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It is remarkable that many of the signaling pathways that promote survival are shared between the EBV-induced proteins, such as EBNA1, LMP1, and LMP2, and other molecules that are upregulated in RS cells. A key role is played by the presence of constitutive nuclear factor (NF)-\u03baB, which is induced by LMP1, as well as by CD30, CD40, tumor necrosis factor (TNF)-\u03b1, and Notch1 interactions, and results in the upregulation of at least 45 genes including chemokines, cytokines, receptors, apoptotic regulators, intracellular signaling molecules, and transcription factors. The other characteristic of classical HL is the presence of an extensive inflammatory infiltrate. Key features of this infiltrate are that it comprises Th2 and T regulatory cells and generally lacks Th1 cells, CD8 cytotoxic T cells, and natural killer (NK) cells. The RS cells appear to induce this infiltrate by the secretion of Th2 type chemokines such as TARC and MDC. The RS cells also produce cytokines that inhibit Th1 responses, as interleukin (IL)-10 and transforming growth factor (TGF)-\u03b2 express CD95 ligand, which induces apoptosis of activated Th1 and CD8 T cells. Other important mechanisms that allow the RS cells to escape an effective anti-EBV immune response include the downregulation of HLA class I in EBV-negative cases or the presence of a polymorphism in HLA class I in EBV-positive cases that allow escape from CD8-mediated cytotoxicity. On the other hand, expression of HLA-G allows the escape from NK cells that would normally recognize the HLA class I-negative RS cells. Overall, the cellular infiltrate in HL appears to play a decisive role in allowing the RS cells to survive by providing an environment that suppresses cytotoxic immune responses and providing cellular interactions and cytokines that support the growth and survival of RS cells. Future therapeutic strategies could focus directly on the NF-\u03baB activation, on various receptors to ligand interactions, on the chemokine and cytokine network, or on the induction of effective anti-EBV latent protein immune responses.<\/jats:p>","DOI":"10.1182\/asheducation-2005.1.231","type":"journal-article","created":{"date-parts":[[2005,11,23]],"date-time":"2005-11-23T01:29:34Z","timestamp":1132709374000},"page":"231-238","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":80,"title":["Immunobiology and Pathophysiology of Hodgkin Lymphomas"],"prefix":"10.1182","volume":"2005","author":[{"given":"Sibrand","family":"Poppema","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"key":"2019111702190242700_R1","doi-asserted-by":"crossref","unstructured":"Wlodarska I, Nooyen P, Maes B, et al. 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