The role of interleukin-1ß in the immune response to contact allergens.

Interleukin-1ß (IL-1ß) is an important pro-inflammatory cytokine that has an effect on almost every cell lineage in the body. By blocking IL-1ß and investigating the IL-1ß signaling pathway, several studies have demonstrated a central role of IL-1ß in the response to contact allergens. This review summarizes the current literature regarding the basic immunological mechanisms mediated by IL-1ß in the different phases of allergic contact dermatitis (ACD) and highlights potential IL-1ß-targeted treatment options, which in the future may be relevant in the treatment of patients with ACD. This review is based primarily on studies using various mouse models and human in vitro studies, since clinical studies on the effect of IL-1ß in ACD are lacking.

Contact Dermatitis in the Elderly: Predisposing Factors, Diagnosis, and Management.

Increased aging of the general population is a well-known fact with serious effects on health systems worldwide. Skin aging involves various immunological and structural changes that increase the risk of numerous skin diseases such as contact dermatitis. Contact dermatitis is characterized by an inflammation of the skin caused by an interaction between the skin and external agents and is divided into irritant and allergic contact dermatitis. Irritant contact dermatitis occurs on skin areas directly exposed to irritant substances, which results in a stream of pro-inflammatory cytokines mediating the skin injury. Asteatotic and perineal irritant contact dermatitis are the most important subtypes of irritant contact dermatitis in the elderly. Allergic contact dermatitis is a T cell-mediated inflammatory reaction and requires a prior sensitization. The most common allergens responsible for allergic contact dermatitis in the elderly are fragrance mix, nickel, and balsam of Peru. Elderly patients with stasis dermatitis, chronic wounds, and chronic venous insufficiency have an increased prevalence of sensitization due to the frequent exposure to topical treatments. In this review, the most common types of contact dermatitis in the elderly are enumerated in order to assist dermatologists and other physicians to identify contact dermatitis in this distinct group of the population.

Contact dermatitis and atopic dermatitis: two tales, an interwoven story.

Atopic dermatitis is a multifactorial disease that can concomitantly occur with irritant or allergic contact dermatitis. The colloquial use of atopic dermatitis and eczema interchangeably has created confusion among patients and providers alike. Atopic skin is a complex entity that involves a defective barrier and biome, an aberrant immune response, and abnormal neural activation, while eczema is a generalized term denoting a particular appearance common to multiple diagnoses including atopic dermatitis and contact dermatitis. The conventional paradigm that simplifies atopic dermatitis and allergic contact dermatitis into distinct Th2 and Th1 processes, respectively, fails to acknowledge potential immunologic intersection points and contributes to impaired disease management. This article will review the complex interplay of atopic dermatitis and contact dermatitis and discuss treatment strategies for recalcitrant cases.

Associations Between Immune Phenotype and Inflammation in Murine Models of Irritant Contact Dermatitis.

Irritant contact dermatitis (ICD), the most common occupational cutaneous illness, is an acute inflammatory response caused by topical irritant exposure. Multiple factors are associated with the manifestation and severity of ICD and contribute to the lack of effective prophylactic and treatment strategies. To determine the pathomechanism of ICD caused by the irritants, benzalkonium chloride (BKC) and JP-8 jet fuel, 2 mouse strains, C57BL/6 and Balb/c, were assessed due to their differential immune predispositions. Dermatitis lesions were obtained for histological examination, cytokine protein expression analysis, and determination of immune cell infiltration via flow cytometric analysis. Following acute (3-day) BKC exposure C57BL/6 skin displayed increased neutrophils and expression of 19 distinct cytokines, but fewer dendritic cells and lower expression of IL-1α and IL-9 as compared with Balb/c skin. Following prolonged (7-day) exposure to BKC, inflammatory cell populations trended similar to 3-day exposure; however, only 6 distinct cytokines were higher in C57BL/6, whereas Balb/c displayed higher expression of IL-27, 28, and 31. Following acute JP-8 exposure, C57BL/6 skin displayed higher levels of γδ T cell infiltration, G and M-CSF expression, but lower populations of neutrophils, monocytes, and dendritic cells compared with Balb/c skin. As with BKC, skin inflammatory cell populations following 7-day JP-8 exposure trended similar to 3-day exposure. However, C57BL/6 skin displayed higher levels of IL-6 and LIF, whereas Balb/c showed increased IL-1ß, IL-27, G-CSF, TNFα, and 7 additional chemokines. These findings further define the pathology of ICD, partially explain individual variation of ICD, and offer insight into biomarkers for risk assessment.

