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: 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
• 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' 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

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/文摘

项目成果

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
• 作者: Wang JH

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.

• DOI: 10.3389/fimmu.2021.663443
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Chen Z;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.