Storming Immune Monogenic Conditions through Multiomic and Gene Editing Approaches

人类免疫系统控制着对感染做出反应并消除变异细胞(如癌细胞)的效率。免疫功能依赖于许多基因的平衡作用，这些基因编码受体、细胞因子、细胞信号分子和转录因子，并受到广泛的环境和表观遗传因素的调节。免疫相关基因的单基因突变，也称为先天性免疫错误(IEI)，为理解免疫适应性提供了独特的例子。IEI单独被认为是罕见疾病，构成了一组免疫疾病，其综合患病率与白血病相似(1/1,000-1/5,000)。对于给定的突变基因，IEI患者可以表现出广泛的表型表达(从无症状到严重受损)和对治疗的不同反应。因此，有一个尚未得到满足的需求，以解决IEI的广泛潜在影响。此前的欧盟财团并未全面解决这些问题。因此，它需要新一代研究人员，他们具备一整套科学、技术和战略技能；并具有广泛的视野，以应对IEI领域的突出挑战。为此，Immerge MSCA DN结合了来自不同临床、基础研究和生物技术环境的领导者的人才，培养了11名博士生。通过我们的研究活动和培训活动，我们将解决该领域的关键挑战：1)通过单细胞和批量多体来评估IEI在不同免疫细胞类型中的功能影响；2)开发计算工具，用于解剖特定IEI背后的改变的细胞通路。3)对IEI进行遗传学校正或建立模型，并开发临床前模型。通过我们的战略，Immerge将产生一个杰出的专业网络，能够开发具有影响力的研究，这些研究将改变该领域，产生个性化药物的工具，并在社会上提高知名度并影响政策制定者

The human immune system controls the efficiency to respond to infections and eliminate aberrant cells, such as cancer cells. Immunefunction depends on the balanced contribution of many genes, encoding for receptors, cytokines, cell signalling molecules andtranscription factors and are modulated by a wide range of environmental and epigenetic factors. Monogenic mutations for immunerelated genes, also known as Inborn Errors of Immunity (IEI), provide unique examples for understanding immune fitness. IEI,individually considered as rare diseases, constitute a group of >400 immune disorders with a combined prevalence similar toleukemias (1/1,000-1/5,000). For a given mutated gene, IEI patients can display a wide range of phenotypic expressivity (fromasymptomatic to severely impaired) and different responses to treatments. Therefore, there is an unmet need to address the wideunderlying impact of IEI. Previous EU consortia have not addressed these questions in full. It is therefore needed a new generation ofresearchers, equipped with a complete set of scientific, technological and strategic skills; and a wide vision to face the outstandingchallenges in the IEI field. To this end, the IMMERGE MSCA DN combines the talent of leaders from different clinical and basic researchand biotech environments to train 11 doctoral candidates. Through our research activity and training activities, we will address keychallenges in the field: 1) To assess the functional impact of IEI in different immune cell types through single cell and bulk multiomics.2) To develop computational tools for dissecting the altered cellular pathways underlying specific IEI. 3) To genetically correct ormodel IEI and develop pre-clinical models. With our strategy, IMMERGE will generate an outstanding network of professionals able todevelop impactful studies that will change the field, generate tools for personalised medicine and generate awareness in the societyand influence policy makers