Contact dermatitis and patch testing for the allergist.

OBJECTIVE: To review of contact dermatitis (CD) and its key allergens and provide updates and recommendations for the practicing allergist. DATA SOURCES: Through the use of various scientific search engines (eg, PubMed and MEDLINE), we reviewed literature on CD, patch tests (PTs), key allergens, occupational dermatitis, and treatment. STUDY SELECTIONS: Studies on CD, important allergens, and PTs were considered. RESULTS: Contact-induced dermatitis may be due to allergic CD, irritant CD, systemic CD, contact urticaria, and protein CD. Key allergens include metals (nickel, gold), topical medicaments (topical corticosteroids), and cosmetics and personal care products (fragrances and preservatives such as methyl- and methylchloro-isothiazolinone). Present relevance of a positive PT result is the combination of definite, probable, and possible relevance and should be correlated with the patient's history and physical examination. Treatment of allergic CD includes identification of relevant allergens, patient education, avoidance, and provision of alternative products the patient can use. CONCLUSION: CD is a common inflammatory skin disease and should be suspected in patients presenting with acute, subacute, or chronic dermatitis. The gold standard for diagnosing allergic CD is a PT. This article provides practical recommendations for the diagnosis and management of CD commonly seen by the allergist in their practice.

IRRITANT AND ALLERGIC CONTACT DERMATITIS - SKIN LESION CHARACTERISTICS.

- Contact skin lesions may be the consequences of contact with various irritants or allergens, or due to other factors (e.g., UV radiation, microbials), intrinsic factors (e.g., in autoimmune responses), or even their combination. There are many substances related to irritant contact dermatitis (CD), causing irritant or toxic effects, e.g., chemical and physical agents, plants, phototoxic agents, airborne irritants, etc. Impaired barrier function (e.g., aberrancies in epidermal pH buffering capabilities) also participates by promoting bacterial biofilms and creating an environment favoring sensitization. Development of allergic CD skin lesions includes complex immune pathways and inflammatory mediators, influenced by both genetic (predominantly filaggrin mutations) and environmental triggers. In the pathogenesis of allergic CD, antimicrobial peptides play a prominent role; they are produced by various skin cells (e.g., keratinocytes, sebocytes) and move to inflamed lesions during an inflammation process. Also, in allergic CD skin lesions, the skin shows different types of immune responses to individual allergens, although clinical manifestations do not depend on the causative allergen type, e.g., nickel stimulates immune activation primarily of the Th1/Th17 and Th22 components. Also important are alarmins, proteases, immunoproteomes, lipids, natural moisturizing factors, tight junctions, smoking, etc. We expect that future perspectives may reveal new pathogenetic factors and scientific data important for the workup and treatment of patients with CD.

Debunking the Myth of Wool Allergy: Reviewing the Evidence for Immune and Non-immune Cutaneous Reactions.

Although wool is commonly believed to cause irritant (non-immune) and hypersensitivity (immune) cutaneous reactions, the evidence basis for this belief and its validity for modern garments have not been critically examined. Publications from the last 100 years, using MEDLINE and Google Scholar, were analysed for evidence that wool causes cutaneous reactions, both immune-mediated (atopic dermatitis exacerbation, contact urticaria, allergic contact dermatitis) and non-immune-mediated (irritant contact dermatitis, itch). Secondary aims of this paper were to examine evidence that lanolin and textile-processing additives (formaldehyde, chromium) cause cutaneous reactions in the context of modern wool-processing techniques. Current evidence does not suggest that wool-fibre is a cutaneous allergen. Furthermore, contact allergy from lanolin, chromium and formaldehyde is highly unlikely with modern wool garments. Cutaneous irritation from wool relates to high fibre diameters (≥ 30-32 µm). Superfine and ultrafine Merino wool do not activate sufficient c-fibres to cause itch, are well tolerated and may benefit eczema management.

