Steven Strubbe, Belgium
Ghent University GE32 Diagnostic SciencesPresenter of 1 Presentation
IN VITRO DISEASE MODELING OF SCID FOR IDENTIFICATION OF GENOTYPE-PHENOTYPE CORRELATIONS
Abstract
Background and Aims
Severe Combined Immune Deficiency (SCID) is a life-threatening disease of the immune system that is caused by genetic defects. SCID patients suffer from opportunistic infections as a result of abrogation of T lymphocyte development and/or function in which B and NK cell development might be affected as well. This results in a heterogeneous spectrum of phenotypes that often complicates diagnosis. Furthermore, the identification of the underlying genetic defect is often confounded by incomplete penetrance, genetic modifiers and ongoing infections. To improve the genotype-phenotype correlation, we evaluated the use of OP9-DLL1 and MS5 stromal cocultures to study the in vitro immune cell differentiation potential of CD34+Lin- hematopoietic precursor cells (HPCs) from SCID patients.
Methods
In this particular case, HPCs were used from a patient that was characterized by a novel splice acceptor mutation in the DCLRE1C gene encoding for Artemis.
Results
The differentiation of T and B cells showed a clear stage-specific developmental defect, associated with the dependency on Artemis function. As anticipated, the differentiation of NK and myeloid cells was not disturbed.
Conclusions
These results thus clearly show the potential of using patient-derived HSCs in these in vitro differentiation cultures to model SCID patients. By defining these genotype-phenotype correlations, the treatment, diagnosis and counseling of these patients can be facilitated. From a fundamental perspective, the in vitro differentiation of patient-derived HPCs can be exploited to address the developmental impact of SCID genes to further elucidate the molecular mechanisms that drive human immune cell development.