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: 24.97). 09/2010; 11(9):814-9. DOI: 10.1038/ni.1919
Source: PubMed

ABSTRACT 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, Aug 20, 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 · 3.21 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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    • "Findings on species differences tend to be neglected, and the skewing of the available data by a publication bias toward positive animal findings has only recently been unraveled (Sena et al. 2010). Just to name few examples, it has been clear before the Seok study that TLR4 signaling, a pivotal process in the inflammatory response, is different in man and mouse (Schmidt et al. 2010), and it is generally known that many inflammatory mediators take very different roles in different species. Even fundamental regulations ranging from neural control of airways (Schlepütz et al. 2012) to the biology of stem cells (Schnerch et al. 2010) are very different between species. "
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