cholecalciferol and Dermatitis--Atopic

Our skin is constantly challenged by microbes but is rarely infected. Cutaneous production of antimicrobial peptides (AMPs) is a primary system for protection, and expression of some AMPs further increases in response to microbial invasion. Cathelicidins are unique AMPs that protect the skin through 2 distinct pathways: (1) direct antimicrobial activity and (2) initiation of a host response resulting in cytokine release, inflammation, angiogenesis, and reepithelialization. Cathelicidin dysfunction emerges as a central factor in the pathogenesis of several cutaneous diseases, including atopic dermatitis, in which cathelicidin is suppressed; rosacea, in which cathelicidin peptides are abnormally processed to forms that induce inflammation; and psoriasis, in which cathelicidin peptide converts self-DNA to a potent stimulus in an autoinflammatory cascade. Recent work identified vitamin D3 as a major factor involved in the regulation of cathelicidin. Therapies targeting control of cathelicidin and other AMPs might provide new approaches in the management of infectious and inflammatory skin diseases.

Topics: Animals; Bacteria; Cathelicidins; Cholecalciferol; Dermatitis, Atopic; Humans; Psoriasis; Rosacea; Skin; Skin Diseases

The advent of new topical agents such as topical calcineurin inhibitors, as well as the reformulations of older agents in new vehicles, has broadened the treatment approaches to psoriasis and atopic dermatitis. The clinician must now consider additional novel physiologic pathways and mechanisms of action as well as expanding options for combination therapy. Combination therapy is especially beneficial when the selected agents possess differing mechanisms of action that provide additive or synergistic efficacy, reducing the required doses of the individual agents compared with monotherapy and potentially limiting side effects. Therapeutic approaches also can be rotated or used in various sequences for maintenance therapy. In psoriasis, a number of trials have demonstrated the effectiveness of combination therapy. Although combination therapy has not been extensively studied in atopic dermatitis, many practitioners combine topical corticosteroids and topical calcineurin inhibitors in their clinical practice because the two drug classes have different and possibly complementary mechanisms of action. For both diseases, the decision as to what agents are combined must also be tempered by patient type, disease presentation or severity, and patient preferences.

Topics: Administration, Topical; Adrenal Cortex Hormones; Anti-Inflammatory Agents; Calcineurin Inhibitors; Cell Division; Cholecalciferol; Clinical Trials as Topic; Cytokines; Dermatitis, Atopic; DNA-Binding Proteins; Drug Therapy, Combination; Gene Expression Regulation; Humans; Immunosuppressive Agents; Male; NF-kappa B; NFATC Transcription Factors; Nuclear Proteins; Psoriasis; Receptors, Cytokine; Retinoids; Transcription Factors

Evidence linking prenatal maternal vitamin D supplementation with the offspring's risk of atopic eczema is inconsistent, with most data coming from observational studies.. To examine the influence of maternal cholecalciferol supplementation during pregnancy on the risk of atopic eczema in the offspring at ages 12, 24 and 48 months.. Within the UK Maternal Vitamin D Osteoporosis Study (MAVIDOS) double-blind, randomized placebo-controlled trial, we examined the relationship of maternal vitamin D supplementation during pregnancy with offspring atopic eczema at ages 12, 24 and 48 months. In MAVIDOS, pregnant women were allocated to either cholecalciferol 1000 IU per day or matched placebo, taken from around 14 weeks' gestation until delivery, with the primary outcome of neonatal whole-body bone mineral content. The prevalence of atopic eczema in the offspring was ascertained at ages 12 (n = 635), 24 (n = 610) and 48 (n = 449) months, based on the UK Working Party criteria for the definition of atopic dermatitis. The trial was registered with ISRCTN (82927713) and EudraCT (2007-001716-23).. The characteristics of mothers and offspring were similar between the intervention and placebo groups, apart from longer breastfeeding duration in the intervention group. Adjusting for breastfeeding duration, offspring of mothers who received cholecalciferol 1000 IU daily had a lower odds ratio (OR) of atopic eczema at age 12 months [OR 0·55, 95% confidence interval (CI) 0·32-0·97, P = 0·04]; this effect weakened and was not statistically significant at ages 24 months (OR 0·76, 95% CI 0·47-1·23) or 48 months (OR 0·75, 95% CI 0·37-1·52). The statistical interaction of intervention and breastfeeding duration in relation to eczema at age 12 months was not significant (P = 0·41), but stratification showed reduced infantile eczema risk in the intervention group for infants breastfed for ≥ 1 month (OR 0·48, 95% CI 0·24-0·94, P = 0·03) but not in those breastfed for < 1 month (OR 0·80, 95% CI 0·29-2·17, P = 0·66).. Our data provide the first randomized controlled trial evidence of a protective effect of antenatal cholecalciferol supplementation on the risk of infantile atopic eczema, with the effect potentially being via increased breast milk cholecalciferol levels. The findings support a developmental influence on atopic eczema, and point to a potentially modifiable perinatal influence on atopic eczema. What is already known about this topic? There are currently no antenatal interventions proven to reduce the incidence of infantile atopic eczema in the general population. However, observational studies have led to speculation that antenatal vitamin D supplementation may be beneficial.

