Allergic Contact Hypersensitivity Research Articles

Mead acid inhibits retinol-induced irritant contact dermatitis via peroxisome proliferator-activated receptor alpha.

Retinol is widely used in topical skincare products to ameliorate skin aging and treat acne and wrinkles; however, retinol and its derivatives occasionally have adverse side effects, including the induction of irritant contact dermatitis. Previously, we reported that mead acid (5,8,11-eicosatrienoic acid), an oleic acid metabolite, ameliorated skin inflammation in dinitrofluorobenzene-induced allergic contact hypersensitivity by inhibiting neutrophil infiltration and leukotriene B4 production by neutrophils. Here, we showed that mead acid also suppresses retinol-induced irritant contact dermatitis. In a murine model, we revealed that mead acid inhibited keratinocyte abnormalities such as keratinocyte hyperproliferation. Consistently, mead acid inhibited p38 MAPK (mitogen-activated protein kinase) phosphorylation, which is an essential signaling pathway in the keratinocyte hyperplasia induced by retinol. These inhibitory effects of mead acid were associated with the prevention of both keratinocyte hyperproliferation and the gene expression of neutrophil chemoattractants, including Cxcl1 and Cxcl2, and they were mediated by a PPAR (peroxisome proliferator-activated receptor)-α pathway. Our findings identified the anti-inflammatory effects of mead acid, the use of which can be expected to minimize the risk of adverse side effects associated with topical retinoid application.

IKKβ increases neuropilin-2 and promotes the inhibitory function of CD9+ Bregs to control allergic diseases

Regulatory B cells (Bregs) potently suppress immune disorders, including allergic contact hypersensitivity (CHS). IKKβ overactivation is prominent in various inflammatory diseases. However, its effect on Bregs has not been defined. This study is to investigate the new regulator and inhibitory mechanism of Bregs. IkkβC46A transgenic mice with a Cys46 mutation, resulting in increased IKKβ activation, were employed for analysis. IL-10-competent CD9+ Bregs were expanded in IkkβC46A mice and B cell specific-IkkβC46A mutation mice. IkkβC46A mutant CD9+ Bregs had stronger suppressive effects on CD4+ and CD8+ T cells in vitro and CHS responses in vivo. The inhibitory CD9+ Bregs from IkkβC46A mice were characterized by upregulated Neuropilin 2 (Nrp2) and IL-10 in comparison with that of Ikkβwt mice. Interestingly, increased expression of Nrp2 was observed in CD9+ Bregs compared with that of CD9- B cells in wild-type mice. The suppressive activity of wild-type CD9+ Bregs in vitro was attenuated by inhibition of Nrp2 on Bregs or silencing its ligand Sema3f on CD4+ T cells. Our findings delineate a distinct role of IKKβ activation in enhancing Bregs to disturb the immune balance. It identifies Nrp2 as a novel regulatory molecule of Bregs that partly contributes to B cell-mediated immune tolerance.

Allergic Contact Cell-Mediated Hypersensitivity in Psoriasis: A Narrative Minireview.

The dysfunctionality of the protective skin barrier in psoriasis allows easier cutaneous penetration of various contact haptens; thus, such patients can develop allergic contact hypersensitivity as a comorbidity. Both skin conditions involve T-cell-mediated mechanisms. Dermatologists and allergists should consider assessing allergic contact cell-mediated hypersensitivity in selected psoriasis patients, especially those with palmoplantar psoriasis and who are refractory to topical treatments, and in patients with psoriasis, with or without arthritis, treated with biologics that present skin lesions clinically suggestive of contact dermatitis.

IL-27 Derived From Macrophages Facilitates IL-15 Production and T Cell Maintenance Following Allergic Hypersensitivity Responses.

Crosstalk between T cells, dendritic cells, and macrophages in temporal leukocyte clusters within barrier tissues provides a new concept for T cell activation in the skin. Activated T cells from these leukocyte clusters play critical roles in the efferent phase of allergic contact hypersensitivity (CHS). However, the cytokines driving maintenance and survival of pathogenic T cells during and following CHS remain mostly unknown. Upon epicutaneous allergen challenge, we here report that macrophages produce IL-27 which then induces IL-15 production from epidermal keratinocytes and dermal myeloid cells within leukocyte clusters. In agreement with the known role of IL-15 as a T cell survival factor and growth cytokine, this signaling axis enhances BCL2 and survival of skin T cells. Genetic depletion or pharmacological blockade of IL-27 in CHS mice leads to abrogated epidermal IL-15 production resulting in a decrease in BCL2 expression in T cells and a decline in dermal CD8+ T cells and T cell cluster numbers. These findings suggest that the IL-27 pathway is an important cytokine for regulating cutaneous T cell immunity.

