Inflammatory plasma signature of chronic hand eczema: Associations with aetiological and clinical subtypes.

BACKGROUND: Chronic hand eczema (CHE) is a highly prevalent, heterogeneous, skin disease that encompasses different aetiological and clinical subtypes. Severe CHE without atopic dermatitis has been associated with systemic inflammation; yet it remains unknown if specific CHE subtypes leave distinct, systemic, molecular signatures. OBJECTIVES: To characterize the inflammatory plasma signature of different aetiological and clinical CHE subtypes. METHODS: We assessed expression levels of 266 inflammatory and cardiovascular disease risk plasma proteins as well as filaggrin gene mutation status in 51 well-characterized CHE patients without concomitant atopic dermatitis and 40 healthy controls. Plasma protein expression was compared between aetiological and clinical CHE subgroups and controls both overall and according to clinical CHE severity. Correlation analyses for biomarkers, clinical and self-reported variables were performed. RESULTS: Very severe, chronic allergic contact dermatitis (ACD) on the hands was associated with a mixed Type 1/Type 2 systemic immune activation as compared with controls. Circulating levels of Type 1/Type 2 inflammatory biomarkers correlated positively with clinical disease severity among CHE patients with ACD. No biomarkers were found, that could discriminate between aetiological subtypes, for example, between ACD and irritant contact dermatitis. Hyperkeratotic CHE showed a distinct, non-atopic dermatitis-like, systemic footprint with upregulation of markers associated with Type 1 inflammation and tumour necrosis factor alpha, but not Type 2 inflammation. Increased levels of CCL19 and CXCL9/10 could discriminate hyperkeratotic CHE from both vesicular and chronic fissured CHE, whereas no difference was found between the latter two subtypes. CONCLUSION: Profiling of systemic biomarkers showed potential for identifying certain CHE subtypes. Peripheral blood levels of inflammatory biomarkers were associated and correlated with the clinical disease severity of chronic ACD on the hands, underlining that this is a systemic disease. We question whether hyperkeratotic CHE should be classified as eczema.

Melatonin prevents allergic airway inflammation in epicutaneously sensitized mice.

PURPOSE: The pathological process of atopic dermatitis (AD) progressing into other types of allergic diseases such as asthma and allergic rhinitis during the first several years of life is often referred to as the atopic march. Although the phenomenon of atopic march has been recognized for decades, how asthma stems from AD is still not fully understood, confounding a universal strategy to effectively protect people from the atopic march. METHODS: We established experimental atopic march mice by first inducing allergic dermatitis with 0.5% fluorescein isothiocyante (FITC) applied to the skin, followed by an ovalbumin (OVA) airway challenge. In addition, by examining serum immunoglobulin (Ig) concentrations, airway cytokines, the levels of oxidative stress markers, histopathological changes in lung tissue and airway hyperresponsiveness (AHR), we were able to validate the successful establishment of the model. Furthermore, by detecting the attenuating effects of melatonin (MT) and the levels of oxidative stress in the atopic march mice, we explored the potential molecular mechanisms involved in the development of atopic march. RESULTS: By successfully establishing an experimental atopic march mouse model, we were able to demonstrate that overproduction of oxidative stress in the lung significantly up-regulated the activation of nuclear factor-κB (NF-κB) signaling pathways causing thymic stromal lymphopoietin (TSLP) release, which further promotes the development of atopic march. CONCLUSIONS: To mitigate the development of the atopic march, antioxidants such as MT may be imperative to inhibit NF-κB activation in the lung, especially after the onset of AD.

Phloretin alleviates dinitrochlorobenzene-induced dermatitis in BALB/c mice.

