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  • br Guidance of B cell localization by EBI br EBI

    2019-10-08


    Guidance of B cell localization by EBI2
    EBI2 expression and B cell disease Although chemoattractant receptors of the GPR family play essential roles in coordinating the migration of lymphocytes for efficient responses against pathogens, their dysregulation can result in the initiation or progression of inflammatory and autoimmune disorders. Involvement of EBI2 with inflammation has been suggested by the association of polymorphisms in the gene encoding EBI2 with susceptibility to type 1 diabetes and other inflammatory diseases [39]. In rats, EBI2 has been shown to regulate the inflammatory response of macrophages [39], but its role in regulating autoimmune Mouse FGF21 / Fibroblast Growth Factor 21 Protein (His Tag) in diabetes has not yet been investigated. EBI2 has also been found to be among the group of dysregulated genes in systemic lupus erythematosus patients, and is reported to be downregulated in peripheral blood cells from lupus patients compared to healthy controls [40]. Furthermore, EBI2 maps to a chromosomal region that shows linkage in genome-wide scans of lupus patients 41, 42. Several studies have also linked regulation of EBI2 expression to human neoplastic diseases, such as acute myeloid leukemia, chronic lymphocytic leukemia, and diffuse large B cell lymphoma 43, 44, 45, 46. Gene expression profiling has indicated that EBI2 expression is downregulated in follicular and GC B-like diffuse large B cell lymphoma 45, 46. It is yet to be determined whether this low expression of EBI2 is somehow involved in cancer progression or simply reflects the expression of EBI2 by the original cell type prior to transformation. As mentioned above, infection of human B cells by Epstein–Barr virus induces high levels of EBI2 [18]. Upregulation of EBI2 on infected B cells is likely to mediate the observed propensity of Epstein–Barr virus-positive B cells to accumulate in interfollicular regions and avoid GCs 47, 48. During infectious mononucleosis this might be a strategy of Epstein–Barr virus to direct infected B cells to microenvironments conducive for their survival and to escape immune surveillance.
    Concluding remarks The GPR nature of EBI2 makes this receptor a highly suitable target for pharmaceutical intervention with small molecule drugs. The structural motifs critical for EBI2 function and the location and composition of its ligand-binding domain in EBI2 have started to be elucidated 49, 50. This information will facilitate future efforts to design novel therapeutic agents that may serve as agonists or antagonists for EBI2 to modulate inflammatory and autoimmune diseases or advance vaccine strategies.
    Acknowledgments
    Introduction Oxysterols are oxygenated derivatives of cholesterol or some of its precursors [1]. Oxygenated forms of phytosterols and cholestanoic acids may also be included in the group [2,3]. Endogenous oxysterols can be formed in two ways – enzymatically or non-enzymatically. The enzymatic mechanism is more likely to result in oxygenation of the side chain, whereas the non-enzymatic mechanism, which in most cases involves reaction with reactive oxygen species [4,5], more often produces ring oxysterols. Some oxysterols, however, can be created by both mechanisms. Oxysterols have been long known to play a vital role in cellular cholesterol homeostasis [1,6]. In recent years, oxysterols have seen an increase in scientific interest due to new findings regarding their function in the cell membrane structure [7,8] and their participation in the physiology of in the immune system [3,9], neuronal development [9] and mesenchymal stem cell differentiation [10]. Oxysterols have also been found to be involved in various pathological conditions, including neurodegenerative diseases, type 2 diabetes mellitus, age-related macular degeneration and cataract formation [8,[11], [12], [13], [14]], atherosclerosis [8,15], and cancer [16]. Oxysterols interact with numerous molecular targets and affect multiple signaling pathways, e.g. Hedgehog [17,18], Wnt [18], mTOR [19,20], or Notch [21]. This paper aims to provide a summary of key genes in oxysterol pathways and their variants that play either well-established or putative functional roles in human cancer (Fig. 1). Due to the complexity of the roles oxysterols play in cells, we selected only the genes most closely linked with oxysterols and focused on the consequences of oxysterol-related genetics for cancer risk and prognosis.