Characterization and Quantitation of Personal Exposures to Epoxy Paints in Construction Using a Combination of Novel Personal Samplers and Analytical Techniques: CIP-10MI, Liquid Chromatography-Tandem Mass Spectrometry and Ion Chromatography.

Epoxy resins are extremely versatile products that are widely used in construction for coatings, adhesives, primers, and sealers. Occupational exposures to epoxies cause allergic contact dermatitis, occupational asthma, hypersensitivity pneumonitis (epoxy-resin lung) and acute decline in lung function. Despite these health concerns, there is a striking paucity of quantitative exposure data to epoxy resins in construction. The lack of practical analytical methods and suitable personal samplers for monitoring of reactive two-component epoxide systems in real-world applications has been an unmet challenge for decades. Sampling and analysis methods for epoxies should be able to collect the paint aerosols efficiently, stop polymerization reactions at the time of sample collection, and subsequently provide detailed multispecies characterization of epoxides, as well as the total epoxide group (TEG) content of a sample, to properly document the chemical composition of exposures to epoxide paints. In this work, we present the development and application of two new complementary quantitative analytical methods-liquid chromatography-tandem mass spectrometry with online ultraviolet detection and ion chromatography (IC)-for multispecies characterization of raw products, as well as inhalation and skin exposures to epoxy formulations in real-world construction applications. A novel personal sampler, CIP-10MI, was used for personal sampling of airborne epoxies. We report for the first time the results of personal inhalation and potential skin exposures to individual monomers and oligomers of bisphenol A diglycidyl ether (BADGE), as well as TEG, during metal structure coatings in construction; compare analytical results of the two analytical methods; and provide recommendations for method selection in future field studies. High inhalation and potential skin exposures to epoxies point to the need for interventions to reduce exposures among painters in construction.

CD4+ Resident Memory T Cells Mediate Long-Term Local Skin Immune Memory of Contact Hypersensitivity in BALB/c Mice.

In allergic contact dermatitis (ACD) and contact hypersensitivity (CHS), the healed skin shows greater swelling than the naïve skin in the same individual upon re-exposure to the same hapten. This “local skin memory” (LSM) in healed skin was maintained for a prolonged period of time and mediated by skin CD8+-resident memory T (TRM) cells in C57BL/6 mice. However, the number of CD4+ T cells is elevated in ACD-healed human skin, and the contribution of CD4+ TRM cells to the formation of LSM currently remains unclear. We herein demonstrated that immediately after CHS subsided, the healed skin in BALB/c mice showed an accumulation of hapten-specific CD4+ and CD8+ TRM cells, with a predominance of CD4+ TRM cells. The presence of CD4+ or CD8+ TRM cells in the healed skin was sufficient for the induction of a flare-up reaction upon a re-challenge. The CD4+ and CD8+ TRM cells both produced interferon-γ and tumor necrosis factor early after the re-challenge. Moreover, while CD8+ TRM cells gradually decreased over time and were eventually lost from the healed skin at 40–51 weeks after the resolution of CHS, the CD4+ TRM cell numbers remained elevated during this period. The present results indicate that the long-term maintenance of LSM is mediated by CD4+ TRM cells, and thus CD4+ TRM cells are an important target for the treatment of recurrent human ACD.

Nickel induces inflammatory activation via NF-κB, MAPKs, IRF3 and NLRP3 inflammasome signaling pathways in macrophages.

Nickel (Ni), an environmental hazard, widely causes allergic contact hypersensitivity worldwide. Despite that Ni-stimulated pro-inflammatory response is vital in allergy, the underlying molecular mechanisms remain largely unclear. Here, we demonstrated that NiCl2 activated nuclear factor kappa B (NF-κB), mitogen-activated protein kinases (MAPKs) and interferon regulatory factor 3 (IRF3) signaling pathways in primary bone marrow-derived macrophages (BMDMs), leading to the altered transcription levels of interleukin-1β (IL-1β), -6, -8, -18, tumor necrosis factor-α (TNF-α) and interferon β (INF-β). We also found that nickel chloride (NiCl2) activated Nod-like receptor 3 (NLRP3) inflammasome pathway, resulting in the proteolytic cleavage and release of IL-1β. NiCl2 induced the accumulation of mitochondrial reactive oxygen species (mtROS) and the release of mitochondrial DNA (mtDNA), thus activating NLRP3 inflammasome pathway. Additionally, NiCl2-induced apoptosis was dependent on the generation of mtROS, and caspase-1 activation might also partly contribute to the apoptotic process. Altogether, abovementioned results indicate that NiCl2 induces inflammatory activation in BMDMs via NF-κB, MAPKs, IRF3 signaling pathways as well as NLRP3 inflammasome pathway, which provides a mechanism to improve the efficiency of treatment against Ni-induced allergic reactions.

