Impaired IFNγ-Signaling and Mycobacterial Clearance in IFNγR1-Deficient Human iPSC-Derived Macrophages

Neehus, Anna-Lena; Lam, Jenny K.W.; Haake, Kathrin; Merkert, Sylvia; Schmidt, Nico; Mucci, Adele; Ackermann, Mania; Schubert, Madline; Happle, Christine; Kühnel, Mark Philipp; Blank, Patrick; Philipp, Friederike; Goethe, Ralph; Jonigk, Danny; Martin, Ulrich; Kalinke, Ulrich; Baumann, Ulrich; Schambach, Axel; Roesler, Joachim; Lachmann, Nico

doi:10.1016/j.stemcr.2017.11.011

Cited by 25 publications

(15 citation statements)

References 23 publications

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“…After establishing patient-specific iPSCs, we subjected established iPSC-clones to a hematopoietic differentiation protocol to generate patient specific macrophages. We previously highlighted the role of macrophages in MSMD [42] and also the feasibility of using limited patient samples to recapitulate the phenotype in vitro [43]. As PBMC-derived monocytes may be difficult to obtain and current cell systems to study the MSMD pathophysiology have certain shortcomings, we emphasize the MSMD iPSC-macrophage model as a new tool for disease modelling and drug screening.…”

Section: Discussionmentioning

confidence: 99%

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

Haake

Neehus

Buchegger

et al. 2020

Cells

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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.

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Section: Discussionmentioning

confidence: 99%

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

Haake

Neehus

Buchegger

et al. 2020

Cells

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“…In summary, iPSC-derived macrophages are highly suitable for studying complex primary immunodeficiencies. This was convincingly demonstrated for pulmonary alveolar proteinosis [ 20 ] or mendelian susceptibility to mycobacterial disease [ 21 ]. However, in VEO-IBD, not only macrophages are affected by the impaired IL-10 signaling pathway.…”

Section: Discussionmentioning

confidence: 91%

“…Several colonies, i.e., iPSC clones, were manually picked and three clones were selected for functional analysis named IBD1, IBD3, and IBD5 iPSCs. The iPSC clone C16 was described before and served as healthy control in several disease studies associated with defects in macrophage functions [ 19 , 20 , 21 , 22 ].…”

Section: Methodsmentioning

confidence: 99%

Genetic Correction of IL-10RB Deficiency Reconstitutes Anti-Inflammatory Regulation in iPSC-Derived Macrophages

Hoffmann

Sens

Brennig

et al. 2021

JPM

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Patient material from rare diseases such as very early-onset inflammatory bowel disease (VEO-IBD) is often limited. The use of patient-derived induced pluripotent stem cells (iPSCs) for disease modeling is a promising approach to investigate disease pathomechanisms and therapeutic strategies. We successfully developed VEO-IBD patient-derived iPSC lines harboring a mutation in the IL-10 receptor β-chain (IL-10RB) associated with defective IL-10 signaling. To characterize the disease phenotype, healthy control and VEO-IBD iPSCs were differentiated into macrophages. IL-10 stimulation induced characteristic signal transducer and activator of transcription 3 (STAT3) and suppressor of cytokine signaling 3 (SOCS3) downstream signaling and anti-inflammatory regulation of lipopolysaccharide (LPS)-mediated cytokine secretion in healthy control iPSC-derived macrophages. In contrast, IL-10 stimulation of macrophages derived from patient iPSCs did not result in STAT3 phosphorylation and subsequent SOCS3 expression, recapitulating the phenotype of cells from patients with IL-10RB deficiency. In line with this, LPS-induced cytokine secretion (e.g., IL-6 and tumor necrosis factor-α (TNF-α)) could not be downregulated by exogenous IL-10 stimulation in VEO-IBD iPSC-derived macrophages. Correction of the IL-10RB defect via lentiviral gene therapy or genome editing in the adeno-associated virus integration site 1 (AAVS1) safe harbor locus led to reconstitution of the anti-inflammatory response. Corrected cells showed IL-10RB expression, IL-10-inducible phosphorylation of STAT3, and subsequent SOCS3 expression. Furthermore, LPS-mediated TNF-α secretion could be modulated by IL-10 stimulation in gene-edited VEO-IBD iPSC-derived macrophages. Our established disease models provide the opportunity to identify and validate new curative molecular therapies and to investigate phenotypes and consequences of additional individual IL-10 signaling pathway-dependent VEO-IBD mutations.

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“…Mendelian susceptibility to mycobacterial disease is a group of inborn errors that identifies 12 genetic defects (IFN-GR1, IFN-GR2, IL-12B, IL-12RB1, IL-12RB2, IL-23R, STAT1, IRF8, TYK2, SPPL2A, NF-Kappa B Essential Modulator (NEMO) and Cytochrome b- 245 Beta Chain (CYBB)) predisposing patients to virulent mycobacteria 1. These patients have no haematological nor immunological abnormalities; however, these patients have a deficiency in IFN-G immunity, resulting in disseminated and life-threatening mycobacterial infection 8. Deficiencies affecting the innate immune response have been shown to be associated with viral measles vaccine infections.…”

Section: Discussionmentioning

confidence: 99%

Diagnosing inborn error of immunity following the presentation of a complicated acquired infection after MMRV vaccine administration

et al. 2020

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Live vaccine-acquired infection should attest for the occurrence of inborn errors of immunity. Autosomal recessive immunodeficiency 31B, a result of a signal transducer and activator of transcription 1 genetic mutation, results in defected interferon pathways: interferon alpha/beta and interferon gamma. These interferons are crucial for the defence against viral and mycobacterial infections. Recognition is important for preventive and therapeutic approaches. Herein, we report the presentation of a newly diagnosed 13-month-old child with immunodeficiency 31B after presenting with disseminated measles and varicella infection after Measles, Mumps, Rubella and Varicella vaccination.

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Impaired IFNγ-Signaling and Mycobacterial Clearance in IFNγR1-Deficient Human iPSC-Derived Macrophages

Cited by 25 publications

References 23 publications

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

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

Genetic Correction of IL-10RB Deficiency Reconstitutes Anti-Inflammatory Regulation in iPSC-Derived Macrophages

Diagnosing inborn error of immunity following the presentation of a complicated acquired infection after MMRV vaccine administration

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