Immune Imbalance

 

The cornerstone of Treg dysfunction lies in FOXP3 instability and impaired expression, which critically disrupt the development, maintenance, and suppressive capacity of Tregs. This FOXP3 dysregulation is predominantly driven by a very specific immune imbalance characterized by:

 

• Elevated Interleukin-6 (IL-6) 

• Elevated Tumor Necrosis Factor-Alpha (TNF-α) 

• IL-2 Deficiency

 

Elevated IL-6

 

The development of Tregs relies heavily on a protein known as TGF-β. When TGF-β is alone, it promotes the expression of FOXP3, which is the gene expression that drives the development of Tregs, helping to maintain immune tolerance and prevent autoimmunity. 

 

However in the presence of pro-inflammatory cytokines, particularly interleukin-6 (IL-6), this balance shifts. IL-6, essentially acts as a switch interfering with FOXP3 induction, thereby inhibiting Treg development, and even promoting the development of pro-inflammatory TH17 cells over Tregs’, which tips the immune balance toward autoimmunity. 

 

It is important to note that chronic IL-6 responses encourage immune cells to upregulate IL-6 receptor expression, making them hyper-responsive to IL-6 and strongly activating the STAT3 signaling pathway. This then amplifies their resistance to Treg-mediated suppression, even when Tregs are present and functional. This underscores that the severity of autoimmune activity influences the complexity and duration of achieving disease control and remission. [1][2][3]

 

Elevated TNF-α

 

TNF-α is a major inflammatory molecule that plays a role in driving immune system attacks. One of the ways it contributes to autoimmunity is by interfering with the stability of FOXP3, the master switch allowing Tregs to suppress excessive immune responses and maintain balance. Without stable FOXP3, Tregs lose their ability to control overactive immune cells effectively. As a result, immune cells become less regulated, leading to stronger and longer-lasting inflammation, a cornerstone of autoimmunity.

 

TNF-α also makes the immune attack stronger by activating dendritic cells, which turn on immune responses. This leads to hyperactive immune activity, making it harder for Tregs to control inflammatory responses.[6]

 

IL-2 Deficiency

 

The cytokine Interleukin-2 (IL-2) plays a critical role in the survival, development, and function of Tregs. This is because IL-2 is essential for maintaining the expression of FOXP3, the key gene expression that defines Treg identity and stability. Without IL-2 signaling, FOXP3 expression is reduced, compromising the formation and maintenance of Tregs.[8]
 

Chronic immune activation progressively depletes Interleukin-2 (IL-2) availability, as persistent inflammation shifts immune resources toward effector T-cell expansion and pro-inflammatory pathways, IL-2 synthesis becomes insufficient to support Treg survival and function. This IL-2 deficiency further destabilizes FOXP3 expression, exacerbating Treg collapse and loss of peripheral tolerance, fueling the progression toward autoimmunity.[21]

 

Chronic Infections

 

A central underlying factor contributing to the immune imbalance associated with Treg Dysfunction is the presence of chronic infections, which serve as persistent immunological triggers. These include:

 

• SIBO

• Candiadiasis

• Helminth infection

• Protozoa Infection

• Herpes Simplex Virus

• Epstein Barr Virus

• Mycotoxicosis

 

During these infections, both IL-6 and TNF-α are elevated as part of the body’s highly coordinated immune response. The process begins when invading pathogens, such as bacteria, viruses, fungi, and parasites are recognized by receptors, located on immune cells.

These receptors identify molecular patterns on the pathogenic microbes themselves, and the recognition of these patterns activates intracellular signaling cascades, prominently the NF-κB pathway, which triggers the transcription and release of TNF-α and IL-6. 

TNF-α, acts as an early amplifier of inflammation, recruiting additional immune cells and promoting further cytokine release. IL-6 modulates T cell differentiation, enhancing antibody production, and regulates systemic inflammation. [19][20] While these processes are vital for controlling infections, the persistent release of IL-6 and TNF-α drives Treg dysfunction as detailed below.

