Latex sensitivity in a macaque (Macaca mulatta)

BACKGROUND AND HISTORY: An adult Macaca mulatta was examined because of a history of multiple episodes of conjunctivitis and an acute, pruritic, dermatitic eruption that affected the axillary and inguinal regions, forearms, thorax, and neck. METHODS AND RESULTS: Results of corneal staining, examination of skin scrapings and feces, fungal culture, CBC, and a thyroid profile (thyroxine/triiodothyronine concentrations) were negative or normal, with the exception of eosinophilia (1,040/mm3). Examination of a punch biopsy specimen of the skin indicated chronic, nonsuppurative eosinophilic dermatitis. Skin patch testing against 25 contact allergens was negative for a delayed-type hypersensitivity reaction. Allergen-specific IgE testing, using six monkey chow additives, also yielded negative results, but testing against latex revealed a strong positive result (0.74 KU/L) consistent with a latex allergy. A skin prick test performed by use of a latex supernatant revealed significant inflammation at the latex site at 72 h and one week. Vinyl gloves were substituted for latex gloves, and that resulted in a marked decrease in erythema, pruritus, and lichenification with no flares of dermatitis for four years. Repeat skin biopsy fourteen weeks after the original biopsy revealed normal epidermis; however, mild chronic active nonsuppurative, perifolliculitis persisted. CONCLUSION: Latex can induce allergic dermatitis in nonhuman primates and should be included in the differen tial diagnosis for atopic dermatitis.     

Analysis of porcine MUC4 gene as a candidate gene for prolificacy QTL on SSC13 in an Iberian × Meishan F2 population

Background

Canine atopic dermatitis (AD) is a common, heritable, chronic allergic skin condition prevalent in the West Highland White Terrier (WHWT). In canine AD, environmental allergens trigger an inflammatory response causing visible skin lesions and chronic pruritus that can lead to secondary bacterial and yeast infections. The disorder shares many of the clinical and histopathological characteristics of human AD and represents an animal model of this disorder that could be used to further elucidate genetic causes of human AD. Microsatellite markers genotyped in families of WHWTs affected with AD were used to perform a genome-wide linkage study in order to isolate chromosomal regions associated with the disorder.

Results

Blood samples and health questionnaires were collected from 108 WHWTs spanning three families. A linkage simulation using these 108 dogs showed high power to detect a highly penetrant mutation. Ninety WHWTs were genotyped using markers from the Minimal Screening Set 2 (MSS-2). Two hundred and fifty six markers were informative and were used for linkage analysis. Using a LOD score of 2.7 as a significance threshold, no chromosomal regions were identified with significant linkage to AD. LOD scores greater than 1.0 were located in a 56 cM region of chromosome 7.

Conclusions

The study was unable to detect any chromosomal regions significantly linked to canine AD. This could be a result of factors such as environmental modification of phenotype, incorrect assignment of phenotype, a mutation of low penetrance, or incomplete genome coverage. A genome-wide SNP association study in a larger cohort of WHWTs may prove more successful by providing higher density coverage and higher statistical power.     

Pathology of spontaneous dermatitis in CBy.ALY-aly mice.

CBy.ALY-aly/aly (C-aly) mice develop progressive dermatitis in areas of the face and dorsal neck from around three months of age. Staphylococcus aureus was detected in the skin lesions of C-aly mice. However, even when the mice were raised under S. aureus free conditions, a similar, though less severe, dermatitis was still observed. The mice showed a marked increase in the number of eosinophils in the peripheral blood and skin lesions, with no changes in plasma IgE levels. These findings suggest that the dermatitis of these mice may be an atypical allergic condition with little or no involvement of IgE. C-aly mice may be a useful animal model of chronic dermatitis or pruritus without elevated IgE levels.     

