CD4+ T cells producing interleukin (IL)‐17, IL‐22 and interferon‐γ are major effector T cells in nickel allergy

Background It has been suggested that interleukin (IL)‐17 and IL‐22 play important roles in the elicitation of human allergic contact dermatitis; however, the frequencies of T cell subtypes producing IL‐17 and IL‐22 in human allergic contact dermatitis are unknown. Objectives To determine the frequencies of CD4⁺, CD8⁺ and γδ T cells producing IL‐17, IL‐22 and interferon (IFN)‐γ in the blood and skin from nickel‐allergic patients. Patients/materials/methods Blood samples were collected from 14 patients and 17 controls, and analysed by flow cytometry. Biopsies were taken from 5 patients and 6 controls, and analysed by immunohistochemistry and flow cytometry of skin lymphocytes. Results We found an increased frequency of γδ T cells in the blood, but no differences in the distribution of cytokine‐producing CLA⁺ T cell subtypes in nickel‐allergic patients as compared with controls. In nickel‐allergic patients, there was massive cellular infiltration dominated by CD4⁺ T cells producing IL‐17, IL‐22 and IFN‐γ in nickel‐challenged skin but not in vehicle‐challenged skin. Conclusion CD4⁺ T cells producing IL‐17, IL‐22 and IFN‐γ are important effector cells in the eczematous reactions of nickel‐induced allergic contact dermatitis in humans.     

Characterization of the T cell response in allergic contact dermatitis caused by corticosteroids

Background Delayed allergic hypersensitivity reactions have classically been described as type IV reactions, which are caused by T cells; however, the respective roles of CD4⁺ and CD8⁺ cells are yet to be defined. A central role for CD8⁺ cytotoxic T cells as effector cells has been suggested. Objectives To determine the type of T cell involved in corticosteroid allergy. Methods We analysed the kinetics of T cell recruitment and the cytokine production profile in positive patch tests of 27 corticosteroid‐sensitized patients, as compared with control sites and control subjects. Skin biopsies, collected at 8, 24 and 48 hr following drug application, were embedded in paraffin for histological and immunohistological staining, and, in some cases, also deep‐frozen for gene expression analyses. Results CD3⁺ T cells were rapidly recruited in concert with the positivity of the patch test sites. High levels of interleukin (IL)‐4, IL‐5 and, to a lesser extent, interferon‐γ suggested that both Th2 and Th1 cytokines were implicated. IL‐4 was also produced by γδ T cell receptor (TCR) lymphocytes. Conclusions This study showed that, in allergic contact dermatitis caused by corticosteroids, the inflammatory infiltrate is composed of CD3⁺ T cells with a predominant Th2 cytokine profile, among which IL‐4 is also produced by γδ TCR lymphocytes.     

Allergic and toxic contact dermatitis: inflammatory cell subtypes in epicutaneous test reactions

Histochemical and immunohistochemical techniques were used to identify T lymphocytes, mononuclear phagocytes and plasma cells in situ from allergic and toxic epicutaneous test reactions. Intraccllular α-naphthyl acetate esterase (ANAE), endogenous peroxidase and immunoglobulin were used as markers for inflammatory cells. In allergic contact dermatitis 76 ± 7% of all cells were ANAE-positiveT lymphocytes, 13 ± 6% mononuclear phagocytes and 12 ± 6%), ANAE-negative cells. In toxic skin lesions the corresponding values were 64 ± 20%, 18 ± 15% and 18 ± 6%, respectively. There were no statistically significant differences between the allergic and toxic skin reactions. The basic reaction type in allergic and toxic contact dermatitis seems to be similar, with possibly some qualitative and quantitative differences.     

