The Th1/Th2 Balance, Zinc, Glutathione, Prostaglandin Production and the Possible Relationship to the Establishment of Asthma

There is evidence to suggest that allergen-reactive type 2 helper T cells (Th2) play a triggering role in the activation and/or recruitment of IgE antibody-producing B cells, mast cells and eosinophils, i.e. the cellular triad involved in the allergic or asthma  inflammation.¹²²

In the Th1-Th2 paradigm, these two seemingly unrelated events, IgE formation and eosinophilia, can be viewed as parts of the same process: both are stimulated and maintained by Th2-type immune responses. 

Careful observations have shown repeatedly that Th2 cytokines predominate in the airways of individuals with allergic rhinitis and asthma. 

In some experimental animal models of these disorders, blocking Th2 cytokines can moderate and even stop these events. The cytokines produced when non-allergic individuals are exposed to these same antigens are generally of the Th1 type.

Thus, whether a given individual will develop allergies and asthma may depend on whether the immune response to allergens is skewed toward predominantly Th1 or Th2 responses. 

This in turn begs the question of what determines whether the response to these foreign substances will be skewed one way or the other.¹⁷²

Thanks to progress in zinc research, it is now possible to describe in more detail how zinc ions (Zn++) and nitrogen monoxide (NO), together with glutathione (GSH) and its oxidized form, GSSG, help to regulate immune responses to antigens. 

NO appears to be able to liberate Zn++ from metallothionein (MT), an intracellular storage molecule for metal ions such as zinc (Zn++) and copper (Cu). 

A zinc deficiency can lead to a premature transition from efficient Th1-dependent cellular antiviral immune functions to Th2-dependent humoral immune functions. 

Deficiencies of zinc, NO and/or GSH shift the Th1/Th2 balance towards Th2, as do deficiencies of any of the essential nutrients (ENs) - a group that includes methionine, cysteine, arginine, vitamins A, B, C and E, zinc and selenium (Se) - because these are necessary for the synthesis and maintenance of sufficient amounts of GSH, MT and NO.

Under Th2, levels of interleukin-4 (II-4), II-6, II-10, leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) are raised, while levels of II-2, Zn++, NO and other substances are lowered. 

Moreover, a sufficiency of Zn++ and NO prevents a shift of the Th1/Th2 balance towards Th2. 

Research makes it look likely that deficiencies of ENs such as zinc promote the proliferation of Th2 cells at the expense of Th1 cells. Zinc deficiency also promotes cancer. 

Under the influence of Th1 cells, zinc inhibits the growth of tumors by activating the endogenous tumour-suppressor endostatin, which inhibits angiogenesis. 

The modern Western diet, with its excess of refined products such as sugar, alcohol and fats, often contains, per calorie, a deficiency of ENs such as zinc, selenium and vitamins A, B, C and E, which results in disturbed immune functions, a shifted Th1/Th2 balance, chronic (viral) infections, obesity, atherosclerosis, autoimmunity, allergies and cancer. 

In view of this, an optimization of dietary composition would seem to give the best chance of beating (viral) epidemics and common (chronic) diseases at a realistic price.¹²³

Airway allergic reactions enlist diverse cells and a multitude of chemical mediators that are responsible for the clinical symptoms of allergic rhinitis and asthma. 

Experiments in vitro and in animal models, as well as increasingly numerous studies in atopic human subjects, are revealing that an orchestrated continuum of cellular activities leading to airway allergic inflammation is set in motion in genetically predisposed individuals at the first exposure to a novel antigen. 

This sensitization step likely depends on differentiation of and cytokine release by Th2 lymphocytes. Among Th2-derived cytokines, IL-4 potently enhances B-lymphocyte generation of immunoglobulin E antibodies. 

The attachment of these antibodies to specific receptors on airway mast cells sets the stage for an acute inflammatory response on subsequent antigen exposure because IgE cross-linking by a bound antigen activates mast cells to release numerous inflammatory mediators. 

These mast cell-derived mediators collectively produce acute-phase clinical symptoms by enhancing vascular leak, bronchospasm, and activation of nociceptive neurons linked to parasympathetic reflexes. 

Simultaneously, some mast cell mediators up- regulate expression on endothelial cells of adhesion molecules for leukocytes (eosinophils, but also basophils and lymphocytes), which are key elements in the late-phase allergic response. 

Chemoattractant molecules released during the acute phase draw these leukocytes to airways during a relatively symptom-free recruitment phase, where they later release a plethora of cytokines and tissue-damaging proteases that herald a second wave of airway inflammatory trauma (late-phase response). 

The repetition of these processes, with the possible establishment in airway mucosa of memory T lymphocytes and eosinophils that are maintained by paracrine and autocrine cytokine stimulation, may account for airway hypersensitivity and chronic airway symptoms.¹²⁴

While the mechanisms underlying the preferential activation by environmental allergens of Th2 cells in atopic individuals still remain obscure, the above studies suggest a possible role of EN deficiencies and the consequential shift from Th1 to Th2 in the primary establishment of inflammation in asthma. 

This would provide a possible explanation for the enigma of abnormalities of regulatory mechanisms of Th2 development and/or function which may be responsible for Th2 responses against common environmental allergens in atopic people. 

The new insights in the pathophysiology of T cell responses in atopic diseases provide exciting opportunities for the development of novel immunotherapeutic strategies such as nutritional influences.