Relevance of contact sensitizations in occupational dermatitis patients with special focus on patch testing of workplace materials.

BACKGROUND: Studies on patch testing with workplace materials and evaluation of current occupational relevance of positive patch test reactions are scarce in patients with occupational dermatitis (OD). OBJECTIVES: To identify frequent sensitizations with occupational relevance and to determine the value of patch testing with workplace materials in OD patients. PATIENTS AND METHODS: Results and clinical data of 654 patients with suspected OD patch tested between 2013 and 2017 were analysed. RESULTS: Occupational allergic contact dermatitis was diagnosed in 113 (17.3%) patients. Mechanics had the widest range of occupational sensitizations. Sensitization to epoxy resin was rated occupationally relevant in almost all handicraft trades. Among positive patch test reactions to workplace products, those to water-based metal working fluids and leave-on cosmetic products were most frequent. Despite frequent testing, protective gloves only rarely elicited positive reactions. Preservatives and rubber compounds were most frequently identified as currently occupationally relevant. CONCLUSIONS: Rubber allergy is occupationally relevant especially in healthcare workers and cleaners. Generally, preservatives including formaldehyde releasers are important allergens in OD patients. Leave-on cosmetic products must not be forgotten as allergen sources. Patch testing both workplace materials and standardized test preparations has a complementary value and is beneficial for the diagnostic work-up of OD patients.

Health education decreases incidence of hand eczema in metal work apprentices: Results of a controlled intervention study.

BACKGROUND: Metal work apprentices (MWAs) frequently develop work-related hand eczema (HE). OBJECTIVES: To evaluate the effect of health education on incidence of work-related HE in MWAs and to assess confounding factors. MATERIALS/METHODS: In a prospective controlled intervention study, 131 MWAs received educational training on prevention of HE, whereas 172 MWAs and 118 office work apprentices served as controls. At baseline and during three yearly follow-ups, questionnaires were completed and hands were examined. Saliva samples were collected for assessment of filaggrin (FLG) null mutations and an explorative genome-wide association study (GWAS), and levels of various cytokines were assessed from stratum corneum samples. RESULTS: The 2-year and 3-year incidence of HE in the metalwork control group was 20.9% and 32.6%, respectively, which was significantly higher than in the intervention group (odds ratio [OR] 2.63, 95% confidence interval [CI] 1.31 to 5.28, P < .01 and OR 3.47, 95% CI 1.88 to 6.40, P < .0001). The knowledge score was higher in unaffected MWAs (P < .05). Other factors significantly associated with developing HE in MWAs were smoking cigarettes (P < .01) and FLG mutations (P < .001). No significant associations were found regarding epidermal cytokine levels and GWAS. CONCLUSIONS: Health education is effective in primary prevention of HE in MWAs. Individual factors should be considered in targeted counseling.

Transient epidermal barrier deficiency and lowered allergic threshold in filaggrin-hornerin (FlgHrnr-/- ) double-deficient mice.

BACKGROUND: Filaggrin (Flg) and hornerin (Hrnr) share similar structural and functional features. Both proteins have been implicated as essential proteins for skin barrier maintenance. Loss-of-function mutations of these genes constitute a risk factor for atopic dermatitis and eczema-related asthma. Furthermore, both FLG and HRNR protein levels are downregulated in patients with atopic dermatitis. Thus, mice deficient for Flg and Hrnr provide a novel model to study skin barrier impairment and the susceptibility for cutaneous inflammation. METHODS: By using appropriate targeting vectors and breeding strategies, we established a homozygous FlgHrnr double-deficient (FlgHrnr-/- ) mouse model lacking both genes including the intergenomic sequence. RESULTS: Neonates appeared normal, but developed a transient scaly phenotype with overall flaky appearance, but no overt skin phenotype in adulthood, thereby reflecting a subclinical barrier defect seen in humans. Structurally, FlgHrnr-/- mice displayed a markedly reduced granular layer and a condensed cornified layer. Functionally, FlgHrnr-/- mice showed permeability abnormalities and metabolic aberrations regarding the production of natural moisturizing factors (NMFs) in the stratum corneum. Surprisingly, although the immune system revealed no aberrations under steady-state conditions, FlgHrnr-/- mice are predisposed to mount an allergic contact dermatitis, especially at hapten threshold levels eliciting allergic reactions. CONCLUSIONS: Together, our FlgHrnr-/- mouse model nicely reflects the epicutaneous sensitization susceptibilities and inflammatory reactions to environmental insults in humans with impaired skin barrier functions.

