TH17 & Autoimmunity

You probably have heard by now about the relationship between Th2 dominance and autoimmune disease. You may have also heard that too much inflammation leads to autoimmune disorders. But how does inflammation trigger tissue destruction? This article explains a bit about how the different parts of the immune system play a role in developing a chronic inflammatory condition and how imbalance within the immune system can lead to tissue destruction. 

There are many different types of Immune cells known as T-helper cells (Th1, Th2, Th9, Th17, Th22). When they are all in balance and the body functions the way it should, everything runs smoothly and inflammation can resolve itself without damaging the cells of the body. However, when there are imbalances within the immune system, it can lead to long lasting damage and a cascade of inflammatory reactions.

I have written an article on TH1 and TH2 immune cells which you can go ahead and read before diving into some more complicated immunology and learning about TH17 cells. Immunology is not a simple and light topic and there is a lot I did not get into and cover in this article as it would get too complicated. I did try to keep this article as simple and straight forward as possible while still explaining the main points of immune dysregulation.

What is Inflammation?

Inflammation is at the center of heart disease, diabetes, alzheimers, fibromyalgia, muscular-skeletal issues, etc.

If you have damage to tissues or an infection in tissues, fibroblasts (collagen-producing cell) and macrophages (phagocytic cell that “eats” toxic cells) will send signals to the immune system that will diffuse out from the cells. These chemical signals will hit the wall of the venule (vein) near the damaged or infected site and will cause the expression of adhesion molecules which will make the neutrophils (White Blood Cells) stick to the wall of the vein. These neutrophils come in and then engulf the bacteria (infection) or toxin to then remove it from the tissue.

Once the neutrophils have done their job and engulfed the bacteria or toxins, they send out their own signals which will attract monocytes to come into the tissue and engulf the neutrophils (after they have engulfed the bacteria or toxin) and eliminate them via lymph drainage.  The clearance of neutrophils out of the tissue promotes a decrease of inflammation and this is how the inflammatory process is resolved (see image above).

As mentioned above, once neutrophils are signaled into the tissue by macrophages, their job is to “eat” any toxins, debris or bacteria to clean out the tissue. Macrophages then have to come in and “eat” the now toxic neutrophil and get it out of the tissue via the lymphatic system in a timely manner. When this occurs as it should, inflammation is resolved and everything remains in balance. However, in the case of autoimmunity and chronic inflammation, this phase is too often left unresolved. Below is an image of a wound on the skin and how the immune system comes in to heal the wound.

Once neutrophils have engulfed the toxin or bacteria, they are now considered toxic and need to be removed by the lymphatic system before they undergo programmed cell death (apoptosis). EPA and DHA (found in cod liver oil) promote the pro-resolving set of mechanisms in the inflammatory process to clear neutrophils out of the tissues. Macrophages release chemicals when they engulf neutrophils which are prostaglandin E2 (PGE2), Iinterleukin10, etc which are fundamentally anti-inflammatory chemicals. If there are too many neutrophils coming into the tissue and not enough monocytes, then you get a different sequence. Neutrophils have a 6-10 hour half life which means half of them will die after 6-10 hours and they will undergo necrosis (spilling out their toxic contents back into the body). So when the neutrophils come in and phagocytize the bacteria or toxins but don’t have enough monocytes to clear them out, they sit in the tissue and eventually die off by bursting open and releasing all the toxic substances back into the tissues.  So if the neutrophil cannot get phagocytized by the macrophages, it will shift and become a necrotic neutrophil and it will undergo secondary necrosis which means its contents (toxic debris) will spill out back into the lymph. Releasing cellular debris back into the body means more neutrophils will be triggered to come into the area. The more neutrophils come in, the more damage you will have because neutrophils also spill out neutrophilic granules containing lysosomes. These granules will spill out and destroy the surrounding tissue causing damage to the extracellular matrix. This new damage leads to more neutrophil influx. To reiterate, when too many neutrophils come in but don’t get cleared out by macrophages quickly enough, they end up destroying tissues. This is chronic inflammation. This is how tissue is destroyed in the autoimmune process. Excessive neutrophil influx and insufficient monocyte influx leads to unresolved inflammation in the body which then turns chronic.

So to recap, we are constantly having damage to tissues and bacteria entering the cells in our body (anywhere in the body including the skin). In order to protect our tissues, our body releases neutrophils which are in charge of cleaning up the junk from the tissues. After the neutrophils have cleaned up, monocytes are signaled to come into the tissue, eat the neutrophils and carry them out of the tissue via the lymphatic system before they burst open and dump out their toxic content. The issue is that because we have so many inflammatory triggers in our body, we have more neutrophil production than monocyte production. This leaves the neutrophils sitting out in tissues for too long and eventually they burst open and spill out their toxic content (secondary necrosis) which then damages the tissue and that signals more neutrophils to come in, clean up, burst open and spill their toxic content and repeat this cycle again. This is how chronic inflammation forms. A lack of resolution leads to chronic tissue damage. Ensuring you’re consuming enough EPA and DHA daily (paired with antioxidants such as glutathione) will help the immune system produce more monocytes to clear tissue debris. The image above explains this process. 