Atopic dermatitis (AD) is a chronic inflammatory disease of the skin that substantially affects a patient's quality of life. While steroids are the most common therapy used to temporally alleviate the symptoms of AD, effective and nontoxic alternatives are urgently needed. In this study, we utilized a natural, plant-derived phenolic compound, phloretin, to treat allergic contact dermatitis (ACD) on the dorsal skin of mice. In addition, the effectiveness of phloretin was evaluated using a mouse model of ACD triggered by 2,4-dinitrochlorobenzene (DNCB). In our experimental setting, phloretin was orally administered to BALB/c mice for 21 consecutive days, and then, the lesions were examined histologically. Our data revealed that phloretin reduced the process of epidermal thickening and decreased the infiltration of mast cells into the lesion regions, subsequently reducing the levels of histamine and the pro-inflammatory cytokines interleukin (IL)-6, IL-4, thymic stromal lymphopoietin (TSLP), interferon-γ (IFN-γ) and IL-17A in the serum. These changes were associated with lower serum levels after phloretin treatment. In addition, we observed that the mitogen-activated protein kinase (MAPK) and NF-κB pathways in the dermal tissues of the phloretin-treated rodents were suppressed compared to those in the AD-like skin regions. Furthermore, phloretin appeared to limit the overproliferation of splenocytes in response to DNCB stimulation, reducing the number of IFN-γ-, IL-4-, and IL-17A-producing CD4+ T cells in the spleen back to their normal ranges. Taken together, we discovered a new therapeutic role of phloretin using a mouse model of DNCB-induced ACD, as shown by the alleviated AD-like symptoms and the reversed immunopathological effects. Therefore, we believe that phloretin has the potential to be utilized as an alternative therapeutic agent for treating AD.

Potential classification of chemical immunologic response based on gene expression profiles.

Occupational immune diseases are a serious public health burden and are often a result of exposure to low molecular weight (LMW) chemicals. The complete immunological mechanisms driving these responses are not fully understood which has made the classification of chemical allergens difficult. Antimicrobials are a large group of immunologically-diverse LMW agents. In these studies, mice were dermally exposed to representative antimicrobial chemicals (sensitizers: didecyldimethylammonium chloride (DDAC), ortho-phthalaldehyde (OPA), irritants: benzal-konium chloride (BAC), and adjuvant: triclosan (TCS)) and the mRNA expression of cytokines and cellular mediators was evaluated using real-time qPCR in various tissues over a 7-days period. All antimicrobials caused increases in the mRNA expression of the danger signals Tslp (skin), and S100a8 (skin, blood, lung). Expression of the TH2 cytokine Il4 peaked at different timepoints for the chemicals based on exposure duration. Unique expression profiles were identified for OPA (Il10 in lymph node, Il4 and Il13 in lung) and TCS (Tlr4 in skin). Additionally, all chemicals except OPA induced decreased expression of the cellular adhesion molecule Ecad. Overall, the results from these studies suggest that unique gene expression profiles are implicated following dermal exposure to various antimicrobial agents, warranting the need for additional studies. In order to advance the development of preventative and therapeutic strategies to combat immunological disease, underlying mechanisms of antimicrobial-induced immunomodulation must be fully understood. This understanding will aid in the development of more effective methods to screen for chemical toxicity, and may potentially lead to more effective treatment strategies for those suffering from immune diseases.

Prevalence and Prevention of Contact Dermatitis Caused by FreeStyle Libre: A Monocentric Experience.

OBJECTIVE: Cutaneous adverse events (CAE) from FreeStyle Libre include allergic contact dermatitis (ACD) caused by the allergen isobornyl acrylate (IBOA). We aim to report CAE from this glucose sensor, ACD to IBOA in particular, and the outcome of using barrier films as a prevention. RESEARCH DESIGN AND METHODS: A monocentric, retrospective review of medical files from adult and pediatric patients with diabetes using Freestyle Libre, in the period between December 2016 and April 2019, was performed with a focus on CAE. RESULTS: Fifty-seven of 1,036 patients with diabetes (5.5%) were referred to our dermatology department because of CAE from FreeStyle Libre. Thirty-nine of 1,036 (3.8%) had ACD due to IBOA. Only two patients, of whom one sensitized to IBOA, had a benefit from using barrier films. CONCLUSIONS: CAE occurred in 5.5% of FreeStyle Libre users, and 3.8% suffered from ACD due to IBOA. Barrier films had limited value in the prevention.

Silkworm dropping extract ameliorate trimellitic anhydride-induced allergic contact dermatitis by regulating Th1/Th2 immune response.

