Immunobiology and pathophysiology of Hodgkin lymphomas.
Immunobiology and pathophysiology of Hodgkin lymphomas.
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DOI：
10.1182/asheducation-2005.1.231
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发表时间：
2005-01-01
期刊：
影响因子：
--
通讯作者：
Poppema, Sibrand
中科院分区：
文献类型：
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作者：
Poppema, Sibrand
经典霍奇金淋巴瘤（HL）的特征在于存在Reed-Sternberg（RS）细胞，其是转化的后生殖中心B细胞，由于它们没有经历成功的免疫球蛋白基因重排而注定凋亡。几种机制，包括EB病毒（EBV）的潜伏感染，允许这些细胞存活。值得注意的是，许多促进存活的信号传导途径在EBV诱导的蛋白质（如EBNA1、LMP1和LMP2）和在RS细胞中上调的其他分子之间共享。组成性核因子（NF）-kappaB的存在发挥了关键作用，其由LMP 1以及CD30、CD40、肿瘤坏死因子（TNF）-α和Notch1相互作用诱导，并导致至少45种基因的上调，包括趋化因子、细胞因子、受体、凋亡调节因子、细胞内信号传导分子和转录因子。经典HL的另一个特征是存在广泛的炎性浸润。这种浸润的关键特征是它包含Th2和T调节细胞，并且通常缺乏Th1细胞、CD8细胞毒性T细胞和自然杀伤（NK）细胞。RS细胞似乎通过分泌Th2型趋化因子如TARC和MDC来诱导这种浸润。RS细胞还产生抑制Th1应答的细胞因子，因为白细胞介素（IL）-10和转化生长因子（TGF）-β表达CD95配体，其诱导活化的Th1和CD8 T细胞的凋亡。其他重要的机制，使RS细胞逃避有效的抗EBV免疫应答包括下调HLA I类在EBV阴性的情况下，或存在的多态性，在HLA I类EBV阳性的情况下，允许逃避CD8介导的细胞毒性。另一方面，HLA-G的表达允许从通常识别HLA I类阴性RS细胞的NK细胞逃逸。总体而言，HL中的细胞浸润似乎通过提供抑制细胞毒性免疫应答的环境并提供支持RS细胞生长和存活的细胞相互作用和细胞因子，在允许RS细胞存活方面发挥决定性作用。未来的治疗策略可以直接集中在NF-κ B活化，各种受体与配体的相互作用，趋化因子和细胞因子网络，或诱导有效的抗EBV潜伏蛋白免疫应答。
Classical Hodgkin lymphoma (HL) is characterized by the presence of Reed-Sternberg (RS) cells, which are transformed post-germinal center B cells destined for apoptosis since they have not undergone successful immunoglobulin gene rearrangement. Several mechanisms, including latent infection by Epstein-Barr virus (EBV), allow these cells to survive. 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)-kappaB, which is induced by LMP1, as well as by CD30, CD40, tumor necrosis factor (TNF)-alpha, 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)-beta 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-kappaB 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.