Browsing by Author "Hari, Aswin"

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    Toll-Like Receptors: Role in Dermatological Disease
    (2010-08-22) Hari, Aswin; Flach, Tracy L.; Shi, Yan; Mydlarski, P. Régine
    Toll-like receptors (TLRs) are a class of conserved receptors that recognize pathogen-associated molecular patterns (PAMPs) present in microbes. In humans, at least ten TLRs have been identified, and their recognition targets range from bacterial endotoxins to lipopeptides, DNA, dsRNA, ssRNA, fungal products, and several host factors. Of dermatological interest, these receptors are expressed on several skin cells including keratinocytes, melanocytes, and Langerhans cells. TLRs are essential in identifying microbial products and are known to link the innate and adaptive immune systems. Over the years, there have been significant advances in our understanding of TLRs in skin inflammation, cutaneous malignancies, and defence mechanisms. In this paper, we will describe the association between TLRs and various skin pathologies and discuss proposed TLR therapeutics.
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    Toll-Like Receptors: Role in Dermatological Disease
    (Hindawi Publishing Corporation, 2010-07-01) Hari, Aswin; Flach, Tracy L.; Shi, Yan; Mydlarski, P. Régine
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    Unraveling mechanisms behind cross presentation during phagocytic signaling
    (2014-01-29) Hari, Aswin; Shi, Yan
    MHC class I antigens come from endogenous syntheses, while class II antigens are obtained extracellularly via endocytosis. Cross presentation is the link between the two by which external antigens are targeted to the MHC class I pathway. It is generally accepted that particulate antigens are more efficient in this pathway switch. However the reason behind this phenomenon is unknown. We report that dendritic cell engagement of a phagocytic target limits endocytic maturation and inhibits the associated proteolytic activities. In this scenario, early endosomes show reduced progression towards late endosomes/lysosomes and remain spatially close to the cell membrane. In phagocytosis, the microtubular (MT) system, including tubulin filaments and microtubule organization centers (MTOCs), are heavily skewed toward the engulfed particulate matter; the remaining cytoplasmic volumes are relatively devoid of MT presence. This is accompanied by a reduced centripetal movement inward and the maturation of endosomes. The antigen processing in these arrested endosomes is under the control of Nicotinamide adenine dinucleotide phosphate-oxidase (NAPDH)-associated ROS. We also show that cathepsin S is responsible for the generation of the class I epitope for cross presentation. The rerouted antigen presentation is at least 40 fold more efficient than the same amount of antigen delivered through the phagocytic pathway, and is operational in vivo. Our results suggest that in DCs in addition to solid structure uptake, phagocytosis directs a coordinated set of enzymatic and cytoskeletal events that regulate endosomal trafficking and maturation. As a consequence, external soluble antigens are driven away from their conventional MHC class II processing, into the class I cross presentation pathway.