Botaceuticals

Immunity x medicinal plants – Back to basics

This series of articles on medicinal plants and immunity follows our call to share as much scientific information as possible. This way, the natural health sector can get on today with the development of tomorrow's products, always more efficient, and more relevant in the complex area of immunity.

These articles are not intended to provide treatment recommendations for the ongoing epidemic.
INTRODUCTION

In a matter of weeks, the topic of immunity has invaded the world of natural health products. The subject will still be on everyone's lips during the coming months (years?). Medicinal plants have a role to play in this area. Many products that promote "immune health" are already on the market.
However, from an immunologist's perspective, the concept of "immune boost" is probably as vague as the concept of "better taste" for a chef.
Immunology is among the most complex medical existing disciplines and is underpinned by the most subtle "biochemical machinery". The complexity is such that the scientific world still debates its various aspects every day.

Yet tomorrow, doctors, pharmacists, and other health professionals will no longer settle for "this plant is perfect for boosting immunity". They will want to know the ins and outs, the molecular mechanisms involved, to develop comprehensive and cutting-edge solutions for optimal "immune health". Therefore, it is crucial to take Phytotherapy and Aromatherapy a little further in terms of immunity.

We do not pretend to be a great expert in immunology; some information will be incomplete and an immunologist will see shortcuts.
However, we are convinced that if all the experts in medicinal plants collaborate, natural products will have their place in “tomorrow's immune health".

We wish to initiate this dynamic with a series of articles. Still, tackling the question under various aspects, it’s essential to me to make a "brief" reminder of the cellular elements and molecular elements that are involved in the mechanisms of "natural defenses". Back to basics!
1. ON THE CELLULAR LEVEL

To develop the best natural solutions for "tomorrow's immune health", it is essential to look at the global effect of the selected medicinal plants. It is also necessary to understand the cellular and molecular actors involved in this beneficial effect. Keeping this in mind, here is a very brief summary of the "cellular stakeholders" involved in immune defenses. Each plant that will be discussed in the next articles can be assessed based on its potential influence on each of the molecular actors.

1.1. Macrophages

Macrophages are the ultimate phagocytic cells. These cells are in charge of cleaning cellular debris and other foreign bodies like viral particles, bacteria, etc. 
They also act, to a lesser extent than dendritic cells (see below), as antigen-presenting cells. Note that macrophages can have distinctive names depending on the organ in which they are found: Kupffer cells in the liver, microglia in the brain, alveolar macrophages in the lungs, …
Besides, they can also have " different phenotypes" following a so-called polarization phenomenon. To simplify, they can be polarized in the form M1 (considered as the mode of defense) or M2 (considered to be the mode of "cleaning for reconstruction").

Simply put:
  • macrophages are the garbage collectors of the body and ensure the elimination of waste
  • to a lower degree, they also inform other immune cells of the nature of what they have collected as foreign bodies to ensure monitoring in terms of protection

What is their role in the context of a natural blend?

Many medicinal plants can impact the activity of macrophages. Some can favor a specific polarization: M1 or M2. Others influence the production capacity of nitric oxide (NO) which is an offensive mechanism of macrophages. Some even modulate the differentiation of monocytes into macrophages. Therefore, it is essential to make sure that a combination of different natural components don’t have opposite actions. Otherwise, the overall effect will be minimized.
1.2. Dendritic cells

Dendritic cells (DCs) are the ultimate antigen-presenting cells. They are present in tissues in contact with the environment: skin, digestive system, lungs, … There, they take foreign elements and present them to other immune cells to ensure "immune monitoring".

Simply put:

  • dendritic cells are the scouts of the immune system
  • they "take samples" at the border between the body and the outside and inform the defense system of the nature of their discovery

What is their role in the context of a natural blend?

Certain plants can promote the activation of dendritic cells and therefore support "alertness" of the immune system.