A lurking threat: transfer of peanut allergy through peripheral blood stem cell transplantation.

BACKGROUND: There exist several reports of atopy and allergen-specific IgE-mediated hypersensitivity transferred by bone marrow transplantation, and it has been concluded that the transfer of allergic reactivity results from adoptive transfer of IgE-producing donor-derived B- and/or plasma cells. To the best of our knowledge we report the first case of peanut allergy after PBSCT. CASE PRESENTATION: A 55-year-old anciently non allergic man with secondary acute myeloid leukemia (AML) received an allogeneic peripheral blood stem cell transplantation from a matched unrelated donor following reduced-intensity conditioning. On day 32 after PBSCT, while still on prophylactic systemic immunosuppression, the patient noticed a first episode of angioedema with swelling of the nasal and oral mucosa 30 min after consuming peanut puffs. In a second episode, eight months after PBSCT, he again developed angioedema, generalized pruritus and nausea within minutes after eating biscuits containing hazelnut and peanut. Moreover, after topical application of a peanut oil-containing ointment, the patient experienced facial erythema and angioedema. Nine months after PBSCT an evaluation for peanut allergy revealed a highly increased specific IgE to peanut of 75.9 kU/l. Accordingly, skin prick tests for peanut extract were also positive. In consequence, the patient was counseled to strictly avoid peanut-related products, and provided with an emergency set. No adverse allergic events have occurred since for an observation time of 15 months after PBSCT. The stem cell donor was contacted and confirmed intolerance to peanuts. His specific serum IgE pattern nine month after PBSCT harvest was analysed and showed similar sensitization profiles compared to those of the transplant recipient. CONCLUSIONS: Because of the close temporal association between the onset of allergic symptoms in the PBSC recipient it is reasonable to assume that the acquired peanut allergy had been transferred from the donor to the recipient by the PBSC graft.

Targeting IgE in Severe Atopic Dermatitis with a Combination of Immunoadsorption and Omalizumab.

Patients with atopic dermatitis (AD) tend to have greatly elevated levels of serum immunoglobulin E (IgE). However, the role of IgE in the pathogenesis of AD is debated. This investigator-initiated open-label pilot study evaluates an anti-IgE-treatment approach by combining extracorporeal immunoadsorption and anti-IgE antibody omalizumab in 10 patients with severe, therapy-refractory AD. IgE levels decreased after immunoadsorption and decreased continuously in all patients during anti-IgE therapy. The reverse trend was observed during 6 months follow-up without treatment. In parallel with these observations, an improvement in AD was observed during the treatment period, with aggravation during follow-up. Further research is needed, based on the principle of reducing IgE levels in order to improve clinical symptoms, using a combination anti-IgE treatment approach, adjusted according to IgE levels.

Allergic contact dermatitis in psoriasis patients: typical, delayed, and non-interacting.

