Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema

Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema. and bacteria [2,3]. However, recent progress in the field has broadened their roles in many immune responses [4], ranging from innate defense against venoms of bees and snakes [5] to multiple aspects of adaptive immune responses such as antigen presentation and leukocyte recruitment to draining lymph nodes [6] as well as downmodulation of immune responses [7]. Their pathogenic roles have been extended to include not only allergic diseases and helminth and bacterial infection, but also autoimmune diseases [8,9], allograft tolerance [10], angiogenesis in tissue repair [11], and carcinogenesis [12,13]. The high-affinity receptor for IgE (FcRI) expressed on mast cells (and basophils) consists of four subunits (2): an IgE-binding chain, a signal-amplifying, receptor-stabilizing chain, Darapladib and two disulfide-bonded chains that are the main signal transducers [14]. Upon encounter with multivalent antigen, IgE-bound FcRI on mast cells become aggregated or crosslinked, leading to cell activation [15]. Activated mast cells secrete three classes of substances: (1) preformed chemical and protein mediators, such as histamine, serotonin, heparin and chondroitin sulfates, proteases, major basic protein, acid hydrolases, cathepsin, etc., (2) lipid mediators, such as prostaglandins, leukotrienes, and platelet-activating factor (PAF), and (3) preformed and/or de novo synthesized growth factors, cytokines, and chemokines, such as tumor necrosis factor (TNF)-, TGF-, MIP-1, MCP-1, VEGF, IFN-//, GM-CSF, IL-1/, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-16, IL-18, IL-25, etc. (Fig. 1). Open in a separate window Physique 1 Mast cells secrete a wide array of preformed and de novo synthesized proinflammatory and immunomodulatory mediators upon stimulation by 4933436N17Rik IgE and antigen or other stimuli. The mediators may contribute to various aspects of systemic and local immune responses in AD. Anaphylactic responses to insect stings, injected medications, foods, and other agents are thought to be caused by IgE/antigen-dependent mast cell activation [16]. In addition to this classic pathway of systemic anaphylaxis [17,18], IgG antibodies can also induce anaphylaxis in a basophil-dependent manner in the mouse [19]. Histamine is usually primarily responsible for the development of shock in the classic pathway. In contrast, PAF is responsible in the latter alternative pathway. Despite the earlier controversy around the role of mast cells in asthma [20], recent studies clearly showed their importance [21,22]: mast cells can markedly enhance antigen-dependent airway hyperresponsiveness, airway eosinophil infiltration, and an increase in the number of proliferating cells in the airway epithelium that are induced in mouse models of asthma that either Darapladib omit artificial adjuvants or use low doses of antigen challenge; mast cells’ roles Darapladib were also shown in a chronic asthma model [23]. In asthmatics, mast cells infiltrate airway easy muscle and contribute to persistent inflammation in the airways [24-26]. The best evidence for the pivotal role of IgE and therefore that of FcRI in human asthma came from clinical studies demonstrating that anti-IgE mAb Omalizumab decreases serum IgE levels and allergen-induced bronchoconstriction [27,28]. The most critical tool that has driven the high-paced findings is usually mast cell engraftment into mast cell-deficient animals, by which one can confirm that defects or abnormal observations on mast cell-deficient animals can be reversed by providing exogenous mast cells [29]. Stem cell factor (SCF) is a critical growth and differentiation factor for mast cell development [30,31]. c-Kit is usually its receptor tyrosine kinase. Loss-of-function mutations in gene loci for this ligand (mice have been a choice for mast cell engraftment for more than two decades. However, these mice have various.