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

人体免疫系统控制着我们对感染和其他疾病的反应。然而，其功能在个体之间有很大差异。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，并且相对较好地理解。但在许多情况下，分子原因是完全未知的，这使得这些罕见疾病难以诊断和治疗。在这个项目中，我们将使用尖端的多组学分析和综合生物信息学分析来剖析常见可变免疫缺陷（CVID，ORPHA：#1572），一个典型的罕见的初级抗体缺乏症（PAD），其中受损的B细胞功能导致复发性感染的分子途径。CVID个体的一个子集（约25%）显示一种或几种已知与PAD相关的单基因变异。我们将使用这种遗传学解决的情况下，以确定复发性表观基因组，转录和/或蛋白质组学畸变的CVID的基础上，我们将利用已确定的模式，以提高诊断，分层和机制的理解CVID患者未知的遗传和/或非遗传原因。我们还将纳入选择性伊加缺乏症（IgAD）患者，因为其可能作为CVID的前序，为早期准确的分子诊断和疾病分层开辟了可能性。在该项目中，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，根据受影响细胞通路的分子解剖，提供了一种新的CVID患者系统分类。我们的方法将直接使PAD患者受益，并为基于多组学技术的PAD个性化管理提供了一个视角，这些技术具有成本效益，可供临床免疫学和罕见病专家使用。

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.