Th1/Th2 Balance in Young Subjects: Relationship with Cytokine Levels and Metabolic Profile

aliml

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Purpose: We aim to identify Th1 and Th2 cell clusters in young subjects, including their clinical and metabolic characteristics and the Th1/Th2 balance.

Patients and methods: A total of 100 participants were included. The frequencies of Th1 and Th2 cells in peripheral blood were determined by flow cytometry. Serum C-reactive protein was measured using a turbidimetric assay, and insulin levels were quantified with an enzyme-linked immunosorbent assay. Circulating cytokine levels were analyzed using a multiplex system.

Results: A cluster analysis was performed to determine the Th1/Th2 balance in a group of young people, and 3 clusters were formed with the following characteristics:

1) Th1 Dominance - subjects with a higher prevalence of hyperglycemia (38%), dyslipidemia (38-75%), and insulin resistance (50%), as well as a higher percentage of Th1 cells and Th1/Th2 ratio, including elevated IFN-ɣ levels;
2) Th2 Dominance - subjects with a lower prevalence of hyperglycemia (23%) and insulin resistance (15.4%), but a higher prevalence of dyslipidemia (8-85%) with a predominance of Th2 cells, and lower Th1/Th2 ratio;
3) Th1/Th2 Balance - subjects with a lower prevalence of hyperglycemia (6%), insulin resistance (41%), and dyslipidemia (10-63%), as well as a balance of Th1 and Th2 cells and lower Th1/Th2 ratio, including low IFN-ɣ levels. Positive correlations between Th1 cells with IFN-γ, IL-12, and IL-1β and between Th2 cells with IFN-γ, IL-2, and IL-4 were found (p < 0.05).

A significant increase in Th1 cells was observed in the presence of hyperglycemia and high LDL-C levels, as well as increased Th2 cells in the absence of abdominal obesity and high blood pressure, including low HDL-C levels. The Th1/Th2 ratio was higher (Th1 Dominance) in the group with high cardiometabolic risk (p = 0.03).

Conclusion:
In conclusion, three distinct clusters of subjects were identified in a young population. The largest cluster showed a balanced Th1/Th2 response with some metabolic abnormalities, followed by the group tending toward a Th2 response and fewer metabolic abnormalities, and the smallest group tending toward a Th1 response and the presence of hyperglycemia and dyslipidemia. These findings support the hypothesis that chronic low-grade inflammation is related to cardiometabolic risk profile at a young age.




The following have been associated with Th1 Dominance:
  • Delayed food sensitivities: This might be evidenced by getting inflammation from food, yet the effects aren’t necessarily immediate [8].
  • Fatigue: After meals and acute exercise or fatigue, in general, have been described as more severe in Th1 dominance. Scientists think Th1 cells increase the cytokine interferon-gamma, which increases other cytokines like IL-1b and TNF-alpha. These may cause fatigue via suppression of orexin neurons. TNF-alpha may also be elevated in Th2 dominance because it can be released by IL-1 and mast cells, but it’s likely more elevated in Th1 dominance. Proper human data for this link are lacking [9, 10, 9].
  • IBS: A couple of small studies suggested that people with IBS may be more likely to be Th1 dominant (elevated IL-12), though findings have been inconclusive. Interferon is hypothesized to reduce serotonin in the gut and increase oxidative stress (by activating IDO). However, there are many inconsistencies and people with Th2 overactivity can also have IBS [11, 12].
  • Rheumatoid arthritis [13]
  • Hashimoto’s thyroiditis (IL-18) [14, 15]
  • Low T3/Euthyroid sick syndrome: When levels of T3 and/or T4 are low but the thyroid gland does not appear to be dysfunctional. This syndrome has been linked with higher IL-6, Interferon gamma, TNF-alpha, and IL-1b. However, there’s not enough evidence to draw any conclusions [16. 17. 18. 19].
  • Potentially more thin: According to some clinical observations that remain unproven, the majority of Th1 dominant people tend to be relatively thin. Some researchers think this might be explained by 2 mechanisms:
    • 1) TNF-alpha and IL-1beta inhibit orexin, which may decrease appetite. TNF-alpha also seems to lead to increased fat-burning in animals and insulin resistance in fat cells. Small studies found that anti-TNF-alpha therapy may result in weight gain – an average of 5.5 kg or 11 pounds in only 12 weeks. Larger human studies are needed [20, 21].
    • 2) Interferon-gamma, like TNF-alpha, is hypothesized to create insulin resistance in fat cells and differentiation of fat cells, which may prevent fat storing. There are many other aspects to hunger and weight gain that this theory doesn’t take into account, though [22, 23].
  • IBD: may be characterized by a different cellular subset: Th17 cells and IL-18, a pattern loosely connected with Th1 dominance [24, 25].
  • Psoriasis and rosacea [26, 27]
  • Celiac disease [28]
  • Crohn’s disease [29]
  • Type 1 diabetes [30]
  • PCOS (IL-18) [31]
  • Alzheimer’s (IL-18) [32, 33]
  • Lupus (also Th2) [34]
  • Multiple sclerosis (also Th2) [35]
  • Guillain-Barré syndrome [36]
  • Post-infectious IBS [37]
  • Behcet’s [38]
  • Vitiligo (Th1 chemokine) [39]
  • Inflammation after the following: Strep, mono (EBV), HPV, herpes, pneumonia, H. pylori or Cytomegalovirus. These are common infections that also invoke the Th1 system; in some people, the immune system remains active after these infections. In some environments, this may have been a survival advantage that made people more likely to survive into adulthood and bear offspring [40, 41, 42, 43, 44, 45].
  • Chemotherapy-induced neuropathy has increased CCL2 and IFNy, and lower levels of IL-10 [46, 47].
Learn about factors that may balance an elevated Th1 system.

