The effects of immunostimulatory herbal supplements on autoimmune skin diseases

Abstract

The use of herbal supplements that promise to improve immune health has gained popularity among dermatology patients. However, there is little to no evidence that herbal supplements improve dermatological conditions. Several in vitro and in vivo studes have shown that Spirulina platensis, Aphanizomenon flos-aqua, Chlorella, Echinacea, and alfalfa activate immune cells, via certain cytokines and chemokines. Case reports suggest the association of ingesting immunostimulatory herbs and the clinical onset or flares of diseases characterized by an exaggerated immune response such as lupus erythematosus, dermatomyositis and autoimmune blistering disorders. Therefore, it is imperative to investigate the prevalence of herbal supplement use in this patient population. In addition, in vitro studies should examine the underlying mechanisms by which herbs stimulate immune pathways that are already overactive in autoimmune patients.

Capsule Summary

How does this article integrate into what was already known?

Spirulina, Aphanizomenon flos-aqua, Chlorella, Echinacea and alfalfa have been shown to stimulate the immune system. The use of these herbs may be associated with the precipitation or flare of autoimmune skin diseases.

How does it change practice?

Patients with autoimmune diseases should be screened for supplement use and should be advised to avoid these immunostimulatory herbs.

Introduction

Complementary and alternative medicine (CAM) has increased in popularity in the United States.¹ A growing number of dermatology patients use CAM,^{2, 3} with estimates of their lifetime CAM use ranging from 35 to 69%.² The most common types of CAM are herbal and dietary supplements.¹ Herbal supplement sales in the US increased by almost 10% from 2017–2018, marking the greatest increase in sales growth in the past two decades.⁴ Products marketed to boost immune health were one of the main drivers of herbal supplement sales.⁴ However, despite being touted as natural health remedies, there is little to no evidence of treatment efficacy.³ Moreover, there is mounting evidence that certain herbal supplements have adverse dermatologic health effects, including exacerbating pre-existing autoimmune skin diseases or even precipitating the onset of such diseases.^{2, 5–10} (Table I)

Table I.

Herbs that are reported to induce or trigger autoimmune skin diseases

Microalgae Spirulina platensis (also known as Arthrospira platensis) 10, 21 Aphanizomenon flos-aquae10

Purple cornflower (Echinacea purpurea)10, 64

Alfalfa / lucerne (Medicago sativa)19, 22

Since an overactive immune system is one of the main drivers of autoimmune diseases, there is a concern that consuming immunostimulatory herb-based supplements may lead to clinical exacerbations and overall worsening of autoimmune skin diseases.^{10, 11} Various in vivo and in vitro studies have demonstrated that herbs such as Spirulina platensis, Aphanizomenon flos-aqua, Chlorella, Echinacea, and alfalfa are immunostimulatory (Table II).^12–18 Indeed, there have been several reports of the association of herbal supplement use and the acute onset and/or flare of autoimmune cutaneous diseases, including dermatomyositis (DM),^{10, 19, 20} pemphigus/pemphigoid,^{10, 21} and lupus erythematosus (Table III).²²

Table II.

Immune mechanisms of herb-induced immunostimulation

Herb	Mechanism of immune stimulation
Spirulina	• Increases NK cell activity.15, 18, 43, 49  • Activates Toll-like receptors and increases NK-mediated IFN secretion via elevated IL-12 and IL-18.15  • Increases gene expression of cytokines IL–8, MCP-1, MIP-1α, MIP-1β, IP-10, TNF–α, IL-1β, and the enzyme COX-2.44  • Acts on Th1 cells and increases production of Th1 cytokines, such as IL-2 and IFN-γ.18, 71, 72
Aphanizomenon flos-aquae	• Activates NK Cells.53  • Activates NF-kappa B18 and increases TNF-α and IL-1β expression.17, 18
Chlorella	• Increases TNF-α and IL-1β expression.18  • Augments Th1 cells response.  • Increases NK cell activity and production of IFN-γ and IL-12.56
Echinacea	• Increases extracellular cytotoxic effects of macrophages to similar levels compared to IFN-γ.13  • Increases production of various interleukins, including IL-1, IL-10 and TNF-α.12  • Stimulates NK cell activity and increases antibody-dependent cell cytotoxicity.61
Alfalfa	• Novel epitopes created by L-canavine-laden aberrant proteins trigger autoantibody production or cytotoxicity.69

Table III.