Observations on the Antipruritic Effect of Guanethidine in Atopic Dermatitis

Guanethidine, 0.75 to 1.25 mg. per kg. per day, was found to alleviate the pruritus of acute atopic dermatitis in 19 out of 20 patients. It was not effective in patients with other dermatoses. An apparent partial tolerance to this treatment developed in six out of 10 patients re-treated. It had little or no therapeutic effect in 10 patients with a variety of other pruritic dermatoses, suggesting that this drug has a specific antipruritic action in patients with atopic dermatitis. In a double-blind study, 11 of 12 patients with atopic dermatitis treated with guanethidine experienced relief of pruritus. Four out of 12 patients using a placebo had complete or partial relief. Guanethidine, 1% to 10%, used topically was therapeutically no more effective than placebo. In view of the reported side effects and the anesthetic hazard encountered with guanethidine, further long-term studies are indicated before this drug is adopted for clinical use in the treatment of atopic dermatitis. The findings support the hypothesis that atopic dermatitis may be a manifestation of a hereditary defect in cutaneous noradrenaline binding.     

CC chemokine ligand 18, an atopic dermatitis-associated and dendritic cell-derived chemokine, is regulated by staphylococcal products and allergen exposure

Atopic dermatitis is a chronic inflammatory skin disease with a steadily increasing prevalence. Exposure to allergens or bacterial superantigens triggers T and dendritic cell (DC) recruitment and induces atopic skin inflammation. In this study, we report that among all known chemokines CCL18/DC-CK1/PARC represents the most highly expressed ligand in atopic dermatitis. Moreover, CCL18 expression is associated with an atopic dermatitis phenotype when compared with other chronic inflammatory skin diseases. DCs either dispersed within the dermis or clustering at sites showing perivascular infiltrates are abundant sources of CCL18. In vitro, microbial products including LPS, peptidoglycan, and mannan, as well as the T cell-derived activation signal CD40L, induced CCL18 in monocytes. In contrast to monocytes, monocyte-derived, interstitial-type, and Langerhans-type DCs showed a constitutive and abundant expression of CCL18. In comparison to Langerhans cells, interstitial-type DCs produced higher constitutive levels of CCL18. In vivo, topical exposure to the relevant allergen or the superantigen staphylococcal enterotoxin B, resulted in a significant induction of CCL18 in atopic dermatitis patients. Furthermore, in nonatopic NiSO4-sensitized individuals, only relevant allergen but not irritant exposure resulted in the induction of CCL18. Taken together, findings of the present study demonstrate that CCL18 is associated with an atopy/allergy skin phenotype, and is expressed at the interface between the environment and the host by cells constantly screening foreign Ags. Its regulation by allergen exposure and microbial products suggests an important role for CCL18 in the initiation and amplification of atopic skin inflammation.     

Old drugs,new tricks: Emerging role of drug repurposing in the management of atopic dermatitis

Atopic dermatitis is a chronic recurring pruritic inflammatory skin disease manifested by increased pro-inflammatory mediators which lead to dry, thickened, cracked, scaly skin. The current treatment options for atopic dermatitis management comprise drawbacks and leave unmet effective clinical needs. So, the approach for repurposing existing drugs for atopic dermatitis management may potentially overcome these unmet needs. Diseases that share the common pathophysiological pathways with atopic dermatitis can serve as a foundation for the repurposing of drugs. Drugs used in the management of cancer, rheumatoid arthritis, and other immune-mediated diseases such as psoriasis are under investigation to know the potential in atopic dermatitis management by utilizing repurposing strategies for a novel therapeutic indication. This review mainly envisages the probable repurposing of drugs for the management of atopic dermatitis disease; the barriers and regulatory aspects involved in the repurposing of existing drugs.     

A novel organogermanium protected atopic dermatitis induced by oxazolone

Atopic dermatitis (AD) is a chronic inflammatory disease of the skin that is often associated with other atopic diseases, such as asthma and allergic rhinitis. Although topical steroids have widely been prescribed for patients with AD, skin abnormalities are frequently observed after prolonged steroid treatment. In this study, a novel water-soluble organogermanium compound (Ge-Vit) was prepared because organogermanium is a known INF-γ inducer. The Ge-Vit treatment decreased the basal TEWL and IgE production and attenuated the disruption of the skin barrier function in a murine model of chronic contact dermatitis. The histological examination further supported the anti-AD activities. These results suggested that Ge-Vit can be a useful drug candidate for treating atopic dermatitis.     