The following have been associated with Th2 Dominance:
  • IgE-related allergies, which are immediate and can be measured by skin scratch tests [57]
  • Seasonal allergies
  • Airway constriction
  • Asthma
  • Nasal drip
  • Mucus
  • Eczema (Dermatitis)
  • Hay fever (Allergic rhinitis)
  • GERD or Increased stomach acidity
  • Excess histamine or what some people call “histamine intolerance”
  • Hives (Urticaria)
  • Chronic Fatigue Syndrome [58]
  • Autism [59]
  • Uveitis, Grave’s disease, Sjogren’s, Oral Lichen Planus, SLE (also Th1 dominant) [60, 61, 62, 63]
Learn about factors that may help rebalance an elevated Th2.

 
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aliml

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Hypothesis I - Th2 Dominance Increases Cancer Risk


Chronic inflammation may promote cancer, and reducing inflammation may improve survival from cancer. The inflammatory response occurs through increased T-helper 1 (Th1) immunity and decreased T-helper 2 (Th2) immunity. Tumor-associated macrophage (TAM) promote cancer progression is common population for Th2 dominant in the tumor microenvironment. Moreover, cancer-associated fibroblast (CAF) and regulatory T cell (Treg) were also the Th2 dominant subsets has been reported in many cancer types. Numerous signaling networks connect tumor cells with inflammatory cells. However, the mechanism underlying recruitment and infiltration of inflammatory cells into the tumor stroma remains unclear. Tumor cells may be escape from the immune system to avoid eliminated by immune cells. To a tumor cell, an infiltrating immune cell might be a " friend " that skews it toward the Th2 dominant and promote tumor growth, or a " foe " that skews it toward the Th1 dominant and enhance tumor regression.

Naive T cells become Th1 cells or Th2 cells, following the stimulation by different factors. In Th1 immunity, cells produce pro-inflammatory cytokines, such as interleukin-2 (IL2), interferon-gamma (IFN-γ), and tumor necrosis factor-beta (TNF-β). In Th2 immunity, cells produce antiinflammatory cytokines, such as IL-4, IL-5, IL-6, IL-10, and IL-13. In normal circumstances, Th1 immunity and Th2 immunity approach a balance. But, the presence of tumor cells disrupts this balance. This occuring increased Th2 immunity and decreased Th1 immunity, because of down-regulation of adaptive immunity. This eventually leads to tumor progression. However, if Th1 immunity becomes predominant, this stimulation of immunity can lead to tumor regression.

Effects-of-Th1-Th2-on-tumor-progression-Naive-T-cells-become-Th1-cells-or-Th2-cells.png




Hypothesis II - Hot Nature Increases Cancer Risk


Purpose: The purpose of this study was to assess differences in persons of a Hot or Cold nature, in terms of changes in their neuroendocrine and immune systems.

Materials and methods: Thirty-seven (37) male volunteers (20-40 years old) were divided into two groups, by whether they had a Hot or Cold nature. In addition, the Warmth/Coldness ratio of all the volunteers was assessed. Plasma concentrations of epinephrine, norepinephrine and cortisol, and also the concentrations of interferon (IFN)-gamma and interleukin (IL)-4 produced by peripheral blood mononuclear cells stimulated by mitogen were measured.

Results: The results showed that norepinephrine/epinephrine and norepinephrine/cortisol ratios were significantly higher, and that there was a borderline significantly increased IL-4/IFN-gamma ratio in the Hot nature group compared with those in the Cold nature group. In addition, there was a significant linear positive correlation between the norepinephrine/epinephrine and Warmth/Coldness ratios and a significant nonlinear association between the IL-4/IFN-gamma and Warmth/Coldness ratios.

Conclusions: It can be deduced that the persons of a Hot nature had more sympathetic nervous system activity, less adrenal sympathetic, adrenal corticosteroid, and parasympathetic nervous system activities and more deviation of the immune system toward T-helper 2 (Th2) responses than the persons of a Cold nature. Moreover, the activity of the sympathetic nervous system was increased and adrenal sympathetic was decreased with an increasing Warmth/Coldness ratio. Furthermore, when the person's nature veered toward extreme Warmth or extreme Coldness, the deviation of the immune system toward Th2-like responses was greater, but this increased deviation was much more marked when veering toward extreme Warmth than toward extreme Coldness.
 
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