2.5. Some biological aspects of atopic disorders

2.5.1. Regulation of immunity

Immunity is a state of resistance, or protection from pathogenic micro-organisms (Kelley 2001). The immune system can be divided into innate (antigen-nonspecific) and acquired (adaptive/antigen-specific) immunity. Innate immunity is present at all times in normal individuals, and is thus fully functional before infectious agents enter the body. An adaptive immune response is a specific reaction of the body to the challenge by an immunogen. Immune responses are contributed by antigen-presenting cells, such as monocytes/macrophages, which are components of innate immunity, and on the other hand by T helper (Th) lymphocyte subclasses Th1 and Th2, which are involved in acquired immunity (Elenkov & Chrousos 1999, Elenkov et al. 2000, Kelley 2001, Schwarz et al. 2001). These Th subclasses secrete a distinct cytokine profile (Figure 1): Th1 cells produce mainly interleukin-2 (IL-2), tumor necrosis factor β (TNF-β ), and interferon-γ (INF-γ ), all three of which promote cellular immunity. Th2 cells secrete primarily IL-4, IL-5, IL-10 and IL-13, all of which favour humoral immunity (Elenkov et al. 2000, Buske-Kirschbaum et al. 2001).

Naive (antigen-inexperienced) Th0 cells are precursors of Th1 and Th2 cells (Figure 1). IL-12, which is produced by antigen-presenting cells, is a major inducer of Th1 shift, and thus is favouring cellular immunity, whereas IL-4 and IL-10, while stimulating Th2 differentiation, are promoting humoral immunity by stimulating the growth and activation of mast cells and eosinophils, the differentiation of B cells into antibody-secreting B cells, and B cell immunoglobulin to switch to IgE. Th1 and Th2 responses inhibit each other (Elenkov & Chrousos 1999, Elenkov et al. 2000).

2.5.2. Immediate hypersensitivity

In atopic patients, naive Th0 cells are stimulated by an environmental allergen to differentiate into Th2 cells. IL-4, produced by Th2 cells, is required for the differentiation of B cells to produce high levels of IgE specific for that antigen. IgE binds to the circulating basophils and mast cells in different tissues. When these cell-associated antibodies are cross-linked by antigen, the cells are activated and they rapidly release preformed mediators – e.g., biogenic amines such as histamine – stored in the cytoplasmic granules of the mast cells and basophils. In addition, a rapid synthesis of lipid-derived mediators – prostaglandins and leukotrienes – and cytokines takes place. The biogenic amines and lipid mediators are responsible for the acute phase reaction of immediate hypersensitivity while they cause increased vascular permeability, vasodilatation as well as bronchial and visceral smooth muscle contraction. Cytokines and lipid mediators contribute to an allergic inflammation, which is part of the late phase reaction beginning 2 to 4 hours after the acute phase reaction. The late phase reaction achieves its maximum in about 24 hours and then it gradually subsides (Abbas et al. 2000, Buske-Kirschbaum et al. 2001). The most severe manifestation of the immediate hypersensitivity is anaphylaxis, in which airways can be restricted to the point of asphyxiation and a cardiovascular collapse can occur, which can lead to a person’s death (Abbas et al. 2000).

2.5.3. Allergen-specific T-cell memory

The foetal immune response is dominated by Th2 cytokines (Prescott et al. 1998). It has been suggested that this Th2 polarization is an evolutionary adaptation and aimed to protect the foeto-placental unit against the toxic effects of proinflammatory cytokines such as INF-γ (Lin et al. 1993, Prescott et al. 1998). Further, it has also been shown that virtually all newborn infants have a Th2-skewed immunity (Prescott et al. 1998). In healthy, non-atopic individuals, this Th2 dominance is shifted toward the Th1 cytokine phenotype during early childhood whereas the long term Th2-skewed allergen-specific immunologic memory is being developed among atopic persons (Prescott et al. 1998, 1999).