Immunology 101: Balancing T helper cells and T regulatory cells – www.returntoedencosmetics.com

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Immunology 101: Balancing T helper cells and T regulatory cells

DISCLAIMER:  I am NOT an immunologist. 

I’ve only been researching the area of immunology and autoimmune disease for ~1 year (in contrast, I’ve been researching ingredients and ingredient compatibility for skincare products for 10 years). 

I’ve researched a LOT of subjects over the years, and immunology is by far the most difficult subject I’ve ever researched.  Why is this topic so difficult?  It seems more so than almost any other topic I’ve looked into, there are many contradictory studies in this area, specifically regarding the stimulating/reducing effect of various supplements on the different immune pathways.

Part of the reason for this is that as I’ll show in a few minutes, minor differences in which signaling molecules are upregulated by a supplement can impact the pathway along which a naïve T helper cell (also known as Th0 cell or CD4+ cell) becomes one of a number of T helper cells (Th#, where # is something other than 0) or a T regulatory cell (don’t worry, we’ll talk about this in plain English in a minute).

Despite this being a very difficult subject, I truly believe I can help provide a comprehensive perspective to the novice in this area (and hopefully help those who are not novice but still befuddled a bit by what’s going on here). 

Please note:  what I'm talking about below in no way replaces the first course of action with autoimmune disease... if you can figure out the trigger, avoid it! 

So, if you have Celiac, the info below is NOT going to enable you to eat wheat. 

What the info below should do is help you reduce symptom severity and (hopefully) reduce the frequency of flare-ups in both internal autoimmune diseases such as Hashimoto's and topical autoimmune diseases such as psoriasis.  With most autoimmune diseases, it is oftentimes difficult to identify or difficult to completely avoid triggers.

As you’re reading, please take the discussion below (particularly regarding supplements for immune modulation) with a grain of salt – not only am I still learning (true of everything I research), but research is still being done to fully flesh out this field.

Now that you’re confident in my “expert” opinion 😊, let’s get to talking!

Immune modulation

Okay, I’m speaking for the collective “we” here, but I don’t think I’m wrong in saying that we have always been taught that boosting our immune system is a good thing.

But… did you know that too much stimulation can cause autoimmune disease?

Researchers have learned volumes in this area over the past decade or so and are still making discoveries regarding the immune system.

The BIG question today is, what do you know about Th1, Th2, Th17, and Treg cells?

If the answer is “nothing”, don’t click the close button yet.  I’m here to walk you through as painlessly as possible.

To get started, let’s take a look at the pathway first.

Th1 dominance, Th2 dominant autoimmune disease, Th17 and autoimmunity, Treg and immune modulation

https://www.researchgate.net/figure/Illustrative-scheme-of-naive-T-cell-differentiation-into-Th1-Th2-Th17-or-Treg-cells_fig1_293634274

Okay, so, what the heck does this figure mean?  It means, that in the presence of different signaling molecules, the naïve T cell can become one of many different types of immune cells – either one of the T helper cells (Th1, Th2, Th17 for example) OR a T regulatory cell. 

T helper cells promote an immune response, and T regulatory cells suppress an immune response.

Along each of the paths leading to each type of T helper cell and to the Treg cell, you’ll see one or two abbreviations (ex. IL-4, IFN-g, IL-12, etc.).  Each of these abbreviations specify a type of signaling molecule.  The naïve T cell in the presence of these molecules is prone to convert into the type of T cell the pathway points to.

Let’s look at an example – a naïve T cell in the presence of interleukin-6 (abbreviated IL-6) and transforming growth factor-Beta (TGF-b) will turn into a Th17 type of T helper cell.  And, what does that RORc (dark red circle inside the Th17 cell) mean?  Well, RORc is the type of gene that Th17 cells express, and RORc allows synthesis (creation) of three different signaling molecules (see the black arrow pointing from the Th17 cell to IL-17, IL-21, IL-22?  Well, those are the three signaling molecules that Th17 cells expressing RORc make).  Pretty simple, right?