1.3. Granulocytes

Granulocytes (also called polynuclear) are leukocytes or white blood cells. As their name suggests, they are characterized by the presence of intracellular granules. Those contain various molecules that can be released to locally modulate different inflammatory mechanisms.
There are 3 main categories of granulocytes: neutrophils, basophils, and acidophiles (also called eosinophils).

Basophils and acidophiles are rarely considered in the development of "natural defense" solutions. Basophils' primary role is to positively modulate an allergic reaction. As for acidophiles, their primary function is pest control. Furthermore, they will also negatively modulate an allergic response. These two types of granulocytes are taken into consideration in the context of "allergy products".

Like macrophages, neutrophilic granulocytes are considered phagocytes. They collect bacteria and other cellular debris, but unlike macrophages, their phagocytosis process involves their death.

Simply put:

  • neutrophilic granulocytes are like a swarm of bees: they are very numerous, their life expectancy is relatively short and they "bite" only once before dying
  • basophils and acidophiles will be discussed in the allergy section

What is their role in the context of a natural blend?

Fostering the action of neutrophilic granulocytes could prove to be interesting. In Phytotherapy, this action often results in a positive effect on the phenomenon of phagocytosis (neutrophils and macrophages). At the same time, any ingredient that activates basophils and risks generating an allergic reaction will be avoided.

1.4. Mast cells

Mast cells are leukocytes that also release granules containing substances that modulate the inflammatory response.
In mast cells those substances are mainly histamine, heparin and serotonin. These cells play a crucial role in allergic reactions.

Simply put:

  • mast cells are the critical cells in the allergic reaction
  • they release histamine, heparin and serotonin

What is their role in the context of a natural blend?

Although some medicinal plants can modulate the activity of mast cells, these properties are of little interest in the context of natural defenses.

1.5. NK cells

Natural Killer (NK) cells are specific lymphocytes that act as offensive cells of the innate immune system. They can induce the destruction of infected cells, like T-cells, but also directly attack bacterial pathogens like neutrophil granulocytes.

Others hypothesize that NK cells are an "alternative" to T-cells, which preferentially attack infected cells that don’t have MHC1 on their cell surface (classic contamination signal). In other words, they would be particularly important in a context where an intracellular pathogen could "disguise" its host cell as a healthy cell. It should be noted that this hypothesis also made it possible to highlight the potential role of NK cells in the fight against specific tumor cells, which "disguise themselves as healthy cells".

Simply put:

  • NK cells are offensive cells that can lead to the destruction of infected cells
  • they are particularly useful against pathogens that go unnoticed in their host cell
  • they are a bit like immune counter-espionage, which will flush out the most discreet infiltrators

What is their role in the context of a natural blend?

Certain plants can promote the activity of NK cells. Scientific literature mainly highlights these properties in an oncological framework. Indeed, increased vigilance of NK cells has a potential against certain cancers.

1.6. B-lymphocytes

B-cells are responsible for the humoral or extracellular adaptive immunity. They work by producing antibodies in the blood and lymph. These antibodies are molecules that bind to pathogenic elements and promote their phagocytosis. Therefore, they limit the action of those pathogens.
There are 2 main categories of B-lymphocytes:
  • Plasma cells that produce the antibodies necessary for humoral immunity
  • Memory B-cells that facilitate future fast immune responses in the event of a new infection because they remember the pathogen.

Simply put:

  • B-lymphocytes are the cells that, based on the antigens presented to them, produce the molecular tools necessary for extracellular defense: antibodies
  • there are plasma cells and memory B-cells

What is their role in the context of a natural blend? 

B-lymphocytes are of capital importance in the context of adaptive immunity. Unfortunately, plants that can directly modulate their efficiency are rare. However, it should be noted that some of them seem to be able to limit the cellular integration of specific pathogens. It is not impossible that this effect indirectly promotes the effectiveness of humoral defenses.
1.7. T-cells 

Like B-cells, T-cells are critical cells in adaptive immunity. T-cells are the key players in cellular immunity. They are in charge of identifying infected cells and destroying them, but their immune role does not stop there.
There are a large number of different T-lymphocytes with particular functions. We can distinguish them by the molecules that they express on their cell surface. In particular the Cluster of differentiation (CD) and T-cell receptor (TRC), which are specific according to the type of T-lymphocyte.