MANAGEMENT OF ATOPIC DERMATITIS—A Preliminary Report

A treatment regimen for atopic dermatitis (disseminated neurodermatitis) which attempts to cope with the factors of dry skin and retention of sweat was successful in a series of 22 consecutive patients, all of whom remain under observation. Objectives of the treatment are: Preservation of the natural lipid surface film, avoidance of controllable stimuli to sweating, avoidance of greases and oils topically applied, control of bacterial infection in the skin, resolution of active dermatitis with topical corticosteroids in vehicles low in lipids or free of them, and correction of existing keratoderma. This program does not purport to alter atopic constitutional factors.Among the 22 patients were seven with severe dermatitis requiring prolonged, continuous or intermittent, systemic corticosteroid therapy who were treated and had no exacerbation for periods up to ten months at the time of last report. The total daily dose of topical corticosteroid is small. Systemic corticosteroid therapy was withdrawn at the initiation of this treatment and has not been reinstituted. No untoward reactions have been observed.Results to date warrant treatment and long term observation of additional patients to determine the ultimate value of this method.     

ATOPIC DERMATITIS DUE TO SENSITIVITY TO POLLEN

Observation of 100 patients with atopic dermatitis due to hypersensitivity to pollen over a period of 12 years emphasized certain important diagnostic and therapeutic features. The incidence was higher in females than in males and higher in middle and old age than in the earlier years.Pollen dermatitis may be the sole or major manifestation of allergy; 43 patients gave no history of other allergic symptoms. It may involve any or all areas of the body. The site or the distribution of lesions or the nature of the lesions gave no clue as to the diagnosis of pollen sensitivity.The character of the eruption varied widely from patient to patient and in given patients from week to week at times.Atopic dermatitis due to pollen sensitivity may be purely seasonal, perennial with seasonal exacerbations or perennial without seasonal variation.Reactions to skin testing with pollens suspected as allergens may be positive, equivocal or negative. In 58 patients there were positive correlative skin reactions to pollens.The diagnosis of atopic dermatitis due to pollen sensitivity, and the composition of the desensitizing antigen or antigens, must be based primarily on the clinical history and the area of residence.Most patients could tolerate only very weak dilutions at the beginning of desensitization therapy. Strong dilutions caused exacerbation of the dermatitis.Good or excellent results were obtained with perennial pollen desensitization therapy administered over long periods. In 13 patients good results took four to eight years of desensitization therapy. Fifty required less than two years. Tolerance of the patient for a given dose of antigen should determine the maximum dilution used in therapy.     

Clinical efficacy of blue light full body irradiation as treatment option for severe atopic dermatitis

Background

Therapy of atopic dermatitis (AD) relies on immunosuppression and/or UV irradiation. Here, we assessed clinical efficacy and histopathological alterations induced by blue light-treatment of AD within an observational, non-interventional study.

Methodology/Principal Findings

36 patients with severe, chronic AD resisting long term disease control with local corticosteroids were included. Treatment consisted of one cycle of 5 consecutive blue light-irradiations (28.9 J/cm²). Patients were instructed to ask for treatment upon disease exacerbation despite interval therapy with topical corticosteroids. The majority of patients noted first improvements after 2–3 cycles. The EASI score was improved by 41% and 54% after 3 and 6 months, respectively (p≤0.005, and p≤0.002). Significant improvement of pruritus, sleep and life quality was noted especially after 6 months. Also, frequency and intensity of disease exacerbations and the usage of topical corticosteroids was reduced. Finally, immunohistochemistry of skin biopsies obtained at baseline and after 5 and 15 days revealed that, unlike UV light, blue light-treatment did not induce Langerhans cell or T cell depletion from skin.

Conclusions/Significance

Blue light-irradiation may represent a suitable treatment option for AD providing long term control of disease. Future studies with larger patient cohorts within a randomized, placebo-controlled clinical trial are required to confirm this observation.     