Th1 dominance, Th1 stimulating supplements, Th2 dominance, Th2 supplements, Treg cells, Treg stimulating, balancing the immune system, autoimmunity, autoimmune disorder, autoimmune disease, topical treatment for rosacea, topical treatment for psoriasis, topical treatment for eczema, psoriasis flares, topical resveratrol, resveratrol cream, topical licorice, licorice lotion

https://www.researchgate.net/figure/Illustrative-scheme-of-naive-T-cell-differentiation-into-Th1-Th2-Th17-or-Treg-cells_fig1_293634274

Now what about those red lines?  Well, the presence of certain signaling molecules can prevent the conversion of a naïve T cell down a particular pathway even when the right signaling molecules are present

Let me explain this.  First, let’s look at the red lines.  You’ll see that the red lines cross some of the black lines, which means they DO NOT interfere with that particular pathway.  You’ll also see that where the red lines end there’s a small perpendicular line at the end of the main red line, and the red lines end either at a T helper/T reg cell or along a pathway. 

The red lines ending at a cell indicate these signaling molecules block the cell from expressing their own signaling molecules.  The red lines ending on a pathway indicate the signaling molecules block creation of the cell type that’s at the end of the pathway.

Here’s an example – when IL-4 or interferon-gamma (IFN-g) are present, they can prevent a naïve T cell from becoming a Th17 type cell EVEN when IL-6 AND TGF-b are present.

When IL-6 is present, it prevents Treg cells from expressing IL-10 and TGF-b.  

Now, you’ll notice that Th1 cells produce IFN-g, Th2 cells produce IL-4, and Treg cells produce TGF-b.  These three signaling molecules are required to make Th1, Th2, and Treg cells, respectively.  In other words, these three pathways have a positive feedback loop built in. 

Why does that matter?  Well, it matters in cases such as autoimmune disease, pregnancy, and cancer (I know, three things you never want to see in the same sentence).  I’ll discuss why this feedback loop is SO important to healthy pregnancy and disease in a future post, but for now, let’s turn the focus from immunology 101 to how this applies to autoimmune diseases.

Th1 dominant autoimmune diseases are typically:

  • Psoriasis
  • Rosacea
  • Lichen Planus2
  • Alopecia Areata15
  • Multiple Sclerosis (MS)1
  • Crohn’s Disease2
  • Celiac Disease2
  • Autoimmune Thyroiditis (both Hashimoto’s and Grave’s)
  • Rheumatoid Arthritis

Th2 dominant autoimmune diseases are typically:

  • Allergic Dermatitis
  • Atopic Eczema
  • Systemic Lupus Erythematosus (SLE)1
  • Sjögren's syndrome(SS)1
  • Lupus
  • Scleroderma
  • Sinusitis
  • Inflammatory Bowel Disease
  • Asthma
  • Allergies
  • Cancer (poor outcome)16
  • Ulcerative Colitis
  • Multiple chemical sensitivity

I say typically because of course, we’re ALL individuals, and we are all capable of a unique presentation of a known disease, and exceptions to these generalizations listed above are well documented in literature3.

So, now that I have your attention, how can you find out if you’re Th1, Th2, or Th17 (yep, we’ll circle back around to Th17 here in a bit).

Well, you can do one of the following to figure out which type of immune imbalance you have:

  • Have a good doctor.
  • Have a good functional medicine practitioner.
  • Test for yourself.

For number 1 – GOOD LUCK.  Seriously, I’ve seen no less than half a dozen doctors and asked them to test which type of T helper cell dominance I have.  And, I’ve gotten either blank stares, vague excuses, schooling up, or other answers that essentially mean “No, we don’t test for that”.

For number 2 – If you find one great!

For number 3 – here’s how to test yourself:

_____________________________________________________________

If you think you’re Th1 dominant, then take one or two supplements from this list and see if your symptoms improve. 

Th2 stimulating supplements (to balance Th1 dominance):

  • Quercetin
  • Turmeric/Curcumin
  • Resveratrol
  • Hemp seed oil
  • Selenium
  • Caffeine
  • Green tea extract (this likely works not by stimulating Th2 but rather by suppressing the Th1 and Th17 pathway, Green tea extract also increases Treg and inhibits pro-inflammatory signaling molecules5)
  • Pine bark extract
  • Asparagus
  • Papaya
  • Cinnamon

If you ARE Th2 dominant, the list above will likely make your conditions worse.