Topics: Child; Child, Preschool; Cholecalciferol; Dermatitis, Atopic; Dietary Supplements; Double-Blind Method; Female; Humans; Infant; Infant, Newborn; Osteoporosis; Pregnancy; Vitamin D; Vitamins

Atopic dermatitis (AD) is the most common chronic and recurrent skin disease during infancy.. This study was aimed at evaluating the effect of synbiotic and vitamin D3 supplements on the severity of AD among infants under 1 year of age.. This double-blind, randomized clinical trial study was conducted on 81 subjects with AD in Sabzevar, Iran in 2018. Subjects were randomly assigned to three groups. Synbiotic group was administered a dose of five drops/day of synbiotic in addition to routine treatment. Vitamin D3 group was administered 1000 units (IU) of vitamin D3 daily in addition to routine treatment. Control group just received routine treatments. The severity of AD was evaluated using SCORing Atopic Dermatitis (SCORAD) at baseline and two months' follow-up.. The mean age of subjects was 4.87 ± 3.5 and 59.26% (. Findings suggest that multistrain synbiotic and vitamin D3 supplements administration along with routine treatments, as complementary therapies, may be effective in reducing the severity of AD in infants.

Topics: Cholecalciferol; Dermatitis, Atopic; Double-Blind Method; Eczema; Humans; Infant; Male; Severity of Illness Index; Synbiotics; Treatment Outcome; Vitamin D

Atopic dermatitis is a highly prevalent, chronic, relapsing disease in both adults and children. On the severity spectrum, lower-end patients benefit from small amounts of topical anti-inflammatory treatments (TAT), whereas higher-end patients need systemic immunosuppressants; in-between patients are treated with TAT and phototherapy. The major therapeutic challenge in this population is the long-term control of disease activity, and the current TAT-based pro-active strategy does not meet all their needs. Immunosuppressants are used as long-term control add-on treatments, but they are restricted to the most severely affected patients because of safety concerns. In addition, neither immunosuppressants nor other strategies have been properly evaluated in the long term despite long-term control having been acknowledged as one of the most important core outcome domains to be targeted in atopic dermatitis trials. Safe add-on therapies, rigorously evaluated for long-term control of the disease, are therefore needed. Phototherapy and vitamin D supplementation are both good candidates.. This is a multicenter, national, randomized, superiority, crossover trial testing add-on phototherapy (one winter under spaced sessions of phototherapy and one winter under observation) among subjects receiving standard care (i.e., TAT). On the same population, we will test the long-term control provided by oral supplementation of vitamin D versus placebo in a randomized, superiority, double-blind, parallel-group trial. The primary outcomes are (1) repeat measures of the PO-SCORAD severity score over 1 year and (2) cumulate consumption of TAT (number of tubes) during the winter. They will be tested following a hierarchical testing procedure. The secondary outcomes will be measures repeated over 2 years of investigator-based severity scores, patient-reported severity and quality of life scores, serum vitamin D levels, weeks during which the disease is well-controlled, inter-visit cumulate consumption of TAT, and synthetic patient-reported satisfaction at the end of each winter.. This study includes two separate 2-year pragmatic trials designed to evaluate the efficacy of vitamin D supplementation and pro-active phototherapy for primary care atopic dermatitis patients receiving TAT on long-term control of disease activity. The experimental design enables the study of both interventions and exploration of the interaction between vitamin D and phototherapy. A pragmatic trial is particularly suited to the assessment of long-term control. This study explores the possibility of new and safe therapeutic strategies for the control of long-term atopic dermatitis, and is an example of efficacy research that is unlikely to be sponsored by industrialists. A potentially effective low-cost therapeutic strategy for long-term control is essential for patients and public health.. ClinicalTrials.gov Identifier: NCT02537509 , first received: 1 September 2015.

