Association Between Severe Acute Contact Dermatitis Due to Nigella sativa Oil and Epidermal Apoptosis.

Importance: Nigella sativa oil (NSO) is widely used for cosmetic and culinary purposes. Cases of severe acute contact dermatitis due to NSO are poorly described, with no histologic description. Objectives: To describe the clinical and histologic features of severe acute contact dermatitis due to NSO and investigate the components responsible for such eruptions. Design, Setting, and Participants: A case series study of 3 patients with contact dermatitis admitted to the dermatology department between August 21, 2009, and February 19, 2017, was conducted. All patients had been referred to the dermatology department for acute contact dermatitis due to NSO and had patch tests performed. Main Outcomes and Measures: Clinical and histologic features of the cutaneous eruptions, length of hospital stay, chemical analysis of NSO, and results of patch tests. Results: Three patients (3 women; median age, 27 years [range, 20-47 years]) were included in the case series. All patients had polymorphic skin lesions spreading beyond the area of NSO application: typical and atypical targets, patches with central blisters, erythematous or purpuric plaques with a positive Nikolsky sign mimicking Stevens-Johnson syndrome, or toxic epidermal necrolysis. Two patients had pustules. They had severe impairment, with more than 15% skin detachment and fever. The results of skin biopsies showed epidermal apoptosis characterized by vacuolar alteration of the basal layer, keratinocyte apoptosis, and a moderate perivascular infiltrate of lymphocytes in the dermis. The results of patch tests using the patients' NSO were all positive. The results of gas chromatography combined with mass spectrometry performed on the NSO of 1 patient identified several constituent substances, mainly terpenes, thymoquinone, linoleic acid, and fatty acids. Conclusions and Relevance: These cases suggest that acute contact dermatitis due to NSO may induce topically triggered epidermal apoptosis, previously described as the concept of acute syndrome of apoptotic pan epidermolysis. Thymoquinone and p-cymene may be the main agents involved in the pathophysiologic characteristics of this acute contact dermatitis. Clinicians should be aware of such severe reactions to NSO and report these cases to pharmacovigilance authorities.

Central neural activation following contact sensitivity peripheral immune challenge: evidence of brain-immune regulation through C fibres.

This study tested the hypothesis that peripheral immune challenges will produce predictable activation patterns in the rat brain consistent with sympathetic excitation. As part of examining this hypothesis, this study asked whether central activation is dependent on capsaicin-sensitive C-fibres. We induced skin contact sensitivity immune responses with 2,4-dinitrochlorobenzene (DNCB), in the presence or absence of the acute C-fibre toxin capsaicin (8-methyl-N-vanillyl-6-nonenamide) to trigger immune responses with and without diminished activity of C-fibres. Innovative blood-oxygen-level-dependent functional magnetic resonance imaging data revealed that the skin contact sensitivity immune responses induced with DNCB were associated with localized increases in brain neuronal activity in treated rats. This response was diminished by pre-treatment with capsaicin 1 week before scans. In the same animals, we found expression of the immediate early gene c-Fos in sub-regions of the amygdala and hypothalamic sympathetic brain nuclei. Significant increases in c-Fos expression were found in the supraoptic nucleus, central amygdala and medial habenula following immune challenges. Our results support the idea that selective brain regions, some of which are associated with sympathetic function, process or modulate immune function through pathways that are partially dependent on C-fibres. Together with previous studies demonstrating the motor control pathways from brain to immune targets, these findings indicate a central neuroimmune system to monitor host status and coordinate appropriate host responses.

Toxalbumin exposures: 12 years' experience of U.S. poison centers.

