Mendelian susceptibility to mycobacterial disease (MSMD) is caused by inborn errors of interferon gamma (IFNgamma) immunity and is characterized by severe infections by weakly virulent mycobacteria. Although IFNgamma is the macrophage-activating factor, macrophages from these patients have never been studied. We demonstrate the generation of heterozygous and compound heterozygous (iMSMD-cohet) induced pluripotent stem cells (iPSCs) from a single chimeric patient, who suffered from complete autosomal recessive IFNgammaR1 deficiency and received bone-marrow transplantation. Loss of IFNgammaR1 expression had no influence on the macrophage differentiation potential of patient-specific iPSCs. In contrast, lack of IFNgammaR1 in iMSMD-cohet macrophages abolished IFNgamma-dependent phosphorylation of STAT1 and induction of IFNgamma-downstream targets such as IRF-1, SOCS-3, and IDO. As a consequence, iMSMD-cohet macrophages show impaired upregulation of HLA-DR and reduced intracellular killing of Bacillus Calmette-Guerin. We provide a disease-modeling platform that might be suited to investigate novel treatment options for MSMD and to gain insights into IFNgamma signaling in macrophages.
- Neehus, A. L.
- Lam, J.
- Haake, K.
- Merkert, S.
- Schmidt, N.
- Mucci, A.
- Ackermann, M.
- Schubert, M.
- Happle, C.
- Kuhnel, M. P.
- Blank, P.
- Philipp, F.
- Goethe, R.
- Jonigk, D.
- Martin, U.
- Kalinke, U.
- Baumann, U.
- Schambach, A.
- Roesler, J.
- Lachmann, N.
Keywords
- Bcg
- IFNgammaR1
- Msmd
- hematopoiesis
- iPSC
- macrophages
- mycobacteria
