B Cell immunodeficiency in BENTA disease

BENTA 病中的 B 细胞免疫缺陷

• 批准号: 8623594
• 负责人: Andrew L Snow
• 金额: $ 22.69万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8623594
• 关键词: Affect; Animal Model; Antibodies; Antibody Formation; Antigen Receptors; Antigens; Autoimmune Diseases; B cell differentiation; B lymphoid malignancy; B-Cell Activation; B-Cell Development; B-Cell Lymphomas; B-Lymphocytes; Biochemical; Biochemical Pathway; Blood specimen; CD3 Antigens; Cell Survival; Cell physiology; Cells; Chronic; Clinical; Coupled; Defect; Development; Disease; Disease model; Exhibits; Failure; Family; Funding Opportunities; Gene Mutation; Generations; Genes; Glean; Goals; Homeostasis; Human; Humoral Immunities; Immune; Immune response; Immune system; Immunoglobulin Class Switching; Immunologic Deficiency Syndromes; In Vitro; Infection; Inherited; Investigation; JAK3 gene; Knock-in Mouse; Knowledge; Leukocytes; Life; Ligands; Link; Lymphocyte; Lymphoid; Lymphoproliferative Disorders; Mature B-Lymphocyte; Memory; Memory B-Lymphocyte; Missense Mutation; Modeling; Molecular; Mus; Mutation; NFKBIA gene; Natural Immunity; Oncogenic; Organ; Patients; Phenotype; Plasma; Point Mutation; Polysaccharides; Predisposition; Protein Family; Proteins; Receptor Signaling; Research; Resources; Rest; Sampling; Scaffolding Protein; Severe Combined Immunodeficiency; Signal Pathway; Signal Transduction; Signaling Protein; Somatic Mutation; Sorting - Cell Movement; Specimen; Spleen; Splenomegaly; T cell anergy; T cell differentiation; T-Lymphocyte; Testing; Therapeutic Intervention; Toll-like receptors; Transgenic Organisms; Vaccines; Work; base; congenital immunodeficiency; cytokine; gain of function; gain of function mutation; immune function; in vivo; insight; large cell Diffuse non-Hodgkin' s lymphoma; mouse model; mutant; novel; novel therapeutic intervention; plasma cell differentiation; public health relevance; research study; response; transcription factor; tumor

PROJECT SUMMARY/ABSTRACT The study of either autoimmune and immunodeficiency disorders can provide important and often surprising knowledge about specific genes that control the number and function of white blood cells. Debilitating genetic mutations in CARD11, a key signaling protein in lymphocytes, manifest as severe combined immunodeficiency in mice and humans. On the other hand, spontaneous mutations that inappropriately turn CARD11 signaling on have been described in ~10% of B cell lymphomas that demonstrate continuous activation of NF-¿B, a family of proteins that governs multiple genes associated with cell survival, proliferation and differentiation. We recently characterized a new human disorder in which activating, germline- encoded CARD11 mutations cause spleen enlargement and selective expansion of B cells, even though CARD11 signaling is thought to be highly similar in B and T cells. Paradoxically, patients with this disease (termed B cell Expansion with NF-¿B and T cell Anergy, or BENTA) also show immune system deficits including specific antibody deficiency. The long-term objective of this project is to elucidate how inherited gain-of-function mutations in CARD11 differentially affect B and T cells and ultimately contribute to a novel primary immunodeficiency. Using blood samples from BENTA patients, we will determine if impaired B cell differentiation and antibody secretion is primarily explained by a B cell intrinsic signaling defect or a failure of T cells to provide sufficient "help" to responding B cells. Our analyses will pinpoint specific molecules and biochemical pathways that are disrupted by active CARD11 signaling directly in primary cells from affected patients, an invaluable resource that we have unique access to. Moreover, we will create the first animal model of BENTA disease by introducing the identical, inherited point mutations we discovered in humans into mice. Our proposed experiments with these mice will finally allow us to study perturbations in early lymphocyte development and test B cell responses to defined antigens in vivo in an intact host, which is simply not possible with human patients. This combined approach will significantly revise our understanding of how CARD11 functions as a critical, differential regulator of B versus T cell function. Insights gleaned from a more thorough investigation of this novel PID will hopefully inform new therapeutic approaches for treating BENTA and other immunological disorders that share common features.

项目摘要/摘要 对自身免疫和免疫缺陷障碍的研究可以提供重要的，并且经常提供 关于控制白细胞数量和功能的特定基因的惊人知识。 Card11中的遗传突变是衰弱的遗传突变，这是一种淋巴细胞中的关键信号蛋白，表现为严重 小鼠和人类的免疫缺陷。另一方面，赞助的突变 在〜10％的B细胞淋巴瘤中，已经描述了不适当的Card11信号传导，证明了 NF-¿B的连续激活，该家族控制与细胞存活相关的多个基因的蛋白质， 增殖和分化。我们最近描述了一种新的人类疾病，其中激活种系 - 编码的Card11突变会导致脾脏增强和B细胞的选择性扩展，即使 Card11信号在B和T细胞中被认为高度相似。矛盾的是，患有这种疾病的患者 （称为b细胞扩展，NF-€和T细胞消极或Benta）也显示出免疫系统缺陷 包括特定的抗体缺乏。该项目的长期目标是阐明如何继承 Card11的功能性突变差异影响B和T细胞，并最终有助于A 新型初级免疫缺陷。 使用Benta患者的血液样本，我们将确定B细胞分化受损和 抗体分泌主要是通过B细胞固有信号传导缺陷或T细胞失败提供的 足够的“帮助”反应B细胞。我们的分析将查明特定分子和生化途径 直接在受影响患者的原代细胞中受到主动Card11信号的破坏，这是一个无价的 我们具有独特访问权限的资源。此外，我们将通过 引入了我们在人类中发现的相同的遗传点突变。我们提出的 这些小鼠的实验最终将使我们能够研究早期淋巴细胞发育和 测试B细胞对完整宿主中体内定义抗原的反应，人类根本不可能 患者。这种合并的方法将大大修改我们对Card11如何发挥作用的理解 B与T细胞功能的关键，差分调节剂。从更彻底的调查中收集的见解 这个小说的PID希望能为治疗Benta和其他免疫学的新治疗方法提供信息 共同特征的疾病。