Allergic contact dermatitis to basic red 46 occurring in an HIV-positive patient

A 41-year-old HIV-positive man presented with a 2-month history of a generalized pruritic rash, which had started on his feet. Patch testing made a diagnosis of allergic contact dermatitis to the textile dye basic red 46, likely to have been present in his dark-blue-coloured socks. Complete resolution of his symptoms occurred with avoidance of these socks. The patient had developed allergic contact dermatitis with a low CD4 T lymphocyte count of 361 cells/microl (normal range 410-1545 cells/microl). This raised the question of the level of CD4 count necessary for an individual to develop allergic contact dermatitis to an allergen, given its role in delayed hypersensitivity. It was concluded that a low CD4 count as a result of HIV infection does not decrease the ability of an individual to develop allergic contact dermatitis. Whereas the effector role in delayed type 4 hypersensitivity reactions is mediated by CD4 T lymphocytes, in allergic contact dermatitis it appears that CD4 T lymphocytes have the suppressor role, with CD8 T lymphocytes having the effector role.     

Mechanisms of resolution of allergic contact dermatitis

Photoallergic and allergic contact dermatitis are examples of type IV hypersensitivity reactions that involve T cell-mediated immune responses against haptens that come into contact with the skin. These two types of allergies differ in that for routine contact allergens, the hapten is usually a chemically reactive species that readily couples to host proteins; for photoallergic reactions, UV light (320–400 nm) is necessary to generate (“photoactivate”) the chemically reactive hapten. From this point on, both photoallergic and allergic contact dermatitis are likely to proceed along the same pathways. For both types of cutaneous delayed-type hypersensitivity, there are naturally occurring mechanisms that terminate this type of T cell-mediated inflammation (tolerance induction). An important tolerance mechanism in the skin involves the induction of T-cell clonal anergy by “amateur” antigen-presenting cells such as keratinocytes. Advances in the understanding of the molecular pathways of T-cell activation and inactivation by antigen-presenting cells have identified critical signaling molecules such as B7/BB-1 antigen. The overexpression of these signaling molecules by the keratinocytes of transgenic mice disrupts the normal kinetics of resolution of murine contact hypersensitivity. These animals have prolonged contact hypersensitivity reactions that resemble some chronic dermatologic conditions in humans. This animal model may be a useful tool to better understand chronic allergic and photoallergic contact dermatitis.     

Acute stress enhances contact dermatitis by promoting nuclear factor‐κB DNA‐binding activity and interleukin‐18 expression in mice

Psychological stress adversely affects the immune system, and aggravates various skin diseases, such as psoriasis, alopecia areata and atopic dermatitis. However, the precise underlying mechanisms remain to be elucidated. The goal of this study was to use a murine restraint stress model to determine the mechanisms by which psychological stress modulates immune response in contact dermatitis. In the present study, mice were sensitized and challenged on the skin with 2,4‐dinitrofluorobenzene. Acute restraint stress was administrated to healthy or sensitized mice before challenge, and nuclear factor (NF)‐κB DNA‐binding activation of nuclear protein and expression of interleukin (IL)‐18 mRNA in murine spleen lymphocytes was detected. Chemical sympathectomy was performed using the neurotoxin 6‐hydroxy‐dopamine to determine the effect of the sympathetic nervous system. The experiment showed that restraint stress induced a series of changes which include increasing of NF‐κB DNA‐binding activity and IL‐18 mRNA expression in spleen lymphocytes and enhancement of contact hypersensitivity response, and these changes may be mediated by the sympathetic nervous system. These findings provide new insights into the roles of the nervous system in the aggravation of skin diseases.     

