Unraveling the molecular pathophysiological landscape in primary immunodeficiencies to improve personalized medicine approaches.

揭示原发性免疫缺陷的分子病理生理学景观，以改进个性化医疗方法。

• 批准号: 458854985
• 负责人: Professor Dr. Bodo Grimbacher
• 金额: --
• 依托单位: Centrum für Chronische Immundefizienz (CCI)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2021
• 资助国家: 德国
• 起止时间: 2020-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/458854985?language=en
• 关键词: Unraveling; molecular; pathophysiological; landscape; primary

Inborn errors of immunity (IEI) are a group of heterogeneous disorders in which the immune system’s response to external pathogens or to internal self-antigens is impaired. This loss of immune homeostasis may be present in up to 0.2% of people and does not manifest equally in all individuals. Some may develop mild, some moderate and some very severe phenotypes ranging from an increased infection susceptibility to life-threatening infections, often combined with different types and degrees of autoimmunity, auto-inflammation and malignancy. In the minority of patients with IEI, a monogenic defect can fully explain the disease, while in other patients, rare genetic variants partially contribute to the pathogenesis of the disorder (risk alleles). Over the last years we genotyped more than 5,000 individuals with IEI at the University Hospitals of Freiburg and Munich. In most of these patients (~3,500), all protein-coding genes of the genome were screened for disease-causing mutations, whereas in some (~1,500), only a subset of 50-150 genes was screened by a targeted gene panel. The yield of a genetic diagnosis varied between 20-40%, depending on the method employed, the possibility of functionally characterization, and the availability of additional family members. A genetic diagnosis has an important impact on patient management, as patients benefit from a targeted treatment that significantly improves disease prognosis and quality of life. Therefore, the first aim of this project is to continue our genotyping efforts by analysing the entire exome in patients who have not been genotyped yet or who had a negative result after a targeted gene panel analysis. This could also lead to the discovery of novel gene defects, which contributes to the overall and continuous increase in diagnostic yield in IEI. However, in some of these genetically defined conditions, the molecular pathophysiology is not entirely understood; thus, additional explanations are currently being explored. For instance, differences in gene regulation/expression -controlled by epigenetic factors- or differences in gut microbiota composition could influence disease penetrance and severity. The second aim is to explore the transcriptomic profiles of key immune-related cells in IEI patients with distinct monogenic defects. A deeper understanding of the differentially affected cell populations and altered cellular pathways will help to develop better targeted therapies with small molecule drugs or biologicals. The third aim is to address the role of the gut microbiome as a disease modifying factor in selected cohorts of IEI patients with variable expressivity and/or incomplete penetrance. A better understanding of how the gut microbiome modulates the disease course and severity in IEI will help to develop more effective therapeutic options and to override the limitation of currently existing treatments. This sequencing grant is complemented by eight already funded research projects.

先天性免疫缺陷（IEI）是一组异质性疾病，其中免疫系统对外部病原体或内部自身抗原的反应受损。这种免疫稳态的丧失可能存在于高达0.2%的人群中，并且在所有个体中并不平等。有些可能发展为轻度、中度和非常严重的表型，从感染易感性增加到危及生命的感染，通常伴有不同类型和程度的自身免疫、自身炎症和恶性肿瘤。在少数IEI患者中，单基因缺陷可以完全解释该疾病，而在其他患者中，罕见的遗传变异部分促成了该疾病的发病机制（风险等位基因）。在过去的几年里，我们在弗赖堡和慕尼黑的大学医院对5,000多名IEI患者进行了基因分型。在这些患者中的大多数（约3，500）中，基因组的所有蛋白质编码基因都被筛选出致病突变，而在一些（约1，500）中，只有50-150个基因的子集被靶向基因组筛选。遗传诊断的产率在20- 40%之间变化，这取决于所采用的方法、功能表征的可能性以及其他家族成员的可用性。基因诊断对患者管理具有重要影响，因为患者受益于有针对性的治疗，可显着改善疾病预后和生活质量。因此，本项目的第一个目的是通过分析尚未进行基因分型或在靶向基因组分析后结果为阴性的患者的整个外显子组来继续我们的基因分型工作。这也可能导致发现新的基因缺陷，这有助于IEI诊断率的整体和持续增加。然而，在其中一些遗传定义的疾病中，分子病理生理学尚未完全了解;因此，目前正在探索其他解释。例如，基因调控/表达的差异-由表观遗传因素控制-或肠道微生物群组成的差异可能会影响疾病的发病率和严重程度。第二个目的是探索具有明显单基因缺陷的IEI患者中关键免疫相关细胞的转录组学谱。更深入地了解差异影响的细胞群和改变的细胞通路将有助于开发更好的小分子药物或生物制剂靶向治疗。第三个目的是解决肠道微生物组作为疾病修饰因子在具有可变表达性和/或不完全表达性的IEI患者的选定队列中的作用。更好地了解肠道微生物组如何调节IEI的病程和严重程度将有助于开发更有效的治疗方案，并克服现有治疗方法的局限性。这项测序补助金由八个已经资助的研究项目补充。