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  • br Conflict of interest statement br Acknowledgement We than

    2019-06-12


    Conflict of interest statement
    Acknowledgement We thank the constant support of nanomedicine research from the Ming Hsieh Institute for Research on Engineering-Medicine for Cancer. The authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.
    Introduction CCL22 Chemokine is one of a group of heparin binding proteins that induce migration and extravasation of chronically activated Th2 BGB324 into the skin. They produce their action through binding to G protein-coupled receptor (CCR4) which in turn increase intracellular Ca++ mobilization that affect cytoskeleton-induced movement and increase the affinity of targeted cells to adhesion molecules [1]. The adhesion molecules E-selectin and intracellular adhesion molecule 1 (ICAM-1) are greatly upregulated in the dermal post capillary venules by cytokines released by skin resident antigen presenting cells like Langerhans dendritic cells. Langerhans dendritic cells can also produce activated T cell chemokines such as CCL22 on local endothelium which resulted in recruitment of cutaneous leukocyte antigenpositive (CLA+)and chemokine receptor 4 positive (CCR4+)CD4+ CD25+ FoxP3+ regulatory T cells in antigen non specific manner. In the skin, regulatory T cells encounter their cognate antigen specific Langerhans dendritic cells. So, they become activated and expanded to suppress activation and proliferation of effector T cells. This pool of suppressive T cells is prohibited in skin autoimmune diseases treated by Corticosteroides, Calcineurin inhibitors and VitD3 because they induce IL-10 expression which in turn inhibit CCL22 production by skin dendritic cells like Langerhans dendritic cells.
    Macrophage derived chemokine (MDC) CCL22 (Chemokine ligand 22) or Macrophage Derived Chemokine “MDC” was discovered in macrophages but it is also produced by activated B lymphocytes and dendritic cells [2]. It was also called “Stimulated T cell Chemotactic Protein-1” (STCP-1) [3] and ABCD-1 (activated B cell-derived chemokine-1) or DC/B- CK (DC and B cell-derived chemokine) in mice [2,4]. In human, CCL22 gene is found in a mini cluster in chromosome 16q13 near gene of CCL17 (or, thymus and activation-regulated chemokine: TARC) and their Chemokines have homeostatic and inflammatory activity [5]. CCL22 and CCL17 bind the same receptor (CCR4) and induce Ca++ mobilization and chemo-attracting action on Th2 lymphocytes [6] with a preferential effect on CD4+ regulatory T lymphocytes [7]. CCL22 is constitutively expressed in dendritic cells, B cells, and macrophages whereas NK cells, monocytes, and CD4 lymphocytes express CCL22 after appropriate stimulation [8]. Langerhans dendritic cells, which are skin-epidermis populated immature dendritic cells, can also express CCL22 but only after maturation, however in mice it becomes the most abundantly expressed gene [4,9]. Although it is difficult to extrapolate these results to human, but langerhans dendritic cells had already taken a great consideration as homeostatic dendritic cells in human.
    Langerhans dendritic cells and immune homeostasis in the skin When langerhans cells encounter antigen in the epidermis, they drain to skin regional lymph node in response to CCL21 due to CCR7/CCL21 interaction. In lymph node, langerhans Dendritic cells present antigen to naïve T cells to become effector memory T Cells that express CLA (Cutaneus leukocytes Antigen) and CCR4 (the receptor for CCL22) beside the central memory T cells which reside in skin lymphoid organ and express E-selectin (adhesion molecule) and CCR7(the receptor for CCL21 and CCL19) Fig. 1. However, there are another pathways for trafficking Langerhans dendritic cells at steady state [10]. Upon second antigen encounter, effector memory T Cells home to skin in antigen nonspecific manner from regional skin lymph node through chemokine mediated homing. On the other hand; langerhans cells expand also long lived resident effector memory T cells [11].