Therapeutic Implications of a Barrier-based Pathogenesis of Atopic Dermatitis

Elias, Peter M.

doi:10.5021/ad.2010.22.3.245

Cited by 58 publications

(37 citation statements)

References 87 publications

(92 reference statements)

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“…Human epidermis is colonized by a specialized subset of APCs known as Langerhans cells (LCs). In patients with AD, persistent LC stimulation through a defective skin barrier can result in chronic T H 2-driven atopic inflammation 3 . Because filaggrin is involved in collapsing keratinocytes to form the densely packed stratum corneum, it is thought to play a crucial role in maintaining physical skin barrier integrity 4, 5.…”

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confidence: 99%

Filaggrin-null mutations are associated with increased maturation markers on Langerhans cells

Leitch

Natafji

et al. 2016

Journal of Allergy and Clinical Immunology

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BackgroundMutations in the gene encoding filaggrin (FLG), an epidermal structural protein, are the strongest risk factor identified for the development of atopic dermatitis (AD). Up to 50% of patients with moderate-to-severe AD in European populations have FLG-null alleles compared with a general population frequency of 7% to 10%.ObjectiveThis study aimed to investigate the relationship between FLG-null mutations and epidermal antigen-presenting cell (APC) maturation in subjects with and without AD. Additionally, we investigated whether the cis isomer of urocanic acid (UCA), a filaggrin breakdown product, exerts immunomodulatory effects on dendritic cells.MethodsEpidermal APCs from nonlesional skin were assessed by using flow cytometry (n = 27) and confocal microscopy (n = 16). Monocyte-derived dendritic cells from healthy volunteers were used to assess the effects of cis- and trans-UCA on dendritic cell phenotype by using flow cytometry (n = 11).ResultsEpidermal APCs from FLG-null subjects had increased CD11c expression. Confocal microscopy confirmed this and additionally revealed an increased number of epidermal CD83+ Langerhans cells in FLG-null subjects. In vitro differentiation in the presence of cis-UCA significantly reduced costimulatory molecule expression on monocyte-derived dendritic cells from healthy volunteers and increased their ability to induce a regulatory T-cell phenotype in mixed lymphocyte reactions.ConclusionsWe show that subjects with FLG-null mutations have more mature Langerhans cells in nonlesional skin irrespective of whether they have AD. We also demonstrate that cis-UCA reduces maturation of dendritic cells and increases their capacity to induce regulatory T cells, suggesting a novel link between filaggrin deficiency and immune dysregulation.

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confidence: 99%

Filaggrin-null mutations are associated with increased maturation markers on Langerhans cells

Leitch

Natafji

et al. 2016

Journal of Allergy and Clinical Immunology

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“…Research conducted over the last decade indicates that GCs, released in response to stress, cultivate Th2 responses while inhibiting Th1 cell responses (24). It has also become clear that patients with AD may have a hyperacute response to stress in terms of T-cell and mast cell activation, HPA dysregulation, neurogenic inflammatory mediator expression and release, and a disruption of normal epidermal barrier function (31, 133, 134). Studies have suggested that psychological stress in AD is at least partially responsible for the above derangement in immune response and that this polarity may be established following stress in early childhood (60, 135).…”

Section: Discussionmentioning

confidence: 99%

Psychoneuroimmunology of Psychological Stress and Atopic Dermatitis: Pathophysiologic and Therapeutic Updates

Suárez¹,

Feramisco²,

Koo³

et al. 2012

Acta Derm Venerol

186

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Atopic dermatitis is a chronic inflammatory skin disease characterized by impaired epidermal barrier function, inflammatory infiltration, extensive pruritus and a clinical course defined by symptomatic flares and remissions. The mechanisms of disease exacerbation are still poorly understood. Clinical occurrence of atopic dermatitis is often associated with psychological stress. In response to stress, upregulation of neuropeptide mediators in the brain, endocrine organs, and peripheral nervous system directly affect immune and resident cells in the skin. Lesional and non-lesional skin of patients with atopic dermatitis demonstrates increased mast cells and mast cell-nerve fiber contacts. In the setting of stress, sensory nerves release neuromediators that regulate inflammatory and immune responses, as well as barrier function. Progress towards elucidating these neuroimmune connections will refine our understanding of how emotional stress influences atopic dermatitis. Moreover, psychopharmacologic agents that modulate neuronal receptors or the amplification circuits of inflammation are attractive options for the treatment of not only atopic dermatitis, but also other stress-mediated inflammatory skin diseases.

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“…Conversely, some researchers claim that barrier repair therapy may reduce secondary colonization of pathogenic Staphylococcus aureus by targeted correction of lipid biochemical abnormalities [21]. …”

Section: Treatment Of Skin Infectionsmentioning

confidence: 99%

Barrier-Restoring Therapies in Atopic Dermatitis: Current Approaches and Future Perspectives

Valdman-Grinshpoun

Ben‐Amitai

Zvulunov

2012

Dermatology Research and Practice

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Atopic dermatitis is a multifactorial, chronic relapsing, inflammatory disease, characterized by xerosis, eczematous lesions, and pruritus. The latter usually leads to an “itch-scratch” cycle that may compromise the epidermal barrier. Skin barrier abnormalities in atopic dermatitis may result from mutations in the gene encoding for filaggrin, which plays an important role in the formation of cornified cytosol. Barrier abnormalities render the skin more permeable to irritants, allergens, and microorganisms. Treatment of atopic dermatitis must be directed to control the itching, suppress the inflammation, and restore the skin barrier. Emollients, both creams and ointments, improve the barrier function of stratum corneum by providing it with water and lipids. Studies on atopic dermatitis and barrier repair treatment show that adequate lipid replacement therapy reduces the inflammation and restores epidermal function. Efforts directed to develop immunomodulators that interfere with cytokine-induced skin barrier dysfunction, provide a promising strategy for treatment of atopic dermatitis. Moreover, an impressive proliferation of more than 80 clinical studies focusing on topical treatments in atopic dermatitis led to growing expectations for better therapies.

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Therapeutic Implications of a Barrier-based Pathogenesis of Atopic Dermatitis

Cited by 58 publications

References 87 publications

Filaggrin-null mutations are associated with increased maturation markers on Langerhans cells

Filaggrin-null mutations are associated with increased maturation markers on Langerhans cells

Psychoneuroimmunology of Psychological Stress and Atopic Dermatitis: Pathophysiologic and Therapeutic Updates

Barrier-Restoring Therapies in Atopic Dermatitis: Current Approaches and Future Perspectives

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