Reports of activation of autoimmune skin disease following ingestion of herbal supplements

Herbal supplement	Autoimmune skin disease
Food supplement containing Spirulina platensis, Ginkgo biloba, and ginseng	Pemphigus vulgaris10
You’re My Everything®, a supplement containing Spirulina platensis, Alphanizomenon flos-aquae, organic cayenne pepper, and methylsulfonylmethane	Dermatomyositis10
Spirulina	Mixed immunoblistering disorder with features of bullous pemphigoid and pemphigus foliaceus confirmed via histopathology and direct/indirect immunofluorescence21
Spirulina	Dermatomyositis20
Echinacea	Erythema nodosum64
Echinacea	Pemphigus vulgaris10
Alfalfa	Systemic lupus erythematosus22
Isalean® weight loss shake (contains alfalfa and a proprietary enzyme blend of Aspergillus oryzae, Rhizopus oryzae, Trichoderma longibrachiatum, Saccharomyces cerevisiae, Bacillus subtilis, Ananas comosus, Aspergillus niger)	Dermatomyositis19

Immunostimulation is a key step in autoimmune skin disorders

The pathophysiology of autoimmune skin diseases involves the complex combination of environmental exposures, genetic risk factors, and cellular communication between the skin and the immune system.^{23, 24} Regardless of the inciting event, the common theme in these disorders is the activation of immune cells and their receptors, and the secretion of cytokines and chemokines that result in an exaggerated host immune response.¹¹

Cutaneous Lupus Erythematosus

Innate and adaptive immune cells play a crucial role in cutaneous lupus erythematosus (CLE).²⁵ Plasmacytoid dendritic cells (pDCs) in CLE produce elevated levels of type I interferons (IFN-α and IFN-β) compared to what is expected in a normal viral defense.²⁶ Type I interferons subsequently recruit CXR3+ lymphocytes in the skin, promoting a Th1 inflammatory response.²⁷ Tumor necrosis factor-alpha (TNF-α) is a primary cytokine that recruits immune cells, promotes the release of secondary cytokines, and induces the production of nuclear antigens on the cell surface, which results in antibody production and autoreactivity.²⁸ The involvement of both innate and adaptive immune systems in CLE suggests that stimulation of either immune pathway results in acute onsets and/or flares of disease.

Dermatomyositis

Both cellular and humoral immunity play a role in the pathogenesis of muscle and skin disease in DM.^29–32 Inflammatory CD4 T cells and dendritic cells infiltrate the perimysial blood vessels, perifascicular myofibers, and superficial perivascular dermal tissue, leading to atrophy and lichenoid/interface reactions in the muscle and skin, respectively.^30–32 Type I interferons activate antigen presenting cells and upregulate autoantigens that drive antibody production, as well as cause direct tissue injury.³⁰ Inflammatory cytokines such as TNF-α and interleukin (IL)-6 perpetuate inflammation and cause cell death in the muscle and skin tissue.³²

Pemphigus

Although desmoglein antibodies are sufficient to cause acantholysis in pemphigus,³³ B cells and T cells, and the cytokines that they secrete, can induce and maintain pathogenic autoantibody production.³⁴ TNF-α, IL-6 and IL-8 have been found in the sera and blister fluid of pemphigus patients.^{34, 35} These cytokines do not induce blister formation, but are involved in the inflammatory cascade accompanying acantholysis.³⁵

Herbs stimulate the immune system along pathways that are similarly activated in autoimmune skin conditions

Microalgae

Food-grade microalgae that are manufactured as herbal supplements include Spirulina, Aphanizomenon flos-aquae, and Chlorella. These herbs have been commercialized for human use because of their nutritional value, including reported high protein, vitamin, mineral, and fiber content, and purported health benefits.^36–38 Numerous animal and human studies have shown that these algae are immune-stimulating (Table II). Several case reports have illustrated the connection between microalgae-containing supplement intake and autoimmune skin diseases (Table III).