Topics: Administration, Cutaneous; Administration, Oral; Anti-Inflammatory Agents; Cholecalciferol; Combined Modality Therapy; Cross-Over Studies; Dermatitis, Atopic; Dietary Supplements; Double-Blind Method; France; Humans; Multicenter Studies as Topic; Pragmatic Clinical Trials as Topic; Seasons; Time Factors; Treatment Outcome; Ultraviolet Therapy

Vitamin D has immunomodulatory effects both in the innate and adaptive immune systems, and there is growing scientific evidence demonstrating its relevance in inflammatory processes such as AD.. If vitamin D3 promotes the skin immune system, then it should improve the response to treatment of patients with AD.. A randomized, double-blind placebo-controlled clinical trial was conducted, which included 65 patients with AD according to Hanifin-Rajka criteria and the severity scale (SCORAD). The patients were divided into two groups to receive either vitamin D3 5000 IU/day (n = 33) or placebo (n = 32), plus baseline therapy (topical steroid, soap substitute, and emollient) during 3 months.. Fifty-eight of the 65 enrolled subjects were included in the analysis. At the end of the intervention, the treated group achieved higher levels of 25(OH)D (P < 0.001). At week 12, those patients who registered serum levels of 25(OH)D ≥20 ng/ml, regardless of whether or not they had received supplementation, showed a lower SCORAD compared to those with levels <20 ng/ml (P < 0.001). Eighty percent of the patients with serum levels <20 ng/ml (n = 9) had moderate-severe AD despite standard treatment. Vitamin D levels ≥20 ng/ml associated with baseline therapy strongly favored remission of atopic dermatitis (P = 0.03). No significant differences were found between patients with serum levels of ≥20 ng/ml vs. ≥30 ng/ml.. Reaching serum levels of 25(OH)D > 20 ng/ml in conjunction with standard therapy is sufficient to achieve a reduction in severity (SCORAD) in patients with AD.

Topics: Administration, Cutaneous; Administration, Oral; Adolescent; Adult; Child; Child, Preschool; Cholecalciferol; Dermatitis, Atopic; Dietary Supplements; Double-Blind Method; Drug Therapy, Combination; Emollients; Female; Humans; Male; Middle Aged; Severity of Illness Index; Steroids; Vitamin D; Vitamins; Young Adult

Subjects with atopic dermatitis (AD) have defects in antimicrobial peptide (AMP) production possibly contributing to an increased risk of infections. In laboratory models, vitamin D can alter innate immunity by increasing AMP production.. To determine if AD severity correlates with baseline vitamin D levels, and to test whether supplementation with oral vitamin D alters AMP production in AD skin.. This was a multi-centre, placebo-controlled, double-blind study in 30 subjects with AD, 30 non-atopic subjects, and 16 subjects with psoriasis. Subjects were randomized to receive either 4000 IU of cholecalciferol or placebo for 21 days. At baseline and day 21, levels of 25-hydroxyvitamin D (25OHD), cathelicidin, HBD-3, IL-13, and Eczema Area and Severity Index (EASI) and Rajka-Langeland scores were obtained.. At baseline, 20% of AD subjects had serum 25OHD below 20 ng/mL. Low serum 25OHD correlated with increased Fitzpatrick Skin Type and elevated BMI, but not AD severity. After 21 days of oral cholecalciferol, mean serum 25OHD increased, but there was no significant change in skin cathelicidin, HBD-3, IL-13 or EASI scores.. This study illustrated that darker skin types and elevated BMI are important risk factors for vitamin D deficiency in subjects with AD, and highlighted the possibility that seasonality and locale may be potent contributors to cathelicidin induction through their effect on steady state 25OHD levels. Given the molecular links between vitamin D and immune function, further study of vitamin D supplementation in subjects with AD is warranted.

Topics: Adult; Cholecalciferol; Dermatitis, Atopic; Dietary Supplements; Double-Blind Method; Female; Humans; Male; Severity of Illness Index; Vitamin D; Vitamins

Epidemiologic and preclinical data, and a small randomized trial in Boston, suggest that vitamin D supplementation may improve winter-related atopic dermatitis (AD).. To determine the effect of vitamin D supplementation on winter-related AD.. We performed a randomized, double-blind, placebo-controlled trial of Mongolian children with winter-related AD (clinicaltrials.gov identifier: NCT00879424). Baseline eligibility included age 2 to 17 years, AD score 10 to 72 using the Eczema Area and Severity Index (EASI), and winter-related AD (eg, history of AD worsening during the fall-to-winter transition). Subjects were enrolled in Ulaanbaatar during winter and randomly assigned to oral cholecalciferol (1000 IU/day) versus placebo for 1 month. All children and parents received emollient and patient education about AD and basic skin care. The main outcomes were changes in EASI score and in Investigator's Global Assessment.. The 107 enrolled children had a mean age of 9 years (SD 5), and 59% were male. Their median age of AD onset was 3 months (interquartile range 2 months to 1 year) and mean EASI score at baseline 21 (SD 9). One-month follow-up data were available for 104 (97%) children. Compared with placebo, vitamin D supplementation for 1 month produced a clinically and statistically significant improvement in EASI score (adjusted mean change: -6.5 vs -3.3, respectively; P = .04). Moreover, change in Investigator's Global Assessment favored vitamin D over placebo (P = .03). There were no adverse effects in either group.. Vitamin D supplementation improved winter-related AD among Mongolian children, a population likely to have vitamin D deficiency in winter.