Let's go ahead and compile a nice table of autoimmune disorders that are TYPICALLY Th1 dominant and the supplements that can help stimulate production of Th2 cells (to bring your immune system into balance).

Typical Th1 Dominant Autoimmune Disorders Supplements shown to stimulate production of Th2 Cells (to counter Th1 dominant autoimmune disorders)
Psoriasis Quercetin
Rosacea

Hemp seed oil

Lichen Planus2 Resveratrol
Alopecia Areata15 Turmeric/Curcumin
Multiple Sclerosis (MS)1 Caffeine
Crohn’s Disease2 Selenium
Celiac Disease2 Pine bark extract
Autoimmune Thyroiditis (both Hashimoto’s and Grave’s) Green tea extract (this likely works not by stimulating Th2 but rather by suppressing the Th1 and Th17 pathway, Green tea extract also increases Treg and inhibits pro-inflammatory signaling molecules5)
Rheumatoid Arthritis Cinnamon
Papaya

_____________________________________________________________

If you think you’re Th2 dominant, then take one or two supplements from the list below and see if your symptoms improve. 

Th1 stimulating supplements (to balance Th2 dominance):

  • Echinacea
  • Astragalus (see NOTE below)
  • Lemon balm
  • Ginger
  • Medicinal mushrooms (Beta-glucan, maitake, reishii)
  • Oats
  • Legumes
  • Dairy
  • Corn
  • Nuts
  • Bananas
  • Yams

NOTE:  Astragalus downregulates Th2 production, but above a certain daily intake, astragalus promotes Th17 production10.  Increased Th17 production can make symptoms worse since Th17 promotes inflammation in the body.

If you ARE Th1 dominant, the list above will likely make your condition worse.

 Typical Th2 Dominant Autoimmune Disorders Supplements shown to stimulate production of Th1 Cells (to counter Th2 dominant autoimmune disorders)
Allergic Dermatitis
Atopic Eczema Echinacea
Systemic Lupus Erythematosus (SLE)1 Astragalus (see NOTE below)
Sjögren's syndrome(SS)1 Lemon balm
Lupus Ginger
Scleroderma Medicinal mushrooms (Beta-glucan, maitake, reishii)
Sinusitis Oats
Inflammatory Bowel Disease Legumes
Asthma Dairy
Allergies Corn
Cancer Nuts
Ulcerative Colitis Bananas
Multiple chemical sensitivity Yams

_____________________________________________________________

So, I know you’re thinking – that’s it?  That’s all I have to do to stabilize my autoimmune condition?

Well, … no.

It’s possible for Th1 and Th2 autoimmune diseases to coexist!  There are two typical possibilities for this:

  • The T helper cells all gang up in one area or another of our bodies.  For instance, if we have asthma, then Th2 cells may dominate in our airways, and if we have Celiac disease, then Th1 cells may dominate in our intestines.
  • We don't have enough Tregulatory (also known as Tsuppressor or Treg) cells to counterbalance the T helper cells.

Let's pause for a breath before we move on.

dandelion, dandelion on blue background, stars on blue background, dandelion from below

 

And, now, before we talk about the counterbalancing effect of Treg cells, let's cover one more class of T helper cells…

______________________________________________________________

Th17 helper cells promote inflammatory responses and enhance autoimmune responses (NOT a good thing)

The Th17 class of T helper cells became recognized as a distinct class of T helper cells in 20099.  Th17 cells are generally regarded as pro-inflammatory and these cell counts are higher in several autoimmune diseases (MS, psoriasis, RA). 

Of course, healthy levels of Th17 cells, which are typically found lining the mucosa of the body (think GI tract), are also very important in preventing infection. 

Last couple things on Th17 – this is the only T helper cell shown in Figure 1 that doesn’t have a positive feedback mechanism:  in other words, the Th17 cells do not make any signaling molecules responsible for making more Th17 cells (either IL-6 or TGF-b).  And, while Th1 and Th2 cells make signaling molecules that suppress generation of Th17 cells, Th17 does not suppress (or VERY weakly suppresses) generation of Th1 and Th2 cells9.