Proposal of inducible skin‐associated lymphoid tissue (iSALT)

In the 1980s, Streilein et al. introduced the term ‘skinassociated lymphoid tissue (SALT)’ based on observations that revealed the existence of T cells and dendritic cells (DCs) in the skin and that T cells are activated in the skin draining lymph nodes. However, in the perspective of SALT, it remains still unclear whether and how cellular components in the skin interact with each other. In addition, whether the T‐cell activation occurs in the skin in situ has also been unrevealed. With the close observation of a skin specimen obtained from a patient with contact dermatitis, we discovered that dermal DCs (dDCs) clustered and closely attached to T cells. Thus, we hypothesized that this clustering might be essential for the establishment of the dermatitis and the T‐cell activation in situ. Through the detailed examination of the elicitation phase of contact hypersensitivity as a murine model of contact dermatitis, we demonstrated the formation of sequential leukocyte clusters at the postcapillary venules. The clusters include perivascular macrophages that are activated by IL‐1a produced by keratinocytes and dDCs that are attracted by these macrophages through CXCL2 signalling, both of which are essential for the efficient activation of memory T cells in situ. The structure does not exist in the steady state, but is ‘induced’ in response to local inflammatory conditions. Herein, we propose that this structure to be termed as ‘inducible SALT (iSALT)’.     

Allergic contact dermatitis: the cellular effectors

Contact hypersensitivity reactions are mediated by lymphocytic effector cells. Until recently it was believed that the most important of these were CD4+ T lymphocytes. However, there is growing evidence that in many instances the predominant effector cell may be a CD8+ T lymphocyte, with in some instances CD4+ cells performing a counter-regulatory function. Here we review the roles of CD4+ T helper (Th) cells and CD8+ T cytotoxic (Tc) cells, and their main functional subpopulations (respectively, Th1 and Th2 cells and Tc1 and Tc2 cells) in the elicitation of contact hypersensitivity reactions and consider the implications of effector cell selectivity for the biology of allergic contact dermatitis.     

Anti-inflammatory and immune-regulatory mechanisms prevent contact hypersensitivity to Arnica montana L

Sesquiterpene lactones (SL), secondary plant metabolites from flowerheads of Arnica, exert anti-inflammatory effects mainly by preventing nuclear factor (NF)-kappaB activation because of alkylation of the p65 subunit. Despite its known immunosuppressive action, Arnica has been classified as a plant with strong potency to induce allergic contact dermatitis. Here we examined the dual role of SL as anti-inflammatory compounds and contact allergens in vitro and in vivo. We tested the anti-inflammatory and allergenic potential of SL in the mouse contact hypersensitivity model. We also used dendritic cells to study the activation of NF-kappaB and the secretion of interleukin (IL)-12 in the presence of different doses of SL in vitro. Arnica tinctures and SL potently suppressed NF-kappaB activation and IL-12 production in dendritic cells at high concentrations, but had immunostimulatory effects at low concentrations. Contact hypersensitivity could not be induced in the mouse model, even when Arnica tinctures or SL were applied undiluted to inflamed skin. In contrast, Arnica tinctures suppressed contact hypersensitivity to the strong contact sensitizer trinitrochlorobenzene and activation of dendritic cells. However, contact hypersensitivity to Arnica tincture could be induced in acutely CD4-depleted MHC II knockout mice. These results suggest that induction of contact hypersensitivity by Arnica is prevented by its anti-inflammatory effect and immunosuppression as a result of immune regulation in immunocompetent mice.     

Influence of Th2 cells on hair cycle/growth after repeated cutaneous application of hapten

Exposure to contact allergens in order to produce allergic contact dermatitis (ACD) seems to induce hair cycle/growth, but the mechanism of this remains unclear. In the current study, we investigated this mechanism and found that repeated application of hapten induced production of interleukin (IL)‐4 in lymph‐node immune cells. In addition, hair growth was induced in mice after the adoptive transfer of T‐helper (Th)2 cells that had been purified from mice exposed to repeated cutaneous application of hapten. These findings lead us to speculate that Th2 cells that are repeatedly hapten‐sensitized are recruited to hapten‐challenged skin areas, and thus stimulate the production of IL‐4 in the vicinity of the hair follicles, which influences hair cycle/growth. Our results may provide fundamental insights into the mechanism of contact hypersensitivity‐induced hair cycle/growth.     