BACKGROUND: Toxalbumins are natural plant toxins purported to be highly toxic. The purpose was to evaluate toxalbumin exposures reported to U.S. poison centers to determine plants involved and their toxicities. METHODS: A retrospective review of National Poison Data System data on acute toxalbumin exposures with known outcomes from 2000 through 2011 was performed. RESULTS: There were 1164 exposures. The majority involved one route (1135; 97.5%), mostly ingestions (904; 79.7%) or dermal (166; 14.3%). Most patients developed no effects (694; 59.6%) or minor effects (374; 32.1%). Moderate or major effects occurred in 8.3% with 66.6% ingestions and 23.9% dermal. There were no deaths. Exposures to the plants Ricinus communis and Robinia pseudoacacia were most common (33.8% and 32.9%, respectively), with gastrointestinal effects from R. communis (vomiting 19.6%, diarrhea 8.9%, nausea 7.9%) and dermal effects from R. pseudoacacia (puncture 28.7%, dermal irritation/pain 27.9%, and edema 13.3%). CONCLUSIONS: While toxalbumin plant exposures were generally well-tolerated, continued evaluation of risk is warranted since plants were primarily identified by the public. Major effects occurred in under 1% of cases overall, and not at all following unintentional ingestions. These findings should help allay concerns that unintentional ingestions of toxalbumin plants by young children will cause serious toxicity and possibly death.

Sulfur spring dermatitis.

Thermal sulfur baths are a form of balneotherapy promoted in many cultures for improvement of skin conditions; however, certain uncommon skin problems may occur after bathing in hot sulfur springs. We report the case of a 65-year-old man who presented with multiple confluent, punched-out, round ulcers with peripheral erythema on the thighs and shins after bathing in a hot sulfur spring. Histopathologic examination revealed homogeneous coagulation necrosis of the epidermis and papillary dermis. Tissue cultures showed no evidence of a microbial infection. The histopathologic findings and clinical course were consistent with a superficial second-degree burn. When patients present with these findings, sulfur spring dermatitis should be considered in the differential diagnosis. Moreover, the patient's clinical history is crucial for correct diagnosis.

Fragility of epidermis and its consequence in dermatology.

The skin is the largest organ of the body, providing a protective barrier against bacteria, chemicals and physical insults while maintaining homeostasis in the internal environment. Such a barrier function the skin ensures protection against excessive water loss. The skin's immune defence consists of several facets, including immediate, non-specific mechanisms (innate immunity) and delayed, stimulus-specific responses (adaptive immunity), which contribute to fending off a wide range of potentially invasive microorganisms. This article is an overview of all known data about 'fragile skin'. Fragile skin is defined as skin with lower resistance to aggressions. Fragile skin can be classified into four categories up to its origin: physiological fragile skin (age, location), pathological fragile skin (acute and chronic), circumstantial fragile skin (due to environmental extrinsic factors or intrinsic factors such as stress) and iatrogenic fragile skin. This article includes the epidemiologic data, pathologic description of fragile skin with pathophysiological bases (mechanical and immunological role of skin barrier) and clinical description of fragile skin in atopic dermatitis, in acne, in rosacea, in psoriasis, in contact dermatitis and other dermatologic pathologies. This article includes also clinical cases and differential diagnosis of fragile skin (reactive skin) in face in adult population. In conclusion, fragile skin is very frequent worldwide and its prevalence varies between 25% and 52% in Caucasian, African and Asian population.

P2X7 receptor is required for neutrophil accumulation in a mouse model of irritant contact dermatitis.

Irritant contact dermatitis (ICD) is an inflammatory reaction caused by chemical toxicity on the skin. The P2X7 receptor (P2X7R) is a key mediator of cytokine release, which recruits immune cells to sites of inflammation. We investigated the role of P2X7R in croton oil (CrO)-induced ICD using in vitro and in vivo approaches. ICD was induced in vivo by CrO application on the mouse ear and in vitro by incubation of murine macrophages and dendritic cells (DCs) with CrO and ATP. Infiltrating cells were identified by flow cytometry, histology and myeloperoxidase (MPO) determination. Effects of the ATP scavenger apyrase were assessed to investigate further the role of P2X7R in ICD. Animals were also treated with N-1330, a caspase-1 inhibitor, or with clodronate, which induces macrophage apoptosis. CrO application induced severe inflammatory Gr1(+) cell infiltration and increased MPO levels in the mouse ear. Selective P2X7R antagonism with A438079 or genetic P2X7R deletion reduced the neutrophil infiltration. Clodronate administration significantly reduced Gr1(+) cell infiltration and local IL-1ß levels. In vitro experiments confirmed that A438079 or apyrase treatment prevented the increase in IL-1ß that was evoked by macrophage and DC incubation with CrO and ATP. These data support a key role for P2X7 in ICD-mediated inflammation via modulation of inflammatory cells. It is tempting to suggest that P2X7R inhibition might be an alternative ICD treatment.

