9 Disrupted Th1 - Th2 homeostasis (Th2 dominance)

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From: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1414923/">The role of TNF-alpha in T-cell-mediated inflammation depends on the Th1/Th2 cytokine balance.</a>

The role of tumour necrosis factor-alpha (TNF-alpha) in tuberculosis is paradoxical because although there is much evidence for a protective role, there is also evidence that it plays a part in the tissue damage that characterizes human disease. We have shown previously that TNF-alpha frequently induces necrosis when injected into sites undergoing delayed-type hypersensitivity (DTH) responses to mycobacterial antigen. This is dependent on CD4+ T cells. However the presence of this sensitivity to TNF-alpha-induced necrosis depended on the immunization protocol. We have tested the hypothesis that sensitivity to TNF-alpha depends on the cytokine profile of the induced T-cell response. All subcutaneous doses of mycobacterial immunogen used (10(7) to 10(9) organisms) primed spleen cells so that they secreted interferon-gamma (IFN-gamma) and interleukin-2 (IL-2) when cultured in vitro with soluble antigen. However priming for production of IL-4 was dose dependent as in other systems, and was produced at all times from 7 to 30 days after immunization with 10(9) organisms. Time-course studies over 30 days showed that sensitivity to TNF-alpha was found in DTH sites of animals primed for IL-4 and IFN-gamma production, but not in animals primed only for the Th1 cytokines. We suggest therefore that the paradoxical role of TNF-alpha can be resolved. In 'pure' Th1 responses it may act as an additional macrophage-activating factor. In mixed Th1 + Th2 or Th0 responses it may cause tissue damage. This mixed pattern is characteristic of tuberculosis, and of the late stage of many chronic infections where elimination of the infecting organism is failing, and chronic tissue damage is seen.

From: <a href="https://www.conqueringfatigue.com/cfs-th-2-dominant-condition/">https://www.conqueringfatigue.com/cfs-th-2-dominant-condition/</a>

Research clearly shows one of the most common imbalances in patients with chronic fatigue syndrome is within the immune system. Cytokines are the hormonal messengers responsible for most of the effects in the immune system. Although there are many, cytokines can be functionally divided into two groups: those that are pro-inflammatory and those that are anti-inflammatory but that promote allergic responses.

A certain type of immune cell, called Helper T cells, are regarded as being the most prolific cytokine producers. This subset of immune cells can be further subdivided into Th1 and Th2, and the cytokines they produce are known as Th1-type cytokines and Th2-type cytokines.

Th1- and Th2-helper cells direct different immune response pathways.

Th1 cells drive the type-1 pathway (referred to as “cellular immunity”) to fight viruses and other intracellular pathogens.

Th2 cells drive the type-2 pathway (referred to as “humoral immunity”) and up-regulate antibody production to fight extracellular organisms.

Over-activation of either pattern can cause disease, and either pathway can down-regulate the other. And it has been theorised that certain conditions are a Th 1 or Th 2 state. Some research suggests CFS is primarily  a Th2 dominant state.

But the hypothesis has major inconsistencies; human cytokine activities rarely fall into exclusive pro- Th1 or -Th2 patterns.

</blockquote>

The Th1 pathway, when it is overreactive, can generate organ-specific autoimmune disease (e.g., arthritis, multiple sclerosis, type 1 diabetes). The Th 2 pathway is seen as underlying allergy and related IgE-based disease, and predisposing to systemic autoimmune disease.

But these stereotypes have proven to be over-simplistic, with the result that the hypothesis is increasingly criticised.

</blockquote>

A number of natural compounds have a tendency to push either side of the Th1/Th2 balance.

Green tea is one such substance.

However others have a balancing beneficial effect. For example, the long chain omega-3 fatty acids EPA and DHA  significantly benefit diverse inflammatory and autoimmune conditions without any specific Th1/Th2 effect.

Th1 stimulating compounds

<ul>

<li>Echinacea</li>

<li>astragalus</li>

<li>Licorice root</li>

<li>Beta-sitosterol</li>

<li>Ashwaganda</li>

<li>Panax ginseng</li>

<li>Mushrooms (Maitake, Reishi, Shiitake)</li>

<li>Chlorella</li>

<li>Grape seed extract</li>

</ul>

Th2 stimulating compounds

<ul>

<li>Green tea</li>

<li>Resveratrol</li>

<li>Pycnogenol</li>

<li>Curcumin</li>

<li>Genistein</li>

<li>Quercetin</li>

</ul>

Interestingy pregnancy is a Th 2 dominant state and this may be why individuals may experience complete resolution of symptoms in certain conditions such as Rheumatoid Arthritis (thought to be a Th 1 dominant state). Also, several studies have demonstrated decreased prevalence of allergic diseases (a Th 2 dominant state) in patients with Rheumatoid Arthritis. However,

The findings from various human and animal studies do not support such a clear-cut role for Th1 as the driving force in RA.

