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  • The histologic finding that EBV infected B cells in

    2020-08-13

    The histologic finding that EBV-infected Axitinib in infectious mononucleosis tend to avoid the GCs and instead accumulate under the epithelium of certain mucosal tissues34, 129 could be explained by the above-mentioned expression patterns of chemokine receptors on EBV-infected B cells. CXCR4 and CXCR5 respond to their ligands, which are highly expressed in the center of lymphoid follicles and thereby direct B cells to GC formation. CCL20 and CCL28, on the other hand, are normally expressed by the epithelial cells of mucosal tissues such as salivary glands and the tonsils.130, 131, 132 As such, downregulation of CXCR4 and CXCR5 and upregulation of CCR6 and CCR10 could ensure migration toward the tonsillary epithelial cells. EBV also induces the expression of the mRNA levels of CCR9, which is responsible for B cell homing to mucosal tissues, as well as C5AR1, the receptor for the complement factor C5a. Alterations of the expression level of the aforementioned molecules may cause the EBV-infected cells to be retained in the interfollicular region of the tonsils. The manipulation of the chemokine system by EBV seems to be in favor of the virus infection, but it is likely that some of the regulation also reflects cell protection against the intruding virus and antiviral immune responses. As such, it was found that EBV-infected cells as well as EBV negative cells expressing LMP1 upregulate the expression of CCL17 and CCL22, known to preferentially attract Th2 cells and regulatory T cells via CCR4. This expression pattern would benefit the virus and skew the immune response away from a Th1 and CTL response. In contrast, EBV-infected cells were found to upregulate CCL3, CCL4, and CCL5, which are known to attract Th1 cells and activated CTL via CCR5. Expression of CCL5 was also found to be elevated in LMP1 expressing cells as well as Burkitt\'s lymphoma cell lines. Thus, the chemokine system may work in favor of both the virus and the immune system. Regardless of its effect on EBV infection, the chemokine system has been found to be regulated in both nasopharyngeal cancer and Hodgkin lymphoma. As such, Hodgkin and Reed–Sternberg (HRS) cells from Hodgkin lymphoma and nasopharyngeal carcinoma cells have been shown to express CXCL8 and CCL17. Furthermore, Hodgkin lymphoma cells express high levels of CXCL9, CXCL10, CCL3, CCL5, and CCL11.
    EBV-Associated Diseases Primary EBV infection often occurs in young immunocompetent children and is asymptomatic or present with nonspecific mild symptoms. However, given that EBV was originally identified in Burkitt\'s lymphoma cells and has the unique ability to transform resting B cells into highly proliferating lymphoblasts, it is not surprising that this virus is associated with a number of cancers in both immunocompromised and immunocompetent patients. In addition, EBV has been associated with autoimmune diseases involving infected Axitinib B cells (see Table 3 for an overview of confirmed EBV-associated diseases).
    Drug-Target Potential 7TM receptors and in particular class A receptors to which the 7TM receptors mentioned in this review belong, are highly druggable molecules. Approximately, 35% of all currently marketed drugs target class A 7TM receptors. There is no specific antiviral treatment for EBV. Current treatment strategies for EBV-associated lymphomas include B cell antibodies (rituximab, chimeric, and monoclonal antibody against CD20), reducing immunosuppression, EBV-specific CTL infusion, and chemotherapy for PTLDs; and anti-HIV treatment for HIV-associated lymphomas.158, 159 The use of rituximab in particular has dramatically changed the overall survival of PTLD patients, but a strategy directed specifically against EBV-infected cells and genes, which play a role in the EBV-mediated pathogenesis, could likely reduce the incidence of malignancies. As such, BILF1 constitutes an obvious target as it plays a role for EBV immune evasion56, 61, 62 and has oncogenic properties both in vitro and in vivo. EBI2 has been shown to have proliferative effects ex vivo and in addition, the receptor is upregulated in PTLDs. Though the role of EBI2 in EBV life cycle is still uncertain, the aforementioned knowledge suggests that EBI2 could play a role in EBV-mediated lymphoma development and therefore EBI2 constitutes another potential drug target. Finally, the chemokine expression pattern is skewed in both Hodgkin lymphoma and nasopharyngeal carcinoma meaning that inhibition of some chemokine receptors could prove beneficial in the antiviral treatment strategy.