010 IL-27 in macrophages mediates T cell survival and dermal cluster formation in allergic contact hypersensitivity

010 IL-27 in macrophages mediates T cell survival and dermal cluster formation in allergic contact hypersensitivity

(E)‑phenethyl 3‑(3,5‑dihydroxy‑4‑isopropylphenyl) acrylate gel improves DNFB-induced allergic contact hypersensitivity via regulating the balance of Th1/Th2/Th17/Treg cell subsets

(E)‑phenethyl 3‑(3,5‑dihydroxy‑4‑isopropylphenyl) acrylate gels (THCA354) is a novel polyphenols acrylic acid derivative. To investigate the immunoregulatory mechanisms of THCA354, we established a mouse model of 2,4‑dinitrofluorobenzene (DNFB)-induced allergic contact dermatitis (ACD). Responses of Th1, Th2, Th17 and regulatory T cells (Tregs) were determined by flow cytometry, reverse-transcriptase polymerase chain reaction (RT-PCR) and enzyme linked immunosorbent assay (ELISA). Our study found that topical application of THCA354 gel could inhibit ear swelling, reduce inflammatory cell infiltration, down-regulate Th1/Th17 responses and enhance Th2/Treg responses. These findings indicated that THCA354 gel exerted its immunotherapeutic effects by modulating the balance of Th1/Th2/Th17/Treg cell subsets, suggesting that THCA354 gel could be used as a promising drug candidate for intervention of ACD.

Immune-modulation via IgD B-cell receptor suppresses allergic skin inflammation in experimental contact hypersensitivity models despite of a Th2-favoured humoral response

Atopic dermatitis (AD) and allergic contact dermatitis (ACD) are common skin inflammatory conditions. B and T cells are strongly implicated in allergic contact hypersensitivity (CHS) conditions. Activation of IgD B-cell receptor (BCR) by anti-IgD stimulation depletes mature B cells and modulates T-helper cell type 1/2 (Th1/2) responses in vivo. It is not known whether these effects by anti-IgD exacerbates or ameliorates chronic skin inflammations. This study investigated the effects of anti-IgD and B-cell depleting anti-CD20 antibody on skin inflammation in CHS murine models. Chronic CHS were induced by challenges with allergens trimellitic anhydride (TMA) or 2,4 dinitrochlorobenzene (DNCB). Mice were treated with an anti-IgD or anti-CD20 at various time-points following allergen challenges. This study revealed that early therapeutic treatments with anti-IgD at 4 h after allergen challenge significantly reduced skin inflammation in both TMA- and DNCB-induced CHS models (P < 0.05). In contrast, anti-CD20 treatment exacerbated skin inflammation in DNCB-induced CHS despite of an extensive B cell depletion (P < 0.05). Anti-IgD treatment depleted mature CD19+IgD+ B cells but enhanced allergen-specific IgM and total IgE productions, suggesting a Th2-favoured humoral response. Anti-IgD reduced neutrophilic infiltrations but increases accumulation of mast cells in dermal tissues. The anti-inflammatory effects of anti-IgD were supported by evidence of an increase in the percentage of regulatory B cells and T cells. Collectively, this study demonstrates that immune-modulation by anti-IgD treatment suppresses Th2-mediated allergic skin inflammation in murine models despite a skew toward a Th2-favvoured humoral response and therefore may present a novel treatment for chronic human AD and ACD.