Allergic contact dermatitis (ACD) is an inflammatory skin disease caused by hapten-specific immune response. Silkworm droppings are known to exert beneficial effects during the treatment of inflammatory diseases. Here, we studied whether topical treatment and oral administration of silkworm dropping extract (SDE) ameliorate trimellitic anhydride (TMA)-induced ACD. In ACD mice model, SDE treatment significantly suppressed the increase in both ear thickness and serum IgE levels. Furthermore, IL-1ß and TNF-α levels were reduced by SDE. In allergic responses, SDE treatment significantly attenuated the production of the Th2-associated cytokine IL-4 in both ear tissue and draining lymph nodes. However, it increased the production of the Th1-mediated cytokine IL-12. Thus, these results showed that SDE attenuated TMA-induced ACD symptoms through regulation of Th1/Th2 immune response. Taken together, we suggest that SDE treatment might be a potential agent in the prevention or therapy of Th2-mediated inflammatory skin diseases such as ACD and atopic dermatitis. ABBREVIATIONS: ACD: allergic contact dermatitis; AD: atopic dermatitis; APC: antigen presenting cells; CCL: chemokine (C-C motif) ligand; CCR: C-C chemokine receptor; Dex: dexamethasone; ELISA: enzyme-linked immunosorbent assay; IFN: interferon; Ig: immunoglobulin; IL: interleukin; OVA: ovalbumin; PS: prednisolone; SDE: silkworm dropping extract; Th: T helper; TMA: trimellitic anhydride; TNF: tumor necrosis factor.

IL-26 in allergic contact dermatitis: Resource in a state of readiness.

In this study, we investigated the role of IL-26 in allergic contact dermatitis (ACD), highlighting its' contribute in the cytotoxic mechanism responsible for the tissue injury. IL-26 is a signature Th17 cytokine, and immune cells are its predominant sources. Recently, it has shown that Th17 cell-derived-IL-26 functions like an antimicrobial peptide. Here, we hypothesized that IL-26 could be involved in cytotoxicity mechanism that underlies ACD. Indeed, we have attributed a role to IL-26 in this context, through PBMC cytotoxicity assays vs HaCat. To demonstrate that IL-26 was effectively involved in this activity, we performed the assay using transfected ACD PBMCs by siRNA for IL-26. Indeed, we demonstrated that these cells were less able to kill keratinocytes compared with ACD PBMCs (P < .01). In conclusion, our findings support the idea that this emergent cytokine, IL-26, is implicated in the killing mechanisms of KC observed during ACD.

The role of toll-like receptor 3 in chronic contact hypersensitivity induced by repeated elicitation.

BACKGROUND: Accumulating evidence suggests that Toll-like receptor (TLR)-3 signaling is involved in non-infectious immune and inflammatory reactions as well as in viral infections. The skin of patients with atopic dermatitis (AD) is often infected with virus and bacteria, leading to the aggravation of atopic symptoms. These findings suggest TLR3 signaling may be involved in the pathogenesis of AD, but the exact role of TLR3 in AD remains to be defined. OBJECTIVE: The purpose of this study was to investigate the role of TLR3 in chronic contact hypersensitivity reactions induced by repeated elicitation, resembling the features of AD. METHODS: Wild-type (WT) and Toll-like receptor 3 knockout (Tlr3 KO) mice were sensitized, and chronic contact hypersensitivity reactions were elicited in their ear skin via repeated application of a hapten, 2,4,6-trinitro-1-chlorobenzene (TNCB) or oxazolone. RESULTS: The Tlr3 KO mice exhibited less ear swelling, less leukocyte infiltration into the skin, and lower serum total IgE levels than WT mice after hapten challenge. The Tlr3 KO mice also displayed lower expression levels of inflammatory cytokines (interleukin (IL)-33, IL-4, IL-10, and interferon-ɤ in their TNCB-treated ear skin than WT mice. CONCLUSION: These results showed that TLR3 deficiency suppressed the development of chronic contact hypersensitivity reactions, suggesting that TLR3 signaling may participate in the pathogenesis of AD.

Elevation of Circulating Th17/Th22 Cells Exposed to Low-Level Formaldehyde and Its Relevance to Formaldehyde-Induced Occupational Allergic Contact Dermatitis.