</blockquote>

<h4>Other Highlights From The Research</h4>

<h4>Glutathione, Oxidative Stress and CFS</h4>

Depletion of glutathione…results in lowered Th1 activity and higher Th2 activity; GSH repletion had just the opposite effect. Thus, it seems immune activity can have Th1 or Th2 character depending on the relative antioxidant status of the cells directing the process.

</blockquote>

It does seem increased oxidative stress may favour a Th2-dominated immune state. We at Conquering Fatigue Successfully frequently see low glutathione levels and increased levels of oxidative stress in our clients.

Also, Mercury depletes glutathione and polarizes toward Th2 dominance.

<h4>Parasites, glutathione and CFS</h4>

Because parasite infections will often modestly deplete glutathione, the human Th 2 orientation to parasites could be an adaptation based on a glutathione depletion

<h4>DHEA & Th 1/2 balance</h4>

Dehydroepiandrosterone (DHEA) is produced by the adrenal glands. As one of the effectors of the hypothalamic-pituitary- adrenal (HPA) axis, DHEA supports the body’s adaptive stress responses. It may also be involved in immune regulation. DHEA’s involvement in immune homeostasis is anti-Th2/pro-Th1.

<h4>Progesterone</h4>

May up-regulate Th2.

<h4>Selenium</h4>

When selenium deficient animals are supplemented with selenium, IL-2 action (a Th1 cytokine) is enhanced. This is likely to benefit the type-1 pathway and thereby improve antiviral, antibacterial, and antifungal resistance.

IL- 2 status (Th1 cytokine) in these subjects and found that IL- 2 and IFN-gamma declined during the depletion phase and was corrected by repletion.

<h4>Probiotics</h4>

Probiotics may also down-regulate conditions linked to Th 2 over-activation. Both type-1 and type-2 cytokine patterns can be partially restored.

<h4>But Be Warned</h4>

Research is very mixed on this topic and we can not say convincingly that CFS is a Th 2 dominant state. What we can say is that it appears to be more common, but there are CFS patients who are Th 1 dominant. We at Conquering Fatigue Successfully, recommend (a) working with an experienced practitioner and (b) testing to investigate which ‘side’ of the immune system is more active. There is real risk of exacerbating symptoms by taking products that stimulate the wrong branch of the immune system. This may be one of those topics where we also have to remember to “first, do no harm”. The following quotes highlight the complexity of this topic:

published studies on Th1/Th2 dominance often downplay the dendritic cells (DCs), monocyte-macrophages, and other antigen-presenting cells

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Meaning there are other immune cells that may influence Th1/Th2 balance which need to be considered.

many other dynamic factors influence Th1/Th2 maturation. Among these are: antigen dose, nature of the antigen, direct cell-to-cell interaction with APCs, the diversity and relative intensity of these interactions, and the cytokine receptors available on the naive cell.

</blockquote>

Meaning there are many other variables to consider when on the topic of Th1/2 balancing and these include things like the virus or bacteria that may be initiating an immune response.

Whether right or wrong, the Th1/Th2 hypothesis is a “top-down” model of cell interaction that assumes one class of immune cells is especially equipped to supervise the others. Many lines of evidence indicate this model is overly simplistic and requires major modification to satisfy the discordant data.

</blockquote>

Meaning we can’t rely on this theory! The below quote provides clarity on what can be considered moving forward. Supporting the immune system through lifestyle medicine is a safe and effective strategy.

One advantage inherent in the more collective model for immune functioning is that keeping the immune system healthy and mobilizing it against disease would depend more on giving the body systemic support than on deploying tailored magic immunotherapeutics. Proven  immunomodulators such as mushroom extracts take on significant relevance. Fish oils, vitamin C, glutathione, and other antioxidants, as well as numerous plant extracts can further enhance immune cell functionality.

In managing immune hypofunction or other dysfunction, it is crucial to manage all forms of stress. Rooks reported diverse stressors, including sleep deprivation, calorie restriction, excessive exercise, examination <a href="https://www.conqueringfatigue.com/stress/" target="_blank">stress</a>, and cardiopulmonary bypass surgery, down-regulate Th1 and up-regulate Th2 activity. These effects are mediated mainly by glucocorticoids, but also by the catecholamine hormones epinephrine and norepinephrine. As heroic efforts to tailor technological immune therapies go forward, the best immune intervention tools continue to be lifestyle modification, vitamins, minerals, orthomolecules, and selected nontoxic phytotherapies.

</blockquote>

Stress is key concept to understand and we recommend reading our articles on this topic: <a href="https://www.conqueringfatigue.com/stress/" target="blank">click here</a> and <a href="https://www.conqueringfatigue.com/key-concepts/" target="blank">here</a>.

<h4>Chronic Fatigue Syndrome – A Th2 dominant condition? Summary</h4>

We cannot say with 100% certainty that CFS is a Th2 dominant state, but current research suggests the majority of patients are. Based on the fact that some patients are in a Th1 dominant state, and that stimulating the pathway can significantly worsen the condition, testing is of the upmost importance if wanting to explore this path. Past health history may shed further light on this, as mentioned improvements during pregnancy may provide compelling evidence, but testing would still be beneficial to confirm any suspicions and also is an effective method of monitoring any interventions put in to place.