Modeling MyD88 Deficiency In Vitro Provides New Insights in Its Function.

Autor:	Craig-Mueller N; Institute for Transfusion Medicine and Gene Therapy, Medical Center-University of Freiburg, Freiburg, Germany.; Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Freiburg, Germany.; MD Program, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Hammad R; Institute for Transfusion Medicine and Gene Therapy, Medical Center-University of Freiburg, Freiburg, Germany.; Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Freiburg, Germany.; PhD Program, Faculty of Biology, University of Freiburg, Freiburg, Germany., Elling R; Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Freiburg, Germany.; Institute for Immunodeficiency, Medical Center-University of Freiburg, Freiburg, Germany.; Center for Pediatrics and Adolescent Medicine, Medical Center-University of Freiburg, Freiburg, Germany., Alzubi J; Institute for Transfusion Medicine and Gene Therapy, Medical Center-University of Freiburg, Freiburg, Germany.; Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Freiburg, Germany., Timm B; Institute for Transfusion Medicine and Gene Therapy, Medical Center-University of Freiburg, Freiburg, Germany.; Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Freiburg, Germany., Kolter J; Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Freiburg, Germany.; Institute for Immunodeficiency, Medical Center-University of Freiburg, Freiburg, Germany., Knelangen N; Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Freiburg, Germany.; Institute for Immunodeficiency, Medical Center-University of Freiburg, Freiburg, Germany., Bednarski C; Institute for Transfusion Medicine and Gene Therapy, Medical Center-University of Freiburg, Freiburg, Germany.; Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Freiburg, Germany., Gläser B; Institute of Human Genetics, Medical Center-University of Freiburg, Freiburg, Germany., Ammann S; Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Freiburg, Germany.; Institute for Immunodeficiency, Medical Center-University of Freiburg, Freiburg, Germany., Ivics Z; Division of Medical Biotechnology, Paul-Ehrlich Institute, Langen, Germany., Fischer J; Institute of Human Genetics, Medical Center-University of Freiburg, Freiburg, Germany.; Faculty of Medicine, University of Freiburg, Freiburg, Germany., Speckmann C; Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Freiburg, Germany.; Center for Pediatrics and Adolescent Medicine, Medical Center-University of Freiburg, Freiburg, Germany.; Faculty of Medicine, University of Freiburg, Freiburg, Germany., Schwarz K; Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service Baden-Württemberg-Hessen, and Institute for Transfusion Medicine, University of Ulm, Ulm, Germany., Lachmann N; Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.; REBIRTH Cluster for Regenerative and Translational Medicine, Hannover, Germany., Ehl S; Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Freiburg, Germany.; Institute for Immunodeficiency, Medical Center-University of Freiburg, Freiburg, Germany.; Faculty of Medicine, University of Freiburg, Freiburg, Germany., Moritz T; Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.; REBIRTH Cluster for Regenerative and Translational Medicine, Hannover, Germany., Henneke P; Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Freiburg, Germany.; Institute for Immunodeficiency, Medical Center-University of Freiburg, Freiburg, Germany.; Center for Pediatrics and Adolescent Medicine, Medical Center-University of Freiburg, Freiburg, Germany.; Faculty of Medicine, University of Freiburg, Freiburg, Germany., Cathomen T; Institute for Transfusion Medicine and Gene Therapy, Medical Center-University of Freiburg, Freiburg, Germany.; Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Freiburg, Germany.; Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2020 Dec 23; Vol. 11, pp. 608802. Date of Electronic Publication: 2020 Dec 23 (Print Publication: 2020).
DOI:	10.3389/fimmu.2020.608802
Abstrakt:	Inherited defects in MyD88 and IRAK4, two regulators in Toll-like receptor (TLR) signaling, are clinically highly relevant, but still incompletely understood. MyD88- and IRAK4-deficient patients are exceedingly susceptible to a narrow spectrum of pathogens, with ∼50% lethality in the first years of life. To better understand the underlying molecular and cellular characteristics that determine disease progression, we aimed at modeling the cellular response to pathogens in vitro . To this end, we determined the immunophenotype of monocytes and macrophages derived from MyD88- and IRAK4-deficient patients. We recognized that macrophages derived from both patients were particularly poorly activated by streptococci, indicating that both signaling intermediates are essential for the immune response to facultative pathogens. To characterize this defect in more detail, we generated induced pluripotent stem cells (iPSCs) of fibroblasts derived from an MyD88-deficient patient. The underlying genetic defect was corrected using Sleeping Beauty transposon vectors encoding either the long (L) or the short (S) MYD88 isoform, respectively. Macrophages derived from these iPSC lines (iMacs) expressed typical macrophage markers, stably produced either MyD88 isoform, and showed robust phagocytic activity. Notably, iMacs expressing MyD88-L, but not MyD88-S, exhibited similar responses to external stimuli, including cytokine release patterns, as compared to genetically normal iMacs. Thus, the two MyD88 isoforms assume distinct functions in signaling. In conclusion, iPSC technology, in combination with efficient myeloid differentiation protocols, provides a valuable and inexhaustible source of macrophages, which can be used for disease modeling. Moreover, iPSC-derived macrophages may eventually aid in stabilizing MyD88-deficient patients during pyogenic infections. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2020 Craig-Mueller, Hammad, Elling, Alzubi, Timm, Kolter, Knelangen, Bednarski, Gläser, Ammann, Ivics, Fischer, Speckmann, Schwarz, Lachmann, Ehl, Moritz, Henneke and Cathomen.)
Databáze:	MEDLINE
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