Langerhans cells are critical in the development of atopic dermatitis-like inflammation and symptoms in mice

Genetic or vitamin D3-induced overexpression of thymic stromal lymphopoietin (TSLP) by keratinocytes results in an atopic dermatitis (AD)-like inflammatory phenotype in mice echoing the discovery of high TSLP expression in epidermis from AD patients. Although skin dendritic cells (DC) are suspected to be involved in AD, direct evidence of a pathogenetic role for skin DC in TSLP-induced skin inflammation has not yet been demonstrated. In a mouse model of AD, i.e. mice treated with the low-calcemic vitamin D3 analogue, MC903, we show that epidermal Langerhans cells (LC)-depleted mice treated with MC903 do neither develop AD-like inflammation nor increased serum IgE as compared to vitamin D3 analogue-treated control mice. Accordingly, we show that, in mice treated with MC903 or in K14-TSLP transgenic mice, expression of maturation markers by LC is increased whereas maturation of dermal DC is not altered. Moreover, only LC are responsible for the polarization of naive CD4+ T cells to a Th2 phenotype, i.e. decrease in interferon-gamma and increase in interleukin (IL)-13 production by CD4+ T cells. This effect of LC on T-lymphocytes does not require OX40-L/CD134 and is mediated by a concomitant down-regulation of IL-12 and CD70. Although it was previously stated that TSLP up-regulates the production of thymus and activation-regulated chemokine (TARC)/chemokine (C-C motif) ligand 17 (CCL17) and macrophage-derived chemokine (MDC)/CCL22 by human LC in vitro, our work shows that production of these Th2- cell attracting chemokines is increased only in keratinocytes in response to TSLP overexpression. These results demonstrate that LC are required for the development of AD in mouse models of AD involving epidermal TSLP overexpression.

SOCS3 regulates onset and maintenance of TH2- mediated allergic responses

Members of the suppressor of cytokine signaling (SOCS) family are involved in the pathogenesis of many inflammatory diseases. SOCS-3 is predominantly expressed in T-helper type 2 (TH2) cells, but its role in TH2-related allergic diseases remains to be investigated. In this study we provide a strong correlation between SOCS-3 expression and the pathology of asthma and atopic dermatitis, as well as serum IgE levels in allergic human patients. SOCS-3 transgenic mice showed increased TH2 responses and multiple pathological features characteristic of asthma in an airway hypersensitivity model system. In contrast, dominant-negative mutant SOCS-3 transgenic mice, as well as mice with a heterozygous deletion of Socs3, had decreased TH2 development. These data indicate that SOCS-3 has an important role in regulating the onset and maintenance of TH2-mediated allergic immune disease, and suggest that SOCS-3 may be a new therapeutic target for the development of antiallergic drugs.

Langerhans cell (LC) proliferation mediates neonatal development, homeostasis, and inflammation-associated expansion of the epidermal LC network.

Most tissues develop from stem cells and precursors that undergo differentiation as their proliferative potential decreases. Mature differentiated cells rarely proliferate and are replaced at the end of their life by new cells derived from precursors. Langerhans cells (LCs) of the epidermis, although of myeloid origin, were shown to renew in tissues independently from the bone marrow, suggesting the existence of a dermal or epidermal progenitor. We investigated the mechanisms involved in LC development and homeostasis. We observed that a single wave of LC precursors was recruited in the epidermis of mice around embryonic day 18 and acquired a dendritic morphology, major histocompatibility complex II, CD11c, and langerin expression immediately after birth. Langerin+ cells then undergo a massive burst of proliferation between postnatal day 2 (P2) and P7, expanding their numbers by 10–20-fold. After the first week of life, we observed low-level proliferation of langerin+ cells within the epidermis. However, in a mouse model of atopic dermatitis (AD), a keratinocyte signal triggered increased epidermal LC proliferation. Similar findings were observed in epidermis from human patients with AD. Therefore, proliferation of differentiated resident cells represents an alternative pathway for development in the newborn, homeostasis, and expansion in adults of selected myeloid cell populations such as LCs. This mechanism may be relevant in locations where leukocyte trafficking is limited.