REMINDER :
All nucleated cells in our body have MHC class I on their cell surface where they display various peptide fragments that are present in their cytoplasm. If those presented fragments are normal, they will be ignored by T-cells. However, if the cell is infected, it will present a fragment of the pathogen on its MHC-I. This will attract TC and its perforins lead to destruction of the infected cell.
DC’s, macrophages and B-cells express MHC class II on their cell surface who present antigens obtained from extracellular sources when they engulfed them. DC’s and macrophages are non-specific and present a great variety of antigens. B-cells present only a very specific antigen: the one that was bound on their receptor and got internalized. The antigens on MHC-II are recognized by TH that bind on them.

1.7.1. TCR αβ or γδ

Most lymphocytes are called αβ, which means that they express the αβ form of TCR. However, there are also Tγδ-lymphocytes. Although they are in the minority, they have a significant role in the adaptive and innate immunity. They are mainly present in the mucous membranes and other regions of the body that are in contact with the outside world.
1.7.2. CD4+ or CD8+ lymphocytes 

Among the Tαβ-lymphocytes, there are helper lymphocytes that express a CD4 protein on their cell surface and cytotoxic lymphocytes that express CD8. The formers are responsible for modulating the immune response, the latter for eliminating infected cells. 

1.7.3. Different helpers 

Among the Tαβ CD4+-lymphocytes, there are various subcategories including: - Treg or regulatory lymphocytes which can limit the activation of CD8 lymphocytes - Th lymphocytes of which there are several forms: Th1, Th2, Th9, Th17, Th22… they express specific cytokines and intervene in specific mechanisms depending on the form 

Simply put:  

  • T-cells are a heterogeneous group of cells that play many roles primarily associated with adaptive immunity 
  • helper T-lymphocytes modulate the immune response 
  • cytotoxic T-lymphocytes ensure the elimination of the infected cells 
  • the role of Tγδ -lymphocytes is still poorly understood  

What is their role in the context of a natural blend?  

Certain plants seem to have an impact on specific T-lymphocyte populations. These populations play a critical role in "immune health" therefore, it is crucial to consider them. 
Finally, given the limited data available on Tγδ-lymphocytes, it is difficult to take them into account when developing natural formulas. However, they should not be ignored. Their abundant presence on the intestinal level suggests that they could be part of the link that unites microbiota and immunity. 
TO CONCLUDE ON THE CELLULAR LEVEL

The immune system is a complex machine that involves a myriad of separate cells with subtle and interdependent roles. All these cells act in a coordinated manner thanks to molecular communication and not all of these mechanisms are known.

Medicinal plants and their extracts can act on a whole series of cells. Certain extracts are even able to intervene at different levels. When considering the development of natural products intended to promote optimal "immune health", it is therefore essential to take into consideration the global action of each ingredient. The impact on each cell category should also be considered to ensure a perfect mastery of the effect.

In the next articles dealing with plants in the context of immunity (Echinacea, Ginseng, etc.), we will refer, as far as possible, to the specific actions on the different cell types.
2. ON THE MOLECULAR LEVEL

The objective of this second part is to make a brief inventory of "communication" molecules in the context of the immune response, more specifically interleukins. The goal is not to read this article all at once but to get quick explanations about the potential effect of plants on these molecules. 

