Is the filaggrin-histidine-urocanic acid pathway essential for stratum corneum acidification?
- SourceAvailable from: Adelaide A Hebert[Show abstract] [Hide abstract]
ABSTRACT: Atopic dermatitis is an exceedingly common condition that is often difficult to treat. In this review, the pathophysiology and recent developments are discussed to understand how to better treat atopic dermatitis through the improved understanding of the breakdown of the skin barrier in atopic patients. The available treatments that address these barrier defects are discussed in the light of recent publications.09/2012; 1(3). DOI:10.1007/s13671-012-0018-6
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ABSTRACT: Recently a new inhibitory immunoglobulin domain-containing lymphocyte receptor was identified on the basis of its T helper 1 (T(H)1)-selective expression in murine T cell lines, which was named B and T lymphocyte attenuator (BTLA). Several groups have confirmed the initial characterization of BTLA as an inhibitory receptor, which was initially inferred from the mild increases in several parameters of BTLA-deficient mice. The initial expectation that BTLA would interact with a B7 family ligand, such as the B7x protein, was surprisingly overturned with the functional cloning of the actual BTLA ligand as herpesvirus entry mediator (HVEM). This was unexpected largely due to the fact that this interaction represents the convergence of two very different, although each quite extensive, families of receptors and ligands. The interaction of BTLA, which belongs to the CD28 family of the immunoglobulin superfamily, and HVEM, a costimulatory tumor-necrosis factor (TNF) receptor (TNFR), is quite unique in that it is the only receptor-ligand interaction that directly bridges these two families of receptors. This interaction has raised many questions about how receptors from two different families could interact and which are the signaling events downstream of receptor ligation. As we discuss here and recently demonstrated, HVEM interaction with BTLA serves to negatively regulate T cell responses, in contrast to the strong activation observed when HVEM engages its endogenous ligand from the TNF family. Finally, as studies of BTLA are just now beginning to extend beyond the initial characterizations, it is becoming clear that there are many complex issues remaining to be resolved, particularly potential polymorphisms that may engender disease susceptibility in the human.Advances in Immunology 02/2006; 92:157-85. DOI:10.1016/S0065-2776(06)92004-5 · 5.53 Impact Factor
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ABSTRACT: Proteases in the skin are essential to epidermal permeability barrier homeostasis. In addition to their direct proteolytic effects, certain proteases signal to cells by activating protease-activated receptors (PARs), the G-protein-coupled receptors. The expression of functional PAR-2 on human skin and its role in inflammation, pruritus, and skin barrier homeostasis have been demonstrated. Atopic dermatitis (AD) is a multifactorial inflammatory skin disease characterized by genetic barrier defects and allergic inflammation, which is sustained by gene-environmental interactions. Recent studies have revealed aberrant expression and activation of serine proteases and PAR-2 in the lesional skin of AD patients. The imbalance between proteases and protease inhibitors associated with genetic defects in the protease/protease inhibitor encoding genes, increase in skin surface pH, and exposure to proteolytically active allergens contribute to this aberrant protease/ PAR-2 signaling in AD. The increased protease activity in AD leads to abnormal desquamation, degradation of lipid-processing enzymes and antimicrobial peptides, and activation of primary cytokines, thereby leading to permeability barrier dysfunction, inflammation, and defects in the antimicrobial barrier. Moreover, up-regulated proteases stimulate PAR-2 in lesional skin of AD and lead to the production of cytokines and chemokines involved in inflammation and immune responses, itching sensation, and sustained epidermal barrier perturbation with easier allergen penetration. In addition, PAR-2 is an important sensor for exogenous danger molecules, such as exogenous proteases from various allergens, and plays an important role in AD pathogenesis. Together, these findings suggest that protease activity or PAR-2 may be a future target for therapeutic intervention for the treatment of AD.Yonsei medical journal 11/2010; 51(6):808-22. DOI:10.3349/ymj.2010.51.6.808 · 1.26 Impact Factor