Association of MHC region SNPs with irritant susceptibility in healthcare workers.

Irritant contact dermatitis is the most common work-related skin disease, especially affecting workers in "wet-work" occupations. This study was conducted to investigate the association between single nucleotide polymorphisms (SNPs) within the major histocompatibility complex (MHC) and skin irritant response in a group of healthcare workers. 585 volunteer healthcare workers were genotyped for MHC SNPs and patch tested with three different irritants: sodium lauryl sulfate (SLS), sodium hydroxide (NaOH) and benzalkonium chloride (BKC). Genotyping was performed using Illumina Goldengate MHC panels. A number of SNPs within the MHC Class I (OR2B3, TRIM31, TRIM10, TRIM40 and IER3), Class II (HLA-DPA1, HLA-DPB1) and Class III (C2) genes were associated (p < 0.001) with skin response to tested irritants in different genetic models. Linkage disequilibrium patterns and functional annotations identified two SNPs in the TRIM40 (rs1573298) and HLA-DPB1 (rs9277554) genes, with a potential impact on gene regulation. In addition, SNPs in PSMB9 (rs10046277 and ITPR3 (rs499384) were associated with hand dermatitis. The results are of interest as they demonstrate that genetic variations in inflammation-related genes within the MHC can influence chemical-induced skin irritation and may explain the connection between inflamed skin and propensity to subsequent allergic contact sensitization.

Skin Barrier Function and Allergens.

The skin is an important barrier protecting us from mechanical insults, microorganisms, chemicals and allergens, but, importantly, also reducing water loss. A common hallmark for many dermatoses is a compromised skin barrier function, and one could suspect an elevated risk of contact sensitization (CS) and allergy following increased penetration of potential allergens. However, the relationship between common dermatoses such as psoriasis, atopic dermatitis (AD) and irritant contact dermatitis (ICD) and the development of contact allergy (CA) is complex, and depends on immunologic responses and skin barrier status. Psoriasis has traditionally been regarded a Th1-dominated disease, but the discovery of Th17 cells and IL-17 provides new and interesting information regarding the pathogenesis of the disease. Research suggests an inverse relationship between psoriasis and CA, possibly due to increased levels of Th17 cells and its associated cytokines. As for AD, a positive association to CS has been established in epidemiological studies, but is still unresolved. Experimental studies show, however, an inverse relationship between AD and CS. The opposing and antagonistic influences of Th1 (CS) and Th2 (AD) have been proposed as an explanation. Finally, there is convincing evidence that exposure to irritants increases the risk of CS, and patients with ICD are, therefore, at great risk of developing CA. Skin irritation leads to the release of IL-1 and TNF-α, which affects the function of antigen-presenting cells and promotes their migration to local lymph nodes, thus increasing the probability of CS and ultimately the development of CA.

Human sebum extract induces barrier disruption and cytokine expression in murine epidermis.

BACKGROUND: Previous studies have shown that human sebum may play a role in barrier function but with much debate. OBJECTIVE: To elucidate the effects of human sebum on skin barrier function. METHODS: We used hairless mouse skin to study the functional and morphological alternation of epidermis after the application of human sebum. RESULTS: The results showed a significant increase in transepidermal water loss and erythema value, and a decrease in skin hydration, accompanied by epidermal hyperplasia with parakeratosis following sebum application. Nile red staining together with electron microscopic examination confirmed the underlying mechanisms for sebum-induced barrier disruption are related directly to the interaction of sebum with the intracellular lipid lamellae of the SC, thereby leading to the increase in the fluidity of SC intracellular lipids as demonstrated by ATR-FTIR measurement. An inflammatory reaction characterized by an enhanced cytokine cascade, including up-regulation of TNF-α, IL-1α and IL-6, was also observed. On the other hand, there were insignificant expression of thymic stromal lymphopoietin and unchanged serum levels of IgE, suggesting non-immunogenic stimulation by sebum treatment. CONCLUSION: It may be concluded that inflammation induced by excess amount of sebum is more likely an irritant contact dermatitis rather than an allergic one. Moreover, these findings implicated possible relationships between sebum, irritant contact dermatitis, and seborrheic dermatitis.