Development of adjuvant scaffolds from small molecule contact allergens

Abstract Small molecule contact allergens are an understudied class of immunostimulatory compounds that have the potential of being developed into adjuvants. Vaccines remain the most effective tool in preventing disease and adjuvants serve to make vaccines more efficacious by activating the innate immunity. To develop contact allergens molecules as adjuvants, we began by first elucidating the mechanism of allergic contact hypersensitivity. Using contact allergens and their analogues we wanted to define the structural elements necessary for the activation of immune cells. Our initial experiments sought to correlate sensitization potential to chemical reactivity where the latter influenced the initial phase of sensitization, hapten formation. We showed that there is a non-linear relationship between the rate of reactivity of the compounds and the ability to induce IL-8 expression on THP-1 cells. This result suggested that contact allergens modify specific target proteins and hence sterics, as well as electronic nature of the contact allergen, play an important role. Using the insights from this initial study we are developing probes that will allow the identification of the hapten-protein complex formed during the sensitization process in order to understand the recognition mechanism of this complex to immune cell receptors. We envision this study as the first step towards the development of potent adjuvants from contact allergen scaffolds. Additionally, the elucidation of the protein targets of small molecule contact allergens will reveal therapy avenues for the treatment of allergic contact hypersensitivity.

087 IL-27 signaling is relevant for IL-15 production and T cell cluster maintenance in allergic contact hypersensitivity

Allergic contact dermatitis (ACD) results from a T-cell response to hapten/allergens applied to the skin. Following sensitization, specific T-cells are first generated and activated in the lymph node, and some Ag-specific T cells remain in the skin. Re-exposure to the relevant hapten/allergen initiates the efferent phase and clinical expression of ACD, characterized by local T cell activation and recruitment of specific T cells to the sites of allergen challenge. IL-15 is essential for allergic contact hypersensitivity pathogenesis and plays a pivotal role in both T-cell activation, survival and effector functions and, yet, paradoxically, it also provides anti-apoptotic signals in keratinocytes. IL-15 regulation in the skin is not well known. We made the unexpected observation, that in contrast to non-lesional skin of ACD patients, in the skin of 72 hrs patch-tested individuals (effector phase of ACD), IL-15 and anti-apoptotic BCL2 localized to dermal T cell DC clusters and to a much lesser extent to the epidermis. Interestingly, increased BCL2 was expressed in T cells within the clusters and was associated with and directly adjacent to IL-27-producing CD14+ cells in positive patch-tested induced ACD. Monocytic cells, including human DC-like THP1, and murine BMDC up-regulated IL15 mRNA upon IL-27 stimulation. IL-27 was also found to directly stimulate IL15 mRNA in human epidermal keratinocytes in a STAT-1 dependent manner as evidenced by rapid p-STAT1 nuclear translocation and abrogation of this response by silencing STAT1 (p<0.05). We next tested the functional in vivo relevance of IL-27 signaling in a mouse model of hapten/allergen-induced dermal T cell clusters. Administration of IL-27 neutralizing antibody (i.d.) in these mice decreased the number of T cell clusters and resulted in downregulation of BCL2 in T cells supporting a regulatory role of IL-27 on T cell survival possibly via IL-15. Overall, these findings implicate the IL-27 pathway as a potential therapeutic agent in regulating cutaneous T cell immunity.

The Many Faces of Graphene as Protection Barrier. Performance under Microbial Corrosion and Ni Allergy Conditions.

In this work we present a study on the performance of CVD (chemical vapor deposition) graphene coatings grown and transferred on Ni as protection barriers under two scenarios that lead to unwanted metal ion release, microbial corrosion and allergy test conditions. These phenomena have a strong impact in different fields considering nickel (or its alloys) is one of the most widely used metals in industrial and consumer products. Microbial corrosion costs represent fractions of national gross product in different developed countries, whereas Ni allergy is one of the most prevalent allergic conditions in the western world, affecting around 10% of the population. We found that grown graphene coatings act as a protective membrane in biological environments that decreases microbial corrosion of Ni and reduces release of Ni2+ ions (source of Ni allergic contact hypersensitivity) when in contact with sweat. This performance seems not to be connected to the strong orbital hybridization that Ni and graphene interface present, indicating electron transfer might not be playing a main role in the robust response of this nanostructured system. The observed protection from biological environment can be understood in terms of graphene impermeability to transfer Ni2+ ions, which is enhanced for few layers of graphene grown on Ni. We expect our work will provide a new route for application of graphene as a protection coating for metals in biological environments, where current strategies have shown short-term efficiency and have raised health concerns.

Arginase1 Deficiency in Monocytes/Macrophages Upregulates Inducible Nitric Oxide Synthase To Promote Cutaneous Contact Hypersensitivity.

The innate immune components that modulate allergic contact hypersensitivity (CHS) responses are poorly defined. Using human skin from contact dermatitis patients and a mouse model of CHS, we find that hapten allergens disrupt the Arginase1 (Arg1) and inducible NO synthase (iNOS) dynamic in monocytes/macrophages (mono/MΦ), which renders those cells ineffectual in suppressing skin inflammation. Mice lacking Arg1 in MΦ develop increased CHS characterized by elevated ear thickening, mono/MΦ-dominated dermal inflammation, and increased iNOS and IL-6 expression compared with control mice. Treatment of Arg1flox/flox; LysMCre+/- mice with a selective NOS inhibitor or knockout of Nos2, encoding iNOS, significantly ameliorates CHS. Our findings suggest a critical role for Arg1 in mono/MΦ in suppressing CHS through dampening Nos2 expression. These results support that increasing Arg1 may be a potential therapeutic avenue in treating allergic contact dermatitis.

Abstract 2221: Honokiol stimulates immune reactivity in UV-irradiated skin through DNA demethylation-dependent functional activation of dendritic cells in mice

Abstract Solar ultraviolet radiation (UVR), and in particular UVB spectrum (290-320 nm), are considered as a complete carcinogen for cutaneous malignancies. The over-exposure of UVR suppresses the development of allergic contact hypersensitivity (CHS) response in both laboratory animals as well as in humans. CHS response is considered to be a prototypic T-cell mediated immune response. UVR-induced suppression of immune sensitivity has been implicated in skin cancer risk. Therefore, the treatment options which can inhibit UVB-induced suppression of immune sensitivity may be useful in the management of skin cancers, including both melanoma and non-melanoma. Previously, we have shown that topical treatment of honokiol inhibits UVB induced immune suppression, which was associated with the reduction in UVB-induced inflammatory mediators in the mouse skin. Here, we have further determined the underlying mechanism of action of honokiol on UVR-induced immunosuppression including its effect on epigenetic regulators and their relationship with immune sensitivity in mouse skin. Topical treatment of C3H/HeN mice with honokiol (0.5 and 1.0 mg/cm2 skin area) in hydrophilic-cream based topical formulation significantly inhibits UVB-induced suppression of CHS response (P&amp;lt;0.01-0.005), which was associated with reduced levels of DNA methylation as well as Dnmt activity in the mouse skin compared with non-honokiol-treated and UVB-exposed control mice. To characterize the cell population responsible for the honokiol mediated inhibition of UVB-induced immunosuppression, we used an adoptive transfer approach. DNA-methylated (most of cells) dendritic cells (DCs), isolated from the draining lymph nodes of donor mice that had been UVB-exposed and sensitized to 2,4,-dinitrofluorobenzene (DNFB) with and without honokiol (0.5 and 1.0 mg/cm2 skin area) treatment, were transferred into naïve recipient mice. The CHS response of the recipient mice to DNFB was then measured. Honokiol treatment of UVB-exposed donor mice relieved this suppression of the CHS response in naïve mice, while the recipient mice, obtained DNA-methylated DCs from UVB-exposed donor mice that were not treated with honokiol, showed significant suppression in the CHS response. The restoration of CHS response in mice receiving DCs from honokiol treated, UV-exposed donor mice was also associated with enhanced secretion of Th1-type cytokines compared with the Th1-type cytokines from the DCs obtained from non-honokiol-treated and UVB-exposed donor mice. These data suggest that honokiol mediated inhibition of UVB induced suppression of CHS response is associated with functional activation of dendritic cells and that is dependent on DNA demethylation in DCs. Note: This abstract was not presented at the meeting. Citation Format: Santosh K. Katiyar, Tripti Singh, Harish C. Pal, Ram Prasad. Honokiol stimulates immune reactivity in UV-irradiated skin through DNA demethylation-dependent functional activation of dendritic cells in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2221. doi:10.1158/1538-7445.AM2017-2221

678 Biased CXCR3 ligands differentially alter allergic contact hypersensitivity and chemotaxis

678 Biased CXCR3 ligands differentially alter allergic contact hypersensitivity and chemotaxis

LB811 Arginase1 in myeloid cells controls allergic contact hypersensitivity through tempering NOS2-associated inflammation

LB811 Arginase1 in myeloid cells controls allergic contact hypersensitivity through tempering NOS2-associated inflammation

Abstract 2607: Honokiol, a phytochemical from magnolia plant, prevents UV radiation-induced immune suppression in mice through inhibition of PGE2 and DNA methylation

