Combined Immune Deficiency: Links to Repair Defects

在发育和分化为功能性浆细胞的过程中，B细胞经历两次DNA转移， 重组反应、V（D）J和类别转换重组（CSR）以及广泛的体细胞超突变（SHM）过程。这三种反应的功能结果导致产生成熟的免疫系统，该免疫系统是多样的，对抗原具有高亲和力，并表现出广泛的功能。虽然所有这些反应都有利于产生功能齐全的免疫系统，但它们会永久修改DNA中编码的信息，任何错误都可能导致免疫缺陷和/或转化。西奈山医学院的原发性免疫缺陷项目目前正在治疗大量患有严重联合免疫缺陷（SCID）、联合免疫缺陷（CID）和常见变异免疫缺陷（CVID）的患者。虽然在描述SCID的分子病因方面已经取得了很大进展，但目前约有20%的病例仍然来源不明。此外，CID和CVID患者中存在的分子缺陷尚未确定。本申请提出研究以下假设：构成（Aim 1）V（D）J重组和（Aim 2）类别转换重组和体细胞超突变的修复机制的因子的失调和/或突变代表了导致SCID以及一些CID和CVID患者的一些分子缺陷。这一假设将通过使用预先建立的报告系统进行研究。还将研究修复因子的DNA序列和生化活性。 从拟议的分析中获得的结果将有助于了解这些患者中存在的分子缺陷，并有助于为这些危及生命的疾病找到更好的治疗方法。

During development and differentiation into functional plasma cells, B cells undergo two DNA recombination reactions, V(D)J and class switch recombination (CSR), and a process of extensive somatic hypermutation (SHM). The functional consequences of these three reactions result in the production of a mature immune system that is diverse, has high affinity for antigens, and exhibits a wide range of functions. Although all these reactions are beneficial to the generation of a fully functional immune system, they permanently modify the information encoded in the DNA, and any mistake could lead to immune deficiency and/or transformation. The Primary Immune Deficiency Program at Mount Sinai School of Medicine is currently treating a large population of patients with severe combined immune deficiency (SCID), combined immune deficiency (CID) and common variable immune deficiency (CVID). While there has been much progress in delineating the molecular causes of SCID, currently about 20% of all cases are still of unknown origin. In addition, the molecular defects present in patients with CID and CVID have not yet been defined. This application proposes to investigate the hypothesis that deregulation and/or mutations in factors that constitute the repair machinery of (Aim 1) V(D)J recombination and for (Aim 2) class switch recombination and somatic hypermutation represents some of the molecular defects responsible for SCID, and some patients with CID and CVID. This hypothesis will be investigated by using pre-established reporter systems. DNA sequence and biochemical activity of the repair factors will also be investigated. Results obtained from the proposed analysis will help to understand the molecular defects present in these patients and facilitate the path to finding better treatments for these life threatening diseases.