Schmidt M, Raghavan B, Muller V et al.Crucial role for human Toll-like receptor 4 in the development of contact allergy to nickel. Nat Immunol 11:814-819

Department of Dermatology, University Hospital Mannheim, University of Heidelberg, Mannheim, Germany.
Nature Immunology (Impact Factor: 20). 09/2010; 11(9):814-9. DOI: 10.1038/ni.1919
Source: PubMed


Allergies to nickel (Ni(2+)) are the most frequent cause of contact hypersensitivity (CHS) in industrialized countries. The efficient development of CHS requires both a T lymphocyte-specific signal and a proinflammatory signal. Here we show that Ni(2+) triggered an inflammatory response by directly activating human Toll-like receptor 4 (TLR4). Ni(2+)-induced TLR4 activation was species-specific, as mouse TLR4 could not generate this response. Studies with mutant TLR4 proteins revealed that the non-conserved histidines 456 and 458 of human TLR4 are required for activation by Ni(2+) but not by the natural ligand lipopolysaccharide. Accordingly, transgenic expression of human TLR4 in TLR4-deficient mice allowed efficient sensitization to Ni(2+) and elicitation of CHS. Our data implicate site-specific human TLR4 inhibition as a potential strategy for therapeutic intervention in CHS that would not affect vital immune responses.

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Available from: Badrinarayanan Raghavan, Oct 06, 2015
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    • "Although this study provided valuable information on gene expression changes in the elicitation phase of allergic contact dermatitis, it cannot be used to confirm the HaCaT gene signature, as this signature presents part of the sensitization phase. In addition, the mechanisms underlying nickel sensitization are different from other sensitizing chemicals, as sensitization to nickel does not require covalent binding to proteins (Schmidt et al., 2010). The study presented here is aimed to provide a foundation for the human relevance of the HaCaT gene signature. "
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    ABSTRACT: The skin sensitizing potential of chemicals is mainly assessed using animal methods, such as the murine local lymph node assay. Recently, an in vitro assay based ona gene expression signaturein the HaCaT keratinocytecell linewas proposedas an alternative to these animal methods. Here, the human relevance of this gene signature is assessed through exposure of freshly isolated human skin to the chemical allergens dinitrochlorobenzene (DNCB) and diphenylcyclopropenone (DCP). In human skin, the gene signature shows similar direction of regulation as was previously observed in vitro, suggesting that the molecular processes that drive expression of these genes are similar between the HaCaT cell line and freshly isolated skin, providing evidence for the human relevance of the gene signature.
    Toxicology in Vitro 09/2014; 29(1). DOI:10.1016/j.tiv.2014.08.010 · 2.90 Impact Factor
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    • "LPS stimulates innate immunity via Toll-like receptor 4 (TLR4), and TLRs may modify adaptive immunity [30]. Recently, Schmidt et al. reported that Ni directly stimulates human TLR4, but not mouse TLR4, which may be crucial for the development of contact allergy [31]. In this study, we identified the accumulation of T cells in the footpads of Cr plus LPS sensitized–Cr-challenged mice compared with those of Cr without LPS sensitized–Cr-challenged mice. "
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    ABSTRACT: Chromium (Cr) causes delayed-type hypersensitivity reactions possibly mediated by accumulating T cells into allergic inflamed skin, which are called irritants or allergic contact dermatitis. However, accumulating T cells during development of metal allergy are poorly characterized because a suitable animal model is not available. This study aimed to elucidate the skewing of T-cell receptor (TCR) repertoire and cytokine profiles in accumulated T cells in inflamed skin during elucidation of Cr allergy. A novel model of Cr allergy was induced by two sensitizations of Cr plus lipopolysaccharide solution into mouse groin followed by single Cr challenge into the footpad. TCR repertoires and nucleotide sequences of complementary determining region 3 were assessed in accumulated T cells from inflamed skin. Cytokine expression profiles and T-cell phenotypes were determined by qPCR. CD3+CD4+ T cells accumulated in allergic footpads and produced increased T helper 1 (Th1) type cytokines, Fas, and Fas ligand in the footpads after challenge, suggesting CD4+ Th1 cells locally expanded in response to Cr. Accumulated T cells included natural killer (NK) T cells and Cr-specific T cells with VA11-1/VB14-1 usage, suggesting metal-specific T cells driven by invariant NKT cells might contribute to the pathogenesis of Cr allergy.
    PLoS ONE 01/2014; 9(1):e85983. DOI:10.1371/journal.pone.0085983 · 3.23 Impact Factor
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    • "In humans, nickel may cause contact dermatitis, allergic contact urticaria, rhinitis and asthma (Estlander et al. 1993). Schmidt et al. (2010) provided evidence that the Toll Like Receptor (TLR)4 complex plays a role in the mechanisms leading to contact nickel allergy, suggesting that also the innate immune system can substantially contribute to " allergic " reactions. Type IV hypersensitivity reactions are routinely tested with a patch test although in cases of metal hypersensitivity, "
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    ABSTRACT: Emissions of laser printers and photocopiers (LP&P) may be associated with health problems. The aim of this review is to describe the clinical picture that is triggered by exposure to LP&P and the molecular mechanisms underpinning the symptoms. Exposure to LP&P to vulnerable subjects may cause a symptom complex consisting of 1) irritation and hyperresponsiveness of the upper and lower respiratory tract; and 2) chronic fatigue (syndrome, CFS). Symptoms occur within hours after L&P exposure and may last for some days or become chronic with exacerbations following LP&P exposure. Substances that can be found in toners or are generated during the printing process are Silica nanoparticles, Titanium Dioxide nanoparticles, Carbon Black, metals, ozone, volatile organic compounds (VOC), etc. The latter may generate oxidative and nitrosative stress (O&NS), damage-associated molecular patterns molecules, pulmonary and systemic inflammation, and modulate Toll Like Receptor 4 (TRL4)‑related mechanisms. It is concluded that LP&P emissions may cause activation of the TLR4 Radical Cycle and thus be associated with the onset of chronic inflammatory and O&NS illnesses, such as CFS, in some vulnerable individuals. Cinnamon, an antagonist of the TLR4 complex, and Hydrogen, a potent antiinflammatory and oxygen radical scavenger, may have efficacy treating LP&P-induced illness.
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