Cellular & Molecular Defects in Human B Cell Development

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• 批准号: 8901893
• 负责人: CHARLOTTE CUNNINGHAM-RUNDLES
• 金额: $ 192.48万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-15 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8901893
• 关键词: Activities of Daily Living; Adult; Affect; Age; Agonist; Alleles; Amaze; Anti-Bacterial Agents; Antibodies; Antibody Formation; Antibody Response; Antigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B Cell Proliferation; B cell differentiation; B-Cell Development; B-Lymphocytes; Biology; Calcium; Carbohydrates; Cell Differentiation process; Cell Maturation; Cell physiology; Cells; Cellular biology; Characteristics; Child; Chromosome Deletion; Collaborations; Communicable Diseases; Complex; Cyclophilins; DNA; Data; Defect; Deficiency Diseases; Development; Dimensions; Disease; Ectodermal Dysplasia; Employee Strikes; Enzymes; Epithelial Cells; Functional disorder; Genes; Genetic; Genetic Predisposition to Disease; Genotype; Goals; Hospitalization; Human; IgA Deficiency; Immune; Immune system; Immunity; Immunoglobulin A; Immunoglobulin Class Switching; Immunoglobulin G; Immunoglobulin Somatic Hypermutation; Immunoglobulin Switch Recombination; Immunoglobulins; Immunology; Inborn Genetic Diseases; Infant; Instruction; Intestines; Lead; Ligands; Link; Maintenance; Mediating; Memory B-Lymphocyte; Molecular; Molecular Genetics; Mutation; Pathologic Processes; Pathway interactions; Patients; Plasma Cells; Play; Pneumococcal Infections; Polysaccharides; Prevalence; Production; Protein Isoforms; Receptors, Antigen, B-Cell; Relative (related person); Research Personnel; Resources; Role; Signal Transduction; Smith Magenis syndrome; System; TALL-1 protein; TLR7 gene; Techniques; Toll-like receptors; Vaccinated; Work; activation-induced cytidine deaminase; cell growth; density; exome sequencing; experience; genome-wide; human tissue; lymphoid hyperplasia; microbial; mortality; programs; receptor; receptor function; response; success; transcription factor; transcytosis

DESCRIPTION (provided by applicant): Primary immune deficiency diseases provide an unparalleled resource for investigators in human immunology. Although the first primary immune deficiencies were described in infants with severe disease, primary immune defects are found in humans of all ages, leading to characteristic complications and significant mortality. While there have been amazing advances in the understanding many conditions, the more prevalent immune defects which impair B cell function, common variable immune deficiency, IgA deficiency, IgG subclass and specific antibody deficiency, are still largely uncharted territory. In this program we focus on a group of interlocking themes, including the biology of transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and the function of its ligands and toll like receptor ligands (TLR) in B cell differentiation and maturation. Engagement of TACI by its ligands B cell activating factor (BAFF) or a proliferation inducing ligand (APRIL) up-regulate the expression of activation-induced cytidine deaminase (AID), a DNA-editing enzyme essential for both class switch recombination (CSR) and somatic hypermutation (SHM.) These ligands, together with microbial agonists of Toll-like receptors (TLR) can also induce Ig CSR and perhaps even SHM in human B cells. Our data show that both TACI and TLR pathways are essential for the elimination of autoimmune B cells and the development of tolerance in humans. Aside from these pathways, the genetic factors that promote anti-bacterial immunity in humans are largely unknown, thus we have also undertaken a genome-wide approach, investigating patients with no known genetic defect who have experienced severe pneumococcal disease due to impaired Ab response to glycans. These approaches have already defined new primary immune defects and will add an entirely new dimension to the study of B cell defects. These new discoveries made using human tissues clearly promise further advances in understanding human B cell biology. This group of investigators has been drawn together by shared synergy, enthusiasm and passion for this field. Our established collaborations, with a proven track record of ongoing accomplishments, demonstrate the success of this approach. RELEVANCE (See instructions): Defects of the humoral immune system lead to infectious diseases, an inability to be vaccinated, immune dysregulation and autoimmune disease. In this Program Project, we will investigate a group of related human B cell defects, using coordinated genetic and molecular techniques to define these pathological processes. Project 1 - Investigating Blocks to B Cell Memory in CVID (Project Leader: Cunningham-Rundles, C.) Description as provided by applicant: Common variable immune deficiency (CVID) is the clinically most important primary antibody deficiency disease due to prevalence, complications, hospitalizations and requirement for lifelong immune globulin therapy. B cells of patients lack the capacity for normal somatic hyper-mutation and isotype switch, secrete immune globulins poorly, and fail to differentiate into plasma cells. The genetic causes of B cell dysfunction in CVID are largely unknown. Heterozygous mutations in the transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) gene are found in 8-10%, but also in relatives with normal immune globulin levels showing that these are not the main cause of severe B cell dysfunction. However, CVID subjects with TACI mutation especially in heterozygous form are significantly more likely to develop striking lymphoid hyperplasia and autoimmunity. Using human B cells and transfectants with TACI mutations, we will investigate TACI receptor function in humans, examining if monoallellic or biallelic mutations in TACI accelerate BAFF/BAFF-R mediated B cell growth and differentiation. TLR agonists with TACI signals may promote self-reactivity as well as play a role in B cell differentiation in humans, thus we will examine how these may drive B cell proliferation and autoimmunity in CVID, especially when TACI signals are impaired. As human B cells have two structurally different TACI isoforms we will determine the differences in functional capacities, and explore the controls on the production of these naturally occurring isoforms. A current hypothesis is that mutations in TACI could lead to haplo insufficiency; we will investigate this by examining B cell function in patients with the Smith Magenis syndrome, who are heterozygous for a null TACI allele due to a chromosomal deletion. In this project we hypothesize that mutations in TACI found in subjects with CVID and their non immune deficient relatives, can be used to explore how the TACI receptor and its ligands, BAFF and APRIL, control B cell growth and differentiation in humans. These data may be of use in understanding this complex receptor system in human autoimmune disease in general. RELEVANCE: 8-10% of patients CVID have mutations in the gene encoding TACI, a poorly understood B cell receptor that exerts controls on B cell immunity while playing a role in antibody production to carbohydrate antigens. We hypothesize that mutations in this receptor and its isoforms can be used to elucidate the complex functions of this receptor in a human system.