A combination of Olea europaea leaf extract and Spirodela polyrhiza extract alleviates atopic dermatitis by modulating immune balance and skin barrier function in a 1-chloro-2,4-dinitrobenzene-induced murine model

BackgroundAtopic dermatitis is a chronic inflammatory skin disease in humans. Although Olea europaea leaf extract (OLE) and Spirodela polyrhiza extract (SPE) have been used to protect against skin damage, the effects of their combined administration on atopic dermatitis have yet to studied.PurposeIn this study, we evaluated the potential therapeutic effects of an OLE and SPE combination on the progression of atopic dermatitis and the possible mechanisms underlying these effects in 1-chloro-2,4-dinitrobenzene (DNCB)-treated NC/Nga mice.MethodsAtopic dermatitis was induced by topical application of 0.2% w/v DNCB prepared in an olive oil:acetone solution (1:3), and thereafter OLE, SPE and OLE + SPE were administered orally for 5 weeks. We determined atopic dermatitis symptoms, serum IgE levels, and levels of cytokine- and gene expression in the dorsal skin and splenocytes, and performed histological and immune cell subtype analyses. The expression of skin barrier-related proteins (filaggrin, sirtuin 1, and claudin 1) was also evaluated.ResultsThe OLE + SPE combination significantly ameliorated atopic dermatitis symptoms, including dermatitis scores, and reduced epidermal thickness and infiltration of different inflammatory cells in mice with DNCB-induced atopic dermatitis. It also significantly reduced the number of CD4⁺, CD8⁺, and CD4⁺/CD69⁺ T cells; immunoglobulin E-producing B cells (CD23⁺/B220⁺) in the axillary lymph nodes; CD3⁺ T-cell eosinophils (chemokine–chemokine receptor 3⁺/CD11b⁺) in the skin; and CD3⁺ T cells, immunoglobulin E-producing B cells (CD23⁺/B220⁺), and eosinophils in peripheral blood mononuclear cells. Additionally, the experimental combination lowered levels of serum immunoglobulin E and histamine, as well as Th2-mediated cytokines, and interleukin-4, -5, and -13, whereas it increased the levels of Th1-mediated cytokine interferon-γ in splenocytes. Furthermore, the preparation significantly restored expression of the skin barrier-related proteins filaggrin, sirtuin 1, and claudin 1, and also reduced the expression of the inflammatory cytokine interleukin-6 and chemokine–chemokine receptor 3, as well as the pruritus-related cytokine interleukin-31 and interleukin-31 receptor, in atopic dermatitis skin lesions.ConclusionTaken together, our findings indicate that administration of a combination of OLE and SPE can alleviate atopic dermatitis symptoms by regulating immune balance and skin barrier function and may be an effective therapeutic option for the treatment of atopic dermatitis.     

7,8,4′-Trihydroxyisoflavone Attenuates DNCB-Induced Atopic Dermatitis-Like Symptoms in NC/Nga Mice

Atopic dermatitis (AD) is characterized by chronic highly pruritic and relapsing inflammatory skin lesions. Despite its growing prevalence, therapeutic treatments remain limited. Natural immune modulators from herbal extracts or derivatives may be useful for treating AD symptoms. This study examined the effect of 7,8,4′-trihydroxyisoflavone (7,8,4′-THIF), a metabolite of soy isoflavone daidzin, on AD-like symptoms. Repeated epicutaneous application of 2,4-dinitrochlorobenzene (DNCB) was performed on the ear and dorsal skin of NC/Nga mice to induce AD-like symptoms and skin lesions, and 7,8,4′-THIF (200 and 400 nmol) or tacrolimus (100 µg) was applied topically for 3 weeks to assess their anti-pruritic effects. We found that 7,8,4′-THIF alleviated DNCB-induced AD-like symptoms as quantified by skin lesion, dermatitis score, ear thickness, and scratching behavior. Histopathological analysis demonstrated that 7,8,4′-THIF decreased DNCB-induced eosinophil and mast cell infiltration into skin lesions. We also found that 7,8,4′-THIF significantly alleviated DNCB-induced loss of water through the epidermal layer. In addition to reducing the DNCB-induced increase in serum IgE, 7,8,4′-THIF also lowered skin lesion levels of the chemokine thymus and activation regulated chemokine; Th2 cytokines interleukin (IL)-4, IL-5, and IL-13; and Th1 cytokines IL-12 and interferon-γ. These results suggest that 7,8,4′-THIF might be a potential therapeutic candidate for the treatment of atopic dermatitis.     