SOCS2 regulates T helper type 2 differentiation and the generation of type 2 allergic responses

The incidence of allergy and asthma in developed countries is on the increase and this trend looks likely to continue. CD4(+) T helper 2 (Th2) cells are major drivers of these diseases and their commitment is controlled by cytokines such as interleukin 4, which are in turn regulated by the suppressor of cytokine signaling (SOCS) proteins. We report that SOCS2(-/-) CD4(+) T cells show markedly enhanced Th2 differentiation. SOCS2(-/-) mice, as well as RAG1(-/-) mice transferred with SOCS2(-/-) CD4(+) T cells, exhibit elevated type 2 responses after helminth antigen challenge. Moreover, in in vivo models of atopic dermatitis and allergen-induced airway inflammation, SOCS2(-/-) mice show significantly elevated IgE, eosinophilia, type 2 responses, and inflammatory pathology relative to wild-type mice. Finally, after T cell activation, markedly enhanced STAT6 and STAT5 phosphorylation is observed in SOCS2(-/-) T cells, whereas STAT3 phosphorylation is blunted. Thus, we provide the first evidence that SOCS2 plays an important role in regulating Th2 cell expansion and development of the type 2 allergic responses.

IL-31 does not induce normal human ciliated epithelial cells to differentiate into a phenotype consistent with the pathophysiology of asthma

Abstract Background IL-31 is a novel cytokine that has been implicated in allergic diseases such as atopic dermatitis and more recently asthma. While IL-31 has been well studied in skin conditions such as atopic dermatitis, little is known about the role IL-31 plays in asthma and specifically the differentiation process of the bronchial epithelium, which is central to the pathogenesis of allergic asthma. Methods We examined the effects of IL-13 (20 ng/ml), IL-31 (20 ng/ml) and an IL-13/IL-31 combination stimulation (20 ng/ml each) on the in vitro mucociliary differentiation of paediatric bronchial epithelial cells (PBECs) from healthy patients (n=6). IL-31 receptor (IL-31-RA) expression, markers of differentiation (goblet and ciliated cells), transepithelial electrical resistance (TEER), quantification of goblet and ciliated cells, real time PCR for MUC5AC, ELISA for VEGF, EGF and MCP-1 (CCL-2) and ELISA for MUC5AC were assessed. Results We found that well-differentiated PBECs expressed IL-31-RA however it's expression did not increase upon stimulation with IL-31 or either of the other treatments. TEER indicated good formation of tight junctions which was found to be similar across all treatment groups (p=0.9). We found that IL-13 alone significantly reduced the number of ciliated cells compared with unstimulated (IL-13 stimuation: mean=4.8% (SD=2.5); unstimulated: mean=15.9%, (SD=7.4), p

Demographic and psychosocial characteristics of asthmatic children in a Canadian rehabilitation setting

This study investigated the demographic and psychosocial characteristics of patients attending a residential treatment program for children with asthma. Measures of background information and standardized psychosocial variables were administered to 54 inpatients over an 18-month period. Typically, our patients presented with moderate to severe chronic asthma, mostly diagnosed before 3 years of age and often associated with atopic dermatitis. The families exhibited normal levels of emotional bonding and flexibility in response to stress. Psychosocially, most children were experiencing behavioral and school-related problems, with 6-11-year-old boys exhibiting global social competency problems as well. Girls exhibited lower self-esteem. Locus of control was within the normal range for all age groups. Half the children had not previously attended an asthma education program and two-thirds of the family members either smoked and/or had a pet. The treatment implications of these characteristics of our asthma population were considered.

