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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目概要/摘要标题：B 细胞抗原受体 (BCR) 驱动的 B 细胞淋巴瘤发生之间的机制联系和自身免疫非霍奇金淋巴瘤 (NHL) 是一组影响淋巴细胞的异质性恶性肿瘤。总的来说，NHL 是美国第五大常见癌症，超过 90% 的 NHL 源自 B 细胞。脾脏中的 T 细胞和 B 细胞数量大致相等，而淋巴结中的 T 细胞较多。为什么B细胞那么容易发生淋巴瘤吗？这可能是由于 B 细胞特异性 DNA 诱变过程、体细胞超突变（SHM）和类别转换重组（CSR）。 SHM/CSR 由激活诱导启动脱氨酶 (AID) 是产生必需的高亲和力同型转换抗体 (Abs) 所必需的用于抵抗病原体的免疫力。然而，B细胞利用AID产生点突变付出了高昂的代价或 SHM/CSR 期间 DNA 双链断裂 (DSB)。 AID 是一种基因组突变因子，如果失调，可以引起全基因组 DSB，从而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) 对于 B 细胞存活和识别特定抗原至关重要包括自身抗原。然而，单独由 BCR 发出的信号不能在体外诱导 AID 表达和 CSR，目前尚不清楚单独通过抗原激活BCR是否可以诱导体内AID表达。为什么会是这样一个要解决的重要问题？因为这可以作为一种保护机制来保持自我反应 B 细胞免于癌变。如果单独的抗原可以在没有病原体的情况下诱导 AID 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，因为存在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，与异常诱导的 AID 表达一起，将显着增加可能性的肿瘤发生。因此，了解 BCR 信号在 AID 调节中的作用非常重要，对自身免疫和 B 细胞淋巴瘤发生及其机制联系的重要意义介于这两种病理状况之间。在这个提案中，我们将阐明哪些因素调节能力 BCR 诱导 B 细胞中 AID 表达、基因组不稳定和淋巴瘤发生。