Abnormal epidermal barrier in the pathogenesis of contact dermatitis

A crucial role of the epidermal permeability barrier is obvious in contact dermatitis. An intact skin barrier prevents the penetration of harmful substances into the skin. Irritants and allergens that stay on the skin surface and come into contact with the stratum corneum only do not harm the skin. After disruption of the skin barrier, however, irritants may penetrate into the living epidermal layers, injure the keratinocyte membrane, and release cytokines, which leads to inflammation and to irritant contact dermatitis. The skin barrier is often disrupted by chronic exposure to water plus detergents, solvents, or other irritants. A disrupted barrier in irritant contact dermatitis also allows for the penetration of allergens. Allergens may come into contact with Langerhans and T cells, induce immunological reactions, and cause inflammation, which results in allergic contact dermatitis. Treatments in contact dermatitis should restore the skin barrier to prevent relapse of the disease. Topical corticosteroids, most often used in treating contact dermatitis, reduce immunological reactions and inflammation but do not lead to a complete barrier repair. Skin barrier repair is more complete after treatment with calcineurin inhibitors and bland lipid-based emollient; therefore, these preparations should be preferred for long-term treatment of contact dermatitis.     

Contact dermatitis

Contact dermatitis is a common skin disease caused by contact with irritants or allergens. Irritant contact dermatitis is a result of nonspecific irritant factors, which cause activation of mainly innate immunity, resulting in skin inflammation. Contact hypersensitivity, which manifests itself as allergic contact dermatitis, is result of adaptive immune response, where sensitization to hapten-carrier complexes leads to T-cell-mediated contact allergy. Subsequent contact with the hapten results in skin inflammation. This review concentrates on the role of cutaneous receptors in contact dermatitis and highlights potential targets for treatment interventions.     

Comparison of two in vitro dendritic cell maturation models for screening contact sensitizers using a panel of methacrylates

Allergen-induced emigration and maturation of dendritic cells (DC) are pivotal steps in sparking off allergic contact dermatitis. In vitro models, reflecting these steps, may provide tools for assessment of sensitizing capacities of putative contact allergens. Here, we evaluated the applicability of such models for a panel of methacrylate congeners, the sensitizing properties of which were established previously in clinical and experimental animal studies. First, using interleukin-4 (IL-4)/granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced, blood monocyte-derived DC, hapten-induced up-regulation of maturation/ activation markers, including CD80, CD83, CD86, chemokine receptors CXCR4 and CCR5, as well as the drug resistance related molecules P-glycoprotein (Pgp) and lung resistance protein (LRP), were monitored by flow cytometry. Of note, whereas CD86 and CXCR4 were most sensitive in discriminating between the contact sensitizers and irritants included in the panel, i.e. sodium dodecyl sulphate (SDS) and croton oil (CO), assessment of CD83 and LRP expression reflected the relatively lower sensitizing capacity of methyl methacrylate. Second, using ex vivo skin explant cultures, allergen-induced LC migration from epidermal to basal membranous and dermal skin structures was most reliably monitored by CDla, as compared with Pgp, LRP, HLA-DR or CD54 staining. The extent of CD1a+ LC migration was found to closely correlate with the sensitizing capacities of the panel of test compounds. These results support the view that both in vitro models can provide valuable data on contact sensitizing properties, and add chemokine receptors and drug resistance related molecules to the list of DC membrane markers revealing allergenic signaling.     

Non-steroidal and steroidal anti-inflammatory drugs vary in their modulation of dendritic cell function in the elicitation phase of allergic contact dermatitis

The role of dendritic cells (DCs) in allergic contact dermatitis has been clearly demonstrated for the induction phase. However, the situation during the elicitation phase is very complex within a distinct inflammatory response. This study was performed to exploit DC migration in the elicitation phase in a mouse model of allergic contact dermatitis and to evaluate the effects of steroidal and non-steroidal anti-inflammatory drugs (NSAIDs) on DC migration through skin in the elicitation phase of allergic contact dermatitis. Topically and systemically administered acetylsalicylic acid (ASA) did not reduce the inflammatory response. However, systemically administered ASA significantly reduced the DC migration to the draining lymph node. In contrast, topically administered indomethacin reduced the inflammatory response, but had only minor effects on DC migration, whereas diflorasone diacetate reduced both inflammatory reaction and DC migration. Thus, NSAIDs may differ in their inhibitory action in immunological inflammation.     