Spirulina

Spirulina Platensis (also known as Arthrospira platensis) is a type of blue-green algae that has been called a “super food” in the health food industry due to its high protein content and supposed health benefits, such as its possible hypolipidemic, antioxidant, and anti-inflammatory properties.^{39, 40} It is widely used in tablet form or as a powder added to health foods like energy bars, smoothies, and green juices.⁴⁰ Numerous studies have shown that Spirulina suppresses tumorigenesis and viral infections, presumably due to its ability to stimulate the immune system.^{15, 41, 42}

Both in vitro and in vivo studies suggest that specific components of Spirulina have immune-enhancing effects that are primarily mediated via the innate immune system.^{41, 43} Immulina®, a purified functional polysaccharide isolated from Spirulina, was shown to activate nuclear factor kappa-light-chain enhancer of activated B cells (NF-kappa B) in vitro and to dramatically increase IL-1β and TNF-α mRNA in THP-1 human monocytes, with more potent in vitro activation compared to that of lipopolysaccharides (LPS).¹⁷ Similarly, another study found that adding Immulina® to THP-1 human monocytes dose-dependently increased expression of genes encoding cytokines IL–8, monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1 alpha (MIP-1α), macrophage inflammatory protein-1 beta (MIP-1β), interferon gamma-induced protein 10 (IP-10), TNF-α, IL-1β, and the enzyme cyclo-oxygenase-2 (COX-2).⁴⁴ In another study, the addition of Spirulina powder to unstimulated peripheral blood mononuclear cells (PBMCs) also led to significant increases in cytokine levels, including IL-1β, IL-4, and interferon gamma (IFN-γ).¹⁷ Similarly, chicks fed Spirulina had a dose-dependent increase in macrophage concentration and phagocytic activity.¹⁷ They also expressed increased nitric oxide synthase activity, even in the absence of LPS, suggesting that Spirulina may have similar biologic functions as LPS.¹⁷

There is evidence that Spirulina also stimulates natural killer (NK) cells in vivo. In humans who consumed hot water extract of Spirulina, NK activity was upregulated, as measured by increased IFN-γ levels and increased cytolysis.¹⁵ In a pilot study of ten healthy patients who consumed Immulina® 400 mg/day for seven days, there was a 40% average increase in NK cell activity (p<0.01), as measured by killing of K562 tumor cells.⁴³ In a double-blind, placebo-controlled, crossover study, 11 healthy Danish subjects received placebo, 200 mg, or 400 mg Immulina® per day for seven days. After ingesting 200mg or 400mg Immulina®, mRNA expression of natural killer group 2D (NKG2D), an NK cell marker, increased by 37 % (p=0.02) and by 55 % (p=0.0003), respectively. Administration of 400 mg Immulina® also led to a 75% increase in mRNA expression of the NK and T-cell marker perforin (p=0.008).⁴³ Prior studies suggest that Immulina’s® pro-inflammatory effect is primarily mediated via a Toll-like receptor 2 (TLR2) dependent process, further highlighting that components of Spirulina activate the innate immune system.⁴⁵

Although Spirulina’s immunostimulatory effects appear to be mediated primarily via the innate immune system,^{41, 43–50} several studies also suggest that Spirulina stimulates the adaptive immune response.^{46, 47} For instance, numerous parallel studies in which human immunodeficiency virus (HIV)-positive patients received Spirulina supplementation for periods ranging from 2 to 12 months showed an increase in CD4 count and a decrease in viral load.^48–53 Moreover, in a study in which patients ingested Immulina®, subsequent stimulation of CD4 T cells and B cells with Candida albicans antigen in vitro increased T and B cell proliferation for up to 14 days after intake.⁴⁶

While relatively less attention has been focused on the potential adverse dermatologic and health effects of Spirulina, several case reports suggest that Spirulina’s immunostimulatory properties can exacerbate, or even precipitate, autoimmune skin disease (Table III).