Topics: Adolescent; Child; Child, Preschool; Cholecalciferol; Dermatitis, Atopic; Dietary Supplements; Disease Progression; Female; Humans; Male; Mongolia; Seasons; Treatment Outcome; Vitamin D

The role of vitamin D in Atopic Dermatitis (AD) is ambiguous and clinical trials are needed to assess the role of vitamin D in the treatment of AD. The aim of this clinical trial study to evaluate the effect of vitamin D supplementation on patients with AD.. sixty AD patients were included in a randomized, double-blind, placebo-controlled trial study. They were randomly divided into two groups and treated for 60 days: group vitamin D (n=30), and placebo group (n=30). The two groups were as follows: Group D, 1600 IU cholecalciferol (vitamin D) and second group placebo. The severity of AD was evaluated based on SCORAD (Scoring Atopic Dermatitis) and TIS (Three Item Severity score) value by the same trained physician before and after the trial.. According to SCORAD and TIS value index in the vitamin D group showed significant improvement in patients with mild, moderate and severe AD (P<0.05) and in patients who the intake placebo, this improvement didn't showed (P>0.05).. Results mention that supplementation with oral vitamin D dramatically improved disease severity in AD patients.

Topics: Administration, Oral; Adult; Cholecalciferol; Dermatitis, Atopic; Double-Blind Method; Humans; Severity of Illness Index; Treatment Outcome; Vitamins; Young Adult

Atopic dermatitis (AD) is an allergic disease mediated by Th2 cells. In AD, externally stimulated keratinocytes release inflammatory cytokines, such as IL-33 and TSLP. Inflammatory cells infiltrate skin tissue and increase vascular permeability. Therefore, we hypothesized that imatinib mesylate (IMT), which suppresses vascular permeability, may be a candidate therapeutic agent for AD. A vitamin D3 analog (MC903) was administered daily to both ears of Balb/c mice to create a murine AD model to which IMT was applied. The skin lesions were evaluated histopathologically and by immunostaining. Cytokine expression in the skin was assessed by using real-time polymerase chain reaction (PCR) and immunostaining and was investigated using Evans Blue to determine whether IMT suppressed vascular permeability due to histamine. The suppressive effect of TNF-α/IL-4-induced TSLP expression in primary mouse keratinocytes (MKCs) treated with IMT was then investigated. Tslp gene and protein expression in the lesion was measured using real-time PCR and ELISA. The activation of signal transduction was analysed by western blotting. Topical application of IMT significantly reduced ear thickness, Evans blue leakage, and scratch onset. IMT suppressed the number of infiltrating cells (CD4+ T cells, eosinophils, and basophils), and the expression of IL-13, IL-33, and TSLP in a MC903-induced, murine AD model and inhibited TNF-α/IL-4-induced TSLP expression via downregulation of ERK phosphorylation in MKCs. IMT reduced the skin symptoms in a MC903-induced, murine AD model, suggesting that it may have potential as a new treatment for AD.

Topics: Animals; Cholecalciferol; Cytokines; Dermatitis, Atopic; Evans Blue; Imatinib Mesylate; Interleukin-33; Interleukin-4; Keratinocytes; Mice; Mice, Inbred BALB C; Thymic Stromal Lymphopoietin; Tumor Necrosis Factor-alpha

Atopic dermatitis (AD) is a chronic, relapsing, and extremely pruritic inflammatory skin disease with a particular impact on children. AD pathogenesis is not yet fully understood, and there is no curative treatment for this disease. Therefore, several genetically or chemically-induced AD mouse models have been developed. These preclinical mouse models are an indispensable research tool for studying AD pathogenesis and evaluating the efficacy of new candidate AD therapeutics. A commonly used mouse model of AD has been developed using the topical application of a low-calcemic analog of vitamin D3, MC903, to induce AD-like inflammatory phenotypes that closely resemble human AD. Moreover, this model shows a minimal effect on systemic calcium metabolism that is observed in the vitamin D3-induced AD model. Thus, an expanding number of studies use the MC903-induced AD model to interrogate AD pathobiology in vivo and to test new candidate small molecule and monoclonal antibody therapies. This protocol describes in detail functional measurements including the measurement of skin thickness, which is a surrogate marker for ear skin inflammation, as well as itch assessment, histological evaluation to assess the structural changes associated with AD skin inflammation, and preparation of single-cell suspensions from ear skin and draining lymph nodes for the assessment of inflammatory leukocyte subset infiltration in these tissues using flow cytometry. © 2023 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol: Topical application of MC903 induces AD-like skin inflammation Support Protocol 1: Measurement of ear skin thickness Support Protocol 2: Itch assessment Support Protocol 3: Dissection of ear skin and ear draining lymph nodes Support Protocol 4: Histological evaluation and quantification Support Protocol 5: Preparation of single-cell suspension from ear skin and draining lymph nodes for the assessment of inflammatory immune cell infiltration using flow cytometry.