All cells involved in immune defenses act in a coordinated way and as far as possible, on a controlled scale. This coordination is possible thanks to biochemical communication between the various stakeholders. Below, you will find a summary of the functions of several molecules, with a focus on interleukins. Why is this important in the development of a herbal formulation? It is essential to understand that each actor that modulates the immune response is a double-edged sword.
To develop a product intended to maintain optimal "immune health" without mastering the impact of this product would be unappropriated.
2.1. INTERLEUKINS

As their name suggests, interleukins are molecules that allow communication between different cells of the immune system. It is a huge and relatively heterogeneous group. There are a vast number of different interleukins. This "glossary" is not intended to be all-inclusive but it gives a guideline to help your bibliographic research. They will also play a role in future articles in the series "plants and immunity".
Having an idea of the leading roles of each interleukin makes it possible to better understand the impact of medicinal plants that have a direct or indirect influence on the interleukin expression.

2.1.1. Interleukin 1 (IL-1)

IL-1 is a pro-inflammatory cytokine that can be produced by many cells: monocytes, macrophages, epithelial cells, etc.
They exist in two forms: IL-1α and IL-1β. Although their biological effects are relatively similar, they are distinguished by the fact that the α form remains associated with the cell, while the β form is secreted.

From immune defenses, IL-1 is far from harmless since it plays an inducing role in the acute immune response. It can promote the maturation and proliferation of B-lymphocytes and can also stimulate the proliferation of thymocytes (precursor of T-lymphocytes) via the induction of IL-2 secretion.

Its role in a “natural defense” blend:
IL-1 is at the origin of the acute reaction and its excessive stimulation could lead to inflammation or even febrile symptoms. It is therefore not desirable to integrate a medicinal plant that stimulates IL-1 excessively. 
2.1.2. Interleukin 2 (IL-2)

IL-2 is a regulatory cytokine produced by helper T-lymphocytes. They bind on antigen presenting cells (APC): DC’s, macrophages and B-cells with specific antigens presented by their MHC-II. Helper T-cells are thereby activated and differentiate into memory helper T-cells and effector helper T-cells. The latter release IL-2 that helps to activate the cytotoxic T-cells.

IL-2 also has a secondary role in the differentiation/activation of other immune cells such as B-lymphocytes, NK cells and monocytes.

Its role in a "natural defense" blend:
IL-2 plays a crucial role in the vigilance and efficiency of the immune system. Certain medicinal plants can promote IL-2 secretion. Those plants can potentially ensure the alertness of our natural defenses.

2.1.3. Interleukin 3 (IL-3)

Little is known about the roles of IL-3. It is produced by different cell types: T-lymphocytes, mastocytes and eosinophils.
It is supposed to have the ability to influence the proliferation of granulocytes, macrophages and mast cells. It could stimulate myelopoiesis which is the production of bone marrow and all blood cells. It would also have an incidental role as a coactivator in several immune processes.

Its role in a "natural defense" blend:
Stimulating IL-3 could have a positive impact on innate immunity. However, few medicinal plants can influence this interleukin.

2.1.4. Interleukin 4 (IL-4)

Il-4 is a crucial interleukin with a complex role. It is produced by mast cells and T-lymphocytes. It promotes the differentiation of Th2-lymphocytes, which in turn supports the humoral response. Besides, this interleukin also supports the production of immunoglobulins IgE and IgG1.

Its role in a "natural defense" blend:
Stimulation of IL-4 production could lead to excess IgE, an immunoglobulin involved in allergic-type reactions. Consequently, plants that stimulate such production are to be avoided. 
2.1.5. Interleukin 5 (IL-5)

IL-5 is an interleukin that will mainly stimulate the proliferation and activity of eosinophils. So, it plays a role in many forms of allergy and asthma. It is also involved in the stimulation of B-lymphocytes, as well as in the production of IgA. IgA is crucial in the immune function of mucous membranes.

Its role in a "natural defense" blend:
We should avoid selecting plants that stimulate the production of IL-5 to avoid allergic risks.