 

Tissue Injury 

 

When cells become injured, stressed, or die, they release internal molecules into the extracellular space which are recognized by receptors on immune cells. This recognition serves as a danger signal to the immune system, indicating that tissue damage has occurred and trigger intracellular signaling cascades, most notably the nuclear factor kappa B (NF-κB) pathway, which increases the production of IL-6 and TNF-α [19][20] Both of which are responsible for Treg dysfunction and autoimmune development.

 

Psychological Stress [ Sympathetic Dominance ] 

 

Multiple studies have demonstrated that psychological stress is a potent driver of elevated IL-6 levels through dysregulated neuroendocrine and inflammatory pathways. Clinical studies also demonstrate individuals exposed to chronic stress or early life adversity exhibit exaggerated IL-6 when in response to acute stressors, suggesting long-term priming of the inflammatory system from long-term stress,[22] thereby supporting the pathogenesis of autoimmunity.

 

Chronic Stress [ HPA Hypofunction ]

 

When exposed to prolonged stress, mental or physical (inflammatory), the hypothalamic pituitary adrenal (HPA) axis becomes dysregulated, often resulting in blunted cortisol responses. Cortisol normally serves as an anti-inflammatory signal that dampens immune activation, including suppressing cytokines such as IL-6 and TNF-α. A diminished cortisol response removes this critical brake, allowing exaggerated IL-6 and TNF-α production during subsequent inflammatory triggers, [22] thereby supporting the pathogenesis of autoimmunity.

 

Nutritional deficiencies

 

Certain nutrients play a critical role in the development, maintenance, and functional stability of Tregs, primarily through their effects on FOXP3 expression, Treg metabolism, and the broader immune microenvironment. Therefore, certain nutritional deficiencies can compromise Treg development and stability, leaving individuals more susceptible to chronic inflammation and autoimmunity.

 

Heavy Metal Toxicity 

 

Heavy metal toxicity promotes the overproduction of pro-inflammatory cytokines, such as TNF-α and IL-6, which contributes to regulatory T cell (Treg) dysfunction. Additionally, heavy metals induce significant oxidative stress, further impairing Treg function and skewing immune responses toward autoimmunity [46]. Beyond this heavy metals contribute to auto-immune development by binding to specific sulfur groups in the body's proteins, which changes the protein’s structure. This change creates foreign-looking proteins, which the immune system can mistakenly attack. [47]

Oxidative Stress 

 

Elevated levels of reactive oxygen species (ROS) within Tregs are strongly associated with diminished function and impaired expression of FOXP3, the master transcription factor essential for maintaining Treg stability and regulatory capacity. 

 

Furthermore, excessive ROS also drives activation of the mTOR signaling pathway, which skews Treg function away from restraining autoactive responses and toward pro-inflammatory responses, which is characterized by the production of cytokines such as IL-17 upon ROS exposure, further compromising immune tolerance [23]
 

Allergies [ Mast Cell Activation ] [ Histamine Intolerance ] 

 

Mast cells and histamine, both central players in allergic responses, have been shown to impair regulatory Treg function and stability by fostering a pro-inflammatory environment that overrides their restraint on autoreactive immune responses.

 

Mast cells promote the secretion of interleukin-6 (IL-6), which not only diminishes Treg suppressive function but also drives their conversion into pro-inflammatory Th17 cells. Additionally, mast cells express the costimulatory ligand OX40L, which further impairs FOXP3 expression, the master regulator of Treg identity, and facilitates the shift of Tregs toward a pro-inflammatory phenotype.

 

In parallel, histamine disrupts Treg stability by suppressing local levels of transforming growth factor-beta 1 (TGF-β1), a cytokine essential for Treg development, maintenance, and immunosuppressive activity. By limiting TGF-β1 availability, histamine reduces Treg infiltration into inflamed tissues, thereby weakening immune regulation and exacerbating autoimmunity. [24][25]