Comparison of a novel CXCL12/CCL5 dependent migration assay with CXCL8 secretion and CD86 expression for distinguishing sensitizers from non-sensitizers using MUTZ-3 Langerhans cells.

As the induction of contact hypersensitivity is the result of a series of cellular processes, including maturation and migration of epidermal dendritic cells (Langerhans cells (LC)), a battery of assays based on these in vivo events might provide a robust in vitro predictability model for distinguishing sensitizers from non-sensitizers. Therefore, assays with read-out for changes in CD86 expression and CXCL8 secretion were compared with a novel functional assay based on the in vitro migratory behaviour of LC. In all three assays LC derived from the human myeloid-leukaemia-cell-line MUTZ-3 (MUTZ-LC) were used. Exposure of MUTZ-LC to a panel of five sensitizers and three non-sensitizers resulted in increased CD86 expression in only 3/5 sensitizers, but also in 1/3 non-sensitizers. In contrast, CXCL8 secretion was uniformly increased after exposure to all sensitizers, but not after exposure to non-sensitizers. In a transwell migration assay, preferential migration of sensitizer-exposed MUTZ-LC towards CXCL12 was observed (5/5 sensitizers), whereas non-sensitizer-exposed MUTZ-LC only migrated towards CCL5 (3/3 non-sensitizers). In conclusion, the novel MUTZ-LC migration assay and analysis of CXCL8 secretion proved to be more successful than analysis of CD86 in predicting sensitizers from non-sensitizers and therefore warrant further investigation in the field of in vitro assay development.

[Eczematous skin diseases]. / Ekzemás megbetegedések.

The skin, as one of the most important barriers of the human body, protects the inner homeostasis from the harmful environmental influences as well as physical, chemical and biological factors. When the impact of these factors exceeds the tolerance and reproducing capacity of the skin, pathological alterations will develop. If follows from this that dermatology can surely be considered to be a part of environmental medicine. Eczematous diseases are mostly pathological pictures of varied mechanisms developing as a result of environmental influences (irritants, contact allergens, microbes). Since their clinical appearance is similar, it is a serious professional challenge to diagnose them. In this article we present the clinical features, provoking factors of these skin diseases as well as therapeutical possibilities.

The cytokine-dependent MUTZ-3 cell line as an in vitro model for the screening of contact sensitizers.

Langerhans cells (LC) are key mediators of contact allergenicity in the skin. However, no in vitro methods exist which are based on the activation process of LC to predict the sensitization potential of chemicals. In this study, we have evaluated the performances of MUTZ-3, a cytokine-dependent human monocytic cell line, in its response to sensitizers. First, we compared undifferentiated MUTZ-3 cells with several standard human cells such as THP-1, KG-1, HL-60, K-562, and U-937 in their response to the strong sensitizer DNCB and the irritant SDS by monitoring the expression levels of HLA-DR, CD54, and CD86 by flow cytometry. Only MUTZ-3 and THP-1 cells show a strong and specific response to sensitizer, while other cell lines showed very variable responses. Then, we tested MUTZ-3 cells against a wider panel of sensitizers and irritants on a broader spectrum of cell surface markers (HLA-DR, CD40, CD54, CD80, CD86, B7-H1, B7-H2, B7-DC). Of these markers, CD86 proved to be the most reliable since it detected all sensitizers, including benzocaine, a classical false negative in local lymph node assay (LLNA) but not irritants. We confirmed the MUTZ-3 response to DNCB by real-time PCR analysis. Taken together, our data suggest that undifferentiated MUTZ-3 cells may represent a valuable in vitro model for the screening of potential sensitizers.

Evaluation of CD86 expression and MHC class II molecule internalization in THP-1 human monocyte cells as predictive endpoints for contact sensitizers.

