How Th1/Th2 Immune Imbalance Drives Chronic Infections & Inflammation in ME/CFS
The immune system is a powerful defense network, but in ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome), research shows this system doesn’t always function the way it should. One key piece of the puzzle is the balance between two types of immune cells: Th1 and Th2. When this balance is off, it can lead to many of the symptoms ME/CFS patients struggle with—like chronic infections, sensitivities, and even mast cell activation. In this post, we’ll break down what Th1 and Th2 cells are, how they affect ME/CFS, and why T cell exhaustion, aging, and mast cell activation are all part of the picture.
What Are Th1 and Th2 Cells?
Th1 and Th2 cells are two types of T-helper (Th) cells, which are part of your adaptive immune system. They each have different roles:
Th1 cells focus on fighting viruses, bacteria, and intracellular (inside the cell) infections. They help activate other immune cells like macrophages and cytotoxic T cells to clear out infected cells.
Th2 cells help the body respond to allergens, parasites, and extracellular (outside the cell) threats. They are involved in producing antibodies (especially IgE) and supporting mast cells and eosinophils.
Both types of cells use chemical messengers called cytokines to communicate with other parts of the immune system. These cytokines tell immune cells when to activate, multiply, or calm down.
Here’s a quick breakdown of the cytokines, many of which I’m sure you’ve heard of if you follow ME/CFS news:
Th1 cells produce cytokines like:
Interferon-gamma (IFN-γ)
Interleukin-2 (IL-2)
Tumor necrosis factor-beta (TNF-β)
These cytokines stimulate strong antiviral and antibacterial responses.
Th2 cells produce cytokines like:
Interleukin-4 (IL-4)
Interleukin-5 (IL-5)
Interleukin-10 (IL-10)
Interleukin-13 (IL-13)
These cytokines promote antibody production, allergic-type responses, and support mast cells and eosinophils.
A healthy immune system keeps Th1 and Th2 activity in balance, switching between them as needed. But in ME/CFS, research suggests this balance may shift too far toward Th2 dominance, which may contribute to common symptoms like chronic infections and hypersensitivities (Sotzny, 2018).
How Th1/Th2 Imbalance Affects ME/CFS
In many ME/CFS patients, the immune system shows signs of Th2 dominance—meaning the Th2 response is overactive, while the Th1 response is underactive.
This can cause:
Weakened antiviral defense: A lower Th1 response means your immune system has a harder time keeping viruses (like EBV or HHV-6) in check.
Increased allergic-type reactions: Th2 dominance boosts IgE production and mast cell activity, making you more prone to sensitivities and inflammation.
Chronic low-grade inflammation: Ongoing Th2 activity keeps the immune system on edge without effectively resolving the underlying issue.
Why Th2 Dominance May Trigger Mast Cell Activation
One reason mast cell activation syndrome (MCAS) is so common in ME/CFS may be the Th2 shift itself. Th2 cells promote the survival and activation of mast cells, which release histamine and other chemicals responsible for allergic reactions (Thangam, 2018).
With Th2 dominance:
Mast cells become more easily triggered.
Patients may develop sensitivities to foods, chemicals, medications, or environmental triggers.
This overactive mast cell response leads to common MCAS symptoms like flushing, hives, digestive issues, and headaches.
So, the same immune imbalance driving chronic infections in ME/CFS may also be behind the hypersensitivities many patients experience.
The Role of T Cell Exhaustion in ME/CFS
Adding another layer to the story is T cell exhaustion, a recent finding in ME/CFS research (Iu, 2024).
What is T cell exhaustion?
When your immune system is constantly exposed to viruses or stressors, your T cells can become "worn out." These exhausted T cells don’t respond effectively to infections anymore.
In fact, research shows that the pattern of T cell exhaustion in ME/CFS looks very similar to what happens in long-term viral infections (Iu, 2024). The immune system stays switched on for too long, pushing T cells to keep fighting until they burn out and stop working properly.
How does this fit in?
Th1 cells, crucial for fighting infections, become less active.
This further weakens antiviral defense and allows viruses to linger or reactivate.
The imbalance continues, leaving Th2 responses unchecked.
In simple terms, T cell exhaustion makes the Th1/Th2 imbalance worse, trapping the immune system in a cycle of poor infection control, inflammation, and hypersensitivity.
Does Age Affect Th1/Th2 Balance?
Yes, age also plays a role in shifting Th1 and Th2 responses. As people age, the immune system naturally weakens—a process known as immunosenescence (immune system aging). Studies show that:
Th1 activity tends to decline with age.
There is often a shift toward Th2 dominance.
This means older individuals with ME/CFS may experience weakened antiviral defenses and a higher susceptibility to allergic-type reactions. This age-related shift could further complicate immune dysfunction, particularly in those who develop the condition later in life or notice worsening symptoms over time.
Personally, this is something I’ve noticed myself. I was diagnosed with ME/CFS over 25 years ago, and after turning 40, I’ve found my symptoms have gotten harder to manage. It’s likely due to this Th1/Th2 balance.
Supporting Immune Balance in ME/CFS
While there’s no quick fix to rebalance the immune system, certain strategies may help support healthier immune function over time:
Managing viral load: Some patients benefit from antiviral protocols under medical supervision, especially for EBV.
Stress reduction: Techniques like pacing, meditation, or gentle movement can reduce chronic stress that worsens immune dysfunction.
Gut health: A diverse, fiber-rich diet and probiotics may improve immune regulation by supporting the gut microbiome.
Nutritional support: Certain nutrients and hormones can influence Th1/Th2 balance. According to research, low glutathione levels can shift the immune system toward Th2 dominance, while restoring glutathione may help promote a healthier balance (Kidd, 2003).
Other compounds that have shown measurable effects on Th1/Th2 balance include:
Plant sterols and sterolins
These are natural compounds found in many fruits, vegetables, nuts, and seeds. Examples include beta-sitosterol, which is commonly found in foods like avocados, almonds, sunflower seeds, and sesame seeds.
Melatonin
Probiotics
Progesterone
Minerals like selenium and zinc
Final Thoughts
Th1/Th2 imbalance, T cell exhaustion, and mast cell activation are all interconnected pieces of the ME/CFS puzzle. Understanding how they influence each other gives you a clearer picture of what’s happening beneath the surface—and why symptoms like infections, sensitivities, and inflammation are so common. While research continues to evolve, focusing on gentle, supportive strategies to improve immune health is an important step forward.
References
Sotzny F, Blanco J, Capelli E, et al. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome - Evidence for an autoimmune disease. Autoimmun Rev. 2018;17(6):601-609. doi:10.1016/j.autrev.2018.01.009
Thangam EB, Jemima EA, Singh H, et al. The Role of Histamine and Histamine Receptors in Mast Cell-Mediated Allergy and Inflammation: The Hunt for New Therapeutic Targets. Front Immunol. 2018;9:1873. Published 2018 Aug 13. doi:10.3389/fimmu.2018.01873
Iu DS, Maya J, Vu LT, et al. Transcriptional reprogramming primes CD8+ T cells toward exhaustion in Myalgic encephalomyelitis/chronic fatigue syndrome. Proc Natl Acad Sci U S A. 2024;121(50):e2415119121. doi:10.1073/pnas.2415119121
Kidd P. Th1/Th2 balance: the hypothesis, its limitations, and implications for health and disease. Altern Med Rev. 2003;8(3):223-246.