Aphanizomenon flos-aquae

Several in vitro studies suggest that Aphanizomenon flos-aquae activates human monocytes and macrophages.^{18, 54} A water soluble preparation of Aphanizomenon flos-aquae significantly activated NF-kappa B directed luceiferase expression in THP-1 human monocytic cells, and also increased mRNA levels of IL-1β and TNF-α.¹⁸ A follow-up study further found that a specific high molecular weight polysaccharide preparation of Aphanizomenon flos-aquae significantly increased expression of TNF-α and IL-1β to levels comparable to those induced by LPS-activated pathways.¹⁷ Similarly, an in vitro study showed that an extract of Aphanizomenon flos-aquae activates NK cells, as seen by increased CD69 expression, and that this effect depended on the activation of other cells such as monocytes and macrophages.⁵⁴ Furthermore, a 45-year-old white female developed cutaneous DM one day after ingesting a supplement containing this microalga and this association was confirmed via rechallenge.¹⁰ This patient had a TNF-α polymorphism which may have predisposed her to DM.¹⁰

Chlorella

Several Chlorella species exist, with Chlorella vulgaris and Chlorella pyrenoidosa being the most utilized species in the supplement industry.^{10, 36, 55} Some of the cited benefits are lowering of cholesterol levels, prevention of atherosclerotic plaques, and anti-tumor and antimicrobial actions.³⁶

There are no reports of Chlorella inducing autoimmune disorders to date; however, several in vitro and in vivo experiments demonstrate that it can stimulate the immune system.^{17, 56–59} Immurella, a polysaccharide derived from Chlorella pyrenoidosa, substantially increased the mRNA levels of IL-1β and TNF-α in human monocytes.⁵⁴ Oral administration of Chlorella extract augmented the Th1 cell response in both normal and immunocompromised hosts and enhanced resistance to infection with the intracellular Listeria monocytogenes.⁵⁴ A study of healthy Korean volunteers who took 5g of Chlorella for eight weeks showed an increase in the NK cell activity, as well as the production of Th1 cell-induced cytokines IFN-γ, IL-12 and IL1-β.⁵⁴ In a placebo-controlled study of healthy controls, intake of thirty tablets for four weeks of a Chlorella pyrenoidosa-derived supplement resulted in significantly elevated salivary IgA production.⁵⁴

Echinacea

Clinical trials have shown that various preparations of Echinacea, or purple cornflower, shorten the duration and severity of upper respiratory infections (URI).⁶⁰ Echinacea angustifolia, Echinacea purpurea, and Echinacea pallida have been the most commonly studied for their immune-enhancing effects.

One murine study found that stimulation with polysaccharides from E. purpurea activated macrophages to similar levels as stimulation with IFN-γ, independent of prior activation or influence from lymphocytes.¹³ In human macrophages, E. pupurea increased production of IL-1, IL-10 and TNF-α to levels comparable to those induced by LPS.¹² In addition, E. purpurea has been found to stimulate NK cell activity and increase antibody-dependent cell cytotoxicity in vitro in human cells.⁶¹

On the other hand, in a double-blinded, placebo-controlled crossover study in healthy humans, an oral preparation of E. purpurea did not affect macrophage production of TNF-α and IL-1β.⁶² In addition, in a review of five studies of healthy adults consuming E. purpurea, only two studies found a significant increase in the phagocytic activity of neutrophils.⁶³ However, the negative results are difficult to interpret due to differences in methods, baseline variation in phagocytic activity throughout the study, and a limited sample size.⁶³

We found one case report suggesting that Echinacea induced a pemphigus vulgaris flare in a Caucasian man with a previously quiescent disease course. The patient had taken Echinacea supplements for the first time after a URI. He had had several previous URIs which had not triggered his pemphigus vulgaris, suggesting that Echinacea supplements may have played a role in triggering the flare.¹⁰ Similarly, a patient with the flu developed erythema nodosum after ingesting Echinacea. After discontinuing Echinacea, the erythema nodosum improved despite persistence of the flu-like symptoms.⁶⁴