Contact Dermatitis in Older Adults

Contact dermatitis is a significant health problem affecting the elderly. Impaired epidermal barrier function and delayed cutaneous recovery after insult enhances susceptibility to both irritants and allergens. Exposure to more numerous potential sensitizers and for greater durations influences the rate of allergic contact dermatitis in this population.Medical co-morbidities, including stasis dermatitis and venous ulcerations, further exacerbate this clinical picture. However, while these factors tend to increase the degree of sensitization in the elderly, waning immunity can actually decrease such a propensity. This interplay of both intrinsic and extrinsic factors makes a generalization on trends for contact dermatitis in older adults challenging. The literature has varying reports on the overall incidence of allergic contact dermatitis with advancing age. Nevertheless, it does clearly show that sensitivity to topical medicaments increases with age. Irritant contact dermatitis studies are more consistent, with less reactivity (to irritants) in older compared with younger skin. Diagnosis of both irritant and allergic contact dermatitis is based on a thorough history, complete skin examination, and comprehensive patch testing. The mainstay of therapy is avoidance of the offending chemical substances and the use of topical along with systemic therapies, depending on the severity of the condition.     

Epidemiology of occupational skin disease in Singapore 1989-1998

This is an epidemiologic study of occupational skin disease in Singapore. All patients diagnosed with occupational dermatoses in the National Skin Centre, Singapore, over the 10-year period 1989-1998 were studied retrospectively. Irritant contact dermatitis was found to be more common than allergic contact dermatitis. The major sources of occupational dermatitis in Singapore were the metal/engineering, building/construction, electrical/electronics and transport industries. The main irritants were detergents/wet work, solvent and oil/grease. The main allergens were chromate, rubber chemicals and nickel. We concluded that the main sources of occupational skin disease and main allergens in Singapore had remained the same compared to a similar study of occupational skin diseases in 1984-85. Weak irritants are still the predominant causes of occupational irritant contact dermatitis, though the main irritants have changed compared to the previous study, where cutting fluids, cement and solvent were the most common irritants.     

Skin irritants and contact sensitizers induce Langerhans cell migration and maturation at irritant concentration

Skin irritants and contact allergens reduce the number of Langerhans cells (LCs). It has been assumed that this reduction is due their migration to the draining lymph node (LN) for initiating immune sensitization in a host. Skin irritation, however, as opposed to contact allergy is not considered to be an immunological disease. Nevertheless, skin irritants are also known for their adjuvant-like effects on contact allergy, resulting in skin hypersensitivity reactions like toxic dermatitis. The human organotypic skin explant culture (hOSEC) model is used to study the characteristics of chemical-induced migration of CD1a(+) LCs out of the epidermis in relation to irritancy or toxicity. We analysed cells emigrating out of hOSEC for CD1a(+) LCs, CD83(+) mature dendritic cells (DCs) and CCR7(+) LN homing cells. After exposure to a toxic concentration of a non-immunogenic irritant, an increase of CD1a(+)CD83(+) LCs was found in the culture medium. A non-toxic concentration of an sensitizer induced an increase of CD1a(+) cells. About 50% of skin emigrating CD1a(+) LCs were CD83(-) (immature) but all were CCR7(+). Skin irritation by both non-allergenic and allergenic compounds induces LC migration and maturation. In contrast, only allergenic compounds induced LC migration with partial maturation at subtoxic concentration. This effectively demonstrates that irritation is physiologically needed stimuli for inducing LC maturation.     

The Roles of Reactive Oxygen Species Produced by Contact Allergens and Irritants in Monocyte-derived Dendritic Cells

Background

Although reactive oxygen species (ROS) have been produced in both mouse bone marrow-derived dendritic cells (DCs) and XS-106 DCs by contact sensitizers and irritants in previous studies, the generation of ROS in human monocyte-derived DCs (MoDCs) and their role in contact hypersensitivity (CHS) has yet to be elucidated.

