined how the quality of (82.4% from Agaricus bowel diseases decline of faecal
primary studies was unsatisfying and the results were difficult to eval­ blazei Murill, 14.7% calprotectin levels
uate, therefore its use is not justified as first-line treatment. Neverthe­ from Hericium
erinaceum and 2.9%
less, patients who had been given G. lucidum associated with
from G. frondosa)
chemo/radiotherapy appeared more likely to respond positively AndoSan™ extract Crohn disease Improvement of Crohn [133]
compared to chemo/radiotherapy alone. Moreover, their quality of life (82.4% from Agaricus disease symptoms
improved and adverse effects were minimal [126]. In biochemically blazei Murill, 14.7%
recurrent prostate cancer, Agaricus bisporus powder was able to reduce from Hericium
erinaceum and 2.9%
or stabilize PSA levels [127]. In patients with hepatocellular carcinoma, from G. frondosa)
Coriolus versicolor did not impact on time to progression of the disease, AndoSan™ extract Ulcerative Improvement of [134]
but allowed a better quality of life compared to placebo [128]. Antrodia (82.4% from Agaricus colitis ulcerative colitis
cinnamomea administered to patients with advanced gastric, lung, liver, blazei Murill, 14.7% symptoms
from Hericium
breast or colorectal cancer failed to improve the outcomes, in terms of
erinaceum and 2.9%
survival and quality of life [129]. Agaricus blazei Murill extract Ando­ from G. frondosa)
san™ did not have an impact on survival or response to treatment in AndoSan™ extract Allergy Reduction of IgE levels; [135]
patients with multiple myeloma treated with chemotherapy and autol­ (82.4% from Agaricus improvement of allergy
ogous stem cell transplantation, although trends for a longer median blazei Murill, 14.7% and asthma symptoms;
from Hericium reduction of medication
time to further treatment and a shorter period of antibiotics for com­
erinaceum and 2.9% use
plications were noted [130]. from G. frondosa)
A few studies on autoimmune diseases have also been performed, Pleuran Atopic Improvement of [136]
with modest results (Table 6). Andosan™ induced a only a slight dermatitis symptoms; reduction of
flares
decrease of cytokine levels in patients with inflammatory bowel diseases
Pleuran Allergy Reduction of peripheral [138]
in a randomized controlled trial [131], albeit in other studies it appears blood eosinophilia;
to have a stronger anti-inflammatory effect on cytokines with decline of stabilization of IgE levels
faecal calprotectin levels [132] and to improve Crohn’s disease [133] Ganoderma lucidum Rheumatoid None [139]
and ulcerative colitis [134] symptoms in other studies. Andosan™ al­ arthritis
Mushroom-rich diet Rheumatoid Protective role in [140]
lows a significant reduction in IgE levels, in reported general allergy and
arthritis rheumatoid arthritis
asthma symptoms and in medication use during pollen season compared development
to placebo [135]. In an multicentre open study on mild to moderate
atopic dermatitis, a β-glucan-based cream containing pleuran was
effective in improving symptoms, severity and in reducing exacerbations method [147,148] and storage conditions [149] may affect the
[136]. As previously mentioned, pleuran was effective in reducing upper bioavailability and the bioactivity. The route of administration may also
respiratory tract infections risk in athletes [84]. Other studies confirmed have an impact, as some Authors have suggested that mushrooms effect
its beneficial effects in the prevention and treatment of respiratory in­ on immunity could also be mediated by the gut microbiota following
fections, in both adults and children [137], also with an anti-allergic oral intake. In fact, mushrooms may change the intestinal saprophytic
effect [138]. Ganoderma lucidum water extract does not produce signif­ flora, acting as prebiotics, with subsequent modulation of lipemic asset,
icant effect on immune regulation in patients with rheumatoid arthritis immune response and oncogenic potential [150,151]. Furthermore, the
[139], even though mushrooms and other dietary items had a protective dosage for oral or parenteral intake of mushrooms are far from being
role in rheumatoid arthritis development [140]. G. lucidum is also standardized.
effective in significantly improving aerobic endurance, lower body Beside these mechanistic lines of evidence, nonetheless, the major
flexibility and velocity in patients with fibromyalgia [141]. question arising is whether any of these observed changes are of clinical
relevance. In human studies a temporary supplementation with mush­
6. General discussion room compounds obtained slight biochemical variations or a modifica­
tion of the quality of life with no robust evidence of a strong impact on
In the last decade the immunomodulatory role of mushroom com­ the course of diseases, cancerous or autoimmune, possibly depending on
pounds has been proven in numerous conditions and considering that the dose or the duration of the dietary intervention. Promising appli­
the majority of mushrooms are still unknown, we may still speculate on cations are focusing on cancer, as different mushroom extracts showed
real potential of beneficial properties given by this dietary and easily anti-tumor effects, as well as allergies. In the case of oncology, glucans
accessible supplements. Studies on cell lines, murine models and human stimulate macrophages and NK cells, with increased production of pro-
cells have been consistent at confirming an effect on immunity while inflammatory cytokines and activation of humoral immune response
other controversial results have undermined the clinical result of these, against cancer cells [39,40]. NK cells activation has also shown
as the same mushroom extract appears to induce a pro-inflammatory or anti-metastatic activity [81]. In addition, glucans are able to induce the
an anti-inflammatory effect in different studies, sometimes with variable maturation of dendritic cells, to promote CD4 and CD8 lymphocyte
magnitude effects. The most likely scenario is that a multitude of vari­ proliferation and to polarize them towards a type 1 immune response,
ables concur to influence the outcomes, including but not limited to thus enhancing the cellular immune response against cancer cells.
different mushrooms strains [142,143], growing conditions [144], Moreover, an adjuvant effect on vaccines against murine tumors has
developmental stage [145], part of mushroom used [146], extraction been shown [59]. Mushroom proteins also display significant anti-tumor

9
F. Motta et al. Journal of Autoimmunity 117 (2021) 102576

effects in vitro, through T cell-mediated immune response [103], adju­ [16] S.E. Elcombe, S. Naqvi, M.W.M. Van Den Bosch, K.F. MacKenzie, F. Cianfanelli, G.
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