Topics: Animals; Child; Cholecalciferol; Cytokines; Dermatitis, Atopic; Humans; Inflammation; Mice; Skin

Atopic dermatitis (AD) is a multifactorial disease with underlying barrier disruption and altered microbial flora, resulting in dry skin and eczematous inflammation with persistent pruritis. Mouse models have been heavily used to investigate AD pathophysiology. Among various AD mouse models, AD-like inflammation induced by topical calcipotriol, a vitamin D3 analog referred to as MC903 in experimental settings, is a versatile model that can be applied to any strain of mice, which can be used for immunologic and morphologic studies. Herein, we provide basic protocols for the topical application of MC903 and approaches to assess phenotypes. After inducing AD-like inflammation, the skin is harvested for flow cytometry analysis, as well as for histologic and immunofluorescence microscopy analyses. The combination of these approaches enables accurate characterization of the degree of inflammation, type of inflammatory infiltrate, and localization of immune infiltrates. Published 2023. This article is a U.S. Government work and is in the public domain in the USA. Basic Protocol 1: Application of MC903 and gross phenotype assessment Basic Protocol 2: Processing skin for flow cytometry analysis Support Protocol: Skin immune cell surface staining and flow cytometry analysis Basic Protocol 3: Harvesting skin for histologic analysis Basic Protocol 4: Immunofluorescence staining to identify immune cell infiltrates.

Topics: Animals; Cholecalciferol; Dermatitis, Atopic; Inflammation; Mice; Phenotype; Skin

Atopic dermatitis and psoriasis are prevalent chronic inflammatory skin diseases that are characterized by dysfunctional skin barriers and substantially impact patients' quality of life. Vitamin D3 regulates immune responses and keratinocyte differentiation and improves psoriasis symptoms; however, its effects on atopic dermatitis remain unclear. Here, we investigated the effects of calcitriol, an active form of vitamin D3, on an NC/Nga mouse model of atopic dermatitis. We observed that the topical application of calcitriol decreased the dermatitis scores and epidermal thickness of NC/Nga mice with atopic dermatitis compared to untreated mice. In addition, both stratum corneum barrier function as assessed by the measurement of transepidermal water loss and tight junction barrier function as evaluated by biotin tracer permeability assay were improved following calcitriol treatment. Moreover, calcitriol treatment reversed the decrease in the expression of skin barrier-related proteins and decreased the expression of inflammatory cytokines such as interleukin (IL)-13 and IL-33 in mice with atopic dermatitis. These findings suggest that the topical application of calcitriol might improve the symptoms of atopic dermatitis by repairing the dysfunctional epidermal and tight junction barriers. Our results suggest that calcitriol might be a viable therapeutic agent for the treatment of atopic dermatitis in addition to psoriasis.

Topics: Animals; Calcitriol; Cholecalciferol; Cytokines; Dermatitis, Atopic; Disease Models, Animal; Interleukin-13; Mice; Psoriasis; Quality of Life; Skin

The aim of the study was to explore the effect of topical vitamin D3 in atopic dermatitis (AD) induced by ovalbumin (OVA) in contrast with topical betamethasone in mice.. 35 BALB/c adult male mice, weighing between 25-30 gm were used to induce AD by topically sensitizing the dorsal surface of the skin with the OVA patch. Subsequently, treatments were performed in each group by application of vitamin D3 cream (0.0003%), betamethasone cream (0.1%), or vehicles (QV cream) on the skin.. Remarkably, vitamin D3 had a marked improvement in the skin of OVA-induced AD mice. Additionally, vitamin D3 revealed a considerable diminution in the levels of IgE, IL-5, filaggrin, and epidermal thickness, whereas a significant augmentation in the levels of IL-4 and IL-13 was observed when compared with the control group, and histopathological studies had further confirmed these findings.. This study essentially highlighted the anti-inflammatory effect of vitamin D3 by effective alteration in the immunological components responsible for AD. Moreover, this pioneer experimental work represents a new paradigm and sheds a light on the importance of vitamin D3 in the implications of AD. A comprehensive creative approach is crucial to concretely establish and further corroborate vitamin D3 for this therapeutic role.

