Review articleThe TH1/TH2 paradigm in allergy
Introduction
Atopic diseases are genetically determined disorders characterized by an increased ability of B lymphocytes to synthesize IgE antibodies towards ubiquitous antigens (allergens) able to activate the immune system after inhalation or ingestion and after penetration through the skin. IgE antibodies are able to bind to high affinity Fcε receptors (FcεRI) present on the surface of mast cells/basophils. Allergen-induced FcεRI cross-linking triggers the release of vasoactive mediators, chemotactic factors and cytokines that are responsible for the allergic events. Eosinophils are also involved in the pathogenesis of allergic reactions, as these cells usually accumulate at the site of allergic inflammation and release toxic products contributing to tissue damage.
The mechanisms linking IgE-producing B cells, mast cells/basophils and eosinophils in the pathogenesis of allergic reactions have remained unclear until distinct subsets of CD4+ helper T (Th) cells, based on their profile of cytokine secretion, were discovered. The cumulative study on the functional properties of helper Th cell subsets is known as the ‘Th2 hypothesis’ for the pathogenesis of allergic reactions [1]. This review summarizes the role of allergen-reactive Th2 cells in the pathogenesis of human allergic disorders and the possible mechanisms involved in the regulation of Th2 cell development. Finally, it will examine novel therapeutic strategies for atopic diseases, particularly those able to redirect the Th2 response.
Section snippets
The Th1/Th2 paradigm
Murine CD4+ Th1 cells secrete interferon-gamma (IFN-γ), interleukin (IL) 2 and tumor necrosis factor (TNF)-β, which promote macrophage activation, production of opsonizing and complement-fixing antibodies, antibody-dependent cell cytotoxicity, and DTH [2]. For these reasons, it is possible to refer to Th1 cells as cells responsible for phagocyte-dependent host responses [3]. On the other side, Th2 cells, which produce IL-4, IL-5, IL-6, IL-9, IL-10 and IL-13, provide optimal help for antibody
The ‘Th2 hypothesis’ in atopy
As reported above, Th2 cells produce IL-4 and IL-13 which stimulate IgE and IgG4 antibody production, IL-5 which recruits and differentiates eosinophils and IL-10, which together with IL-4 and IL-13, inhibit several macrophage functions, thus explaining why the mast cell/eosinophil/IgE-producing B cell triad is involved in the pathogenesis of allergy [1]. Strong evidence has been accumulated to support this concept that Th2 cells play a central role in atopy.
The study of cytokine profile of
Mechanisms involved in the regulation of Th2 development
The mechanisms responsible for the preferential development of allergen-reactive Th2 cells in atopic subjects have not yet been completely clarified.
Possible genetic alterations favoring allergen-specific Th2 responses in atopic subjects
The possibility that atopic subjects have a genetic dysregulation at level of IL-4 produced by Th cells is supported by several observations. First, CD4+ T cell clones from atopic individuals are able to produce noticeable amounts of IL-4 and IL-5 in response to bacterial antigens, such as PPD and streptokinase, that usually evoke responses with a restricted Th1-like cytokine profile in nonatopic individuals [82]. Second, T-cell clones generated from cord blood lymphocytes of newborns with
New immunotherapeutical approaches in atopy
Based on these new insights and the biotechnological advances, novel opportunities of treatment of allergic disorders can be hypothesized. It may be addressed to target allergen-specific T cells (allergen-specific immunotherapy-IT) or their effector molecules (non allergen-specific IT).
Concluding remarks
There is a general consensus that the Th-cell population contains functionally distinct subsets defined by the patterns of cytokines they produce in response to different types of antigenic stimulation. Although Th1 and Th2 cells were first identified by in vitro analysis of murine T-cell clones, strong evidence now exists for similar subsets in vivo, in mice, rats and humans. These two extremely polarized forms of the specific cellular immune response, evoked by intracellular parasites and
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