Functional Studies.
Inherited diseases that affect the immune system typically change the properties of immune cells. Most immune cells are present in the blood during their life cycle, allowing for sampling of a large range of immune cells with a minimally invasive technique. We then aim to correlate genotype to phenotype, decoding the mechanisms driving immune dysregulation and increased susceptibility to viral infections.
Functional tests therefore play a crucial role in our research. Novel mutations may carry an unknown impact on certain cell types, pathways, or the immune system as a whole. With functional tests, immunophenotyping, and high-throughput imaging, we assess the functional consequences of these gene variants, such as their impact on cytotoxicity, cytokine production, cellular responses, and phenotypic state.
Phenotypic profiling of a large number of single cells from each patient, using an unbiased comprehensive multivariate approach, enables the quantification of the phenotypic state, the molecular make-up, and the microenvironment of each individual cell. In conjunction with large-scale molecular perturbations this allows the generation of a highly quantitative multidimensional dataset from thousands of individual cells in thousands of different conditions per patient. By imaging patient's cells we hope to be able to better characterize and possibly predict the cellular pathways affected by their mutation. The ability to expose these cells to libraries of pharmaceutical compounds additionally enables screening for potential treatments.
Research Projects.
Find out about research projects related to our work on assessing protein function and pathways involved in the regulation of the immune system.
CD48
Recently, we identified a novel inborn error of immunity associated with a heterozygous missense variant in CD48 (c.659C>A, p.S220Y), presenting as HLH-like syndrome. While it is established that both cell surface and soluble CD48 levels increase during viral infections, the contribution of human CD48 in antiviral defense remains elusive. We explore how a diminished CD48 expression impacts viral immune response through functional assays on PBMCs, viral metagenomic sequencing, and LCMV infection in a CD48KO mouse model.
ZNFX1
We encountered several patients with a ZNFX1-deficiency, resulting in severe inflammatory disease and increased susceptibility to viral infections. ZNFX1 is an interferon-stimulated sensor for long dsRNA and can initiate IFN and ISG expression upon RNA virus infection by sensing viral RNAs. We try to elucidate the role of ZNFX1 in viral sensing and the type I interferion-mediated antiviral immune response through functional assays and high-throughput imaging in both iPSC and mouse models.
TTC7A
Mutations in tetratricopeptide repeat domain 7A (TTC7A) and its mouse orthologue Ttc7 result in a multisystemic disease, mostly affecting epithelial barriers and the immune system. Despite successful hematopoietic stem cell transplantation, ongoing progression of gastrointestinal manifestations can be life-threatening in TTC7A-deficient patients.
We focus on pathophysiological characterization of cellular events to decipher mechanistic defects caused by disruptive genetic mutations in Tetratricopeptide repeat (TPR) domain 7 (TTC7A) with the aim to design targeted therapeutics.