Toll-like receptor 3 increases allergic and irritant contact dermatitis.

There is increasing recognition of the role of Toll-like receptor 3 (TLR3) in noninfectious inflammatory diseases, but the function of TLR3 in inflammatory skin diseases is unclear. We investigated the functions of TLR3 in allergic and irritant contact dermatitis (ICD). The contact hypersensitivity (CHS) response was lower in Toll-like receptor 3 knockout (Tlr3 KO) mice, and was greater in TLR3 transgenic (Tg) mice than in wild-type (WT) mice after challenge with 2,4,6-trinitro-1-chlorobenzene. Adoptive transfer of immunized lymph node cells from Tlr3 KO mice induced CHS in WT recipients. In contrast, adoptive transfer of those from WT mice did not fully induce CHS in Tlr3 KO recipients. The ICD reaction following croton oil application was lower in Tlr3 KO mice, and was greater in TLR3 Tg mice than in WT mice. Maturation, migration, and antigen presentation of dendritic cells and proliferation of lymphocytes between WT mice and Tlr3 KO mice were comparable. These results show that TLR3 enhances antigen-independent skin inflammation in the elicitation phase of allergic contact dermatitis and in ICD.

Tracking and quantification of dendritic cell migration and antigen trafficking between the skin and lymph nodes.

Skin-derived dendritic cells (DCs) play a crucial role in the maintenance of immune homeostasis due to their role in antigen trafficking from the skin to the draining lymph nodes (dLNs). To quantify the spatiotemporal regulation of skin-derived DCs in vivo, we generated knock-in mice expressing the photoconvertible fluorescent protein KikGR. By exposing the skin or dLN of these mice to violet light, we were able to label and track the migration and turnover of endogenous skin-derived DCs. Langerhans cells and CD103(+)DCs, including Langerin(+)CD103(+)dermal DCs (DDCs), remained in the dLN for 4-4.5 days after migration from the skin, while CD103(-)DDCs persisted for only two days. Application of a skin irritant (chemical stress) induced a transient >10-fold increase in CD103(-)DDC migration from the skin to the dLN. Tape stripping (mechanical injury) induced a long-lasting four-fold increase in CD103(-)DDC migration to the dLN and accelerated the trafficking of exogenous protein antigens by these cells. Both stresses increased the turnover of CD103(-)DDCs within the dLN, causing these cells to die within one day of arrival. Therefore, CD103(-)DDCs act as sentinels against skin invasion that respond with increased cellular migration and antigen trafficking from the skin to the dLNs.

Dermatitis alérgica de contacto por cosméticos en un consultorio alergoinmunologico / Allergic dermatitis of contact by cosmetics in a alego-immunological doctor`s office

La dermatitis de contacto (DC) es una respuesta inflamatoria de la piel, como resultado del contacto de la misma con múltiples factores externos, frecuentemente contenidos en cosméticos. Las pruebas del parche son el pilar diagnostico. Se evaluó la prevalencia de la dermatitis alérgica de contacto por cosméticos, determinando las relaciones epidemiológicas como: edad, sexo, localización, ocupación y sensibilización. El 70% de los pacientes estudiados fueron DAC y el 30% fuerondermatitis irritativas por contacto (DIC). El 57% de las dermatitis alérgicas estaban asociadas a cosméticos,predominando en el sexo femenino.

