Patient iPSC-Derived Macrophages to Study Inborn Errors of the IFN-? Responsive Pathway.

ABSTRACT: Interferon ? (IFN-?) was shown to be a macrophage activating factor already in 1984. Consistently, inborn errors of IFN-? immunity underlie Mendelian Susceptibility to Mycobacterial Disease (MSMD). MSMD is characterized by genetic predisposition to disease caused by weakly virulent mycobacterial species. Paradoxically, macrophages from patients with MSMD were little tested. Here, we report a disease modeling platform for studying IFN-? related pathologies using macrophages derived from patient specific induced pluripotent stem cells (iPSCs). We used iPSCs from patients with autosomal recessive complete- and partial IFN-?R2 deficiency, partial IFN-?R1 deficiency and complete STAT1 deficiency. Macrophages from all patient iPSCs showed normal morphology and IFN-?-independent functionality like phagocytic uptake of bioparticles and internalization of cytokines. For the IFN-?-dependent functionalities, we observed that the deficiencies played out at various stages of the IFN-? pathway, with the complete IFN-?R2 and complete STAT1 deficient cells showing the most severe phenotypes, in terms of upregulation of surface markers and induction of downstream targets. Although iPSC-derived macrophages with partial IFN-?R1 and IFN-?R2 deficiency still showed residual induction of downstream targets, they did not reduce the mycobacterial growth when challenged with Bacillus Calmette-Guérin. Taken together, we report a disease modeling platform to study the role of macrophages in patients with inborn errors of IFN-? immunity.

SUBMITTER: Haake K 

PROVIDER: S-EPMC7072779 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature