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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：
10646137
负责人：
Jing Hong Wang
金额：
$ 35.64万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10646137
关键词：
Acceleration Address Affect Affinity Antibodies Antigens Autoantibodies Autoantigens Autoimmunity B Cell Proliferation B-Cell Activation B-Cell Antigen Receptor 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 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 Probability Process Production Protein phosphatase Public Health Receptor Activation Receptor Signaling Regulation Role SYK gene Signal Induction Signal Pathway Signal Transduction Spleen T-Lymphocyte TNF Receptor-Associated Factors TRAF2 gene Techniques Testing activation-induced cytidine deaminase genome-wide humoral immunity deficiency 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.

项目总结/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）是一组异质性的恶性肿瘤影响淋巴细胞。总体而言，NHL是美国第五大常见癌症，并且超过90%的NHL是B细胞来源的。脾脏中T细胞和B细胞数量大致相等，淋巴结中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细胞特异性的DNA诱变过程，体细胞突变，超突变（SHM）和类别转换重组（CSR）。SHM/CSR是由激活诱导的这些抗体是产生高亲和力同种型转换抗体（Abs）所必需的，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SHM/CSR期间的DNA双链断裂（DSB）。艾滋病是一种基因组突变，如果失调，引起全基因组DSB，导致染色体易位和淋巴瘤。因此，AID表达式为在感染或免疫过程中，它受到严格控制，仅发生在活化的B细胞中。 B细胞抗原受体（BCR）是B细胞存活和识别特异性抗原所必需的包括自身抗原。然而，单独的BCR信号传导在体外不能诱导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表达。为什么这是一个需要解决的重要问题？因为这可能是一种保护机制，防止B细胞癌变。如果抗原本身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，鉴于丰富的我们体内的自体抗原这种自身抗原对BCR的慢性激活将导致存活和增殖 B细胞，这与异常诱导的AID表达一起，将显著增加肿瘤的发生。因此，理解BCR信号在AID调节中的作用是非常重要的，对自身免疫和B细胞淋巴瘤发生以及这两种病理状态之间的联系在这个建议中，我们将阐明什么因素调节能力，在B细胞中诱导AID表达、基因组不稳定性和淋巴瘤发生。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Why the Outcome of Anti-Tumor Immune Responses is Heterogeneous: A Novel Idea in the Context of Immunological Heterogeneity in Cancers.

DOI：
10.1002/bies.202000024
发表时间：
2020-10
期刊：
BioEssays : news and reviews in molecular, cellular and developmental biology
影响因子：
0
作者：
Wang JH
通讯作者：
Wang JH

Pharmacologic targeting of Nedd8-activating enzyme reinvigorates T-cell responses in lymphoid neoplasia.

DOI：
10.1038/s41375-023-01889-x
发表时间：
2023-06
期刊：
LEUKEMIA
影响因子：
11.4
作者：
Wang, Xiaoguang;Chen, Canping;Vuong, Dan;Rodriguez-Rodriguez, Sonia;Lam, Vi;Roleder, Carly;Wang, Jing H.;Kambhampati, Swetha;Berger, Allison;Pennock, Nathan;Torka, Pallawi;Hernandez-Ilizaliturri, Francisco;Siddiqi, Tanya;Wang, Lili;Xia, Zheng;Danilov, Alexey V.
通讯作者：
Danilov, Alexey V.

How the Signaling Crosstalk of B Cell Receptor (BCR) and Co-Receptors Regulates Antibody Class Switch Recombination: A New Perspective of Checkpoints of BCR Signaling.