2.1.6. Interleukin 6 (IL-6)

IL-6 is a pro-inflammatory molecule involved in the acute reaction. However, its role is not limited to this mechanism. IL-6 seems to influence a large number of physiological processes, from bone metabolism to the production of platelets. Among its effects is the activation of B-lymphocytes, which makes it a particularly remarkable molecule in the context of the immune response.

Its role in a "natural defense" blend:
IL-6 is widely involved in the acute reaction and its excessive stimulation could lead to an exaggerated inflammatory reaction. It is therefore not desirable to integrate a medicinal plant that stimulates IL-6 excessively.

2.1.7. Interleukin 7 (IL-7)

IL-7 can be considered as a growth factor for the precursors of B- and T-lymphocytes. Its primary role is to maintain these cell populations. It has thus an "indirect" immune function.

Its role in a "natural defense" blend:
The interest of IL-7 in a product intended for immune health appears limited. Furthermore, few plants have been identified to influence its expression.
2.1.8. Interleukin 8 (IL-8)

IL-8 is a pro-inflammatory molecule secreted by macrophages and endothelial cells. The primary function is to recruit and activate neutrophilic granulocytes at the inflammatory site.

Its role in a "natural defense" blend:
Like the other molecules linked to localized inflammation, IL-8 isn’t significantly interesting within the framework of a "natural defense" formula. However, its inhibition during infection could have a limiting impact on inflammatory symptoms.

2.1.9. Interleukin 9 (IL-9)

Little is known about IL-9 except that it is an immunomodulatory molecule involved in asthma and produced by helper T-lymphocytes.

Its role in a "natural defense" blend:
By its involvement in asthmatic phenomena, IL-9 stimulation must be avoided in a "natural defense" formulation.

2.1.10. Interleukin 10 (IL-10)

IL-10 is a regulatory molecule that will limit the expression of various other interleukins and interferons. Therefore, it is considered to be anti-inflammatory. It plays the role of a safeguard to avoid an inflammatory runaway, which could be harmful. Its absence also seems to be linked to various autoimmune pathologies.

Its role in a "natural defense" blend:
Most of the medicinal plants recognized as being beneficial for the " immune health "tend to stimulate this regulatory interleukin. This action probably favors maintaining a controlled response and limits the symptoms associated with an outrageous inflammatory response in the event of infection.
2.1.11. Interleukin 11 (IL-11)

Intervening in various mechanisms such as the production of platelets or bone metabolism, the role of IL-11 in the context of immune defenses is relatively poorly understood.

Its role in a "natural defense" blend: Insufficient data.

2.1.12. Interleukin 12 (IL-12)

IL-12 is a cytokine activator of cellular immunity, particularly in the context of viral infections. It will not only activate T-lymphocytes and NK cells but also promote the secretion of interferon IFNγ.

Its role in a "natural defense" blend:
There are only a few medicinal plants that could significantly influence IL-12. This approach should be considered with caution because an excessive expression of IL-12 appears to be correlated with various autoimmune diseases.

2.1.13. Interleukin 13 (IL-13)

The influence of IL-13 on certain parasitic infections, as well as its potential role in asthma, suggests that it occupies multiple roles in the inner workings of the immune system. Mainly produced by Th2-lymphocytes, it also plays a role in stimulating the production of IgE by B-lymphocytes.

Its role in a "natural defense" blend: Insufficient data.
2.1.14. Interleukin 14 (IL-14)

IL-14, also called α-taxilin, can promote the proliferation of B-lymphocytes but inhibit the production of antibodies. It plays a role in parasitic infections but is also implicated in certain lymphomas.

Its role in a "natural defense" blend: Insufficient data.

2.1.15. Interleukin 15 (IL-15)

IL-15 is a cytokine that will stimulate the activity of cytotoxic T-lymphocytes and NK cells. It is a molecule that stimulates cellular immunity. Therefore, it is particularly useful in the context of viral infections. It would also have a positive impact on asthma.

Its role in a "natural defense" blend:
The available data on the role of IL-15 suggest a great interest in the context of viral infections. However, few plants seem able to have a stimulating effect on its production.