描述（由申请人提供）：原发性免疫缺陷疾病为人类免疫学研究人员提供了无与伦比的资源。尽管最初的原发性免疫缺陷是在患有严重疾病的婴儿中描述的，但在所有年龄段的人类中都发现了原发性免疫缺陷，导致特征性并发症和显着的死亡率。虽然在了解许多疾病方面取得了惊人的进展，但损害 B 细胞功能的更普遍的免疫缺陷、常见变异免疫缺陷、IgA 缺陷、IgG 亚类和特异性抗体缺陷在很大程度上仍然是未知领域。在这个项目中，我们重点关注一组相互关联的主题，包括跨膜激活剂、钙调节剂和亲环蛋白配体相互作用物 (TACI) 的生物学及其配体和 Toll 样受体配体 (TLR) 在 B 细胞分化和成熟中的功能。 TACI 与其配体 B 细胞激活因子 (BAFF) 或增殖诱导配体 (APRIL) 的结合上调激活诱导胞苷脱氨酶 (AID) 的表达，AID 是两类转换重组 (CSR) 所必需的 DNA 编辑酶这些配体与 Toll 样受体 (TLR) 的微生物激动剂一起也可以诱导 Ig CSR，甚至可能诱导体细胞超突变 (SHM)。人类 B 细胞。我们的数据表明，TACI 和 TLR 途径对于消除自身免疫 B 细胞和发展人类耐受性至关重要。除了这些途径之外，促进人类抗菌免疫的遗传因素在很大程度上是未知的，因此我们还采取了全基因组方法，调查没有已知遗传缺陷的患者，这些患者由于抗体反应受损而经历了严重的肺炎球菌疾病。聚糖。这些方法已经定义了新的原发性免疫缺陷，并将为 B 细胞缺陷的研究增加一个全新的维度。这些利用人体组织取得的新发现显然有望在理解人类 B 细胞生物学方面取得进一步进展。这群研究人员因对该领域的共同协作、热情和热情而聚集在一起。我们建立的合作以及持续取得的成就的良好记录证明了这种方法的成功。 相关性（参见说明）：体液免疫系统的缺陷会导致传染病、无法接种疫苗、免疫失调和自身免疫性疾病。在这个项目中，我们将研究一组相关的人类 B 细胞缺陷，使用协调的遗传和分子技术来定义这些病理过程。 项目 1 - 研究 CVID 中 B 细胞记忆的阻断（项目负责人：Cunningham-Rundles, C.） 申请人提供的描述：由于患病率、并发症、住院和需要终身免疫球蛋白治疗，常见变异免疫缺陷（CVID）是临床上最重要的原发性抗体缺陷病。患者的B细胞缺乏正常体细胞超突变和同型转换的能力，分泌免疫球蛋白的能力较差，并且不能分化为浆细胞。 CVID 中 B 细胞功能障碍的遗传原因在很大程度上尚不清楚。 8-10% 的跨膜激活剂、钙调节剂和亲环蛋白配体相互作用 (TACI) 基因存在杂合突变，但免疫球蛋白水平正常的亲属中也存在杂合突变，表明这些突变并不是严重 B 细胞功能障碍的主要原因。然而，携带 TACI 突变（尤其是杂合子形式）的 CVID 受试者明显更有可能出现明显的淋巴增生和自身免疫。使用具有 TACI 突变的人类 B 细胞和转染子，我们将研究人类 TACI 受体功能，检查 TACI 中的单等位基因或双等位基因突变是否加速 BAFF/BAFF-R 介导的 B 细胞生长和分化。具有 TACI 信号的 TLR 激动剂可能会促进自身反应性，并在人类 B 细胞分化中发挥作用，因此我们将研究它们如何驱动 CVID 中的 B 细胞增殖和自身免疫，特别是当 TACI 信号受损时。由于人类 B 细胞具有两种结构不同的 TACI 异构体，我们将确定功能能力的差异，并探索对这些天然存在的异构体产生的控制。目前的一个假设是 TACI 突变可能导致单倍体不足。我们将通过检查 Smith Magenis 综合征患者的 B 细胞功能来研究这一点，这些患者由于染色体缺失而具有无效 TACI 等位基因的杂合子。在这个项目中，我们假设在 CVID 受试者及其非免疫缺陷亲属中发现的 TACI 突变可用于探索 TACI 受体及其配体 BAFF 和 APRIL 如何控制人类 B 细胞生长和分化。这些数据可能有助于理解人类自身免疫性疾病中的这种复杂受体系统。 相关性：8-10% 的 CVID 患者的 TACI 编码基因存在突变，TACI 是一种人们知之甚少的 B 细胞受体，它控制 B 细胞免疫，同时在针对碳水化合物抗原的抗体产生中发挥作用。我们假设该受体及其亚型的突变可用于阐明该受体在人体系统中的复杂功能。