_____________________________________________________________

Th17 inhibiting supplements (to suppress creation or expression of Th17 cells):

  • Vitamin A
  • Vitamin D (sunlight!)
  • Sunlight (maybe because of extra Vitamin D generation?)
  • Reduce stress (yeah, I know, Captain Obvious here)
  • CBD
  • THC (NOT an excuse to toke up here people! If you’re doing surgery tomorrow, if lives depend on you, if you’re teaching people, or if you have ANY meaningful job at all, you shouldn’t be toking tonight (or on a regular, seriously, the dope makes you dumb, and I know (and love) plenty of potheads, but it’s SUCH lost potential, and seriously, THC is one of MANY supplements you can take to reduce Th17 levels, so why go there?)
  • Ginger (also reduces Th2)
  • Licorice (Self-Hacked reports that licorice inhibits Th17 but does not impact Treg8)

____________________________________________________________

Treg cells – the suppressor hero!

And, now, let’s talk about Treg cells.

So, Treg cells basically suppress immune response.  Now, I know you’re thinking “Why on earth would I want to suppress my immune response?”  And, that’s a great question, but if you’re suffering an autoimmune disease, then the problem may be that you’ve got too many T helper cells and not enough T regulatory cells.  Treg cells maintain “self tolerance”.

One more thing here – you may have plenty of T regulatory cells but they’re not working right.  We’re going to get (more) technical here for just a minute.

Treg cells express biomarkers called FoxP3, which helps with this whole self-tolerance/immune suppressing action.  Now, some Treg cells are dysfunctional and DO NOT express FoxP3, and in cases where there are a healthy number of Treg cells but autoimmune disease is still present, studies show that the number of Treg cells expressing FoxP3 is lower than in healthy individuals.

Here’s a list of autoimmune diseases that are reported to be impacted either by low numbers of Treg cells or by dysfunctional Treg cells:

  • Eczema
  • Psoriasis
  • Rheumatoid Arthritis
  • Allergies
  • Crohn’s Disease
  • Irritable Bowel Disease (IBD)
  • Autoimmune Thyroiditis (Hashimoto’s or Grave’s Disease) – due to dysfunctional Treg cells

So,… how about increasing the number of Treg cells in those of us with autoimmune disease or how about increasing the number of Treg cells expressing the FoxP3 biomarker?

Well, here are the supplements to help with that.

Treg stimulating supplements (to suppress immune response):

  • Licorice
  • Sufficient Vitamin A intake
  • Sufficient Vitamin D intake
  • N-Acetyl Glucosamine (NAG)

Now, if you’re thinking, “Well, dang, why don’t we just promote the heck out of Treg cell production if we’ve got an autoimmune disease?”  the answer is “BALANCE!”

Cancer cells recruit Treg cells to the tumor (or otherwise are able to get high concentrations of Treg cells in the tumor) so that the immune system doesn’t see the cancerous cells.  Certain viruses also operate this way (think HIV) to keep the immune system from finding it. 

Now before you start trying to boost your immune system and deplete the number of circulating Treg cells, let's remember, Treg cells are vital to helping the body maintain self tolerance.  And, it's not just diseases that use Tregs to their advantage to hide from the body's immune system.  Healthy pregnancies (in other words, life itself) rely on Treg cells to prevent the mother's immune system from attacking and rejecting the fetus.

We’ll talk about this more in a future post, but the takeaway message is:

For a healthy body, BALANCE IS KEY!!!

beach rocks, balanced beach rocks, seesaw beach rocks, beach, blue sky, waves, breaking waves, rocks balanced on a flat rock

So, what does this post have to do with skincare?

Well, you likely noticed eczema, psoriasis, rosacea, and several other skin diseases in the lists above.  My working theory is that for any topical ailments, applying topical products may help dramatically relieve symptoms by helping to balance local levels of the T helper cells.

