Role of WASP and N-WASP in B cell maturation, homing and function

WASP 和 N-WASP 在 B 细胞成熟、归巢和功能中的作用

• 批准号: 8148002
• 负责人: Luigi Daniele Notarangelo
• 金额: $ 21.49万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8148002
• 关键词: Actins; Affect; Allogenic; Antibodies; Antibody Formation; Antigens; Autoimmunity; Autologous; B Cell Proliferation; B cell differentiation; B-Cell Activation; B-Cell Development; B-Lymphocytes; Biochemical; Biology; Blood Platelets; Bone Marrow; CD19 gene; Cell Maturation; Cell physiology; Cells; Chemotaxis; Chimerism; Cicatrix; Clinical; Complex; Cytoskeleton; Data; Defect; Dendritic Cells; Development; Disadvantaged; Dose; Eczema; Event; Gene Mutation; Gene Targeting; Generations; Genes; Genetic Variation; Hematopoietic; Hematopoietic Stem Cell Transplantation; Homing; Human; Humoral Immunities; IgE; Immune; Immunization; Immunoglobulin A; Immunoglobulin Class Switching; Immunoglobulin M; Immunoglobulin Somatic Hypermutation; Immunoglobulin Switch Recombination; In Vitro; Infection; Knock-out; Knockout Mice; Leukocytes; Link; MS4A1 gene; Malignant Neoplasms; Memory; Memory B-Lymphocyte; Microfilaments; Modeling; Molecular Conformation; Mus; Mutation; Patients; Pattern; Peripheral; Plasmablast; Play; Pneumococcal Infections; Polysaccharides; Predisposition; Process; Protein Family; Proteins; Reaction; Rest; Risk; Role; Serum; Spleen; Stem cells; Streptococcus pneumoniae; Structure of germinal center of lymph node; System; T-Independent Antigens; T-Lymphocyte; Testing; Thrombocytopenia; Wiskott-Aldrich Syndrome; X Inactivation; base; blastocyst; cell type; chemokine; gene therapy; humoral immunity deficiency; in vivo; macrophage; novel; peripheral blood; progenitor; response

The Wiskott-Aldrich syndrome (WAS) is a severe immune deficiency, caused by mutations of WASP, that belongs to a family of proteins that control de novo actin nucleation. It is unclear whether defects in humoral immunity observed in patients with WAS and in WASP-/- mice reflect a B-cell intrinsic role of WASP for B cell differentiation, and function, and whether N-WASP may play a compensatory role in these processes. We will test the hypothesis that lack of expression of WASP and/or N-WASP affects B lymphocyte maturation, homing and function in a cell-intrinsic fashion. To this purpose, we will study in vivo competition models between WASP+ and WASP- cells in humans and mice. We will also develop conditional knock-out models in which expression of WASP and/or N-WASP is ablated in B lymphocytes. Specifically, we will: 1) analyze the role of WASP in B cell development and maturation, through the analysis of in vivo competition models both in mice and in humans. The proportion of memory and naive B cells will be analyzed among WASP+ and WASP- cells in carriers of XLT. We will also analyze the role of WASP in germinal center reaction and somatic hypermutation following immunization in WASP+/- mice and in WASP+/- mice in which expression of N-WASP is deleted in B cells. 2) test the hypothesis that the B-cell specific lack of WASP and/or N-WASP affects B cell maturation, homing and function in vivo. To this purpose, we will develop a conditional model of WASP deficiency in B cells. We will test the peripheral distribution and homing of B cells, and response to immunization in mice with B-cell specific lack of WASP and/or N-WASP. We will analyze susceptibility of mice with B-cell-specific deficiency of WASP to invasive S. pneumoniae infection, and explore possible defects in the number of IgM memory B cells in patients with WASP gene mutations. 3) test the hypothesis that the B-cell specific lack of WASP and/or N-WASP affects B cell function in vitro. To this purpose, chemotaxis, activation and class-switch recombination will be studied in vitro in B cells from mice with B-cell specific lack of WASP and/or N-WASP. We anticipate that the results of .this project will allow a better understanding of the biology of WAS, and will be important for development of novel forms of treatment of WAS, including gene therapy.

威斯科特-奥尔德里奇综合征 (WAS) 是一种严重的免疫缺陷，由 WASP 突变引起， 属于控制肌动蛋白从头成核的蛋白质家族。目前尚不清楚是否存在体液缺陷 在 WAS 患者和 WASP-/- 小鼠中观察到的免疫反应反映了 WASP 对 B 细胞的内在 B 细胞作用 分化、功能，以及 N-WASP 是否在这些过程中发挥补偿作用。 我们将检验 WASP 和/或 N-WASP 表达缺失影响 B 淋巴细胞的假设 以细胞固有的方式成熟、归巢和发挥作用。 为此，我们将研究人类和 WASP+ 细胞和 WASP- 细胞之间的体内竞争模型。 老鼠。我们还将开发条件敲除模型，其中 WASP 和/或 N-WASP 的表达是 B淋巴细胞中消融。具体来说，我们将： 1）通过体内分析，分析WASP在B细胞发育成熟中的作用 小鼠和人类的竞争模型。 将分析携带者中 WASP+ 和 WASP- 细胞中记忆和幼稚 B 细胞的比例 XLT。我们还将分析 WASP 在生发中心反应和体细胞超突变中的作用 对 WASP+/- 小鼠和 B 细胞中 N-WASP 表达缺失的 WASP+/- 小鼠进行免疫。 2) 检验 B 细胞特异性缺乏 WASP 和/或 N-WASP 影响 B 细胞成熟的假设， 体内归巢和功能。 为此，我们将开发 B 细胞 WASP 缺陷的条件模型。我们将测试 B 细胞的外周分布和归巢，以及 B 细胞特异性缺乏的小鼠对免疫的反应 WASP 和/或 N-WASP。我们将分析具有 B 细胞特异性 WASP 缺陷的小鼠对 侵袭性肺炎链球菌感染，并探讨 IgM 记忆 B 细胞数量可能存在的缺陷 WASP基因突变患者。 3) 测试 B 细胞特异性缺乏 WASP 和/或 N-WASP 会影响体外 B 细胞功能的假设。 为此，将在来自 B 细胞的体外研究趋化性、激活和类别转换重组。 B 细胞特异性缺乏 WASP 和/或 N-WASP 的小鼠。 我们预计该项目的结果将有助于更好地了解 WAS 的生物学，并将 对于开发 WAS 新型治疗方法（包括基因治疗）非常重要。