• • Key points:
    • • tissue damage, pathogens, viruses, etc (DAMPs and PAMPs) attract neutrophils to come into tissue
      • Neutrophils enter tissue, phagocytize the damages tissue or pathogen
      • Neutrophils send signals for monocyte production and undergo apoptosis (anti-inflammatory mechanism to protect tissues from toxic debris)
      • Macrophages engulf neutrophils and carry them away from tissues via the lymph system
      • Resolution has been achieved and inflammation has subsided.
        • If enough Macrophages do not arrive to clear out neutrophils, inflammation carries on and the pattern repeats leading to major tissue destruction.

See the image below for side effects of unresolved inflammation.

What are TH17 cells?

TH17 cells are created by the immune system when there is infection by extracellular (hollow spaces) pathogens, including Candida and Klebsiella. TH17 cells can promote tissue repair especially via Interleukin 22 (IL22) which maintains epithelial barrier (protective lining) integrity and protects against microbes. A healthy and balanced TH17 response is needed to effectively clear candida overgrowth and keep our tissues healthy. A TH17  response is appropriate to address extracellular pathogens (candida, mold, etc) however there is a risk to promote autoimmunity if the infection is long lasting (chronic) and elicits a lasting TH17 polarization. TH17 polarization is not the cause of autoimmunity but it drives the tissue destruction aspect.

“TH17 cells play a critical role in the pathogenesis of several autoimmune, allergic, and inflammatory diseases, such as multiple sclerosis, rheumatoid arthritis, psoriasis, allergic rhinitis, asthma, allergic contact dermatitis, systemic lupus erythematosus, anti-neutrophil cytoplasmic antibody-associated vasculitis, dermatomyositis, and pemphigus.”

TH17 cells drives inflammatory activation in a way that destroys tissue in the autoimmune process. When someone has an autoimmune disease, it means their immune response is of a style that has allowed the promotion of autoimmune reactivity. Because of this, it is common for individuals with an autoimmune disorder to either have  a second one or develop one down the road. It is also common to have worsening of tissue destruction every time the patient has a flare up and this is due to a mechanism called epitope spreading (this will not be discussed in this article). 

What are the triggers for Immune cell polarization?

Inflammation and the autoimmune process activate each other.  Anything that drives inflammation has the added effect of potentially sparking up a flare in someone’s autoimmune process.

There are three common triggers for inflammation:

1. Stress: Inflammation and stress chemistry drive each other so when an individual is inflamed stress is produced which then drives more inflammation. Likewise, when stress is experienced it drives inflammation which then drives more stress. Stress triggers cortisol and Adrenalin production. Chronic cortisol and adrenaline exposure to body (chronic stress/anxiety) tissues creates a down regulation of sensitivity to cortisol which causes the cortisol receptors to not respond so well after a while. 
2. Pathogenic imbalance: Dysbiosis is another large trigger for inflammation and is a driver of chronic inflammation. Inflammation creates a dysregulation of the immune response that allows fungi, candida, parasites, etc to flourish. This leads to infection.
3. Infection: Infection leads to a TH17 immune response. When the innate immune system (TH1) is too weakened to clear the infection effectively, the infection persists which leads the TH17 response to persist triggering tissue destruction. 

There are many more triggers but the above are some common ones. 

Inflammation (as described above) creates changes that can diminish the efficiency of the innate immune response. Chronic infection is allowed to go forward because if you don’t have efficient innate immune response, the body is not able to fight against viral and fungal infections.  When we lose the status of the innate immune response (TH1 immunity) that pathogen burden can expand and the infection then becomes a driver of chronic inflammation.

Inflammation drives a loss of TH1 status and stress chemistry also drives a loss of TH1 status (as discussed in my previous article). A healthy TH1 immune response is necessary to kill bacteria and fungi and the loss of this status means that the infectious burden increases. The pathogen burden expands and pathogens that are present in hollow spaces in the body that are being kept dampened persist and become chronic. This creates a feedback loop mechanism. The loss of innate immune response and TH1 status have the effect of reinforcing each other because TH1 cells typically drive activation of natural killer cells and macrophages to go after pathogens and vice versa. The Innate immune response supports healthy TH1 response. The cytokine chemistry of a TH1 response helps you inhibit excessive TH2 status. Excessive TH2 response is associated with dysfunction of mucosal tissues and hollow spaces (lungs, sinuses, intestines, bladder, vaginal tract). A person with low TH1 and high TH2 tends to be more vulnerable to problems such as asthma, allergies, sinusitis, URTI, UTI, etc. It is common to see people who are TH2 dominant having more trouble with hollow space immunology (aka recurring yeast infections, etc).

