"Outside-to-inside" (and now back to "outside") pathogenic mechanisms in atopic dermatitis

Abstract

The pathogenesis of atopic dermatitis (AD) has been attributed largely to abnormalities in the adaptive immune system, with key roles played by T-helper 1(Th1)/Th2 cell dysregulation, IgE production, dendritic cell signaling, and mast-cell hyperactivity, resulting in the pruritic, inflammatory dermatosis that characterizes AD (Leung et al., 2004). Accordingly, therapy has been focused on ameliorating Th2-mediated inflammation and pruritus (eg, Leung, 2000). Indeed, there is emerging evidence that inflammation in AD results first from inherited and acquired insults that converge to alter epidermal structure and function, followed by immune system activation, which in turn has negative consequences for skin-barrier homeostasis. This cycle comprises an "outside-inside-outside" model of AD pathogenesis (Elias et al., in press).

Figure 1. Secondary infections can further aggravate barrier abnormality in atopic dermatitis

AD, atopic dermatitis; AMP, adenosine monophosphate; Cer, ceramide; FLG, filaggrin; LEKTI, lymphoepithelial Kazal-type related trypsin inhibitor; PS, psychological stress; RH, relative humidity; Th1, T-helper 1; Th2, T-helper 2 (Modified from Elias et al., in press.)

Figure 2. “Outside–inside–outside” model of AD

Cer, ceramide; FLG, filaggrin; hBD2, human β-defensin-2; Th2, T-helper 2. (From Figure 2. Cer, ceramide; FLG, filaggrin; hBD2, human β-defensin-2; Th2, T-helper 2. (From Steinhoff et al., 2005; modified from Elias et al., in press.)