Objective

The purpose of this study was to determine whether contact allergens and irritants induce ROS in MoDCs and, if so, to evaluate the role of contact allergen and irritant induced-ROS in MoDCs in CHS.

Methods

Production of ROS was measured by 5-(and-6)-chloromethyl-2'',7''-dichlorodihydrofluorescein diacetate (CM-H₂DCFDA) assay. Surface CD86 and HLA-DR molecules were detected by flow cytometry. Protein carbonylation was detected by Western blotting.

Results

ROS were produced by contact allergens such as dinitrochlorobenzene (DNCB) and thimerosal and the irritant benzalkonium chloride (BKC). DNCB-induced, but not BKC-induced, ROS increased surface CD86 and HLA-DR molecules on MoDCs and induced protein carbonylation. These changes were reduced in the presence of antioxidant N-acetyl cysteine.

Conclusion

Our results suggest that DNCB-induced ROS may be different from those induced by irritant BKC. The DNCB-induced ROS may be associated with the CHS response, because they activate surface molecules on DCs that are important for generating immune reactions.     

An update on airborne contact dermatitis: 2007–2011

Background. Reviews on irritant and allergic airborne contact dermatitis have been previously reported in the literature. Materials and methods. Here, we present an update based on recently published airborne‐induced skin reactions. For this survey, we screened the journals Contact Dermatitis, Dermatitis, and included relevant articles from other journals during the period January 2007 to December 2011. We also present the airborne cases observed in our department during the same time period. Results. This survey provides an updated list of causal agents that have produced airborne allergic contact dermatitis, and briefly mentions some other types of skin reaction induced by airborne exposure. The sources of the reactions are multiple: drugs; plants, natural resins, and wood allergens; plastics, rubbers, and glues; preservatives and other chemicals; and metals. Conclusions. Airborne contact dermatitis is frequent, and most of the airborne allergens (and irritants) identified are in occupational settings. Drugs and preservatives have recently become more important causes. Dermatologists and occupational physicians need to be aware of them.     

Phenotyping of epidermal dendritic cells allows the differentiation between extrinsic and intrinsic forms of atopic dermatitis

Atopic dermatitis (AD) is a clinically characteristic, chronic inflammatory skin disease of unknown origin. IgE-mediated uptake and antigen focusing of environmental allergens by dendritic cells (DCs) is assumed to be a central immunopathogenetic event. A so-called intrinsic type of AD (IAD) has been delineated from the more common extrinsic AD (EAD) by normal serum IgE levels, negative RAST tests and negative immediate-type skin reactions towards environmental allergens. The recently characterized human autoantigen Hom S 1 has been proposed to play a part in the pathogenesis of IAD. OBJECTIVES: To compare clinical and laboratory data between patients with IAD and EAD, and to investigate potential differences in the inflammatory micromilieu of the epidermal compartment in IAD and EAD lesions. METHODS: Epidermal DC phenotyping, a recently validated technique based on the three-colour flow cytometric analysis of Langerhans cells and the so-called inflammatory dendritic epidermal cells from epidermal single-cell suspensions, was performed on samples from 69 patients with AD (seven with IAD and 62 with EAD) and 94 controls. RESULTS: Patients with EAD tended to have an earlier onset of disease but similar disease duration and family history of atopic diseases. Quantitative analysis of CD36 expression on DCs as a marker of inflammation, as well as the percentage of inflammatory dendritic epidermal cells in the CD1a+ epidermal DC pool, indicated a comparable disease activity in IAD and EAD. EAD was characterized by a significantly higher FcepsilonRI expression on the CD1a+ epidermal DCs than IAD. Using the FcepsilonRI/FcgammaRII expression ratio as a disease marker for AD, values for IAD fell below the diagnostic cut-off level of 1.5 for this ratio. CONCLUSIONS: While IAD is clinically similar to EAD, the inflammatory microenvironment in this condition seems different from classical EAD and can be distinguished by phenotyping of epidermal DCs.     

