The Genetics, Pathogenesis, and Treatment of Primary Immunodeficiency

原发性免疫缺陷的遗传学、发病机制和治疗

• 批准号: 7964484
• 负责人: Ashish Jain
• 金额: $ 96.02万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7964484
• 关键词: B-Cell Development; B-Lymphocytes; Benign; CD40 Ligand; Cells; Deubiquitinating Enzyme; Disease; Ectodermal Dysplasia; Gene Mutation; Genes; Genetic; Growth; Immune; Immunity; Immunoglobulin Class Switching; Immunoglobulin Switch Recombination; Immunologic Deficiency Syndromes; Incidence; Inflammation; Inherited; Knock-out; Laboratories; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; Mutation; Myeloid Cells; NF-kappa B; NFKB Signaling Pathway; Pathogenesis; Pathway interactions; Patients; Post-Translational Protein Processing; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Site; T-Lymphocyte; TNFRSF5 gene; Ubiquitin; Ubiquitination; Zinc Fingers; base; colitis associated cancer; cytokine; in vivo; prevent; tumor; tumorigenesis

Employing the candidate genetic approach, we previously identified mutations in the gene encoding NEMO (NF- kB essential modulator), an intracellular signaling constituent of the NF-kB pathway, results in ectodermal dysplasia with an immune deficiency. Mutations in the zinc finger domain of NEMO block CD40 mediated activation of NF- kB and prevent B cells from undergoing class switch recombination (CSR) and APCs from synthesizing NF -kB regulated cytokines such as IL -12 or TNF-a when stimulated with CD40 ligand. The zinc finger domain of NEMO is a site for the covalent attachment of ubiquitin and this step is necessary for the full activation of NF-κB. The majority of patients with ectodermal dysplasia with immune deficiency have mutations in the zinc finger domain and we have found that such mutations impair the post- translational modification of NEMO by ubiquitin. Related efforts in the laboratory include making genetically altered mice with targeted mutations in signaling molecules, which regulate NF-κB. CYLD is a deubiquitinating enzyme that targets signaling constituents of the NF-kB signaling pathway, including NEMO. Alteration in CYLD have been described in patients with familial cylindromatosis, a condition characterized by numerous benign adnexal tumors. In mice deficient deficient in CYLD we previously showed that the development of B cells, T cells, and myeloid cells is unaffected in CYLD deficient mice, but that the activation of these cells with mediators of innate and adaptive immunity results in enhanced NF-kB activity and is associated with increased NEMO ubiquitination. CYLD deficient mice are more susceptible to induced colonic inflammation and show a dramatic increase in the incidence of tumors in a colitis associated cancer (CAC) model. These results suggest that CYLD limits inflammation and tumorigenesis by regulating NEMO ubiquitination in vivo. We are now studying the regulatory role of CYLD in other signaling pathways and are making a CYLD knockout NEMO knockin mice.

采用候选遗传学方法，我们先前鉴定了编码NEMO（NF-kB必需调节剂）的基因中的突变，NEMO是NF-kB途径的细胞内信号传导成分，导致具有免疫缺陷的外胚层发育不良。NEMO的锌指结构域中的突变阻断了CD 40介导的NF-κ B的活化，并阻止了B细胞经历类别转换重组（CSR），以及当用CD 40配体刺激时，阻止了APCs合成NF -κ B调节的细胞因子如IL-12或TNF-α。NEMO的锌指结构域是泛素共价连接的位点，这一步骤对于NF- B的完全激活是必需的。 大多数具有免疫缺陷的外胚层发育不良的患者在锌指结构域中具有突变，并且我们已经发现这样的突变损害了泛素对NEMO的翻译后修饰。 实验室的相关工作包括制造具有调节NF- B的信号分子靶向突变的遗传改变小鼠。 CYLD是一种去泛素化酶，靶向NF-κ B信号通路的信号成分，包括NEMO。 CYLD的改变在家族性圆柱瘤病患者中已有报道，这种疾病的特征是许多良性附件肿瘤。在缺乏CYLD的小鼠中，我们先前表明，B细胞、T细胞和骨髓细胞的发育在CYLD缺乏的小鼠中不受影响，但是这些细胞与先天性和适应性免疫介质的激活导致增强的NF-κ B活性，并且与增加的NEMO泛素化相关。CYLD缺陷型小鼠对诱导的结肠炎症更敏感，并且在结肠炎相关癌症（CAC）模型中显示出肿瘤发病率的显著增加。 这些结果表明CYLD通过调节体内NEMO泛素化来限制炎症和肿瘤发生。 我们现在正在研究CYLD在其他信号通路中的调节作用，并正在制造CYLD敲除NEMO敲入小鼠。