Spontaneous atopic dermatitis is mediated by innate immunity, with the secondary lung inflammation of the atopic march requiring adaptive immunity

Abstract

BackgroundAtopic dermatitis (AD) is an inflammatory skin condition that can occur in early life, predisposing to asthma development in a phenomenon known as the atopic march. Although genetic and environmental factors are known to contribute to AD and asthma, the mechanisms underlying the atopic march remain poorly understood. Filaggrin loss-of-function mutations are a major genetic predisposer for the development of AD and progression to AD-associated asthma.ObjectiveWe sought to experimentally address whether filaggrin mutations in mice lead to the development of spontaneous eczematous inflammation and address the aberrant immunologic milieu arising in a mouse model of filaggrin deficiency.MethodsFilaggrin mutant mice were generated on the proallergic BALB/c background, creating a novel model for the assessment of spontaneous AD-like inflammation. Independently recruited AD case collections were analyzed to define associations between filaggrin mutations and immunologic phenotypes.ResultsFilaggrin-deficient mice on a BALB/c background had profound spontaneous AD-like inflammation with progression to compromised pulmonary function with age, reflecting the atopic march in patients with AD. Strikingly, skin inflammation occurs independently of adaptive immunity and is associated with cutaneous expansion of IL-5–producing type 2 innate lymphoid cells. Furthermore, subjects with filaggrin mutations have an increased frequency of type 2 innate lymphoid cells in the skin in comparison with control subjects.ConclusionThis study provides new insights into our understanding of the atopic march, with innate immunity initiating dermatitis and the adaptive immunity required for subsequent development of compromised lung function.

Lce1 Family Members Are Nrf2-Target Genes that Are Induced to Compensate for the Loss of Loricrin

“…Interestingly, deletion of the Lce3b and Lce3c genes has been identified as a susceptibility factor for developing psoriasis (de Cid et al, 2009), which is often accompanied with arthritis (Roberson and Bowcock, 2010). These findings suggest that genetic alterations that impair epidermal barrier function can affect the immune response, which has been documented both clinically (De Benedetto et al, 2012) and experimentally (Fallon et al, 2009; Saunders et al, 2015; Strid et al, 2011). Future studies will determine whether loss-of-function mutations in LOR can affect the immune system and also be a risk factor for developing atopic dermatitis.…”

Interplay between barrier epithelial cells and dendritic cells in allergic sensitization through the lung and the skin

“…The importance of the epidermal barrier function in sensitization to allergens was emphasized by numerous experimental models where proteins involved in barrier integrity were genetically mutated [reviewed in ]. Flg mutant mice on a proallergic Balb/C background developed spontaneous AD‐like inflammation . Additionally, keratinocyte‐specific ablation of corneodesmosin, a structural protein of corneodesmosomes responsible for intercorneocyte adhesion, resulted in a breakdown of the epidermal stratum corneum and AD‐like inflammatory skin response in mice .…”

Emerging roles of innate lymphoid cells in inflammatory diseases: Clinical implications

“…In AD patients, filaggrin mutations cause defects in the skin barrier function and lead to lower E-cadherin expression, 73 resulting in elevated IL-1b levels and an accumulation of ILC2s. 79 This is further amplified by widespread expression of B7-H6 in AD skin, promoting type 2 cytokine production. 78 These two mechanisms lead to persistent activation of ILC2s.…”

“…73,77,79 • Increased ILC3 numbers were detected in psoriatic skin lesions correlating with disease severity.…”