Basis for the barrier abnormality in atopic dermatitis: Outside-inside-outside pathogenic mechanisms

Abstract

Until quite recently, the pathogenesis of atopic dermatitis (AD) has been attributed to primary abnormalities of the immune system. Intensive study revealed the key roles played by T H 1/T H 2 cell dysregulation, IgE production, mast cell hyperactivity, and dendritic cell signaling in the evolution of the chronic, pruritic, inflammatory dermatosis that characterizes AD. Accordingly, current therapy has been largely directed toward ameliorating T H 2-mediated inflammation and pruritus. In this review we will assess emerging evidence that inflammation in AD results from inherited and acquired insults to the barrier and the therapeutic implications of this paradigm. KeywordsAntimicrobial peptides; atopic dermatitis; barrier function; barrier repair; cytokines; filaggrin; pH; psychologic stress; Staphylococcus aureus; serine proteases; T H 2 cells Until recently, atopic dermatitis (AD) has been viewed largely as a disease of immunologic etiology. 1-5 Yet, the epidermis generates a set of protective/defensive functions (Table I) mediated by its unique differentiation end product, the stratum corneum (SC). 6,7 These functions include the permeability barrier, which retards transcutaneous evaporative water loss, allowing survival in a potentially desiccating external environment, and an antimicrobial barrier, which simultaneously encourages colonization by nonpathogenic ''normal'' flora while resisting growth of microbial pathogens. 8 Although both a defective epidermal permeability 9-13 and a propensity to secondary infection 14,15 are well-recognized features of AD, these abnormalities have been widely assumed to reflect downstream consequences of a primary immunologic abnormality (the historical inside-outside view of AD pathogenesis). We and others have long proposed that the permeability barrier abnormality inADis not merely an epiphenomenon but rather the ''driver'' of disease activity (ie, the reverse outside-inside view of disease pathogenesis) 16-19 for the following reasons: (1) the extent of the permeability barrier abnormality parallels the severity of the disease phenotype in AD 9,10,12 ; (2) both clinically uninvolved skin sites and skin cleared of inflammation for as long as 5 years continue to display significant barrier abnormalities 10,13 ; (3) emollient therapy comprises effective ancillary therapy 20 ; and most importantly, (4) specific replacement therapy, which targets the NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript prominent lipid abnormalities that account for the barrier abnormality in AD (see below), corrects both the permeability barrier abnormality and comprises effective anti-inflammatory therapy for AD (see the Therapeutic implications section below). BROAD BARRIER FAILURE IN ADLike permeability barrier dysfunction, the antimicrobial barrier is also compromised in patients with AD. Colonization by Staphylococcus aureus is a common feature of AD, 21 and although colonization is highest on lesional skin, colony counts often are high on the clinically no...

Filaggrin Genotype in Ichthyosis Vulgaris Predicts Abnormalities in Epidermal Structure and Function

“…Disruption of the epidermal barrier skews the cutaneous cytokine milieu toward a Th2 pattern. 26 -29,77-79 However, since Th2 inflammation itself down-regulates FLG expression, 25 as well as expression of several other epidermal proteins of importance for the barrier, 23 it remains unknown how FLG mutations alter skin barrier function. To determine the impact and mechanisms whereby FLG deficiency compromises permeability barrier structure and function, we studied here a cohort of IV patients largely devoid of clinical signs of cutaneous inflammation.…”

“…8 -12,18 Although decreased FLG is widely postulated to account for the epidermal permeability barrier abnormality in IV and AD, 19 -22 the cellular pathogenesis of the barrier defect is not known. It is difficult to assess how FLG deficiency leads to the barrier abnormality in AD, because Th2-dominant inflammation can secondarily com-promise barrier function by multiple mechanisms, 23 including an acquired reduction in FLG. 24,25 Thus, whether FLG deficiency suffices to provoke a barrier abnormality, and how such an abnormality might occur, remain unknown.…”

New insights in the pathogenesis of atopic dermatitis

“…The cause of AD remains to be a subject of debate. Defects in the physical barrier of the skin have been proposed to play a primary role in the pathogenesis of AD (6). However, allergic inflammation, including increased expression of T helper (Th) 2 cytokines such as interleukin (IL)-4 and IL-13, may also induce skin barrier defects in AD (7).…”

Efinaconazole 10% and Tavaborole 5% Penetrate Across Poly-ureaurethane 16%: Results of In Vitro Release Testing and Clinical Implications of Onychodystrophy in Onychomycosis

“…Primary therapy with poly-ureaurethane 16% aims to protect the diseased nail from further insult and desiccation, much as barrier formulations for compromised skin are foundational in promoting barrier repair. 35,36 These IVRT study results reveal that this foundational barrier indeed allows penetration of the topical antifungal agents efinaconazole 10% and tavaborole 5%. Dual therapy with poly-ureaurethane 16% and these agents or oral antifungal therapy, may have the potential to augment outcomes by stabilizing the compromised nail plate primarily and subsequently addressing fungus if present on laboratory analysis.…”