Psoriasis is characterized by an apoptosis-resistant and metabolic active epidermis, while a hallmark for allergic contact dermatitis (ACD) is T cell-induced keratinocyte apoptosis. Here, we induced ACD reactions in psoriasis patients sensitized to nickel (n = 14) to investigate underlying mechanisms of psoriasis and ACD simultaneously. All patients developed a clinically and histologically typical dermatitis upon nickel challenge even in close proximity to pre-existing psoriasis plaques. However, the ACD reaction was delayed as compared to non-psoriatic patients, with a maximum intensity after 7 days. Whole genome expression analysis revealed alterations in numerous pathways related to metabolism and proliferation in non-involved skin of psoriasis patients as compared to non-psoriatic individuals, indicating that even in clinically non-involved skin of psoriasis patients molecular events opposing contact dermatitis may occur. Immunohistochemical comparison of ACD reactions as well as in vitro secretion analysis of lesional T cells showed a higher Th17 and neutrophilic migration as well as epidermal proliferation in psoriasis, while ACD reactions were dominated by cytotoxic CD8+ T cells and a Th2 signature. Based on these findings, we hypothesized an ACD reaction directly on top of a pre-existing psoriasis plaque might influence the clinical course of psoriasis. We observed a strong clinical inflammation with a mixed psoriasis and eczema phenotype in histology. Surprisingly, the initial psoriasis plaque was unaltered after self-limitation of the ACD reaction. We conclude that sensitized psoriasis patients develop a typical, but delayed ACD reaction which might be relevant for patch test evaluation in clinical practice. Psoriasis and ACD are driven by distinct and independent immune mechanisms.

Surface modifications of silica nanoparticles are crucial for their inert versus proinflammatory and immunomodulatory properties.

BACKGROUND: Silica (SiO2) nanoparticles (NPs) are widely used in diverse industrial and biomedical applications. Their applicability depends on surface modifications, which can limit potential health problems. OBJECTIVE: To assess the potential impact of SiO2 NP exposure and NPs chemical modifications in allergic airway inflammation. METHODS: Mice were sensitized by five repetitive intraperitoneal injections of ovalbumin/aluminum hydroxide (1 µg) over 42 days, then intratracheally instilled with plain or modified SiO2 NPs (50 µg/mouse), and subsequently aerosol challenged for 20 minutes with ovalbumin. One or 5 days later, allergic inflammation was evaluated by cell differentiation of bronchoalveolar lavage fluid, lung function and gene expression and histopathology, as well as electron and confocal microscopy of pulmonary tissue. RESULTS: Plain SiO2 NPs induced proinflammatory and immunomodulatory effects in vivo, highlighted by enhanced infiltration of inflammatory cells in the bronchoalveolar lavage fluid, induction of a pulmonary T helper type 2 (Th2) cytokine pattern, differentiation of type 2 macrophages, and by morphological changes in the lung of sensitized mice. These effects were dramatically attenuated using surface-functionalized NPs with amino and phosphate groups, but not with polyethylene glycol. The role of macrophages in taking up SiO2 NPs was confirmed by flow cytometry, confocal microscopy, and gene expression analysis. CONCLUSION: Our data suggest that amino and phosphate surface modifications, but not polyethylene glycol (PEG), mitigate the proinflammatory and immunomodulatory effect of SiO2 NPs in allergic airway inflammation, paving the way for new strategies in the production of nanomaterials with lower health impact for humans.

S1 guideline diagnosis and therapy of cutaneous larva migrans (creeping disease).

GUIDELINE OBJECTIVES: These guidelines aim to enhance patient care by optimizing the diagnosis and treatment of infections due to creeping disease (cutaneous larva migrans) and to raise awareness among doctors of current treatment options. METHODS: S1 guideline, non-systematic literature search, consensus process using a circular letter.

Internalization routes of cell-penetrating melanoma antigen peptides into human dendritic cells.

Optimized delivery of antigens combined with sustainable maturation of dendritic cells (DCs) is crucial for generation of effective antitumoral immune responses. Multiple approaches for ex vivo antigen loading and improvement in immunogenicity have been described. We have recently established a single-step protocol consisting of a fusion peptide (a sequence of the melanoma antigen Melan-A and a cationic cell-penetrating HIV TAT domain) bound in complexes with a toll-like receptor agonist. As the exact cellular uptake mechanisms of TAT-coupled antigens have been a matter of considerable debate and significantly depend on cell type, cargo and concentrations, we evaluated internalization routes into human immature DCs in comparison with non-phagocytic cell lines. We found that Melan-A-TAT fusion peptide uptake by DCs is mainly energy dependent, superior compared with polylysine-coupled Melan-A and significantly higher in DCs as compared with Jurkat cells or HUVECs. Furthermore, we could track the uptake of the fusion peptide exclusively through early endosomes to lysosome compartments after 90 min by fluorescence microscopy and immunoelectron microscopy. Specific endocytosis inhibitors revealed major internalization of the fusion peptide by DCs via clathrin-mediated endocytosis, whereas uptake by non-phagocytic HUVECs differed significantly, involving macropinocytosis as well as clathrin-mediated endocytosis. As our understanding of the processes involved in internalization of TAT-coupled cargos by human DCs broadens, and DC activation becomes available by single-step procedures as described, further development of simultaneous DC maturation and intra-cellular peptide targeting is warranted.