Oral cyclosporin inhibits the expression of contact hypersensitivity in man

The expression of delayed contact hypersensitivity was studied in 6 patients with chronic contact dermatitis treated with cyclosporin A (CsA) 5 mg/Kg/day. Quantitative patch test challenge was used to establish individual dose-response curves and threshold concentration to certain allergens in the European Standard Battery. In all 6 patients, responses were reduced over the whole range of allergen concentrations, and in the 5 in whom the threshold for expression of contact hypersensitivity could be determined, the threshold was raised by CsA therapy. In addition, the clinical manifestations of allergic contact dermatitis underwent complete resolution within 2-3 weeks of CsA therapy. It was concluded that CsA inhibits expression of delayed contact hypersensitivity reactions in human skin.     

Why does allergic contact dermatitis exist?

The skin immune system’s propensity to produce allergic contact dermatitis (ACD) to harmless chemicals, while otherwise being an efficient defence system, represents a dermatological paradox. We postulate that a major role in signalling in ACD is played by Toll‐like receptor (TLR)2 and TLR4, and arises from their activation by extracellular danger‐associated molecular patterns (DAMPs). Ligand activation of TLR4/2 results in the expression of interleukins (ILs) IL‐1β, IL‐6, IL‐12, IL‐18 and IL‐23, tumour necrosis factor‐α and interferon‐α. These cytokines promote acquisition of sensitization, and facilitate elicitation of contact allergy via multiple mechanisms, including the recruitment of CD4+ Th1 and Th17 cells. As Th1 cells secrete large amounts of DAMPs, a DAMP immune circuit (positive‐feedback loop) is created. This is an important driver of skin sensitization and skin inflammation. Pathogenic extracellular bacteria, but not commensal bacteria, produce pathogen‐associated molecular pattern molecules, which stimulate the expression of Th1‐ and Th17‐promoting cytokines via TLR2 and TLR4. This also induces an immune circuit. The ability of the skin immune system to activate host defence mechanisms and to distinguish between pathogenic bacteria and commensals provides an explanation for why skin sensitization and ACD develop, as they are processes that rely on the same biological pathways. These pathways may also shed light on the pathogenesis of chronic pustular inflammatory dermatoses (e.g. acne vulgaris). The existence of safety signals from commensal bacteria, which prevent initiation of these pathways, may provide opportunities for novel therapeutic approaches to the treatment of inflammatory skin diseases.     

The balance between pro‐ and anti‐inflammatory cytokines is crucial in human allergic contact dermatitis pathogenesis: the role of IL‐1 family members

The interleukin (IL)‐1 family includes 11 members that are important in inflammatory processes. It includes various agonists and two antagonists, IL‐1Ra and IL‐36Ra. Our aim was to investigate whether the IL‐1 family is involved in allergic contact dermatitis (ACD). The expression of IL‐1 family members was evaluated by PCR and immunohistochemistry in the positive patch test reaction site (involved skin) and in the uninvolved skin of ACD patients. We also examined these cytokines in an ex vivo model of ACD. The antagonistic activity of IL‐36Ra was evaluated by injecting recombinant IL‐36Ra in uninvolved skin biopsies of ACD patients. IL‐1Ra and IL‐36Ra expression was quantified in mononuclear cells of nickel‐sensitized patients challenged in vitro with nickel. IL‐33 involvement in ACD was investigated by intra‐dermal injection of anti‐IL‐33 in the uninvolved skin of patients ex vivo. Results showed that IL‐1β, IL‐1Ra, IL‐36α, IL‐36β, IL‐36γ and IL‐33 expression, but not IL‐36Ra expression, was enhanced in ACD‐involved skin. Immunohistochemical analysis and ex vivo skin cultures confirmed these results. Injection of anti‐IL‐33 in ACD‐uninvolved skin inhibited IL‐8 expression, whereas IL‐36Ra inhibited IL‐36α, IL‐36β, IL‐36γ and IL‐8 expression. Nickel induced IL‐1Ra expression in lymphocytes of nickel‐sensitized patients. Hence, various IL‐1 agonists and antagonists may be involved in ACD pathogenesis.     