The aim of this study was to explore the usefulness of a human monocyte cell line in the development of in vitro models for predictive testing of contact sensitizers. Several studies have shown that contact sensitizers induce CD86 expression and enhanced internalization of MHC class II molecules in dendritic cells (DCs). We used THP-1, a human monocyte cell line, as a replacement for DCs for evaluation of these phenotypical alterations as predictive endpoints for contact sensitizers. Known sensitizers and irritants were evaluated. After 24-h exposure to samples, the expression of CD86 on THP-1 cells was measured by flow cytometry. Sensitizers such as dinitrochlorobenzene (DNCB), 2-mercaptobenzothiazole (MBT), eugenol, p-phenylenediamine (PPDA) and ammonium tetrachloroplatinate (Pt) enhanced CD86 expression on THP-1 cells, while nickel sulfate, cobalt sulfate and irritants such as methylsalicylate (MS), sodium dodecyl sulfate (SDS) and dimethyl sulfoxide (DMSO) did not augment CD86 expression. A synergistic effect was observed when DNCB and IFN-alpha were added simultaneously to a culture of THP-1 cells. Furthermore, internalization of MHC class II molecules was observed when the cells were treated with some of sensitizers for 2 h. The inducing effects of chemicals on the two phenotypical alterations were the same. These results suggest that these test systems can be used to predict contact-sensitizing ability of chemicals as an in vitro sensitization assay.

Les allergies cutanees / Dermatological allergies

La peau contient tous les elements necessaires pour initier et developper une reponse immune: cellules presentatrices d'antigenes (les cellules de Langerhans epidermiques), lymphocytes T... (AU)

Dual effects of CGRP-antagonist on allergic contact dermatitis in human skin.

There is increasing evidence of an interaction between the nervous and the immune systems. The aim of this study was to investigate the rôle of calcitonin gene-related peptide (CGRP) in the modulation of the elicitation of immediate and delayed, immunological and non-immunological reactions in human skin. CGRP (13 pmol and 39 pmol), and the CGRP-antagonist, CGRP/8-37/, (50 pmol and 500 pmol) were injected intracutaneously prior to provocation tests. Patients with allergy to nickel were provoked with nickel sulfate epicutaneously, and the reactions were evaluated by a clinical scoring system (guidelines of the International Contact Dermatitis Research Group). Patients with allergy to birch pollen were provoked by a prick test with the allergen, and the volume of the weals was measured. The patients were also provoked with tuberculin (delayed immunologic reaction), benzalkonium chloride (irritant contact dermatitis), UV-light and benzoic acid (non-immunologic contact urticaria). The test reactions were estimated by planimetry. CGRP/8-37/ exerted dual effects on allergic contact dermatitis, causing potentiation at a dose of 500 pmol (p= 0.004) and inhibition at a dose of 50 pmol (p=0.012). Other reactions were not significantly affected by the pretreatments. The results suggest that CGRP participates in delayed inflammatory reactions, but is not involved in immediate immunologic reactions.

Imiquimod, a topical immune response modifier, induces migration of Langerhans cells.

Langerhans cells are bone marrow derived dendritic cells that represent the major antigen-presenting cells in the skin. Langerhans cells take up and process antigen within the epidermis and present processed antigen to T lymphocyte in the regional lymph nodes and thus form an integral part of the cutaneous immune response. The cutaneous immune response can be modified by a number of pharmacologic agents, including corticosteroids, cyclosporine, and retinoids as well as physical agents, such as ultraviolet light. For the most part these agents act by suppressing immune function. A topical immune response modifier, imiquimod has been shown to enhance the cutaneous immune response. Imiquimod has anti-viral and anti-tumor effects in animal models and has been approved for the topical treatment of external genital and perianal warts in humans. The biologic activity of imiquimod in part is due to its effect as a cytokine inducer. Preliminary data suggested that imiquimod could have an effect on Langerhans cells. In order to clarify this effect on Langerhans cells, we examined Langerhans cell morphology and migration in imiquimod-treated skin. The density of Ia + cells decreased 2 d after treatment, falling to approximately 43% by day 10. The Ia positive in cells remaining in the skin appeared larger and more dendritic suggesting an activated state. ATPase staining of epidermal sheet confirmed the decreased number of Langerhans cells. To clarify status of Langerhans cells, the activation of B7 was examined. Activation of B7-1 or B7-2 was not detected. Imiquimod, however, did enhance Langerhans cell migration from skin to draining lymph nodes. This enhanced Langerhans cell migration was also associated with an enhanced allergic contact hypersensitivity. These results suggest that the mechanism of modulation of immune response by imiquimod is in part due to effects on Langerhans cells.

