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

点击翻译按钮获取中文摘要

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.