Trends in Immunology
Volume 36, Issue 12, December 2015, Pages 788-801
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Review
The Multi-Modal Immune Pathogenesis of Atopic Eczema

https://doi.org/10.1016/j.it.2015.10.006Get rights and content

Trends

The pathogenesis of atopic eczema (AE) can be better understood if separated, conceptually, into four modules. Distinct combinations of the components of these modules results in the varied presentations of the disease.

Genetics: recent advances highlight the importance of the cutaneous barrier and both innate and adaptive immune deviation.

Microbiota: there is reduced microbiota diversity in AE lesions in the skin, and this reduced diversity has been associated with the disease. The bias towards type 2 immunity seen in AE appears to be also supported by dysbiosis.

Innate immunity: ILC2 and myeloid-derived suppressor cells (MDSCs) contribute to AE pathogenesis, with ILC2s participating in the initiation of disease pathogenesis and MDSCs contributing by failing to terminate inflammation, perpetuating an inflammatory cycle.

Adaptive immunity: acute lesions are triggered by environmental allergens whereas the local microbiota and auto-allergens contribute to chronic disease.

Atopic eczema (AE) is one of the most common inflammatory diseases, often constituting a lifelong burden for afflicted individuals. Recent findings have provided new insights into the pathogenesis of AE, revealing contributions of genetics, skin microbiota, and both innate and adaptive immunity in disease onset and progression. We review these findings here, assembling contributing factors conceptually into four modules that can interact in various ways to ultimately lead to epidermal barrier impairment, unchecked type 2 immunity, and chronic disease. We present this modular framework as a basis for understanding the varied presentations of AE, and in this context we propose a diagnostic and therapeutic algorithm aimed at the precise stratification of AE patients and the implementation of individualized medicine in AE standard of care.

Section snippets

AE: A Complex Disease

AE belongs to the most common human inflammatory diseases, with a prevalence of at least 2–3% in the adult population and 10–30% in infants in the western world. Accordingly, AE has a major impact on total global disease burden [1] and represents a challenge for modern health care systems. Affected patients suffer from acute and often persistent or relapsing eczematous skin lesions that are characterized by erythema, papules, and scaly plaques accompanied by intense pruritus. The underlying

Module 1: The Interplay of Genetic Background and Immunology

The pathogenesis of AE is based on complex genetic traits [7]. Almost 10 years ago a strong association between AE development and loss-of-function mutations in the gene encoding filaggrin was discovered [8]. Filaggrin links keratin filaments with disulfide bonds – a process that leads to epithelial cornification and the generation of a tight physical barrier. In addition, degradation products of filaggrin contribute to skin homeostasis by stabilizing the pH, by ‘moisturing’ the skin, and by

Module 2: The Microbiota and its Role in AE

Analysis of small subunit ribosomal RNA genes (16S rRNA) allows the diversity of microbes in a particular habitat to be assessed [17]. Twin studies using this approach identified interindividual intestinal microbe diversity as well as specific individual bacterial lineages and even similarities among family members [18]. Initial studies comparing cutaneous microbiota also revealed a large inter- and intra-individual diversity [19], and found that gender and exogenous factors such as time since

ILCs: New Players on the Ground

ILCs represent the innate counterpart of T helper cells with comparable cytokine secretion pattern, but lack specific antigen receptors and hematopoietic lineage markers. Similarly to T helper cells, ILC are grouped according to their secreted cytokines into three subsets: ILC1 (IFNγ+), ILC2 (IL-5+, IL-13+) and ILC3 (IL-17+, IL-22+) (reviewed in [42]). Whereas the phenotype and function of mouse ILCs at mucosal surfaces are relatively well understood, understanding their contribution to skin

Module 4: Adaptive Immunity and the Nature of Allergens

Adaptive immunity is activated by the specific recognition of potentially harmful antigens. Whereas in allergic rhinitis misdirected Th2 responses against harmless environmental antigens are directly causative for the symptoms, the contribution of these antigens in AE is under debate. In a subset of newborns and babies a clear association of skin inflammation with ingestion of particular food allergens such as egg, cow milk, or peanut proteins is well established [58], whereas in adults

Concluding Remarks

Dissecting the pathogenesis of AE into different modules allows the heterogeneity of this complex disease to be better characterized. This heterogeneity is increasingly reflected by distinct therapeutic approaches. Therefore, the last section of this review introduces therapeutic strategies and proposes a therapeutic algorithm based on patient stratification (Figure 3). Such an algorithm must recognize the heterogeneity of AE: in some cases causative treatment or even prevention may be

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