Topics: Animals; Anti-Inflammatory Agents; Betamethasone; Cholecalciferol; Cytokines; Dermatitis, Atopic; Disease Models, Animal; Immunoglobulin E; Interleukin-13; Interleukin-4; Interleukin-5; Male; Mice; Mice, Inbred BALB C; Ovalbumin; Skin

Atopic dermatitis (AD) is a severe inflammatory skin disease. Langerhans cells and inflammatory dendritic epidermal cells (IDEC) are located in the epidermis of AD patients and contribute to the inflammatory processes. Both express robustly the high-affinity receptor for IgE, FcεRI, and thereby sense allergens. A beneficial role of vitamin D

Topics: Adult; Aged; Cells, Cultured; Cholecalciferol; Dendritic Cells; Dermatitis, Atopic; Down-Regulation; Female; Humans; Immunoglobulin E; Male; Middle Aged; Promoter Regions, Genetic; Protein Binding; Proto-Oncogene Proteins; Receptors, IgE; Signal Transduction; Trans-Activators; Young Adult; YY1 Transcription Factor

Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease with pruritus and high prevalence. Indeed, 15-30 % of children and 2-10 % of adults from industrialized countries are affected. Acute AD lesions are characterized by epidermal hyperplasia associated with a dominant Th2/Th17 immune response and dermal inflammatory infiltrates. Moreover, the expression of alarmins such as TSLP, IL-33, and IL-25 is upregulated in acute AD lesions. Topical application of vitamin D3 or of its low-calcemic analog MC903 induces changes in skin morphology and inflammation resembling immune perturbations observed in acute lesions of patients with AD. Mice treated with MC903 or vitamin D3 additionally display increased serum IgE levels, as observed in patients with extrinsic AD. Interestingly, these symptoms are not dependent on mouse gender or on genetic background. Thus, the easiness of this mouse model renders it very attractive to study immunologic abnormalities involved in AD development or maintenance. Furthermore, this model might be useful for preclinical studies aiming at unraveling new therapeutic strategies to treat AD. In this chapter, we describe the induction and major features of MC903 and vitamin D3-induced AD-like inflammation in mice.

Topics: Administration, Cutaneous; Animals; Biomarkers; Calcitriol; Cholecalciferol; Dermatitis, Atopic; Disease Models, Animal; Drug Administration Schedule; Ear; Female; Gene Expression; Humans; Immunoglobulins; Keratinocytes; Male; Mice; Mice, Inbred C57BL; Receptors, Cytokine; Skin

Atopic dermatitis (AD) is a widespread inflammatory skin disease with an early onset, characterized by pruritus, eczematous lesions and skin dryness. This chronic relapsing disease is believed to be primarily a result of a defective epidermal barrier function associated with genetic susceptibility, immune hyper-responsiveness of the skin and environmental factors. Although the important role of abnormal immune reactivity in the pathogenesis of AD is widely accepted, the role of regulatory T cells (Tregs) remains elusive. We found that the Treg population is expanded in a mouse model of AD, i.e. mice topically treated with vitamin D3 (VitD). Moreover, mice with AD-like symptoms exhibit increased inducible T-cell costimulator (ICOS)-, cytotoxic T-lymphocyte antigen-4 (CTLA-4)- and Glycoprotein-A repetitions predominant receptor (GARP)-expressing Tregs in skin-draining lymph nodes. Importantly, the differentiation of Tregs into thymus-derived Tregs is favoured in our mouse model of AD. Emigrated skin-derived dendritic cells are required for Treg induction and Langerhans cells are responsible for the biased expansion of thymus-derived Tregs . Intriguingly, thymus-derived Tregs isolated from mice with AD-like symptoms exhibit a Th2 cytokine profile. Thus, AD might favour the expansion of pathogenic Tregs able to produce Th2 cytokines and to promote the disease instead of alleviating symptoms.

Topics: Animals; Cell Differentiation; Cell Proliferation; Cholecalciferol; CTLA-4 Antigen; Cytokines; Dermatitis, Atopic; Disease Models, Animal; Epidermis; Gene Expression Regulation; Humans; Inducible T-Cell Co-Stimulator Protein; Langerhans Cells; Lymph Nodes; Membrane Proteins; Mice; Mice, Inbred C57BL; Signal Transduction; T-Lymphocytes, Cytotoxic; T-Lymphocytes, Regulatory; Th1-Th2 Balance; Thymus Gland

