The Immune Skin Barrier
The immune layer includes resident antigen presenting cells, innate lymphoid cells, adaptive memory cells, and others, all working together. Because cells of the immune level are distributed throughout the skin, this level is highly intertwined with the others. It responds to various signals and directs subsequent behavior of the epithelium.9 For example, cells in the skin express toll-like receptors, a type of pattern recognition receptor that responds to pathogen-associated molecular patterns.33,34 When these receptors are engaged, cells secrete substances such as cytokines and human β-defensins.15 Following impairment of physical barrier, allergens and irritants can come into contact with cells of the immune barrier, particularly Langerhans cells, which process these exogenous haptens and initiate T-cell responses.23 Previous research has shown that disruption of the physical barrier subsequently leads to an increase in Langerhans cells even in the basal layers and upper epidermis where these cells are not usually found. Increased numbers of epidermal Langerhans cells have also been found in allergic contact dermatitis (ACD) and ICD.35
Skin Barrier Dysfunction Can Lead to Allergic Sensitization and Atopic March
Disruptions to the skin barrier increase the likelihood of irritants, pathogens, and allergens provoking inflammatory responses. Because skin barrier compromise can consequentially lead to other allergic reactions such as to food and potentially progress to diseases such as CD, it seems especially important to address disruptions early. Skin barrier disruption has been shown to cause AD early in life, which can subsequently lead to allergic rhinitis and asthma, a phenomenon known as the atopic march.36 AD is a skin disease that causes chronic pruritus often beginning in the first years of life and resolving by adulthood in only about 60% of the population. Numerous studies have pointed to AD as the first step in the progression of the atopic march.37
Furthermore, allergies can develop by sensitization through skin.26 Food sensitization is six times more likely to develop in children with AD than in those without.38 A study of adult workers at a mouse research facility found that physician-diagnosed eczema was a risk factor for mouse sensitization as determined through skin-prick testing and suggests that skin barrier dysfunction may increase risks of aeroallergen sensitization not only in childhood but throughout life.39
However, allergies can develop as a consequence of skin barrier defects even in the absence of the development of AD and the atopic march. In fact, neonatal skin barrier dysfunction at birth predicts food allergies at 2 years of age, even without AD.40 Similarly, even in the absence of AD, children with skin barrier defects are more likely to develop asthma.26
Skin Barrier Dysfunction Can Lead to Contact Dermatitis
CD can be irritant (80%) or allergic (20%) and, unlike AD, can develop later in life. ICD is a non-immunologic, inflammatory reaction to irritating agents including solvents, detergents, alcohol, and other chemicals which result in dose-dependent direct tissue damage. Excessive wetness, due to prolonged contact with water, perspiration, or bodily fluids can also lead to ICD. ICD lesions are typically erythematous, dry, possibly edematous and fissuring, with symptoms of burning, tingling or soreness within minutes to hours of contact with the irritant. ACD is an immunologic, delayed-type hypersensitivity reaction to an allergen, which is usually a small molecular weight molecule or hapten that conjugates with skin proteins and induces activated epidermal keratinocytes to release inflammatory cytokines. This immunologic response eventually leads to sensitization to an allergen upon initial contact, and upon subsequent exposure, an elicitation phase occurs. The main symptoms of ACD are pruritus and the appearance of an erythematous eruption, typically scaly, edematous, or vesicular in the acute stage and lichenified in the chronic stage. The cutaneous eruption due to ACD is usually delayed by a few days.31
Irritants and allergens were once strictly distinguished. However, the distinction is now blurring, as in many cases, CD cannot be definitively attributed to irritant or allergic mechanisms by clinical observation. ICD and ACD commonly overlap as many allergens at high enough concentrations can also act as irritants. For example, strong allergens such as poison ivy are also irritants.23 Dysfunctional skin barriers increase the chance of allergen entry into the epidermis and understanding how to minimize penetration of chemicals is important in preventing CD.
Repair of the Skin Barrier May Be a Therapeutic Strategy in the Prevention of Allergic Sensitization, Atopic March, and Contact Dermatitis
Dysfunction at any functional level of the skin barrier can lead to atopic march, allergies, and CD; therefore, repair of the barrier before these conditions progress is essential. Most research on early intervention in skin barrier repair pertains to AD, however, similar logic can be presumed for prevention of ACD, as ACD shares molecular mechanisms with AD, including increased cellular infiltrates and cytokine activation.41 Additionally, patients with AD are more likely to develop CD.
As dysfunction can occur in various levels of the cutaneous barrier, repair should, therefore, target multiple levels. Recently, a study on infants evaluating the colonization of pathogens on skin demonstrated that increased commensal staphylococci early in life lowered the risk of developing AD by 12 months. The most prevalent species associated with protection from AD development were Staphylococcus epidermidis and Staphylococcus cohnii.42 Furthermore, exposure to antibiotics in the first
year of life increases the risk of childhood AD.43 Collectively, these findings confirm an important role of skin microbiota in the development of cutaneous tolerance and maintaining the skin barrier against allergens.
AD has also been linked to sensitization to food allergens, leading to food allergies. Randomized trials have been conducted to determine the efficacy of applying emollients to newborn babies to prevent AD development in infancy and in childhood.44-47 Daily use of one emollient reduced cumulative incidence of AD at six months.44 Fewer newborns given moisturizers developed AD and those with AD had significantly higher sensitization rates against egg whites.45 Use of a slightly acidic ceramide-rich emollient on newborns showed a trend toward reduced risk of both AD and food sensitization.46 Thus, in the context of preventing allergic sensitization, and atopic march, targeting AD through skin barrier repair via emollient usage in infancy is especially important and research indicates there may be an optimal window of time for doing so.37,48 However, in other skin diseases such as CD that can develop at any age, targeting skin barrier repair via emollient usage later in life may be justified for similar reasons.
The Role of Moisturizers in Skin Barrier Repair
Epicutaneous antigens are sensitizers that lead to allergy development, especially in the setting of a dysfunctional skin barrier. It is important to counsel patients that skincare is as much about what is excluded as it is about what is included in a product. Avoidance of common allergens such as fragrance, unnecessary botanicals, or certain preservatives should be advised, especially for atopic patients.
Emollients can help repair the skin barrier (Figure 2).44-46 Emollients improve the barrier function of the SC by providing water and lipids, and slightly acidic emollients can potentially enhance ceramide synthesis.49 Sufficient lipid replacement therapy reduces inflammation and restores epidermal function. Conventional barrier ointments form protective films over the skin barrier which are impermeable to environmental allergens and irritants but can also trap heat in the area, prevent perspiration, and cause discomfort. They may also be perceived as cosmetically unacceptable, which can directly affect adherence.50 Newer products focus on cosmetically elegant formulations with minimalist ingredient lists, that also seek to promote the delivery of pharmacological substances through the SC.51
Recently, the focus of skincare products that enhance the cutaneous barrier has been on targeting the restoration of the microbiome layer.13,52,53 These newer formulas not only protect the skin but also help manage inflammation and neuromediator activation to preserve both the skin barrier and diversity in microbiota. Incorporation of prebiotics, or components that selectively modulate desired bacterial growth, may be helpful.15 Prebiotics include ingredients like thermal spring waters, such as from La Roche-Posay, France, which have unique mineral components and trace elements.54 Additionally, usage of an emollient containing thermal spring waters, shea butter, and
