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

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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.