B cell antigen receptor (BCR)-driven mechanistic connection between B cell lymphomagenesis and autoimmunity

项目摘要/摘要 标题：B细胞抗原受体(BCR)驱动的B细胞淋巴瘤之间的机制联系 和自身免疫力 非霍奇金淋巴瘤(NHL)是一组影响淋巴细胞的异质性恶性肿瘤。 总体而言，NHL是美国第五大最常见的癌症，超过90%的NHL来自B细胞来源。 脾中T细胞和B细胞数量基本相等，而淋巴结中T细胞数量较多。为什么B细胞 那么容易患淋巴增生症？这可能是由于B细胞特异的DNA突变过程，体细胞 超突变(SHM)和类开关重组(CSR)。SHM/CSR由激活诱导启动 脱氨酶(AID)和产生高亲和力的同型转换抗体(Abs)是必不可少的 对病原体的免疫力。然而，B细胞为利用AID产生点突变付出了高昂的代价 或在SHM/CSR过程中的DNA双链断裂(DSB)。AID是一个基因组突变器，如果调控失调，它可以 导致全基因组的DSB，导致染色体易位和淋巴瘤。因此，AID表达式为 受到严格控制，仅发生在感染或免疫期间激活的B细胞中。 B细胞抗原受体(BCR)是B细胞生存和识别特定抗原所必需的 包括自身抗原。然而，单独通过BCR信号不能在体外诱导AID表达和CSR， 目前还不清楚单独用抗原激活BCR是否能在体内诱导AID的表达。为什么它会如此 需要解决的重要问题是什么？因为这可以作为一种保护机制来保持自我反应 B细胞不会癌变。如果在没有病原体的情况下，单独的抗原可以诱导艾滋病的表达- 相关的共刺激，B细胞可能会产生有害的自身抗体反应，鉴于丰富的 我们体内的自身抗原。这种自身抗原对bcr的慢性激活将导致生存和增殖。 B细胞，这与异常诱导的AID表达一起，将显著增加 关于肿瘤发生的研究。因此，了解BCR信号在AID调节中的作用具有非常重要的意义。 自身免疫与B细胞淋巴瘤发生及其机制联系的重要意义 在这两种病理状态之间。在这项提案中，我们将阐明哪些因素调节着这一能力 Bcr诱导B细胞AID表达、基因组不稳定和淋巴瘤化。

PROJECT SUMMARY/ABSTRACT Title: B cell antigen receptor (BCR)-driven mechanistic connection between B cell lymphomagenesis and autoimmunity Non-Hodgkin's lymphomas (NHL) are a heterogeneous group of malignancies affecting lymphocytes. Collectively, NHL are the fifth most common cancers in the US, and more than 90% of NHL are of B cell origin. There are roughly equal number of T and B cells in spleen and more T cells in lymph nodes. Why are B cells so prone to lymphomagenesis? This is probably due to B cell-specific DNA mutagenesis processes, somatic hypermutation (SHM) and class switch recombination (CSR). SHM/CSR are initiated by activation-induced deaminase (AID) and are required to produce high affinity isotype-switched antibodies (Abs) that are essential for immunity against pathogens. However, B cells pay a high price for utilizing AID to generate point mutations or DNA double-stranded breaks (DSBs) during SHM/CSR. AID is a genome mutator and, if dysregulated, can cause genome-wide DSBs that lead to chromosomal translocations and lymphomas. Hence, AID expression is tightly controlled and only occurs in activated B cells during infection or immunization. B cell antigen receptor (BCR) is essential for B cell survival and for recognizing specific antigens including self-antigens. However, signaling by the BCR alone cannot induce AID expression and CSR in vitro, and it is unclear whether BCR activation by antigen alone can induce AID expression in vivo. Why is it such an important question to be addressed? Because this may serve as a protective mechanism to keep self-reactive B cells from turning cancerous. If antigen alone could induce AID expression in the absence of pathogen- associated co-stimulation, B cells might generate harmful auto-antibody responses, given the abundance of self-antigens in our body. Chronic activation of BCR by such self-antigens will lead to survival and proliferation of B cells, which, together with abnormally induced AID expression, would significantly increase the likelihood of tumorigenesis. Hence, understanding the role of BCR signaling in AID regulation is highly significant, with important implications for autoimmunity and B cell lymphomagenesis as well as the mechanistic connection between these two pathological conditions. In this proposal, we will elucidate what factors regulate the ability of BCR to induce AID expression, genomic instability and lymphomagenesis in B cells.