Impact of vitamin D3 on cutaneous immunity and antimicrobial peptide expression

Antimicrobial peptides (AMPs) are effectors of cutaneous innate immunity and protect primarily against microbial infections. An array of AMPs can be found in and on the skin. Those include peptides that were first discovered for their antimicrobial properties but also proteins with antimicrobial activity first characterized for their activity as chemokines, enzymes, enzyme inhibitors and neuropeptides. Cathelicidins were among the first families of AMPs discovered in skin. They are now known to exert a dual role in innate immune defense: they have direct antimicrobial activity and will also initiate a host cellular response resulting in cytokine release, inflammation and angiogenesis. Altered cathelicidin expression and function was observed in several common inflammatory skin diseases such as atopic dermatitis, rosacea and psoriasis. Until recently the molecular mechanisms underlying cathelicidin regulation were not known. Lately, vitamin D3 was identified as the major regulator of cathelicidin expression and entered the spotlight as an immune modulator with impact on both, innate and adaptive immunity. Therapies targeting vitamin D3 signalling may provide novel approaches for the treatment of infectious and inflammatory skin diseases by affecting both innate and adaptive immune functions through AMP regulation.

Control of cutaneous antimicrobial peptides by vitamin D3

Constant exposure to a wide variety of microbial pathogens represents a major challenge for our skin. Antimicrobial peptides (AMPs) are mediators of cutaneous innate immunity and protect primarily against microbial infections. Cathelicidins were among the first AMPs identified in human skin and recent evidence suggests that they exert a dual role in innate immune defense: At first, due to their antimicrobial activity they kill pathogens directly. In addition, these peptides initiate a potent host response to infection resulting in cytokine release, inflammation and a cellular response. Disturbed cathelicidin expression and function was observed in several common inflammatory skin diseases, such as psoriasis where cathelicidin peptide converts inert self-DNA and self-RNA into an autoimmune stimulus. In atopic dermatitis decreased levels of cathelicidin facilitating microbial superinfections have been discussed. Furthermore, abnormally processed cathelicidin peptides induce inflammation and a vascular response in rosacea. Until recently, the molecular mechanisms underlying cathelicidin regulation were unknown. Recently, the vitamin D3 pathway was identified as the major regulator of cathelicidin expression. Consequently, vitamin D3 entered the spotlight as an immune modulator with impact on both innate and adaptive immunity. Therapies targeting vitamin D3 signaling may provide new approaches for infectious and inflammatory skin diseases by affecting both innate and adaptive immune functions.

Antioxidants and oxidative stress in BAL fluid of atopic asthmatic children

Earlier studies in adults have indicated that increased oxidative stress may occur in the blood and airways of asthmatic subjects. Therefore the aim of this study was to compare the concentrations of antioxidants and protein carbonyls in bronchoalveolar lavage fluid of clinically stable atopic asthmatic children (AA, n = 78) with our recently published reference intervals for nonasthmatic children (C, n = 124). Additionally, lipid peroxidation products (malondialdehyde) in bronchoalveolar lavage fluid and several antioxidants in plasma were determined. Bronchoalveolar lavage concentrations (median and interquartile range) of ascorbate [AA: 0.433 (0.294-0.678) versus C: 0.418 (0.253-0.646) micromol/L], urate [AA: 0.585 (0.412-0.996) versus C: 0.511 (0.372-0.687) micromol/L], alpha-tocopherol [AA: 0.025 (0.014-0.031) versus C: 0.017 (0.017-0.260) micromol/L], and oxidized proteins as reflected by protein carbonyls [AA: 1.222 (0.970-1.635) versus C: 1.243 (0.813-1.685) nmol/mg protein] were similar in both groups (p > 0.05 in all cases). The concentration of protein carbonyls correlated significantly with the number of eosinophils, mast cells, and macrophages in AA children only. Concentrations of oxidized proteins and lipid peroxidation products (malondialdehyde) correlated significantly in AA children (r = 0.614, n = 11, p = 0.044). Serum concentrations of ascorbate, urate, retinol, alpha-tocopherol, beta-carotene, and lycopene were similar in both groups whereas alpha-carotene was significantly reduced in asthmatics. Overall, increased bronchoalveolar lavage eosinophils indicate ongoing airway inflammation, which may increase oxidatively modified proteins as reflected by increased protein carbonyl concentrations.