THE Th1Th2 Paradigm In Ad

Although Th2 cells certainly contribute to the pathogenesis of AD it is now well accepted that TH1 cells also play an important role in maintaining skin inflammation. Therefore, this biphasic character represents one hallmark of AD which is defined by an initial phase with predominately TH2 cytokines switching into a second TH1-like chronic phase.43 TH1 cells are known to secrete IL-2 and IFN-y, induce macrophage activation, and are very effective in controlling infection with intracellular pathogens. In contrast, TH2 cells produce IL-4, IL-5, IL-9, and IL-13 as key signature cytokines and promote excellent humoral immunity, allergic reactions, and resistance to helminthic infections.44,45

In addition to these two main distinct TH cell populations, a further subset of regulatory T cells does exist suppressing both TH1 and TH2 responses. To date, several major groups of these so-called T regulatory (Treg) cells have been described: namely, the naturally occurring CD4+CD25+ cells, the type 1 T regulatory cells (Tr1) and the TH3 cells. The first subset accounts for 5-15% of the peripheral CD4+ T cells and expresses the cytotoxic T-lymphocyte antigen 4 (CTLA-4)46 and the glucocorticoid-induced tumour necrosis factor receptor as markers.47 These cells are generated in the thymus and then exported to peripheral tissues, where they normally hinder potential autoimmune responses. Their mechanism of suppression relies on the inhibition of IL-2Ra chain in target T cells induced by the combined activation of CTLA-4 and membrane-bound TGF-p. Additionally, CD4+CD25+ cells specifically express the forkhead-winged helix transcription factor gene FoxP3 which so far is the most unambiguous marker available to identify this class of Treg cells. Loss of function through mutations in the FoxP3 gene results in a lack of this T-cell subset, and consequently favours the onset of various autoimmune and allergic diseases.48 Similar to the natural Treg cells, Tr1 cells (adaptive T cells) also originate from the thymus but then further differentiate in the periphery under certain conditions of antigenic stimulation. They exert suppressive activity through enhanced IL-10 production whereas TH3 cells mainly produce TGF-P, thereby mediating their regulatory function.

Clear evidence suggests that TH1 and TH2 cells can each arise from the same precursor cell (the naive TH0 cell) under the influence of:

1. T-cell receptor ligation (TCR)

2. the activation of costimulatory molecules

3. the predominance of a given cytokine in the microenvironment

4. the number of postactivation cell divisions,49 whereas the cytokine composition has emerged as key determinant in the outcome of TH responses.

For example, if the TH0 cell is activated in the presence of IL-12 (from a macrophage or dendritic cell) then this cytokine initiates a process of TH1 maturation. Additionally, it synergizes together with IL-2 and IL-18, another cytokine secreted by activated macrophages, to induce IFN-y synthesis.50 Of note, the novel IL-12 family members, such as IL-23 and IL-27, may contribute to the TH1 polarization as well.51,52 Although IL-27 is not sufficient to instruct IFN-y production on its own, it has a profound effect in the early steps of Th1 commitment by controlling IL-12 responsiveness53 while IL-23 functions primarily on effector T cells prolonging and sustaining their IFN-y synthesis.

Conversely, naive T cells activated in the presence of IL-4 down-regulate the IL-12 receptor and differentiate along the TH2 pathway, even if the initial source of this cytokine is still a subject of debate.54,55 However, it is suggested that APC-derived IL-6 mediates Th2 development by inducing early IL-4 production.56 Yet, generation of this phenotype also requires the interaction of two more recently discovered cytokines: namely, IL-19 and IL-25. In vitro data could show that IL-19, expressed by human peripheral blood mononuclear cells and purified monocytes after LPS stimulation,57 up-regulated IL-4 and down-regulated IFN-y in a dose-dependent fashion.58 Similarly, the mast cell and TH2 cell derived cytokine IL-25 induced elevated production levels of IL-4, IL-5, and IL-13.59

T-cell differentiation is a complex process regulated by a network of transcription factors such as GATA-3 and T-bet.60,61 GATA-3 is expressed during TH2 differentiation via pathways that probably involve the IL-4 dependent activation of the signal transducer and activator of transcription (STAT)-6. It suppresses IFN-y, increases the transactivation of the IL-4 promoter, and also directly regulates IL-5 and IL-13 expression in Th2 cells. By contrast, T-bet is exclusively expressed in Th1 cells in a principally STAT-4 dependent manner, mediates IFN-y production and maintains synthesis of the IL-12 receptor y2 chain upon T-cell activation. Thus, a balance between T-bet and GATA-3 is believed to control TH1 and TH2 polarization.

With respect to AD TH2 and TH1 cytokines are both involved in the pathogenesis and their contribution depends on the chronicity of skin lesion. In humans, such a strong T-cell effector dichotomy does not frequently appear but can be observed in patients with autoimmune or allergic diseases as well.62,45 Initially, AD was viewed as a prototypical TH2 disease due to its mainly humoral features. One of the first studies performed in this context was carried out on PBMCs of AD patients indeed providing evidence for increased TH2 activity (IL-4) along with diminished IFN-y release upon mitogen stimulation.63 Many subsequent studies could reproduce this finding even on the level of allergen-specific T cells showing an overproduction of IL-4 in response to the relevant allergen.64,65 Presently, it is well established that TH2 derived cytokines characterize AD patients with acute lesions66 while TH1 derived cytokines are predominant in patients of the chronic stage.67

This Th1/Th2 dysbalance also exists in the local environment of lesional skin and therefore critically modulates the nature, degree, and persistence of inflammation in AD. In this context analysis of skin biopsies using in-situ hybridization revealed significantly greater amounts of Th2 cells positive for IL-4 and IL-13 mRNA whereas in chronic skin lesions IFN-y, IL-5 and IL-12 mRNA expression predominate.68 Furthermore, investigations on allergen patch testing followed by punch biopsies at different time points also showed these biphasic kinetics in cytokine production.69 Figure 9.3 illustrates the acute and chronic features of AD and the involved cellular mechanisms as described above.

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Food Allergies

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