Pimecrolimus -- an anti-inflammatory drug targeting the skin

Pimecrolimus is the most recent member of calcineurin inhibitors available for the therapy for inflammatory skin diseases. It targets T-cells and mast cells and inhibits the production and release of cytokines and other inflammatory mediators, as well as the expression of signals essential for the activation of inflammatory T-lymphocytes. Pimecrolimus has a cell-selective mode of action. In contrast to corticosteroids, it does not affect, e.g., Langerhans'cells/dendritic cells (LC/DC), as demonstrated in vitro with human monocyte-derived DC and in vivo with epidermal LC in mice, nor human primary fibroblasts. As shown in vitro with human skin and by comparison of clinical pharmacokinetic data from patients with atopic dermatitis, pimecrolimus permeates less through skin than tacrolimus and much less than corticosteroids. It, thus, has a lower potential for transcutaneous resorption after topical administration, resulting in a lower risk of systemic effects. Pimecrolimus has high anti-inflammatory activity in animal models of skin inflammation, including a model reflecting neurogenic inflammation, but a more favourable balance of anti-inflammatory vs. immunosuppressive activity than tacrolimus. Pimecrolimus does not affect sensitization in a murine model of allergic contact dermatitis and has a lower potency in various models of immunosuppression after systemic administration, compared to tacrolimus. In conclusion, the results of preclinical studies show that pimecrolimus has a selective pharmacological profile, suited for effective and safe treatment for inflammatory skin diseases.     

Contact dermatitis in athletes

Athletes face numerous hazards in their daily activities. An athlete's skin, in particular, endures repeated exposure to trauma, heat, moisture, and numerous allergens and chemicals. These factors combine with other unique and less well-defined genetically predisposing factors in the athlete's skin to cause both allergic contact dermatitis (ACD) and irritant contact dermatitis (ICD). As with other cases of contact dermatitis, these eruptions in athletes present as a spectrum of acute to subacute to chronic dermatitis. Recognizing the unique environmental irritants and allergens encountered by athletes is paramount to facilitate appropriate therapy and prevention. This review comprehensively examines the literature on contact dermatitis in athletes. The different types of contact dermatitis have been classified under sport-specific subheadings. Furthermore, within each subheading, both ACD and ICD types are discussed.     

Impact of TRPV3 on the development of allergic dermatitis as a dendritic cell modulator

The transient receptor potential channel vanilloid subfamily V member 3 (TRPV3), which functions as a thermosensor in keratinocytes, plays an important role in the development of allergic and itchy dermatitis in rodents. Although real‐time PCR analysis using lesional and non‐lesional skin samples from patients with atopic dermatitis showed that TRPV3 was expressed in lesional skin, the role that TRPV3 plays in patients with dermatitis is still relatively obscure. Here, we determined whether TRPV3 was a dendritic cell (DC) modulator using DS‐Nh mice with a gain‐of‐function mutation in TRPV3 (TRPV3Gly573Ser), because increasing skin temperature is associated with the modulation of dermal dendritic cells (DCs). Interestingly, increased responses to haptens by skin and DCs were observed in DS‐Nh mice compared with those from DS mice with wild‐type TRPV3. Increased thymic stromal lymphopoietin (TSLP) responses were also observed in keratinocytes from DS‐Nh mice compared with those from DS mice. Taken together, we propose that the DS‐Nh mouse is a good model to use in order to better understand the role of this orphan channel and that TRPV3 may represent a new therapeutic target in certain types of dermatitis through the control of DCs.     