2.1.16. Interleukin 16 (IL-16)

IL-16 is a cytokine that plays the role of chemo-attractant: it will recruit a specific cell type in a given area towards cells expressing CD4. Among these, there are T-lymphocytes but also other cell types like monocytes, dendritic cells, etc.

Its role in a "natural defense" blend: Insufficient data.
2.1.17. Interleukin 17 (IL-17)

IL-17 is a pro-inflammatory cytokine. Produced by Th17-lymphocytes, it will stimulate other cells to various pro-inflammatory cytokines. Its excessive activation is linked to multiple autoimmune pathologies.

Its role in a "natural defense" blend:
Given the available data, we will try as much as possible not to stimulate the production of IL-17 to avoid undesirable side effects.

2.1.18. Interleukin 18 (IL-18)

IL-18 is a pro-inflammatory cytokine mainly produced by macrophages. Associated with IL-12 and IL-15, it will also promote the production of IFNγ. Therefore, it will have a positive impact on the immune system in the context of a viral infection.

Its role in a "natural defense" blend:
Given its pro-inflammatory nature, it isn’t desirable to incorporate a medicinal plant that would stimulate IL-18. However, a small action in a product intended for viral infections could be interesting.

2.1.19. Interleukin 19 (IL-19)

Based on the scarce data available, IL-19 could be a pro-inflammatory cytokine due to its ability to induce the production of IL-6.
However, data is insufficient at this stage to draw conclusions or try to consider this aspect in the development of an immune health formulation.

Its role in a "natural defense" blend: Insufficient data.
2.1.20. Interleukin 20 (IL-20)

Based on the scarce data available, IL-20 is a pro-inflammatory cytokine that activates STAT-3 (a regulator of gene expression) at the cutaneous level. It plays a role in pathologies such as psoriasis.

Its role in a "natural defense" blend: Insufficient data.

2.1.21. Interleukin 21 (IL-21)

Critical role in the activation of cytotoxic T-lymphocytes and NK cells.
Its role in a "natural defense" blend: Insufficient data.

2.1.22. Interleukin 22 (IL-22)

Promoting the differentiation of Th17-lymphocytes, it would also have an impact on the release of specific cytokines. Therefore, it can be potentially involved in certain autoimmune pathologies such as psoriasis or Crohn's disease.

Its role in a "natural defense" blend: Insufficient data.
2.2. INTERFERONS

Interferons are cytokines that interfere with viral replication. Although their role in antiviral defenses is crucial, they can also play a role in certain bacterial infections.
We classify interferons classically into 3 main types:

Type I (including IFNα, IFNβ, and IFNΩ):
  • possibly produced by a large cell panel
  • induce a relatively aspecific antiviral response

Type II (including IFNγ):
  • produced by T-lymphocytes under the action of certain interleukins
  • play a crucial role in the context of viral pathologies

Type III (including IFNλ):
  • produced by immune cells
  • seem to play a significant role in the antiviral response

TO CONCLUDE ON THE MOLECULAR LEVEL

It becomes evident that the immune system and its soldiers are incredibly complex. We will see in the next articles, that there are medicinal plants with properties particularly suited to support this biological mechanism.

Long story short, a combination of medicinal plants intended to promote immune health and support natural defenses should ideally have the following characteristics:

  • promote the expression of IL-2, IL-12, and/or IL-15 to ensure optimal vigilance of the immune defenses
  • promote the expression of IL-10 to keep the immune response under control and to avoid an extreme reaction
  • do not stimulate IL-4, IL-5, or IL-17 to avoid an allergic or autoimmune response
  • if the product is not only intended to boost immunity but also to reduce symptoms of winter ailments, we will also promote the inhibition of IL-1, IL-6, IL-8, and/or IL -18

Which plants, plant extracts, and essential oils meet all or part of these characteristics?
That is what we will try to address in the next articles of this series.