Immune dysregulation in atopic dermatitis

Sinke, Jacqueline D.; Rutten, Victor P.M.G.; Willemse, Ton

doi:10.1016/s0165-2427(02)00066-1

Cited by 28 publications

(30 citation statements)

References 40 publications

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“…However, in some patients the disease persists with severe clinical consequences. The cause of AD is currently unknown, but its pathology has been linked to the production of inflammatory cytokines including TNF-α, IL-1β, IL-4, IL-5 and others [38], [39]. Analysis of Notch mutant skin revealed an increased expression of multiple inflammatory cytokines and dermal infiltration of Th2 cells.…”

Section: Discussionmentioning

confidence: 99%

Atopic Dermatitis-Like Disease and Associated Lethal Myeloproliferative Disorder Arise from Loss of Notch Signaling in the Murine Skin

et al. 2010

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BackgroundThe Notch pathway is essential for proper epidermal differentiation during embryonic skin development. Moreover, skin specific loss of Notch signaling in the embryo results in skin barrier defects accompanied by a B-lymphoproliferative disease. However, much less is known about the consequences of loss of Notch signaling after birth.Methodology and Principal FindingsTo study the function of Notch signaling in the skin of adult mice, we made use of a series of conditional gene targeted mice that allow inactivation of several components of the Notch signaling pathway specifically in the skin. We demonstrate that skin-specific inactivation of Notch1 and Notch2 simultaneously, or RBP-J, induces the development of a severe form of atopic dermatitis (AD), characterized by acanthosis, spongiosis and hyperkeratosis, as well as a massive dermal infiltration of eosinophils and mast cells. Likewise, patients suffering from AD, but not psoriasis or lichen planus, have a marked reduction of Notch receptor expression in the skin. Loss of Notch in keratinocytes induces the production of thymic stromal lymphopoietin (TSLP), a cytokine deeply implicated in the pathogenesis of AD. The AD-like associated inflammation is accompanied by a myeloproliferative disorder (MPD) characterized by an increase in immature myeloid populations in the bone marrow and spleen. Transplantation studies revealed that the MPD is cell non-autonomous and caused by dramatic microenvironmental alterations. Genetic studies demontrated that G-CSF mediates the MPD as well as changes in the bone marrow microenvironment leading to osteopenia.SignificanceOur data demonstrate a critical role for Notch in repressing TSLP production in keratinocytes, thereby maintaining integrity of the skin and the hematopoietic system.

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Section: Discussionmentioning

confidence: 99%

Atopic Dermatitis-Like Disease and Associated Lethal Myeloproliferative Disorder Arise from Loss of Notch Signaling in the Murine Skin

et al. 2010

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“…The dog has an increasing importance as an alternative non-murine animal model for several immunological disorders, such as atopic dermatitis [30], asthma [5], hypothyroidism [13], diabetes mellitus [31], autoimmune haemolytic anaemia [11], myopathy [44] and infectious diseases [12]. Considering the importance of DC in these diseases, the present study characterized the canine DC system in more detail.…”

Section: Discussionmentioning

confidence: 99%

Comparative analysis of canine monocyte- and bone-marrow-derived dendritic cells

Gutzwiller

Moulin²,

Zurbriggen

et al. 2010

Vet. Res.

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Dendritic cells (DC) represent a heterogeneous cell family of major importance for innate immune responses against pathogens and antigen presentation during infection, cancer, allergy and autoimmunity. The aim of the present study was to characterize canine DC generated in vitro with respect to their phenotype, responsiveness to toll-like receptor (TLR) ligands and T-cell stimulatory capacity. DC were derived from monocytes (MoDC) and from bone marrow hematopoietic cells cultured with either Flt3-ligand (FL-BMDC) or with GM-CSF (GM-BMDC). All three methods generated cells with typical DC morphology that expressed CD1c, CD11c and CD14, similar to macrophages. However, CD40 was only found on DC, CD206 on MΦ and BMDC, but not on monocytes and MoDC. CD1c was not found on monocytes but on all in vitro differentiated cells. FL-BMDC and GM-BMDC were partially positive for CD4 and CD8. CD45RA was expressed on a subset of FL-BMDC but not on MoDC and GM-BMDC. MoDC and FL-DC responded well to TLR ligands including poly-IC (TLR2), Pam3Cys (TLR3), LPS (TLR4) and imiquimod (TLR7) by up-regulating MHC II and CD86. The generated DC and MΦ showed a stimulatory capacity for lymphocytes, which increased upon maturation with LPS. Taken together, our results are the basis for further characterization of canine DC subsets with respect to their role in inflammation and immune responses.

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“…Frequent characteristics include elevation of eosinophil levels in peripheral blood [9] and increase of staphylococcal colonization in mucosal and skin lesions [4]. Although the pathogenesis of canine AD is complex, involving genetic, environmental and immunological factors, interleukin (IL)-4 and IL-5 produced by T-helper (Th) 2 cells may have especially key roles in its onset and development [23,33]. IL-4 mediates an IgE isotype switch in B cells and IL-5 promotes IgE synthesis induced by IL-4.…”

Section: Introductionmentioning

confidence: 99%

Inhibitory effects of interleukin-10 plasmid DNA on the development of atopic dermatitis-like skin lesions in NC/Nga mice

Jung

Cho

et al. 2010

J Vet Sci

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Interleukin (IL)-10 exerts potent anti-inflammatory effects by suppression of both T-help (Th) 1 and Th2 cells. Previous studies have reported that IL-10 can ameliorate various inflammatory disorders. The present study was performed to examine whether IL-10 plasmid DNA could suppress development of atopic dermatitis (AD)-like skin lesions in NC/Nga mice, as an initial step towards the development of an appliance for use in dogs with AD. Intradermal injection of IL-10 plasmid DNA markedly inhibited the development of AD-like skin lesions, as evidenced by a marked decrease in skin symptoms and reduced inflammation within the skin lesions. Efficacy was confirmed by significant decreases in eosinophil ratio and serum IgE concentration, and a reduction in the number of Staphylococcus aureus recovered from the ear. Moreover, relative mRNA expression levels of IL-4 and interferon-γ in the skin lesions of mice injected with IL-10 plasmid DNA were also decreased compared with those of control mice. Of note, higher serum IL-10 levels in mice injected with IL-10 plasmid DNA were maintained compared with those in control mice. Taken together, the results indicate that IL-10 plasmid DNA can suppress the development of AD-like skin lesions by suppressing both Th1 and Th2 cell responses. Beneficial effects of IL-10 plasmid DNA may be expected in dogs with AD.

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Immune dysregulation in atopic dermatitis

Cited by 28 publications

References 40 publications

Atopic Dermatitis-Like Disease and Associated Lethal Myeloproliferative Disorder Arise from Loss of Notch Signaling in the Murine Skin

Atopic Dermatitis-Like Disease and Associated Lethal Myeloproliferative Disorder Arise from Loss of Notch Signaling in the Murine Skin

Comparative analysis of canine monocyte- and bone-marrow-derived dendritic cells

Inhibitory effects of interleukin-10 plasmid DNA on the development of atopic dermatitis-like skin lesions in NC/Nga mice

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