A comparison of expression of surface-bound immunoglobulin E on antigen-presenting cells in cutaneous tissue between patients with allergic, irritant and atopic dermatitis

The expression of surface-bound immunoglobulin E by dendritic cells within cutaneous tissue has been compared in atopic and contact dermatitis. 45 patients were recruited into 4 groups using clinical criteria and patch testing to a standard series of allergens: atopic (12 cases), allergic contact dermatitis (14 cases), irritant contact dermatitis (10 cases) and the control group (9 cases); using clinical criteria and patch testing to a standard series of allergens. Skin biopsies from each patient were analysed by the indirect immunofluorescence technique. This differentiated 3 patterns of cutaneous IgE distribution: (i) no detectable cutaneous IgE; (ii) detection of IgE solely within the dermis; (iii) detection of IgE within both epidermis and dermis. Detection of IgE within the epidermis was always associated with the presence of IgE within the dermis. In each case, IgE was surface-bound by dendritic cells. Immunoglobulin E was detected within both epidermis and dermis in skin biopsies from 8 (66.7%) atopic patients and 2 (20%) patients with irritant contact dermatitis. No other cases demonstrated IgE deposition within both the epidermis and dermis. Atopic patients were significantly more likely to have detectable IgE deposition, within both epidermis and dermis, than patients with contact dermatitis (allergic and irritant groups combined, p = 0.0011) or controls (p = 0.0049). This finding suggests that the demonstration of IgE within both epidermis and dermis supports a diagnosis of atopic dermatitis. It would therefore be of value in differentiating between atopic and contact dermatitis, where clinical diagnosis is in doubt.     

Murine auricular transepidermal water loss -- a novel approach for evaluating irritant skin reaction in mice

The standard method for evaluating contact allergy in mice is the ear swelling technique. However, in experimental irritant contact dermatitis, the epidermal barrier disruption, that represents a predominant effect of irritants, cannot be assayed by this METHOD: An appropriate method to evaluate barrier disruption is the measurement of transepidermal water loss (TEWL) but to date this has so far been possible only on the trunk of hairless or shaved mice. We therefore developed a new technique to measure the TEWL of mice ears (murine auricular TEWL: MATEWL). After patch testing with irritants and allergens, respectively, we found that the ear swelling method is most suitable for evaluating allergic skin reactions, whereas MATEWL is most appropriate for evaluating irritant skin reactions.     

Occupational allergic contact dermatitis and patch test results of leather workers at two Indonesian tanneries

Background. Tannery workers are at considerable risk of developing occupational contact dermatitis. Occupational skin diseases in tannery workers in newly industrialized countries have been reported, but neither the prevalence of occupational allergic contact dermatitis nor the skin‐sensitizing agents were specifically examined in those studies. Objectives. To assess the prevalence of occupational allergic contact dermatitis in Indonesian tanneries, identify the causative allergens, and propose a tannery work series of patch test allergens. Patients/methods A cross‐sectional study in all workers at two Indonesian tanneries was performed to assess the prevalence of occupational contact dermatitis via a questionnaire‐based interview and skin examination. Workers with occupational contact dermatitis were patch tested to identify the causative allergens. Results. Occupational contact dermatitis was suspected in 77 (16%) of the 472 workers. Thirteen (3%) of these 472 workers were confirmed to have occupational allergic contact dermatitis. Potassium dichromate (9.2%), N,N‐diphenylguanidine (5.3%), benzidine (3.9%) and sodium metabisulfite (2.6%) were found to be the occupationally relevant sensitizers. Conclusions. The sensitization pattern showed some differences from the data in studies reported from other newly industrial countries. We compiled a ‘tannery work series' of allergens for patch testing. A number of these allergens may also be considered for patch testing in patients with (leather) shoe dermatitis.     

FC02.5Investigation of reactions to dental materials

In dentistry there are many potential allergens and irritants. Patients may have an adverse reaction in minutes, hours or days after dental procedures. Dentists use many metals e.g. mercury in amalgam restorations, which may give an oral lichenoid eruption, and gold, and platinum group metals for inlays, crowns or bridges, which may give allergic reactions. Dentists, for dentures, use acrylate resins extensively and traces of which can give rise to allergic symptoms, though most cases are not 'allergic' in origin. Dental personnel have a high frequency of occupational skin problems and may complain of hand dermatitis or itching, facial eruptions or respiratory symptoms. With regard to oral lichenoid lesions, the proportion of patients allergic to mercury on patch testing varies according to series, from 67% down to 8%. In some cases, the mechanism can be irritant as well as allergic. Gold can cause lichenoid eruption or other changes. The role of palladium is still very difficult to judge. Cheilitis is particularly difficult to investigate, as there are many causes. The aetiology is irritant in 33%, allergic contact dermatitis in 25% and atopic eczema in 20%. Benzoates, antioxidants or flavourings in foods sometimes cause lip swelling. Hand dermatitis is common in dental personnel. Common causes are irritancy, latex contact urticaria, and allergic contact dermatitis to acrylates, Myroxolon, fragrance, thiuram and colophonium. In the investigation of reactions in dental patients many things need to be considered and often the cause is not related to the dental materials suspected.     

