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

B细胞抗原受体（BCR）驱动的B细胞淋巴瘤发生与自身免疫之间的机制联系

• 批准号: 9973700
• 负责人: Jing Hong Wang
• 金额: $ 35.57万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-08 至 2021-02-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9973700
• 关键词: Acceleration; Address; Affect; Affinity; Antibodies; Antigens; Autoantibodies; Autoantigens; Autoimmunity; B Cell Proliferation; B-Cell Activation; B-Cell Lymphomas; B-Cell NonHodgkins Lymphoma; B-Lymphocytes; BIRC3 gene; CD80 Antigens; Cancerous; Cell Survival; Cells; Chromosomal translocation; Chronic; DNA; DNA Double Strand Break; Data; Diagnostic; Etiology; Exhibits; Foundations; Genome; Genomic Instability; Genomics; Goals; Hen Egg Lysozyme; Human; Immunity; Immunization; Immunoglobulin Class Switching; Immunoglobulin Somatic Hypermutation; Immunoglobulin Switch Recombination; In Vitro; Infection; Injections; Lead; Licensing; Link; Lymphocyte; Lymphoma; Lymphomagenesis; Malignant Neoplasms; Mantle Cell Lymphoma; Mature B-Lymphocyte; Mediating; Modeling; Mus; Mutagenesis; Mutation; NR0B2 gene; Non-Hodgkin' s Lymphoma; Pathogenesis; Pathologic; Point Mutation; Price; Process; Production; Protein phosphatase; Public Health; Receptor Activation; Receptor Signaling; Receptors, Antigen, B-Cell; Regulation; Role; SYK gene; Signal Pathway; Signal Transduction; Spleen; T-Lymphocyte; TNF Receptor-Associated Factors; TNF receptor-associated factor 3; TRAF2 gene; Techniques; Testing; activation-induced cytidine deaminase; base; genome-wide; in vivo; lymph nodes; mutant; novel; novel therapeutics; pathogen; prognostic; response; tumorigenesis

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.

项目摘要/摘要 标题：B细胞抗原受体（BCR）驱动的机械连接 和自身免疫 非霍奇金的淋巴瘤（NHL）是影响淋巴细胞的异质性恶性肿瘤。 总体而言，NHL是美国第五大癌症，而超过90％的NHL是B细胞起源。 脾脏中的T和B细胞数量大致相等，淋巴结中有更多的T细胞。为什么B细胞是 那么容易淋巴作用吗？这可能是由于B细胞特异性DNA诱变过程，体细胞 超突击（SHM）和类开关重组（CSR）。 SHM/CSR是通过激活诱导的 脱氨酶（AID），并且需要产生必不可少的高亲和力相关抗体（ABS） 为了免疫病原体。但是，B细胞用利用援助产生点突变付出了高昂的代价 SHM/CSR期间或DNA双链断裂（DSB）。辅助是一种基因组突变器，如果失调，可以 引起全基因组DSB，导致染色体易位和淋巴瘤。因此，援助表达是 受到严格控制，仅在感染或免疫期间活化的B细胞发生。 B细胞抗原受体（BCR）对于B细胞存活和识别特定抗原至关重要 包括自我抗原。但是，仅BCR信号传导不能诱导辅助表达和体外CSR， 目前尚不清楚单独通过抗原激活BCR是否可以在体内诱导辅助表达。为什么如此 要解决的重要问题？因为这可能是保持自我反应的保护机制 B细胞转变癌。如果仅抗原可以在没有病原体的情况下诱导辅助表达 相关的共刺激，B细胞可能会产生有害的自身抗体反应，鉴于大量 我们体内的自我抗原。这种自我抗原对BCR的慢性激活将导致生存和增殖 B细胞以及异常诱导的辅助表达的B细胞将显着增加可能性 肿瘤发生。因此，了解BCR信号在辅助调节中的作用非常重要，并且 对自身免疫性和B细胞淋巴作用以及机械连接的重要意义 在这两个病理条件之间。在此提案中，我们将阐明哪些因素调节能力 BCR诱导B细胞中辅助表达，基因组不稳定性和淋巴作用。