The CXCR3 activating chemokines IP-10, Mig, and IP-9 are expressed in allergic but not in irritant patch test reactions.

Differentiation between allergic and irritant contact dermatitis reactions is difficult, as both inflammatory diseases are clinically, histologically, and immunohistologically very similar. Previous studies in mice revealed that the chemokine IP-10 is exclusively expressed in allergic contact dermatitis reactions. In the present study, we investigated whether the mRNA expression of IP-10 and the related CXCR3 activating chemokines, Mig and IP-9 are also differentially expressed in human allergic contact dermatitis and irritant contact dermatitis reactions. Skin biopsies from allergic (13 cases) and sodium lauryl sulfate-induced irritant patch test reactions (13 cases), obtained 1-72 h after patch testing, were studied by means of an in situ hybridization technique. Results of chemokine mRNA expression were correlated with clinical scoring, histology, and immunohistochemical data including the proportion of inflammatory cells expressing CXCR3, the receptor for IP-10, Mig, and IP-9, and ICAM-1 and HLA-DR expression on keratinocytes. IP-10, Mig, and IP-9 mRNA were detected in seven of nine allergic contact dermatitis reactions after 24-72 h, but not in sodium lauryl sulfate-induced irritant contact dermatitis reactions. ICAM-1 expression by keratinocytes was only found in allergic contact dermatitis reactions and correlated with chemokine expression. Moreover, up to 50% of the infiltrating cells in allergic contact dermatitis expressed CXCR3, in contrast to only 20% in irritant contact dermatitis reactions. In conclusion, we have demonstrated differences in chemokine expression between allergic contact dermatitis and irritant contact dermatitis reactions, which might reflect different regulatory mechanisms operating in these diseases and may be an important clue for differentiation between allergic contact dermatitis and irritant contact dermatitis reactions.     

Copper hypersensitivity

The world production of copper is steadily increasing. Although humans are widely exposed to copper‐containing items on the skin and mucosa, allergic reactions to copper are only infrequently reported. To review the chemistry, biology and accessible data to clarify the implications of copper hypersensitivity, a database search of PubMed was performed with the following terms: copper, dermatitis, allergic contact dermatitis, contact hypersensitivity, contact sensitization, contact allergy, patch test, dental, IUD, epidemiology, clinical, and experimental. Human exposure to copper is relatively common. As a metal, it possesses many of the same qualities as nickel, which is a known strong sensitizer. Cumulative data on subjects with presumed related symptoms and/or suspected exposure showed that a weighted average of 3.8% had a positive patch test reaction to copper. We conclude that copper is a very weak sensitizer as compared with other metal compounds. However, in a few and selected cases, copper can result in clinically relevant allergic reactions.     

Lack of effect of ustekinumab in treatment of allergic contact dermatitis

Background. Allergic contact dermatitis is a chronic inflammatory T cell mediated disease that can be recalcitrant to existing treatments. Ustekinumab is a monocloncal antibody blocking IL‐12 and IL‐23, shown to be effective and safe for patients with psoriasis. Despite both IL‐12 and IL‐23 involvement in contact allergy, the effect of Ustekinumab on allergic contact dermatitis has not been reported. Objectives. To evaluate the clinical effect of Ustekinumab in patients with allergic contact dermatitis. Methods. A retrospective, case cohort study of patients with allergic contact dermatitis treated with Ustekinumab in our department. Results. Five patients had been treated with Ustekinumab for allergic contact dermatitis, with limited effect. Conclusion. Our observation suggests that, although theoretically plausible, Ustekinumab does not seem to be a valuable therapeutic approach for chronic allergic contact dermatitis.