Contact dermatitis (AD) is an inflammatory response of the skinas a result of contact with multiple external factors, often containedin cosmetics. Patch tests are the diagnostic pillar. Prevalence of allergic contact dermatitis to cosmetics was evaluatedby determining the epidemiological relationships as age, sex, location, occupation and awareness.70% of the patients studied were DAC and 30% were irritant contact dermatitis (ICD).57% of allergic dermatitis were associated with cosmetics, predominantly in females.

Cytokines and chemokines in irritant contact dermatitis.

Irritant contact dermatitis is a result of activated innate immune response to various external stimuli and consists of complex interplay which involves skin barrier disruption, cellular changes, and release of proinflammatory mediators. In this review, we will focus on key cytokines and chemokines involved in the pathogenesis of irritant contact dermatitis and also contrast the differences between allergic contact dermatitis and irritant contact dermatitis.

Anti-inflammatory effect of a retrovirus-derived immunosuppressive peptide in mouse models.

BACKGROUND: Short dimeric or mulitmeric peptides derived from a highly conserved stretch of amino acids from gammaretroviral envelope proteins has been found to have immunosuppressive properties in vitro. Here we test the hypothesis that such immunosuppressive peptides may serve as immunomodulatory reagents for treatment of inflammatory disorders. RESULTS: The anti-inflammatory effect of a synthetic retrovirus-derived immunosuppressive peptide of 17 amino acids was tested in two murine skin inflammation models, a TPA-induced acute toxic contact eczema model and an oxazolone-induced allergic contact dermatitis. Overall, mice (n = 24) treated with a topically applied cream containing the dimeric immunosuppressive peptide exhibited a reduction of 28.8% in ear thickness (range 20.1-42.5), whereas the application of a scrambled peptide dimer or a monomer of the immunosuppressive peptide remained without effect (p = 0.028). Furthermore, ear biopsies from mice treated with the dimeric immunosuppressive peptide showed a significant reduction in mRNA of the pro-inflammatory cytokines TNF-α, IL-17C, and IL-6 as well as the chemokine CXCL2 compared to mice treated with control peptides. CONCLUSION: Using two murine skin inflammation models, we show that an immunosuppressive retroviral peptide is capable of reducing inflammatory disorders. The results indicate that virus-derived immunosuppressive peptides capable of down-regulating several proinflammatory cytokines may represent a novel class of drugs for the treatment of excess inflammation.

Discovery of GW870086: a potent anti-inflammatory steroid with a unique pharmacological profile.

BACKGROUND AND PURPOSE: Glucocorticoids are highly effective therapies for a range of inflammatory diseases. Advances in the understanding of the diverse molecular mechanisms underpinning glucocorticoid action suggest that anti-inflammatory molecules with reduced side effect liabilities can be discovered. Here we set out to explore whether modification of the 17α position of the steroid nucleus could generate molecules with a unique pharmacological profile and to determine whether such molecules would retain anti-inflammatory activity. EXPERIMENTAL APPROACH: The pharmacological properties of GW870086 were compared with fluticasone propionate (FP) using a range of cellular and in vivo model systems, including extensive gene expression profiling. KEY RESULTS: GW870086 repressed inflammatory cytokine release from lung epithelial cells in a similar manner to FP but antagonized the effect of dexamethasone on MMTV-driven reporter gene transactivation. GW870086 had a strong effect on the expression of some glucocorticoid-regulated genes (such as PTGS2), while having minimal impact on the expression of other known target genes (such as SGK). GW870086 retained the ability to strengthen tight junctions in epithelial cell culture but, unlike FP, was unable to protect the culture from elastase-mediated damage. In murine models of irritant-induced contact dermatitis and ovalbumin-induced allergic inflammation, GW870086 showed comparable anti-inflammatory efficacy to FP. CONCLUSION AND IMPLICATIONS: GW870086 is a potent anti-inflammatory compound with a unique ability to regulate only a subset of those genes that are normally affected by classical glucocorticoids. It has the potential to become a new topical steroid with a different safety profile to existing therapies.