Clinical Presentation of Atopic Dermatitis by Filaggrin Gene Mutation Status during the First 7 Years of Life in a Prospective Cohort Study

Background

Filaggrin null mutations result in impaired skin barrier functions, increase the risk of early onset atopic dermatitis and lead to a more severe and chronic disease. We aimed to characterize the clinical presentation and course of atopic dermatitis associated with filaggrin mutations within the first 7 years of life.

Method

The COPSAC cohort is a prospective, clinical birth cohort study of 411 children born to mothers with a history of asthma followed during their first 7 years of life with scheduled visits every 6 months, as well as visits for acute exacerbations of dermatitis. Atopic dermatitis was defined in accordance with international guidelines and described at every visit using 35 predefined localizations and 10 different characteristics.

Results

A total of 170 (43%) of 397 Caucasian children developed atopic dermatitis. The R501X and/or 2282del4 filaggrin null mutations were present in 26 (15%) of children with atopic dermatitis and were primarily associated with predilection to exposed skin areas (especially the cheeks and back of the hands) and an up-regulation of both acute and chronic dermatitis. Furthermore, we found the filaggrin mutations to be associated with a higher number of unscheduled visits (3.6 vs. 2.7; p = 0.04) and more severe (moderate-severe SCORAD 44% vs. 31%; p = 0.14), and widespread dermatitis (10% vs. 6% of the body area, p<0.001) with an earlier age at onset (246 vs. 473 days, p<0.0001) compared to wild-type.

Conclusion

In children, filaggrin mutations seem to define a specific endotype of atopic dermatitis primarily characterized by predilection to exposed areas of the body, in particular hands and cheeks, and an up-regulation in both acute and chronic morphological markers. Secondary, this endotype is characterized by an early onset of dermatitis and a more severe course, with more generalized dermatitis resulting in more frequent medical consultations.     

Inhibitory effects of polysaccharide-rich extract of Phragmites rhizoma on atopic dermatitis-like skin lesions in NC/Nga mice

AimsPhragmites rhizoma was reported to have anti-oxidative and free radical scavenging activity. It also has been traditionally used to suppress inflammation. In the present study, we aimed to evaluate the topical effects of the polysaccharide-rich extract of P. rhizoma (PEP) on atopic dermatitis.Main methodsWe induced AD-like skin lesions by an extract of the house-dust mite Dermatophagoides farinae (Dfb) in NC/Nga mice, and then performed macroscopic analysis, immunohistochemical staining and measurement of total serum IgE and cytokine production by ELISA.Key findingsTopically applied PEP suppressed dermatitis with a decrease in dermatitis score and scratch number. The histological manifestations of atopic skin lesions including thickened epidermis and increased numbers of mast cells, polymorphonuclear leukocytes and nerve fibers were significantly attenuated. The activation of IgE and the levels of cytokines such as IFN-γ IL-4 and IL-10 were also decreased.SignificanceOur results indicated that PEP might have an inhibitory effect on atopic dermatitis-like lesion and be a promising natural resource in the treatment of atopic dermatitis.     

Small intestinal immune-environmental changes induced by oral tolerance inhibit experimental atopic dermatitis

Atopic dermatitis is a chronic skin inflammatory disease mediated by Th2-type immune responses. Although intestinal immune responses have been shown to play a critical role in the development or prevention of atopic dermatitis, the precise influence of intestinal immunity on atopic dermatitis is incompletely understood. We show here that orally tolerized mice are protected from experimental atopic dermatitis induced by sensitization and epicutaneous (EC) challenge to ovalbumin. Although the expression of Th2-type cytokines in the small intestine of orally tolerized and EC-challenged mice did not change significantly, these mice showed decreased inflammatory responses in the small intestine with restoration of microbial change elicited by the EC challenge. Interestingly, an increase in small intestinal eosinophils was observed with the EC challenge, which was also inhibited by oral tolerance. The role of small intestinal eosinophils and microbiota in the pathogenesis of experimental atopic dermatitis was further substantiated by decreased inflammatory mediators in the small intestine and attenuated Th2-type inflammation in the skin of eosinophil-deficient and microbiota-ablated mice with EC challenges. Based on these data, we propose that the bidirectional interaction between the skin and the intestine has a role in the pathogenesis of atopic dermatitis and that modulation of the intestinal microenvironments could be a therapeutic approach to atopic dermatitis.Subject terms: Allergy, Mucosal immunology     

