Integrative Multi-Omics Analysis of Primary Antibody Deficiency (PAD) Patients for Stratification Accordingto Cellular Pathways

人类的免疫系统控制着我们对感染和其他疾病的反应。然而，它的功能在不同的人之间有很大的差异。某些人有轻微或严重的免疫缺陷，这使他们容易感染、自身免疫和癌症。这些免疫缺陷中的一些是单基因的，相对较好的理解。但在许多情况下，分子原因完全未知，这使得这些罕见的疾病很难诊断和治疗。在这个项目中，我们将使用尖端的多组学图谱和综合生物信息学分析来剖析常见变量免疫缺陷(CVID，Orpha：#1572)的分子途径，这是一种典型的罕见初级抗体缺陷(PAD)，B细胞功能受损会导致反复感染。一部分CVID个体(约25%)表现出一个或几个已知与PAD相关的单基因变异。我们将使用这些基因解决的病例来识别CVID背后的反复出现的表观基因组、转录和/或蛋白质组异常，并将利用已识别的模式来提高对遗传和/或非遗传原因未知的CVID患者的诊断、分层和机制理解。我们还将包括选择性IgA缺乏症(IGAD)患者，因为它可能是CVID的前言，从而为早期准确的分子诊断和疾病分层提供了可能性。在这个项目中，CVID、免疫学、遗传学、表观遗传学、蛋白质组学和生物信息学领域的主要领导者联合起来，基于对受影响细胞路径的分子解剖，对CVID患者进行了新的和系统的分类。我们的方法将使PAD患者直接受益，并为基于多组学技术的PAD个性化管理提供了前景，这些技术具有成本效益，可供临床免疫学和罕见疾病专家使用。

The human immune system controls how we respond to infections and other diseases. However, its functioning differs substantially between individuals. Certain people have mild or severe immune defects, which makes them prone to infections, autoimmunity and cancer. Some of these immunodeficiencies are monogenetic and relatively well understood. But in many cases the molecular cause is entirely unknown, which makes these rare diseases difficult to diagnose and treat. In this project, we will use cutting-edge multi-omics profiling and integrative bioinformatic analysis to dissect the molecular pathways underlying common variable immunodeficiency (CVID, ORPHA: #1572), an archetypical rare primary antibody deficiency (PAD) where impaired B cell function causes recurrent infections. A subset of CVID individuals (~25%) display one or several monogenetic variants known to be associated with PADs. We will use such genetically resolved cases to identify recurrent epigenomic, transcriptomic and/or proteomic aberrations underlying CVID, and we will exploit the identified patterns to improve the diagnosis, stratification and mechanistic understanding of CVID patients with unknown genetic and/or non-genetic causes. We will also include patients with selective IgA deficiency (IgAD) due to its likely role as preamble of CVID, opening up the potential for accurate molecular diagnostics and disease stratification at an early stage. In this project, key leaders in the fields of CVID, immunology, genetics, epigenetics, proteomics and bioinformatics have joined forces to provide a novel and systematic classification of CVID patients based on the molecular dissection of affected cellular pathways. Our approach will directly benefit PAD patients and provide a perspective for personalized management of PAD based on multi-omics technologies that are cost-effective and ready to be used by clinical immunology and rare diseases experts.