I didn’t come up with this theory on my own.  An article published in the Journal of Investigative Dermatology13 took a close look at the disease process of psoriatic skin vs. normal skin and found that T cell expression IN THE SKIN impacted the occurrence of psoriatic lesions. 

Based on this study along with other research regarding the permeation of T cells through the body and the quantity of T cells in the skin leads me to believe that topical application of ingredients that stimulate one T helper cell group over the other (depending on which autoimmune dominance a person has) or topical application of ingredients that stimulate production or healthy operation of Treg cells CAN help relieve flare-ups and suppress symptoms.

So, if you have a Th1 dominant autoimmune skin disease, which are typically:

  • Psoriasis
  • Rosacea
  • Lichen Planus2
  • Alopecia Areata (technically an issue with the hair follicle, but topical product application should help with this one also)
  • Rheumatoid Arthritis (I know this one isn’t topical, but if you’re having problems with any superficial joints, I think topical products can also help with RA)

then, applying products containing Th2 stimulating ingredients such as quercetin, resveratrol, or hempseed oil could help relieve those symptoms. 

Which Return to Eden products contain Th2 stimulating ingredients? 

Shade in a Bottle Day & Night Lotion and Beach Bum After Sun Lotion.  Both of these are vegan products.

What about a Th2 dominant autoimmune skin disease, typically:

  • Allergic Dermatitis
  • Atopic Eczema

Well, we’re coming out with a new lotion to stimulate Th1 cells for everybody in this group, so stay tuned.

Lastly, if you’re just looking to promote Treg cells:

Our REM Time Night Lotion is available with N-acetyl glucosamine.  Please also note this night cream contains niacinamide, which while anti-inflammatory14, I have not yet come across substantial sources indicating whether niacinamide suppresses Th1, Th2, or Th17 cells, so niacinamide may work along a different pathway to reduce inflammation (don’t worry, I’ll do an ingredient spotlight blog post on niacinamide eventually). 

We’re also getting ready to launch a vegan hand and body cream (Meadowfoam + Argan Soothing Hand & Body Lotion) with licorice extract to help promote Treg production.

DISCLAIMER:  The statements made regarding these products have not been evaluated by the Food and Drug Administration. The efficacy of these products has not been confirmed by FDA-approved research. These products are not intended to diagnose, treat, cure or prevent any disease. All information presented here is not meant as a substitute for or alternative to information from healthcare practitioners. Please consult your healthcare professional about potential interactions or other possible complications before using any product. The Federal Food, Drug, and Cosmetic Act requires this notice.

References:

https://www.ncbi.nlm.nih.gov/pubmed/9200929

2 https://autoimmunewellness.com/what-is-the-role-of-th1-and-th2-in-autoimmune-disease/

3 https://www.ncbi.nlm.nih.gov/pubmed/15952931

4 https://drlauryn.com/gut-health/th1-vs-th2-dominance-how-to-boost-your-immune-function-in-autoimmune-disease/

5 https://www.naturalendocrinesolutions.com/archives/regulatory-cells-thyroid-autoimmunity/

6 https://www.jacionline.org/article/S0091-6749(01)52958-9/fulltext

7 https://www.hindawi.com/journals/ecam/2011/548086/

8 https://selfhacked.com/blog/th17/

9 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3299089/

10 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4674621/

11 https://selfhacked.com/blog/treg/

12 https://medium.com/advances-in-biological-science/a-simple-sugar-against-autoimmunity-3cb6a50e0f57

13 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2922675/

14 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2683338/

15 https://www.hindawi.com/journals/jir/2013/348546/

16 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4684115/

https://selfhacked.com/blog/supplements-people-th2-dominant/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3276397/

https://advances.sciencemag.org/content/3/7/e1700492.full

https://www.wjgnet.com/2219-2824/full/v6/i1/39.htm

https://www.hindawi.com/journals/ecam/2011/548086/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4137509/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3299089/

Lyme disease paper - https://www.frontiersin.org/articles/10.3389/fimmu.2017.01373/full

colorectal cancer and IBD, Th17 -  https://advances.sciencemag.org/content/3/7/e1700492.full

rosacea, Th1 dominance - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3315879/

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