Skin barrier disruption: a requirement for allergen sensitization?

Abstract

For at least half a century, noninvasive techniques have been available to quantify skin barrier function, and these have shown that a number of human skin conditions and disorders are associated with defects in skin permeability. In the past decade, several genes responsible for skin barrier defects observed in both monogenetic and complex polygenic disorders have been elucidated and functionally characterized. This has led to an explosion of work in the past 6 years that has identified pathways connecting epidermal barrier disruption and antigen uptake, as well as the quality and/or magnitude of the antigen-specific adaptive immune response. This review will introduce the notion that diseases arise from the dynamic crosstalk that occurs between skin barrier and the immune system using atopic dermatitis or eczema as the disease prototype. Nevertheless, the concepts put forth are highly relevant to a number of antigen-driven disorders for which skin barrier is at least transiently compromised, such as psoriasis, allergic contact dermatitis, and blistering disorders.

Figure 1. TJ penetration of LC dendrites

(a and c) Layers of the stratum granulosum (SG) are designated SG1, SG2, and SG3, counting from the skin surface inwards. In murine epidermis TJs are found in the intercellular spaces between SG2 cells. Blue dotted lines represent TJs. (b and d) Activated LCs (e.g. MHC class II positive) elongate their dendrites to dock with and penetrate epidermal TJs. (a) ZO-1 and claudin-1 accumulate at penetration points (yellow arrows), where novel tricellular TJs are formed between LC dendrites and surrounding keratinocytes to prevent significant barrier disturbance. (b) Rotated views of an activated LC dendrite are shown. EZ-link sulfo-NHS-LC-biotin was applied topically on mouse skin. Trace amounts of this biotin tracer are observed in LC dendrites that have crossed the TJ barrier (arrowheads; upper b). (The images were originally published in JOURNAL OF EXPERIMENTAL MEDICINE (Doi: 10.1084/jem.20091527 (Kubo et al., 2009)). ©Kubo et al., 2009. Originally published in JOURNAL OF EXPERIMENTAL MEDICINE. doi: 10.1084/jem.20091527

Figure 1. TJ penetration of LC dendrites

(a and c) Layers of the stratum granulosum (SG) are designated SG1, SG2, and SG3, counting from the skin surface inwards. In murine epidermis TJs are found in the intercellular spaces between SG2 cells. Blue dotted lines represent TJs. (b and d) Activated LCs (e.g. MHC class II positive) elongate their dendrites to dock with and penetrate epidermal TJs. (a) ZO-1 and claudin-1 accumulate at penetration points (yellow arrows), where novel tricellular TJs are formed between LC dendrites and surrounding keratinocytes to prevent significant barrier disturbance. (b) Rotated views of an activated LC dendrite are shown. EZ-link sulfo-NHS-LC-biotin was applied topically on mouse skin. Trace amounts of this biotin tracer are observed in LC dendrites that have crossed the TJ barrier (arrowheads; upper b). (The images were originally published in JOURNAL OF EXPERIMENTAL MEDICINE (Doi: 10.1084/jem.20091527 (Kubo et al., 2009)). ©Kubo et al., 2009. Originally published in JOURNAL OF EXPERIMENTAL MEDICINE. doi: 10.1084/jem.20091527

Figure 2

The epidermis has two formidable barrier structures that are analogous to a castle’s moat (SC; blue water) and portcullis (TJ; white gate). Epicutaneous sensitization requires that the antigen be engulfed by an antigen presenting cell such as an epidermal dendritic cell or Langerhans cell (LC). (a) Under resting conditions the immune system does not respond to environmental factors such as allergens. (b) When the SC is breached (e.g. drawbridge is down) allergens may cross the moat, but will still be blocked by an intact TJ barrier (portcullis). LC dendrites are found below TJ (e.g. behind the portcullis). (c) When the portcullis is opened (TJ loosened), LC dendrites extend through these weakened TJ and take up allergens and initiate an adaptive immune response. Additionally, it is hypothesized that small allergens may penetrate leaky TJ and be taken up by LC/DC whose dendrites are below the TJ. It is not clear whether a transient break in both epidermal barriers (SC and TJ) are required for LC dendrites to penetrate TJs. This dual barrier system uniquely found in the skin may explain why we do not respond to a myriad of antigens that reach our skin surface daily and therefore why our skin is usually uninflammed.

Figure 3. Epidermal barrier function and immune responses are tightly linked

Primary barrier defects lead to the release of a number of epidermal-derived mediators including ones that are considered pro-Th2 and pro-Th17. Some of these cytokines are released in an autocrine fashion through proteinase-activated receptors (PAR)-2 activation or by epithelial–derived “danger signals” that act on innate immune receptors expressed on keratinocytes. The presumption is that barrier disruption comes in different flavors each resulting in a specific adjuvant profile that would either favor a Th2, Th17 or another adaptive immune response to an antigen. Several Th2 and Th17 products establish an autocrine feedback loop and further aggravate barrier disruption (e.g. secondary barrier defects). To date, this has been best characterized for Th2 cytokines (Huppert et al., 2010; Sehra et al., 2010).