TH1 cells inhibit TH17 cell activity. When a patient tends to lose their TH1 status and increases their TH2 status, both those mechanisms yield an increase in TH17 immune activation and therefor an increase in autoimmune tissue destruction. 

Once the person has lost their innate immunity and TH1 status, there is an increase of TH2 status and this imbalance is what drives dysbiosis and chronic mucosal dysfunctions (asthma, yeast infections, etc). The loss of TH1 status and increase in TH2 and TH17 cell activation, creates the final reinforcement of the autoimmune mechanism. Patients with chronic inflammation and chronic stress have lost their TH1 response and as it diminishes, their capacity to lessen autoimmune responses may also diminish. Loss of TH1 response allows both autoimmunity and pathogen burden to go forward as TH1 keeps pathogens in balance. 

Systemic Inflammation and the Brain

Systemic inflammation is known to drive brain inflammation. What this means is that a person who has had chronic illness and inflammation for a long time, will develop a neuroinflammatory process (depression, anxiety, chronic changes and fatigue). Depression can drive the biology of inflammation because depression is very stressful. A patient with chronic illness is going to have cognitive changes that are a consequence of that brain inflammation and they are likely to experience extreme fatigue.

Other factors can drive inflammation such as blood sugar dysregulation, food sensitivities, environmental response to pollen or toxins, detox defects, problems with hormonal dysregulation, problem with circulatory issues or anemias, etc. 

What roles do TH17 cells play?

TH17 cells are involved in mucosal immunity, autoimmune tissue destruction and promotion of the inflammatory process. A person with an active autoimmune disease is likely to be experiencing tissue destruction driven by TH17 activity, even if the actual autoimmune disease itself is primarily due to a TH1 or TH2 polarization. People who have had gut dysbiosis, respiratory problems or sinus problems for a prolonged period of time may become TH17 dominant which can exist alongside TH1 or TH2 dominance.

There are naïve T-cells in the body which can turn into TH1 and TH2 cells. Naïve T-cells can also turn into TH17 and T-regulatory cells. TGF-β is primarily anti-inflammatory and it is an activating cytokine that helps determine what kind of T-cell polarization we will have. TH17 cell dominance is appropriate when you have infection in hollow spaces such as the vaginal tract, lungs, sinuses, and intestines. However, when you have chronic infection of these hollow spaces in the body you are consistently promoting TH17 cell polarization. If you keep evoking a TH17 response you will promote the tissue destructive aspect of the autoimmune process.

The cytokines that are activating of the TH17 response are Interleukin 6 (IL6), IL21, IL23, TGF-β, and IL1-β(you don’t need to worry about these too much). What you do need to know is that the more inflamed you are, the more you are driving the inflammatory cytokines ( IL1-β, TNFa, IL6 etc) which puts you at higher risk of promoting a TH17 response.

Clinically, if a patient has chronic intestinal dysbiosis, the longer it has been there, the more likely it has promoted the persistence of TH17 polarization.

How does TH17 cell dominance persist?

Interleukin 21 (IL21) is another cytokine released by TH17 cells and it is a promoter of TH17. Once a TH17 cell is made, it will pump out more IL21 which then promotes more TH17 cells to be made which leads to a self driving loop of TH17 cell production. This leads to chronic tissue destruction which leads to chronic and lasting autoimmune flares.

What is a good test to determine if you have TH17 dominance?

You can ask your doctor to test if your Interleukin 6 (IL6) levels are elevated. To do this, they will need to test your C-reactive protein (CRP) which is a lab marker for IL6 activation. High IL6 is what is driving this particular kind of inflammatory process. However, not all inflammation involves high levels of IL6. Not all individuals with IL6 elevation will have elevated CRP however if they do have elevated CRP it is confirmation of elevated IL6. IL6 is made mainly by hepatocytes (liver cells) and Kupffer cells so someone with high IL6 usually also has elevated liver enzymes. Elevation of reverse T3 thyroid hormone is also an indication of elevated IL6.

Hypoferritinemia is common in patients who are chronically inflamed and it is a marker of an IL6 dependent process. Very often patients have low ferriten when they are chronically inflamed. Do keep in mind though that a person can have low ferriten but still have low CRP even if they have dominant TH17 so having a practitioner who can accurately decipher the data is essential in determining the type of dominance present.

Your doctor may also look for elevated neutrophils which is a marker of TH17 activity.

Are Non-steroidal antiinflammatory drugs beneficial to quiet down a TH17 flare?

