Abstract
Interferon γ (IFN-γ) was shown to be a macrophage activating factor already in 1984. Consistently, inborn errors of IFN-γ 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-γ 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-γR2 deficiency, partial IFN-γR1 deficiency and complete STAT1 deficiency. Macrophages from all patient iPSCs showed normal morphology and IFN-γ-independent functionality like phagocytic uptake of bioparticles and internalization of cytokines. For the IFN-γ-dependent functionalities, we observed that the deficiencies played out at various stages of the IFN-γ pathway, with the complete IFN-γR2 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-γR1 and IFN-γR2 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-γ immunity.
Highlights
Since their discovery in 2006 [1], induced pluripotent stem cells have become an extremely valuable tool for drug discovery, autologous cell therapy and disease modeling [2]
The third patient has an autosomal recessive (AR) partial IFNγR1 deficiency due to a start codon mutation (c.2T>A, predicted p.M1K) that possibly leads to residual expression of a functional protein [39]
We could show that induced pluripotent stem cells (iPSCs)-derived macrophages from these patients exhibit varying levels of response to Interferon γ (IFN-γ) and their deficiencies play out at different stages of the pathway
Summary
Since their discovery in 2006 [1], induced pluripotent stem cells (iPSCs) have become an extremely valuable tool for drug discovery, autologous cell therapy and disease modeling [2]. For the latter the possibility of generating patient-specific iPSCs carrying a disease-specific mutation has been useful to study genetic diseases and their underlying mechanisms [3]. The feasibility and usefulness of this approach has been highlighted especially for rare diseases, for which patient material is extremely limited. Cells of the hematopoietic lineages have been especially in the focus because of their high importance for many diseases, for example, primary immunodeficiencies (PIDs). Cells have been differentiated into megakaryocytes to study thrombocytopenia [12]; erythrocytes to model sickle cell disease [13]; hematopoietic progeny and NK cells to study GATA2 deficiency [14] and macrophages to model such diverse diseases as hereditary pulmonary alveolar proteinosis [15], familial Mediterranean fever [16] and Gaucher disease [17]
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