Selective requirements for leukocyte adhesion molecules in models of acute and chronic cutaneous inflammation: participation of E- and P- but not L-selectin.

Adhesion molecules borne by both endothelial cells and circulating leukocytes are in large measure responsible for guiding the process of extravasation. The selectin family has been primarily associated with the early stages of adhesion involving initial contact and rolling. A significant body of evidence has accumulated indicating a fundamental role for the endothelial members of this family, E- and P-selectin, in a variety of inflammatory states and models. Although originally identified as the lymph node-specific lymphocyte homing receptor, L-selectin has also been suggested to play an important role in leukocyte recruitment to sites of inflammation. We have recently demonstrated, using L-selectin-deficient mice, that defects in contact hypersensitivity (CHS) responses are in essence due to the inability of T cells to home to and be sensitized within peripheral lymph nodes, whereas nonspecific effector cells are fully capable of entry into sites of cutaneous inflammation (Catalina et al, J Exp Med 184:2341, 1996). In the present study, we perform an analysis of adhesion molecule usage in two models of skin inflammation and show in both L-selectin-deficient as well as wild-type mice that a combination of P- and E-selectin is crucial for the development of both acute (croton oil) and chronic (contact hypersensitivity) inflammation at sites of the skin, whereas L-selectin does not appear to play a significant role. Moreover, alpha4 integrins are shown to be integral to a CHS but not an acute irritant response, whereas CD44 does not significantly contribute to either. These results provide a systematic examination in one study of major adhesion molecules that are critical in acute and chronic skin inflammation. They reinforce the essential role of the collaboration of E- and P-selectin in both specific and nonspecific skin inflammatory responses and the importance of alpha4 in the specific response only. In addition, they substantiate only a limited role, if any, for L-selectin in these cutaneous effector mechanisms and demonstrate the essential equivalence in this analysis of L-selectin-deficient mice compared with normal mice treated with blocking antibodies.

Modulation of picryl chloride-induced contact hypersensitivity reaction in mice by nitric oxide.

We have studied the possible involvement of nitric oxide (NO) in the contact hypersensitivity reaction. A biphasic response of ear swelling was observed at 2 h (early phase) and 24 h (late phase) after application of the antigen to picryl chloride (PC1)-sensitized CBA/J mice. Intravenous injection of NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), at the time of PC1 challenge, inhibited in a concentration-dependent fashion the antigen-induced contact hypersensitivity reaction. Low-dose (1 mg/kg) L-NAME inhibited the early-phase reaction but not the late-phase reaction. High-dose (250 mg/kg) L-NAME inhibited both early- and late-phase reactions. D-NAME (enantiomer of L-NAME) did not inhibit the antigen-induced ear swelling. High-dose (250 mg/kg) L-arginine increased both early and late phase reactions. D-Arginine (enantiomer of L-arginine) did no increase the antigen-induced ear swelling. L-NAME injection, however, did not suppress phenol-induce irritant inflammation. Treatment of mice undergoing PC1-induced contact hypersensitivity reaction with L-NAME reduced the production of interleukin-2 and interferon-gamma by draining lymph node cells. Treatment with L-arginine, on the other hand increased the production of interleukin-2 and interferon-gamma. These results suggest that NO plays a modulating role in contact hypersensitivity reaction.

Enhanced inflammation and immunosuppression by ultraviolet radiation in xeroderma pigmentosum group A (XPA) model mice.

Xeroderma pigmentosum group A (XPA) gene-deficient mice were developed by gene targeting in mouse embryonic stem cells. To examine whether these XPA-model mice display photodermatologic abnormalities similar to those in human xeroderma pigmentosum, we investigated the effects of acute ultraviolet radiation on the homozygous (-/-) mice compared to the wild type (+/+) and heterozygous (+/-) mice. A single irradiation with ultraviolet B or topical psoralen plus ultraviolet A treatment induced stronger and longer lasting ear swelling in the (-/-) mice than in the (+/+) and (+/-) mice. Histologic changes including epidermal necrosis, cell infiltration, and sunburn cell formation after ultraviolet B radiation were more prominent in the (-/-) model mice than in the control mice. The (-/-) model mice showed damage of ADPase(+)Langerhans cells at a lower ultraviolet B dose than did the control mice. Moreover, the reappearance of ADPase(+)Langerhans cells after ultraviolet B radiation was delayed in the (-/-) mice compared to the control mice. Although contact hypersensitivity was induced equally in all mice, ultraviolet B-induced local and systemic immunosuppression were greatly enhanced in the (-/-) model mice. The data suggest that the XPA gene-deficient mice may be a useful model of human XPA, because the responses to UV radiation in the mice were very similar to those in the patients with XPA. Moreover, it is possible that enhanced ultraviolet immunosuppression is involved in the development of skin cancers in xeroderma pigmentosum.

