Centrum für Chronische Immundefizienz - CCI

Research Areas

In our group, we apply multi-omics analyses and integrate human cohort studies with mouse models to uncover the mechanisms underlying microbiome-regulated immune dysregulation. Our goal is to generate insights that drive the development of innovative therapeutic strategies and personalized treatments for individuals with Inborn Errors of Immunity (IEI) and other immune disorder conditions.

IEI are monogenic disorders characterized by impaired host immune responses, which manifest as recurrent infections, immunodeficiency, auto-inflammation, autoimmunity, allergy, and/or cancer. Notably, the disease penetrance, severity, and expressivity vary among individuals, even those who share the same mutation. However, the modifiers of penetrance and their underlying mechanisms remain largely unknown.

Over the past decades, extensive research has emphasized the indispensable role of the microbiome in maintaining gut homeostasis, particularly in immune-compromised individuals. In patients with common variable immunodeficiency (CVID), microbial diversity has been reported to be significantly lower. However, further investigation using in vivo model is urgently needed to address:

1. What is the correlation between microbiome signatures and disease outcomes in individuals with Inborn Errors of Immunity (IEI)?.
2. Through what mechanisms does the microbiome regulate disease severity?

To this aim, we combine human cohort studies and mouse models in various IEI conditions, such as chronic granulomatous disease (CGD), CTLA-4 haploinsufficiency, NF-κB1 haploinsufficiency, and RELA insufficiency. On the one hand, we dissect microbiome features in severely and mildly affected individuals to uncover how microbial dysbiosis develops with disease progression through shotgun metagenomics of patient stool samples at different disease stages. On the other hand, we establish wildling gene-deficient mouse models—mice harboring naturalized microbiota—that offer the advantage of representing human disease phenotypes and mirroring human responses in clinical trials. 

Furthermore, by conducting multi-omics analyses locally and systemically of the immune landscape, organ pathology, and metabolome profiles in germ-free (GF), specific pathogen-free (SPF), or wildling mice, we aim to elucidate the mechanisms underlying microbiome-regulated pathophysiology in IEI, with a particular focus on mutations in the CTLA4 gene or genes involved in the NF-κB pathway.

This comprehensive approach could significantly enhance our understanding of the interplay between the microbiome and the immune system in the context of immune dysregulation, paving the way for novel therapeutic strategies and personalized medicine. These advancements could benefit not only patients with IEI but also those undergoing immune checkpoint inhibitor therapies, such as anti-CTLA4 treatment.

Wildling Mouse Model

The wildling mice are generated by transferring embryos of SPF mice into pseudo-pregnant female mice caught from the wild forest. These offspring, termed wildlings, retain the genetic background of SPF mice while acquiring a naturalized microbiome that mirrors the one in wild mice. 

Wildlings provide a reliable model for translational research because they:

1. Harbour many bacterial genera found in humans – for example, the pro-inflammatory Proteobacteria – that are completely absent in SPF mice.
2. Exhibit a more mature immune system that resembles that of adults.
3. Mirror human responses observed in clinical trials.

CV

Team