Differential effects of peptidoglycan recognition proteins on experimental atopic and contact dermatitis mediated by Treg and Th17 cells

Skin protects the body from the environment and is an important component of the innate and adaptive immune systems. Atopic dermatitis and contact dermatitis are among the most frequent inflammatory skin diseases and are both determined by multigenic predisposition, environmental factors, and aberrant immune response. Peptidoglycan Recognition Proteins (Pglyrps) are expressed in the skin and we report here that they modulate sensitivity to experimentally-induced atopic dermatitis and contact dermatitis. Pglyrp3(-/-) and Pglyrp4(-/-) mice (but not Pglyrp2(-/-) mice) develop more severe oxazolone-induced atopic dermatitis than wild type (WT) mice. The common mechanism underlying this increased sensitivity of Pglyrp3(-/-) and Pglyrp4(-/-) mice to atopic dermatitis is reduced recruitment of Treg cells to the skin and enhanced production and activation Th17 cells in Pglyrp3(-/-) and Pglyrp4(-/-) mice, which results in more severe inflammation and keratinocyte proliferation. This mechanism is supported by decreased inflammation in Pglyrp3(-/-) mice following in vivo induction of Treg cells by vitamin D or after neutralization of IL-17. By contrast, Pglyrp1(-/-) mice develop less severe oxazolone-induced atopic dermatitis and also oxazolone-induced contact dermatitis than WT mice. Thus, Pglyrp3 and Pglyrp4 limit over-activation of Th17 cells by promoting accumulation of Treg cells at the site of chronic inflammation, which protects the skin from exaggerated inflammatory response to cell activators and allergens, whereas Pglyrp1 has an opposite pro-inflammatory effect in the skin.     

Congenital cutaneous candidiasis diagnosed in cytologic scrapings

Cytologic scrapings of skin vesicles from an eight-day-old newborn who had a generalized maculopapular, vesicular and pustular rash contained mycelia and ovoid spores of fungal organisms. The cytodiagnosis of cutaneous candidiasis was confirmed by the study of a direct smear and a skin biopsy. The candidiasis was congenital; the 15-year-old mother had had vulvar pruritus prior to delivery. Since the variable clinical picture of this disease must be differentiated from those of other types of congenital dermatitis, an early cytologic study of skin scrapings may prove useful for its rapid diagnosis and treatment.     

Intradermal injection of Hsp60 induces cytokine responses in canine atopic and healthy skin

The purpose of this study was to investigate the immunoregulatory potential of Hsp60 in the skin of dogs with atopic dermatitis. Three dogs with chronic atopic dermatitis and four healthy dogs were injected intradermally with Hsp60 and phosphate-buffered saline. Biopsies were taken before testing from non-injected control skin, lesional and non-lesional atopic skin, and 48 and 72 h after injection. Analysis of cytokine messenger RNA was performed using quantitative real-time polymerase chain reaction. Forty-eight hours after Hsp60 injection, a rise in interleukin (IL)-10 was found (P = 0.034) with the highest expression levels in non-lesional atopic and control skin. A rise of transforming growth factor beta (P = 0.015) and IL-12p40 (P = 0.017) was noticed 72 h after Hsp60 injection in control skin. No significant differences were observed for the expression of IL-4, IL-12p35, and interferon gamma. The results indicate that Hsp60 is able to induce cytokines of a regulatory and Th1 phenotype in the skin. Furthermore, this study seems to provide a first indication of deficient Hsp60 response in atopic dermatitis affected skin.