Tachyphylaxis to histamine-induced wheal suppression by topical 0.05% clobetasol propionate in normal versus croton oil-induced dermatitic skin.

BACKGROUND: Patients often tell about reduced effectiveness of topical steroids on repeated use. Tachyphylaxis to these agents has been demonstrated in humans for vasoconstriction and histamine-induced wheal suppression in normal skin, but not in diseased skin. Relevance of these data to diseased skin is not clear. Further, the clinical impression does not appear to match tachyphylaxis shown in normal skin with regard to the time course. OBJECTIVES: To examine whether tachyphylaxis to histamine-induced wheal suppression by a topical steroid occurs in dermatitic skin and to determine its time course vis-à-vis normal skin. METHODS: Pharmacodynamic response to 0.05% clobetasol propionate applied daily under occlusion was measured by histamine-induced wheal suppression assay in 10 individuals. This test was performed on a steroid-treated normal site, on a steroid-treated site where dermatitis was induced by occlusive application of 40% croton oil, and on a vehicle-treated site in each individual at different intervals up to 14 days. RESULTS: Suppression of wheal volume started from second day in steroid-treated sites. There was significant difference in the wheal volume in steroid treated normal vs. dermatitic sites from day 2 to day 10. Maximum wheal suppression occurred earlier in dermatitic skin (day 4 vs. day 6). After this, the volume of wheal started increasing and became equal to control (complete tolerance) on 12th day in dermatitic skin and on 14th day in normal skin. CONCLUSIONS: Time courses of tachyphylaxis to the action of 0.05% clobetasol propionate were significantly different in normal skin and dermatitic skin. Complete tolerance occurred earlier in dermatitic skin compared to normal skin.

Topical cis-urocanic acid suppresses both induction and elicitation of contact hypersensitivity in BALB/C mice.

Cis-urocanic acid, converted from trans-urocanic acid in stratum corneum by ultraviolet B irradiation, has been shown to impair contact hypersensitivity induction. To study whether topical cis-urocanic acid also alters contact hypersensitivity elicitation, as well as immediate hypersensitivity and acute irritation, we treated mice with 1% topical cis-urocanic acid or vehicle prior to induction or elicitation of hypersensitivity to contact allergen oxazolone or respiratory allergen trimellitic anhydride or prior to acute irritation from croton oil. Topical cis-urocanic acid suppressed both induction and elicitation of contact hypersensitivity to oxazolone. However, no effect by cis-urocanic acid on induction or elicitation of trimellitic anhydride allergy or croton oil irritation was seen. The possible efficacy of topical cis-urocanic acid as a treatment of inflammatory skin diseases responsive to ultraviolet B irradiation may be worthwhile to investigate.

Role of nitric oxide in the vasodilator but not exudative component of mustard oil-induced inflammation in rat skin.

The participation of nitric oxide (NO) in the neurogenic inflammatory reaction of the rat hindpaw skin to topical application of mustard oil was examined by the use of NG-nitro-L-arginine methyl ester (L-NAME, 43 mumol kg-1 i.v.), an inhibitor of NO formation. Control rats received the same dose of the inactive enantiomer D-NAME. Vasodilatation was recorded by contactless infrared emission thermography, and plasma protein exudation was measured by the Evans Blue leakage technique and by measurement of the paw volume in anaesthetized rats. L-NAME reduced the cutaneous hyperaemia caused by topical administration of mustard oil by about 50% but did not change the exudative reaction to mustard oil. These findings indicate that NO plays a mediator role in the vasodilator component of neurogenic inflammation in the rat paw skin, whereas the increase in vascular permeability does not appear to depend on NO.