Modeling MyD88 Deficiency In Vitro Provides New Insights in Its Function

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...

Full description

Saved in:

Bibliographic Details
Published in:	Frontiers in immunology Vol. 11; p. 608802
Main Authors:	Craig-Mueller, Nils, Hammad, Ruba, Elling, Roland, Alzubi, Jamal, Timm, Barbara, Kolter, Julia, Knelangen, Nele, Bednarski, Christien, Gläser, Birgitta, Ammann, Sandra, Ivics, Zoltán, Fischer, Judith, Speckmann, Carsten, Schwarz, Klaus, Lachmann, Nico, Ehl, Stephan, Moritz, Thomas, Henneke, Philipp, Cathomen, Toni
Format:	Journal Article
Language:	English
Published:	Switzerland Frontiers Media S.A 23-12-2020
Subjects:	cell therapy iMac Immunology induced pluripotent stem cells (iPSC) IRAK4 MyD88 transposon transposon cell therapy iMac induced pluripotent stem cells (iPSC) gene therapy IRAK4 MyD88 Toll-like receptor
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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 . 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 transposon vectors encoding either the long (L) or the short (S) 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 This article was submitted to Primary Immunodeficiencies, a section of the journal Frontiers in Immunology Reviewed by: Capucine Picard, Hôpital Necker-Enfants Malades, Assistance Publique Hopitaux De Paris, France; Andrea Finocchi, University of Rome Tor Vergata, Italy These authors have contributed equally to this work Edited by: Claudio Pignata, University of Naples Federico II, Italy
ISSN:	1664-3224 1664-3224
DOI:	10.3389/fimmu.2020.608802