Abstract The exposure of ultraviolet radiation (UVR) to murine skin suppresses the development of allergic contact hypersensitivity (CHS) response which is considered to be a prototypic T-cell mediated immune response. UVR-induced suppression of immune system has been implicated in skin cancer risk. Honokiol has been shown to have anti-skin carcinogenic activity, and here we have assessed the effect of honokiol on UVR-induced immunosuppression and its possible mechanism of action. Our CHS experiments revealed that exposure of C3H/HeN mouse skin with UVB radiation (150 mJ/cm2) for 4 consecutive days resulted in significant suppression of CHS response (75%, P&amp;lt;0.001) to the skin contact sensitizer, 2,4-dinitrofluorobenzene (DNFB), which was associated with the enhancement in the levels of cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production. Topical treatment of mice with honokiol (0.5 and 1.0 mg/cm2 skin area) in hydrophilic-cream based topical formulation or indomethacin (50 μg/mouse), a COX-2 inhibitor, significantly inhibits UV radiation-induced suppression of CHS response (P&amp;lt;0.01-0.005). The exposure of mice with UVB resulted in DNA hypermethylation, increase in DNA methyltransferase (Dnmt) activity, and elevated levels of Dnmt proteins in mouse skin, while treatment of mice with honokiol before each UVB exposure reduced the levels of DNA methylation as well as Dnmt activity compared with non-honokiol-treated control mice. The COX-2 deficient mice are resistant to UV-induced suppression of CHS response. Treatment of UVB exposed COX-2-deficient mice with PGE2 (50 μg/mouse/day) results in UV-induced suppression of CHS, increase in DNA methylation and Dnmt activity in the skin. Further, treatment of honokiol reversed the effect of PGE2 on UV-induced suppression of CHS response in COX-2-deficient mice. Treatment of C3H/HeN mice with 5-aza-2’-deoxycytidine (5-Aza-dc, 1.0 mg/kg body weight, i.p.), a DNA demethylating agent, after each UVB exposure restored the CHS response which was associated with a reduction in Dnmt activity and global DNA methylation levels compared to the UV-exposed mice which were not treated with 5-Aza-dc. We also compared the effect of honokiol with commercially available anti-cancer drugs, such as imiquimod and 5-fluorouracil, on CHS response in UV-exposed mice. Topical treatment of mice with equi-molar concentrations of honokiol and cancer drugs did not show significant difference in terms of inhibition of UVB induced immune suppression and thus suggests honokiol as a substitute for these drugs. These findings provide evidence that honokiol acts through inhibition of inflammatory mediators and subsequently DNA demethylation in UVR-exposed mouse skin. Citation Format: Santosh K. Katiyar, Tripti Singh, Ram Prasad. Honokiol, a phytochemical from magnolia plant, prevents UV radiation-induced immune suppression in mice through inhibition of PGE2 and DNA methylation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2607.

Molecular Mechanisms of Nickel Allergy.

Allergic contact hypersensitivity to metals is a delayed-type allergy. Although various metals are known to produce an allergic reaction, nickel is the most frequent cause of metal allergy. Researchers have attempted to elucidate the mechanisms of metal allergy using animal models and human patients. Here, the immunological and molecular mechanisms of metal allergy are described based on the findings of previous studies, including those that were recently published. In addition, the adsorption and excretion of various metals, in particular nickel, is discussed to further understand the pathogenesis of metal allergy.

Transcription factor NFAT1 controls allergic contact hypersensitivity through regulation of activation induced cell death program.

Allergic contact hypersensitivity (CHS) is an inflammatory skin disease mediated by allergen specific T cells. In this study, we investigated the role of transcription factor NFAT1 in the pathogenesis of contact hypersensitivity. NFAT1 knock out (KO) mice spontaneously developed CHS-like skin inflammation in old age. Healthy young NFAT1 KO mice displayed enhanced susceptibility to hapten-induced CHS. Both CD4+ and CD8+ T cells from NFAT1 KO mice displayed hyper-activated properties and produced significantly enhanced levels of inflammatory T helper 1(Th1)/Th17 type cytokines. NFAT1 KO T cells were more resistant to activation induced cell death (AICD), and regulatory T cells derived from these mice showed a partial defect in their suppressor activity. NFAT1 KO T cells displayed a reduced expression of apoptosis associated BCL-2/BH3 family members. Ectopic expression of NFAT1 restored the AICD defect in NFAT1 KO T cells and increased AICD in normal T cells. Recipient Rag2−/− mice transferred with NFAT1 KO T cells showed more severe CHS sensitivity due to a defect in activation induced hapten-reactive T cell apoptosis. Collectively, our results suggest the NFAT1 plays a pivotal role as a genetic switch in CD4+/CD8+ T cell tolerance by regulating AICD process in the T cell mediated skin inflammation.