The genetics of atopic dermatitis: recent findings and future options.
ABSTRACT Atopic dermatitis (AD) is a chronic pruritic skin disease affecting up to 15% of children in industrialized countries. AD belongs to the group of allergic disorders that include food allergy, allergic rhinitis, and asthma. A multifactorial background for AD has been suggested, with genetic as well as environmental factors influencing disease development. Genome-wide screens for AD have been completed in four different populations to date. Interestingly, the susceptibility regions identified for AD show little overlap with asthma susceptibility regions, suggesting that, at least in part, separate genes might be involved in the pathogenesis of the different atopic disorders. Instead, some of the identified regions overlap with susceptibility regions for psoriasis, another chronic skin disease. Thus, genes expressed in the skin might play an important role in AD pathogenesis, in addition to genes influencing atopic diatheses. Although no veritable "AD gene" has been identified by positional cloning to date, examples from other complex genetic disorders such as asthma show that this goal is likely to be reached in the near future. Candidate gene studies, on the other hand, have identified 19 genes that were shown to be associated with AD in at least one study. The results of genome-wide screens as well as candidate gene studies are evaluated here in detail.
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ABSTRACT: Histamine is thought to play a critical role in the synthesis of extracellular matrix in skin and may be involved in tissue remodeling of allergic diseases. Recent studies revealed that periostin, a matricelluar protein, contributed to tissue remodeling; however, a link between periostin and histamine remains unproven. We investigated whether periostin was involved in histamine-induced collagen production. Cultured dermal fibroblasts derived from wild-type (WT) or periostin knockout (PN(-/-)) mice were stimulated with histamine, and then collagen and periostin production were evaluated. Histamine induced collagen gene expression in WT fibroblasts in the late phase but not in the early phase, while no effect on collagen expression was observed in histamine-stimulated PN(-/-) fibroblasts. In WT fibroblasts, histamine directly induced periostin expression in a dose-dependent manner, and an H1 receptor antagonist blocked both periostin and collagen expression. Histamine activated ERK1/2 through the H1 receptor. Periostin induction was inhibited by either H1 antagonist or ERK1/2 inhibitor treatment in vitro and was attenuated in H1R(-/-) mice. Elevated expression of periostin was found in lesional skin from AD patients. These results suggest that histamine mediates periostin induction and collagen production through activation of the H1 receptor-mediated ERK1/2 pathway, furthermore, histamine may accelerate the chronicity of AD.Journal of Investigative Dermatology accepted article preview online, 27 February 2014; doi:10.1038/jid.2014.120.Journal of Investigative Dermatology 02/2014; 134(8). DOI:10.1038/jid.2014.120 · 6.37 Impact Factor
Article: Atopic dermatitis.New England Journal of Medicine 04/2008; 358(14):1483-94. DOI:10.1056/NEJMra074081 · 54.42 Impact Factor
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ABSTRACT: Atopic dermatitis (AD) is a chronic inflammatory skin disease with specific genetic and immunological mechanisms. The rapid development of new techniques in molecular biology had ushered in new discoveries on the role of cytokines, chemokines, and immune cells in the pathogenesis of AD. New polymorphisms of AD are continually being reported in different populations. The physical and immunological barrier of normal intact skin is an important part of the innate immune system that protects the host against microbials and allergens that are associated with AD. Defects in the filaggrin gene FLG may play a role in facilitating exposure to allergens and microbial pathogens, which may induce Th2 polarization. Meanwhile, Th22 cells also play roles in skin barrier impairment through IL-22, and AD is often considered to be a Th2/Th22-dominant allergic disease. Mast cells and eosinophils are also involved in the inflammation via Th2 cytokines. Release of pruritogenic substances by mast cells induces scratching that further disrupts the skin barrier. Th1 and Th17 cells are mainly involved in chronic phase of AD. Keratinocytes also produce proinflammatory cytokines such as thymic stromal lymphopoietin (TSLP), which can further affect Th cells balance. The immunological characteristics of AD may differ for various endotypes and phenotypes. Due to the heterogeneity of the disease, and the redundancies of these mechanisms, our knowledge of the pathophysiology of the disease is still incomplete, which is reflected by the absence of a cure for the disease.Clinical Reviews in Allergy & Immunology 04/2014; DOI:10.1007/s12016-014-8415-1 · 4.73 Impact Factor