OBJECTIVES: The aim of this study was to investigate the effects of formaldehyde exposure on Th17 and Th22 cells and its relevance to human occupational allergic contact dermatitis (OACD). METHODS: Circulating IL17-/IL22-secreting cells and serum IL17/IL22 levels in formaldehyde-exposed workers at Occupational Exposure Limit and nonexposed controls were assessed. RESULTS: The IL17 and IL22 cell population were detected in both CD3CD8 and CD3CD8 cells. The percentages of circulating IL17 and IL22 T cells in the workers with and without ACD history were all elevated, which were more remarkable in the ones with ACD history. Serum levels of IL17 and IL22 between the workers and controls were not significantly different. CONCLUSIONS: Low-level formaldehyde exposure may increase circulating IL17-/IL22-producing T cells (CD8 and CD8), possibly involved in the development of human OACD. But it may not alter serum levels of IL17/IL22 before the appearance of OACD symptoms.

Histamine and Histamine Receptors in Allergic Dermatitis.

In this chapter we will first introduce the pathophysiological process of several skin diseases including allergic dermatitis, a common skin disease, including chronic allergic contact dermatitis (CACD), and atopic dermatitis (AD). In CACD and AD patients, repeated skin exposure to antigens contributes to the development of chronic eczematous lesions. Repeated application of haptens on mice allows emulation of the development of CACD in humans. Further, we will focus on H1, H2, and H4 histamine receptors and their effects on CACD and AD. Histamine-deficient mice, with a knockout histidine decarboxylase (HDC) gene, were used to investigate the role of histamine in CACD and AD. Histamine induces infiltration of inflammatory cells, including mast cells and eosinophils, and elevates Th2 cytokine levels in CACD. Histamine promotes the development of eczematous lesions, elevates IgE serum levels, and induces scratching behavior in CACD. The administration of H1 or H4 receptor antagonists was effective to ameliorate these symptoms in murine CACD models. The combination of H1 and H4 receptor antagonists is a potential therapeutic target for chronic inflammatory skin diseases such as CACD and AD, since combined therapy proved to be more effective than monotherapy.

[Prediction of occupational allergic contact dermatitis induced by formaldehyde by IL17/IL22 secretion cell rest combined with patch test].

Objective: To investigate the possible role of IL17-and IL22-secreting cells combined with patch test for the prediction of formaldehyde-induced occupational allergic contact dermatitis(OACD). Methods: From October 2014 to October 2016, totally 131 formaldehyde-exposed workers(49 cases with inflammatory skin lesions,82 ones without inflammatory skin lesions)and 63 non-exposed health controls were recruited. Patch-test was performed in 49 cases of formaldehyde-exposed workers with inflammatory skin lesions. Circulating IL17+and IL22+Tcell subsets were assessed by flow cytometry(FCM). Results: Among 49 cases of formaldehyde-exposed workers with inflammatory skin lesions,32 cases were with positive patch-test while 17 cases with negative patch-test. The proportions of circulating CD3+CD8-IL17+ and CD3+CD8-IL22+ cells from patch-test(+) formaldehyde-exposed workers were significantly higher than that of patch-test(-)group, formaldehyde-exposed workers without skin lesions and non-exposed controls(P<0.05). The proportions of circulating CD3+CD8-IL17+ and CD3+CD8-IL22+cells from patch-test(-)group and formaldehyde-exposed workers without skin lesions were also higher than that of non-exposed controls(P<0.05). But there was no significant difference between patch-test(-)group and formaldehyde-exposed workers without skin lesions(P>0.05). Peripheral CD3+CD8+IL17+and CD3+CD8+IL22+cells were also detected in spite of small amounts. The percentages of CD3+CD8+IL17+and CD3+CD8+IL22+ cells inperipheral blood from patch-test(+)formaldehyde-exposed workers were enhanced significantly, compared to patch-test(-)group, formaldehyde-exposed workers without skin lesions and non-exposed controls(P<0.05). The proportions of circulating CD3+CD8+IL17+ and CD3+CD8+IL22+ cells from patch-test(-)group and formaldehyde-exposed workers without skin lesions were significantly higher than that of non-exposed controls(P<0.05). But there was no significant difference between patch-test(-) group and formaldehyde-exposed workers without skin lesions(P>0.05). Conclusion: The proportions of circulating IL17+ and IL22+T cells(both CD8-and CD8+)are enhanced in formaldehyde-exposed workers at proposed OEL, possibly involved in the development of formaldehyde-induced OACD.The detection of IL17-and IL22-secreting cells combined with formaldehyde patch test help to screen the workers with allergy property and prevent OACD.