Alfalfa

Earlier experiments on rats, rabbits and monkeys suggested that alfalfa, or lucerne (Medicago sativa), has anti-cholesterol and anti-angiogenic properties, leading to several clinical studies to better examine these effects.^{65, 66} In a pilot study of healthy human volunteers, one subject who ingested up to 160g of ground seeds daily developed lupus-like laboratory abnormalities (pancytopenia, hemolytic anemia, presence of anti-nuclear antibodies, and hypocomplementemia), but was asymptomatic except for splenomegaly.⁶⁷ Similarly, monkeys fed alfalfa sprouts developed a lupus-like syndrome, including an erythematous macular rash.⁶⁸ In another study, four previously healthy patients who consumed 12 to 24 alfalfa tablets per day for up to 7 months developed a symptomatic lupus-like disease, manifesting as rash, joint and muscle pains, and positive antinuclear antibodies.²² After discontinuation of the alfalfa tablets, the symptoms and antinuclear antibodies disappeared.²² According to several more recent case reports, patients developed systemic lupus erythematosus (SLE) or had an exacerbation of their disease, although no cutaneous findings were mentioned in these events.⁶⁹ Moreover, in a case series, two patients who ingested a weight loss shake, with alfalfa being one of the main ingredients, had acute onset/flares of DM shortly after consumption.¹⁹ This weight loss shake also contained other fungi-derived enzymes as proprietary active ingredients.¹⁹

The suspected culprit in alfalfa is L-canavine, which is a non-protein amino acid that is known to replace L-arginine during protein synthesis.^{22, 69} As a result, aberrant misfolded proteins are produced that are then ubiquinated and degraded, leading to peptides that can be presented by major histocompatibility complex molecules to CD4 and CD8 cells.⁶⁹ These novel epitopes created by L-canavine-laden aberrant proteins and apoptotic cells may then trigger a cascade of events that involve either autoantibody production or cytotoxicity.⁶⁹

Given the apparent correlation between afalfa ingestion and disease onset or flares, several experts, including the Lupus Foundation of America, have recommended avoiding the consumption or supplementation of alfalfa among patients with SLE.^69,70

Conclusion

CAM, particularly herbal supplements, is becoming increasingly popular among dermatology patients. Microalgae (Spirulina, Aphanizomenon flos-aqua, Chlorella), Echinacea, and alfalfa have been shown in several studies to upregulate cytokines and inflammatory pathways that are already aberrantly increased in a variety of autoimmune skin diseases. At the same time, case reports suggest that there is a connection between herbal supplement use and skin disease onset or flare. Therefore, it is reasonable to screen patients with autoimmune skin diseases for herbal supplement use and to encourage compliance with evidence-based treatment instead. Future research should investigate whether there is a temporal relationship between ingestion and flare or acute onset of the disease utilizing a larger cohort of patients. In addition, in vitro studies could be performed to investigate how herbal supplements affect cytokines and to identify pathways that are upregulated specifically in patients with autoimmune skin diseases.

ABBREVIATIONS:

CAM

Complementary and alternative medicine

CLE

Cutaneous lupus erythematosus

DM

Dermatomyositis

AIBD

Autoimmune blistering disorders

pDCs

Plasmacytoid dendritic cells

IFN-α

Interferon-alpha

IFN-β

Interferon-beta

TLRs

Toll-like receptors

NF-kappa B

Nuclear factor kappa-light-chain enhancer of activated B cells

IL

Interleukin

TNF-α

Tumor necrosis factor alpha

MCP-1

Monocyte chemoattractant protein-1

MIP-1α

Macrophage inflammatory protein-1 alpha

MIP-1β

Macrophage inflammatory protein-1 beta

IP-10

Interferon gamma-induced protein 10

COX-2

Cyclo-oxygenase-2

PBMCs

Peripheral blood mononuclear cells

NK

Natural killer

LPS

Lipopolysaccharide

NKG2D

Natural killer group 2D

Th1

T helper type 1

Th2

T helper type 2

SLE

Systemic lupus erythematosus

URI

Upper respiratory tract infection