Atopic dermatitis (AD) affects 10% to 20% of children worldwide. Its severity may be inversely correlated with 25-hydroxyvitamin D (25OHD) levels. Although low levels of vitamin D (VD) can cause rickets in infants, VD deficiency rickets is an unusual presentation in teenagers. We report the case of a 14-year-old girl with severe AD and fish allergy since early childhood. She lived at high latitude (with less sun exposure) and, because of her atopic disorders, avoided sunlight and fish. Laboratory studies showed elevated alkaline phosphatase and parathyroid hormone levels and low serum calcium; her serum 25OHD level was <12 nmol/L. A radiograph of the wrist showed a radiolucent band in the distal metaphysis of the radius with marginal sclerosis. She was diagnosed as having hypocalcemic rickets due to VD deficiency. Treatment with VD increased her 25OHD level to 44 nmol/L, with normalization of alkaline phosphatase, parathyroid hormone, and calcium. Moreover, we observed a dramatic improvement in her AD severity with VD treatment. This case demonstrates the complex interaction between VD deficiency, AD, and food allergy. We advise a high index of suspicion of VD deficiency rickets in children of all ages with AD, particularly during accelerated growth periods and in the presence of other risk factors such as darker skin, living at high latitude, sun avoidance, and low intake of VD-rich foods. The concomitant improvement in bone-related parameters and AD severity may reflect a double benefit of VD treatment, a possibility that warrants research on VD as potential treatment for AD.

Topics: Adolescent; Cholecalciferol; Dermatitis, Atopic; Female; Humans; Rickets; Severity of Illness Index; Vitamins

Recent investigations have shown atopic dermatitis (AD) results from the interplay of epidermal barrier defects, immune dysfunction and environmental triggers. These discoveries teach the importance of addressing all of these factors in treating patients. The barrier issues remind us of the need for moisturizers, especially after bathing, to replenish lipids and decrease water loss. Addition of dilute sodium hypochlorite (bleach) to bathwater often improves the dermatitis of children with moderate-to-severe dermatitis, especially with a history of staphylococcal infection. Oral vitamin D(3) has been suggested to increase the deficient antimicrobial peptide that results from cutaneous inflammation, although studies to date are inconclusive. Topical corticosteroids and calcineurin inhibitors continue to predominate as therapy and, to date, their safety record seems good, despite the Black Box warning issued in the United States. Poor compliance may explain the failure to respond to therapy, and contact dermatitis from topical application of emollients and medications may mimic AD, erroneously suggesting recalcitrance. For patients with severe AD, administration of systemic immunosuppressants may be required; ongoing studies of newer agents, including biologics, may revolutionize therapy for individuals with severe dermatitis, providing more targeted therapy in the future.

Topics: Administration, Topical; Anti-Inflammatory Agents; Antimicrobial Cationic Peptides; Cholecalciferol; Cytokines; Dermatitis, Atopic; Emollients; Filaggrin Proteins; Humans; Immunosuppressive Agents; Interleukins; Intermediate Filament Proteins; Peptide Hydrolases; Thymic Stromal Lymphopoietin

Skin lesions with atopic dermatitis (AD) are associated with dysregulated expression of LL-37 and enhanced expression of IL-22, thymic stromal lymphopoietin (TSLP), IL-25, IL-31, and oncostatin M. Vitamin D3 enhances LL-37 production in keratinocytes. This study aimed to examine the serum levels of LL-37 and vitamin D3 and their regulation of cytokine production in patients with AD.. Serum levels of LL-37 and 25-hydroxyvitamin D3 were analyzed by ELISA. The effects of 1,25-dihydroxyvitamin D3 or LL-37 on cytokine production in T cells or keratinocytes were analyzed by ELISA and real-time PCR.. Serum levels of LL-37 and 25-hydroxyvitamin D3 were decreased in patients with AD compared to normal donors and were correlated in both groups. Serum levels of LL-37 correlated with those of oncostatin M and IL-31 in normal donors and patients with AD, while 25-hydroxyvitamin D3 levels did so only in normal donors. 1,25-dihydroxyvitamin D3 increased LL-37 production in human keratinocytes and neutrophils. 1,25-dihydroxyvitamin D3 and LL-37 enhanced the oncostatin M and IL-31 production in CD3/28-stimulated T cells, but did not alter IL-25 and TSLP production in TNF-α-stimulated keratinocytes. In CD3/28-stimulated T cells, 1,25-dihydroxyvitamin D3 reduced the IL-22 production, while LL-37 enhanced it. These effects of 1,25-dihydroxyvitamin D3 and LL-37 were suppressed by vitamin D receptor antagonist and pertussis toxin, respectively.. Systemic vitamin D3 levels are reduced in patients with AD, which may contribute to decreased systemic LL-37 levels. LL-37 may systemically potentiate the oncostatin M and IL-31 production in normal donors and patients with AD, while vitamin D3 may do so only in normal donors.