Luminex LiquiChip System for the Evaluation of Cytokine Levels in Patients with Contact Dermatitis to Potassium Dichromate.

BACKGROUND: Allergic contact dermatitis (ACD) is associated with increased production of cytokines. The patch test is the "gold-standard" diagnostic method, but it poses a risk of false results. OBJECTIVE: To evaluate a novel laboratory technique, the Luminex LiquiChip, which simultaneously measures blood levels of multiple cytokines, as a diagnostic tool in patients with chrome-induced ACD. METHODS: The study group included 20 patients with ACD and relevant patch test results for potassium dichromate and 19 patients with ACD for nickel or fragrance as control. Peripheral blood mononuclear cells (PBMCs) were cultured in the presence and absence of potassium dichromate. The Luminex LiquiChip was used to measure levels of the following cytokines: granulocyte-macrophage colony-stimulating factor, interleukin (IL)-1ß, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, interferon-γ, and tumor necrosis factor (TNF)-α. RESULTS: Potassium dichromate-stimulated PBMCs secreted significantly higher amounts of all cytokines except TNF-α than nonstimulated PBMCs. PBMCs from patients with ACD to chromium secreted significantly higher amounts of all cytokines tested, except IL-4, compared to PBMCs from patients with ACD to nickel or fragrance. CONCLUSIONS: Potassium dichromate stimulates the production of both Th1- and Th2-type cytokines in patients with chrome allergy. The Luminex LiquiChip is a promising in vitro method and may serve as a diagnostic tool for ACD.

Nickel allergy: blood and periodontal evaluation after orthodontic treatment / Alergia ao níquel: avaliação periodontal e sanguínea após o tratamento ortodôntico

The aim of this study was to assess periodontal status and bloodparameters in orthodontic patients with nickel allergy one monthafter removal of brackets. Ninety-six randomly selected patientswere initially evaluated. Allergy to nickel was diagnosed using apatch test. After determining the prevalence of subjects allergic tonickel, two groups were formed: 16 allergic (experimental) and 16non-allergic (control) patients. Their periodontal status wasdetermined regularly by a single, blinded, duly calibrated examinerusing the Lõe Index (GI) and their blood was tested (complete bloodtest, including nickel and IgE levels) after nine months oforthodontic treatment and again one month after removing theorthodontic appliances. Statistical analyses included paired andnon-paired t-tests, Mann-Whitney, Wilcoxon, McNemar and lineartrend chi-square tests (p≤0.05). Comparison of the values recordedduring orthodontic treatment and one month after removing theappliances showed that in the allergic group there was significantincrease in eosinophils (p=0.046), basophils (p=0.001) andmonocytes (p=0.002), and decrease in number of bands (p=0.000),while in the control group, there was increase in lymphocytes(p=0.039) and decrease in segmented neutrophils (p=0.030) andIgE levels (p=0.001). In both groups, plasma nickel levels increased(p=0.010; p=0.039) and GI scores decreased. One month afterremoving the brackets, blood and periodontal parameters frompatients with and without nickel allergy were similar.