Immunologie der Kontaktallergie

Contact allergy is a skin disease that is caused by the reaction of the immune system to low molecular weight chemicals. A hallmark of contact allergens is their chemical reactivity, which is not exhibited by toxic irritants. Covalent binding of contact allergens to or complex formation with proteins is essential for the activation of the immune system. As a consequence antigenic epitopes are formed, which are recognized by contact allergen-specific T cells. The generation of effector and memory T cells causes the high antigen specificity and the repeated antigen-specific skin reaction of contact allergy. New findings reveal that the less specific reaction of the innate immune system to contact allergens closely resembles the reaction to an infection. Therefore, contact allergy can be viewed as an immunologic misunderstanding since the skin contact with chemical allergens is interpreted as an infection. The growing understanding of the molecular and cellular pathologic mechanisms of contact allergy can aid the development of specific therapies and of in vitro alternatives to animal testing for the identification of contact allergens.     

A preliminary report of the occupation of patients evaluated in patch test clinics.

BACKGROUND: The interplay between the occupational environment and worker's skin can result in contact dermatitis of both irritant and allergic types. Other forms of dermatitis can also be influenced by occupational exposures. OBJECTIVE: The aim of this study is to compare the occupations and allergens of occupational contact dermatitis cases with nonoccupational contact dermatitis cases. METHODS: Diagnostic patch testing with allergens of the North American Contact Dermatitis Group and occupational coding by the National Institute for Occupational Safety and Health methods. RESULTS: Of 2,889 patients referred for evaluation of contact dermatitis, 839 patients (29%) were found to have occupational contact dermatitis. Of the 839 cases deemed occupational, 455 cases (54%) were primarily allergic in nature and 270 cases (32%) were primarily irritant in nature. The remaining 14% were diagnoses other than contact dermatitis, aggravated by work. The occupation most commonly found to have allergic contact dermatitis was nursing. Allergens strongly associated with occupational exposure were thiuram, carbamates, epoxy, and ethylenediamine. CONCLUSION: Some contact allergens are more commonly associated with occupational contact dermatitis. Nursing and nursing support are occupations most likely to be overrepresented in contact dermatitis clinics.     

Turnover and kinetics of epidermal langerhans cells and their dendritic precursor cells in experimental contact dermatitis

The numerical density of epidermal Langerhans cells (LCs) in contact sensitivity and toxic contact dermatitis is still a matter of controvery, mainly due to changes in the phenotypic markers of this antigen-presenting cell during the skin reactions. Since the electron microscopic detection of Birbeck granules is the most reliable marker for the identification of normal and pathologically altered LCs, we performed an ultrastructural-morphometric time-course analysis to evaluate their epidermal turnover in the earskin of BALB/c mice after painting the ears with the hapten 2,4-dinitrofluorobenzene and the irritant croton oil. The counts revealed degeneration and depletion of epidermal LCs in both allergic and toxic dermatitis. In contrast, a slightly increased number of activated epidermal LCs was found during contact sensitization. All experimental procedures resulted in an enhanced immigration of so-called indeterminate dendritic cells which also became ultrastructurally activated and often showed Birbeck granule-like formations at their cell membrane. Immunohistochemistry with the monoclonal antibody 4F7, a new marker for dendritic precursor cells of LCs, demonstrated a significant increase in these accessory cells in the epidermis. Our results indicate that contact sensitivity and toxic skin reactions are characterized by complex but distinct changes in the turnover, kinetics and cellular properties of epidermal LCs and their dendritic precursor cells. Received: 16 March 1995