Prostaglandin E2 (PGE2) is a critical molecule in the immune system that regulates the activation, maturation, migration, and cytokine secretion of several immune cells, particularly those involved in innate immunity such as macrophages, neutrophils, natural killer cells, and dendritic cells. PGE2 is essential to make sure there is sufficient macrophages present to clean out the neutrophils from tissue before they undergo necrosis and spill out their toxic contents back into the body. 

NSAIDS block PGE2 and if you block PGE2 in a patient who has IL6 (inflammatory cytokine)  in their tissues, what you are left with is TGF-β and IL6 dominance and this will promote a TH17 response. Chronic use of NSAIDS will create a situation where the person will have constant inflammatory activation. NSAIDS should only be used for a brief period of time as stated on the label. 

Can you cure autoimmune diseases?

A cure is said to have occurred when every trace and symptom of a disease is eradicated from the body. Autoimmune disease is not curable, it is manageable and can be put into remission indefinitely but it cannot be cured. The reason is because memory cells are created in the body and are self renewing. Because of these memory cells, your body will always have the tendency to a flare if there are triggers present (high levels of stress, bad diet, chronic infection, viruses, etc). You can keep the autoimmune disease dormant and you can keep the entire immune system relaxed too but cannot cure it. The goal is to get the autoimmune process to be in a dormant state (decrease the frequency, duration and intensity of flares) so that the individual can lead a normal life. 

Supplements to down-regulate TH17 cells

A person who needs TH1 support will have chronic infectious processes whereas a person who needs to calm down excessive TH2 response is a person with chronic allergies, asthma, and hollow space immune dysregulation (recurring yeast infections). Supporting the TH1 response will quiet down the TH17 and TH2 response. A person who has hollow space dysfunction is a person who will have tendency to autoimmune process so it is essential to address chronic dysbiosis.

Viral pathogens are also known drivers of autoimmune activation.  A good TH1 response tends to inhibit viruses so people who have lost their TH1 response tend to have greater viral (EBV, HSV, etc) and bacterial burdens (both infected/dysbiotic and autoimmune). TH1 support will help quiet down pathogen burden and autoimmune flares. When trying to quiet down inflammation and TH17 dominance you need to support TH1 production. The previous article I wrote about TH1 and TH2 immune cells shares many supplements that can help support a good TH1 immune response. 

Below are some ways you can reduce inflammation and support TH1 status while down-regulating TH17.

Supplements to quiet down a flare:

• • • Sulforphane: can help calm down an autoimmune flare by inhibiting NFkB
    • Quercetin: reduces histamine
    • Resvertrol: this is highly anti-inflammatory and can help to calm down the inflammation when having a flare up 
    • Curcumin should also be used during flares but should be paired with Vitamin D and the above supplements.

• Supplements to down-regulate TH17 response:
•  
  • • Vitamin A
    • Fish oil (has to be taken with liposomal glutathione or NAC
      • • DHA can convert into neuroprostanes which can be inflammatory so make sure to have adequate antioxidant status such as glutathione or NAC. Loading up on fish oil can change a persons blood clotting characteristics so always check with a practitioner before taking supplements.
    • Astragalus (down regulate stress response)
    • Ginseng (down-regulate stress response)

Supplements to promote TH1 response:

• • • Berberine
    • Baicalin (down-regulates IL6)
    • Sulforaphane
    • Ginger

Supplements to down-regulate TH2 dominance:

• • • Astragalus
    • Perilla extract
    • N-acetyl-cysteine
    • Quercetin

Supplements to reduce pathogenic burden:

• • • Candaclear four
    • Black walnut
    • Caprylic acid

Intermittent fasting can also be very beneficial to reduce inflammation. If someone has a poor response to a high fat diet (too many fatty acids in circulation), has high cholesterol, blood sugar imbalance (too much glucose), too much oxidative stress, are too acidic, etc, they can benefit from fasting.

Autoimmunity is extremely complex and is not as simple as trying to quiet down TH1. There are individuals with autoimmune disorders who have TH1 dominance so it is always important to work with a skilled practitioner who understands immunology to help you address your autoimmune conditions safely.

*This article is not meant to render medical advice and supplements mentioned should only be taken under the guidance of your health care practitioner.*

Resources

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4. J. Clin. Invest. 1998. 101: 809-898. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGFb, PGE2, and PAF.
5. The consequence of apoptosis in autoimmunity. J. Autoimmun. 31 (2008) 257-262. 
6. Klinker MW, Lundy SK. Multiple Mechanisms of Immune Suppression by B lymphocytes. Mol Med. 2012 Feb 10; 18: 123-37.
7. Beverly R. E. A. Dixon, Rafat Hossain, Rachna V. Patel, Holly M. Scott Algood. Th17 Cells in Helicobacter pylori Infection: a Dichotomy of Help and Harm. DOI: 10.1128/IAI.00363-19.