Immunostimulatory activity of murine keratinocyte-derived exosomes.

It has long been known that keratinocytes influence cutaneous immunity through secretion of soluble factors. Exosomes, small membrane vesicles of endocytotic origin, have been implicated in intercellular communication processes such as the transfer of tumor cell antigens and the activation of recipient dendritic cells (DC). However, little is known about immunomodulatory functions of keratinocyte-derived exosomes. To address this question, we analysed exosome secretion of the murine keratinocyte cell line MPEK under steady state as well as inflammatory conditions (+/- IFNγ). These exosomes were readily taken up by bone marrow-derived DC (BMDC) in vitro resulting in a matured phenotype, as evidenced by increased CD40 expression as well as by the production of large amounts of IL-6, IL-10 and IL-12. When the transfer of antigen-specific information through exosomes was investigated, it was found that keratinocytes took up antigen (ovalbumin) and transferred it to their exosomes. However, these antigen-harbouring exosomes failed to induce antigen-specific T cell responses via BMDC. Together, this novel biological function suggests that keratinocytes are able to direct unspecific immune processes but do not elicit specific immune responses.

Atypical location of lymphocytoma cutis in a child.

Lyme borreliosis is a common infectious disease that can affect myocardial muscle or the central nervous system if not treated at an early stage. Here we report a unique case of an atypical location of lymphocytoma cutis in a 3-year-old boy. Histologic and immunohistochemical analysis revealed the correct diagnosis.

Diesel exhaust particles impair endothelial progenitor cells, compromise endothelial integrity, reduce neoangiogenesis, and increase atherogenesis in mice.

The mechanisms of the harmful cardiovascular effects of small particulate matter are incompletely understood. Endothelial progenitor cells (EPCs) predict outcome of patients with vascular disease. The aim of our study was to examine the effects of diesel exhaust particles (DEP) on EPC and on the associated vascular damage in mice. C57Bl/6 mice were exposed to DEP. 2 µg DEP/day was applicated intranasally for 3 weeks. Exposure to DEP reduced DiLDL/lectin positive EPC to 58.4 ± 5.6% (p < 0.005). Migratory capacity was reduced to 65.8 ± 3.9% (p < 0.0001). In ApoE(-/-) mice, DEP application reduced the number of EPC to 75.6 ± 6.4% (p < 0.005) and EPC migration to 58.5 ± 6.8% (p < 0.005). Neoangiogenesis was reduced to 39.5 ± 14.6% (p < 0.005). Atherogenesis was profoundly increased by DEP treatment (157.7 ± 18.1% vs. controls, p < 0.05). In cultured human EPC, DEP (0.1-100 µg/mL) reduced migratory capacity to 25 ± 2.6% (p < 0.001). The number of colony-forming units was reduced to 8.8 ± 0.9% (p < 0.001) and production of reactive oxygen species was elevated by DEP treatment (p < 0.001). Furthermore, DEP treatment increased apoptosis of EPC (to 266 ± 62% of control, p < 0.05). In a blood-brain barrier model, DEP treatment impaired endothelial cell integrity during oxygen-glucose deprivation (p < 0.001). Diesel exhaust particles impair endothelial progenitor cell number and function in vivo and in vitro. The reduction in EPC was associated with impaired neoangiogenesis and a marked increase in atherosclerotic lesion formation.