Topics: Antimicrobial Cationic Peptides; Cathelicidins; Cells, Cultured; Cholecalciferol; Dermatitis, Atopic; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Humans; Interleukins; Keratinocytes; Neutrophils; Oncostatin M; Real-Time Polymerase Chain Reaction

Reduced production of antimicrobial peptides was proposed to contribute to susceptibility for skin infections in atopic dermatitis (AD). Focusing on the human cathelicidin protein, hCAP18, the aim of the present study was to explore whether reduced hCAP18 expression is a constitutive trait in AD and if established inducers affect the expression of hCAP18 in the skin of AD. First, we compared levels of hCAP18 mRNA between lesional skin in AD and psoriasis and verified significantly lower expression of hCAP18 mRNA in AD. In non-lesional skin, however, there was no difference between AD, psoriasis and healthy, indicating that there is no constitutive defect in the production of hCAP18 in AD patients. In healthy skin, hCAP18 was reported to be rapidly induced following wounding and here we verified this pattern in healthy controls and in psoriasis. In AD lesions, however, the expression of hCAP18 mRNA was markedly suppressed following wounding. Obviously, the inflammation in AD lesions neutralizes the expected induction of hCAP18 and even induces suppression. Notably, the mechanism to upregulate hCAP18 following vitamin D treatment was functional in lesional as well as in non-lesional AD indicating that the CAMP gene is normally regulated in this respect. In addition, cultured primary keratinocytes from non-lesional skin of psoriasis, AD and healthy skin, upregulated hCAP18mRNA following treatment with vitamin D. Itching is a hallmark of AD and scratching inevitably injures the skin. Failure to upregulate hCAP18 in eczema following injury is likely to affect antimicrobial protection and tissue repair in AD.

Topics: Adult; Aged; Antimicrobial Cationic Peptides; Cathelicidins; Cells, Cultured; Cholecalciferol; Dermatitis, Atopic; Down-Regulation; Female; Humans; Keratinocytes; Lipopolysaccharide Receptors; Male; Middle Aged; Psoriasis; Skin; Wounds and Injuries; Young Adult

Innate immune responses involve the production of antimicrobial peptides (AMPs), chemokines, and cytokines. We report here the identification of B-cell leukemia (Bcl)-3 as a modulator of innate immune signaling in keratinocytes. In this study, it is shown that Bcl-3 is inducible by the Th2 cytokines IL-4 and IL-13 and is overexpressed in lesional skin of atopic dermatitis (AD) patients. Bcl-3 was shown to be important to cutaneous innate immune responses as silencing of Bcl-3 by small-interfering RNA (siRNA) reversed the downregulatory effect of IL-4 on the HBD3 expression. Bcl-3 silencing enhanced vitamin D3 (1,25D3)-induced gene expression of cathelicidin AMP in keratinocytes, suggesting a negative regulatory function on cathelicidin transcription. Furthermore, 1,25D3 suppressed Bcl-3 expression in vitro and in vivo. This study identified Bcl-3 as an important modulator of cutaneous innate immune responses and its possible therapeutic role in AD.

Topics: Amino Acid Sequence; Antimicrobial Cationic Peptides; B-Cell Lymphoma 3 Protein; Cathelicidins; Cells, Cultured; Cholecalciferol; Dermatitis, Atopic; Humans; Immunity, Innate; Interleukin-13; Interleukin-4; Interleukin-6; Interleukin-8; Keratinocytes; Molecular Sequence Data; NF-kappa B p50 Subunit; Proto-Oncogene Proteins; Transcription Factors

Hapten-specific and mast-cell-dependent biphasic (immediate and delayed-onset) cutaneous reactions were induced in a murine model by intravenous injection of anti-DNP IgE antibodies followed by a skin test. Four daily applications of topical 1 alpha,24(OH)2D3 ointment significantly inhibited both the immediate and the delayed-onset cutaneous reactions in a dose-dependent fashion, as well as the croton-oil-induced cutaneous reaction and DNFB contact sensitivity reaction. 1 alpha,24(OH)2D3 itself did not show any sensitizing or irritant potential. The inhibitory effect of 1 alpha,24(OH)2D3 on these reactions was limited to the application site and no systemic effect was observed. Another vitamin D3 analog 1 alpha,25(OH)2D3, also showed an inhibitory effect on IgE-mediated cutaneous reactions. These results suggest that topically applied 1 alpha,24(OH)2D3 might modulate IgE-mediated cutaneous reactions and could thus be useful in the treatment of certain human cutaneous disorders other than psoriasis and related keratinizing disorders.

Topics: Administration, Topical; Animals; Antibodies, Anti-Idiotypic; Bone Marrow Cells; Cells, Cultured; Cholecalciferol; Croton Oil; Dermatitis, Atopic; Dinitrochlorobenzene; Dinitrofluorobenzene; Dinitrophenols; Dose-Response Relationship, Drug; Down-Regulation; Ear, External; Female; Haptens; Immunoglobulin E; Mice; Mice, Inbred BALB C; T-Lymphocytes