O objetivo do presente estudo foi avaliar a condição periodontal eos parâmetros sanguíneos em pacientes alérgicos ao níquel, ummês após remoção dos aparelhos. Noventa e seis pacientesselecionados aleatoriamente foram inicialmente avaliadas. Alergiaao níquel foi diagnosticada usando um teste de contato. Após adeterminação da prevalência de alergia ao níquel, formaram-sedois grupos: 16 pacientes alérgicos (experimental) e 16 nãoalérgicos (controle). Condição periodontal foi diagnosticadaatravés do Índice de Lõe (IG). Parâmetros sanguíneos foramdeterminados por meio de um exame de sangue completo,incluindo a quantificação de níquel e níveis de IgE. Avaliações doestado periodontal foram realizados por um único examinador deforma cega, devidamente calibrado e amostras de sangue foramtomadas depois de nove meses de tratamento e um mês após aremoção dos aparelhos ortodônticos. Análise estatística utilizadafoi testes t pareado e não pareado, Mann-Whitney, Wilcoxon,McNemar e qui-quadrado de tendência linear (p≤0,05). Emcomparação com os valores observados durante o tratamento, onúmero de eosinófilos (p=0,046), basófilos (p=0,001) e monócitos(p=0,002) aumentou significativamente depois da remoção dosaparelhos ortodônticos, ao passo que o número de bastões(p=0,000) diminuiu entre os períodos no grupo alérgico. O númerode linfócitos (p=0,039) aumentou no grupo controle e o número desegmentados (p=0,030) diminuiu. A diminuição dos níveis de IgE(p=0,001) entre os períodos ocorreu no grupo de controle. Níveisde níquel no plasma aumentou após a remoção de aparelhosortodônticos em ambos os grupos (p=0,010; p=0,039). O IGdiminuiu em ambos os grupos. Parâmetros periodontais esanguíneos de pacientes com alergia ao níquel foram semelhantesaos não alérgicos um mês após a remoção dos aparelhos.

Cutaneous exposure to agglomerates of silica nanoparticles and allergen results in IgE-biased immune response and increased sensitivity to anaphylaxis in mice.

BACKGROUND: The skin is a key route of human exposure to nanomaterials, which typically occurs simultaneously with exposure to other chemical and environmental allergen. However, little is known about the hazards of nanomaterial exposure via the skin, particularly when accompanied by exposure to other substances. RESULTS: Repeated topical treatment of both ears and the shaved upper back of NC/Nga mice, which are models for human atopic dermatitis (AD), with a mixture of mite extract and silica nanoparticles induced AD-like skin lesions. Measurements of ear thickness and histologic analyses revealed that cutaneous exposure to silica nanoparticles did not aggravate AD-like skin lesions. Instead, concurrent cutaneous exposure to mite allergens and silica nanoparticles resulted in the low-level production of allergen-specific IgGs, including both the Th2-related IgG1 and Th1-related IgG2a subtypes, with few changes in allergen-specific IgE concentrations and in Th1 and Th2 immune responses. In addition, these changes in immune responses increased the sensitivity to anaphylaxis. Low-level IgG production was induced when the mice were exposed to allergen-silica nanoparticle agglomerates but not when the mice exposed to nanoparticles applied separately from the allergen or to well-dispersed nanoparticles. CONCLUSIONS: Our data suggest that silica nanoparticles themselves do not directly affect the allergen-specific immune response after concurrent topical application of nanoparticles and allergen. However, when present in allergen-adsorbed agglomerates, silica nanoparticles led to a low IgG/IgE ratio, a key risk factor of human atopic allergies. We suggest that minimizing interactions between nanomaterials and allergens will increase the safety of nanomaterials applied to skin.

Serum osteopontin levels in disseminated allergic contact dermatitis.

PURPOSE: The aim of the study was to evaluate serum osteopontin (OPN) concentrations in patients with disseminated form of allergic contact dermatitis (ACD), and to assess the relationship between serum OPN level and disease severity. PATIENTS AND METHODS: Twenty-four patients with numerous allergic contact dermatitis lesions and twenty-two age- and sex-matched healthy subjects as a control group were enrolled in the study. Serum osteopontin levels were measured in the ACD patients twice: in the acute stage and during disease remission by ELISA. RESULTS: Serum OPN concentrations were significantly increased in patients with disseminated ACD examined in the acute stage as compared to healthy subjects and ACD patients during remission (p<0.01 and p<0.001, respectively). In the ACD patients with extensive skin lesions (EASI>10), OPN serum levels were significantly higher than in those with mild disease (EASI<10). CONCLUSIONS: Acute disseminated ACD is characterized by elevated serum concentrations of osteopontin, with levels depending on ACD severity, which indicates its role in the elicitation phase of allergic contact dermatitis. The possibility of inhibition of OPN activity may create a new therapeutic perspective in severe forms of this troublesome skin disease.