Epigenetic, transcriptional, and functional characterization of myeloid cells in familial Mediterranean fever
Rutger J. Röring,
Wenchao Li,
Ruiqi Liu,
Mariolina Bruno,
Bowen Zhang,
Priya A. Debisarun,
Orsolya Gaal,
Medeea Badii,
Viola Klück,
Simone J.C.F.M. Moorlag,
Frank van de Veerdonk,
Yang Li,
Leo A.B. Joosten,
Mihai G. Netea
Affiliations
Rutger J. Röring
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud university medical center, Nijmegen, the Netherlands
Wenchao Li
Department of Computational Biology for Individualised Medicine, Centre for Individualised Infection Medicine (CiiM), a joint venture between the Helmholtz-Centre for Infection Research (HZI) and Hannover Medical School (MHH), Hannover, Germany; TWINCORE, a joint venture between the Helmholtz-Centre for Infection Research (HZI) and Hannover Medical School (MHH), Hannover, Germany
Ruiqi Liu
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud university medical center, Nijmegen, the Netherlands
Mariolina Bruno
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud university medical center, Nijmegen, the Netherlands
Bowen Zhang
Department of Computational Biology for Individualised Medicine, Centre for Individualised Infection Medicine (CiiM), a joint venture between the Helmholtz-Centre for Infection Research (HZI) and Hannover Medical School (MHH), Hannover, Germany; TWINCORE, a joint venture between the Helmholtz-Centre for Infection Research (HZI) and Hannover Medical School (MHH), Hannover, Germany; State Key Laboratory of Earth Surface Process and Resource Ecology and Ministry of Education Key Laboratory for Biodiversity Science and Ecological Engineering, College of Life Sciences, Beijing Normal University, Beijing 100875, China
Priya A. Debisarun
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud university medical center, Nijmegen, the Netherlands
Orsolya Gaal
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud university medical center, Nijmegen, the Netherlands; Department of Medical Genetics, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj- Napoca, Romania
Medeea Badii
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud university medical center, Nijmegen, the Netherlands; Department of Medical Genetics, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj- Napoca, Romania
Viola Klück
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud university medical center, Nijmegen, the Netherlands
Simone J.C.F.M. Moorlag
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud university medical center, Nijmegen, the Netherlands
Frank van de Veerdonk
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud university medical center, Nijmegen, the Netherlands
Yang Li
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud university medical center, Nijmegen, the Netherlands; Department of Computational Biology for Individualised Medicine, Centre for Individualised Infection Medicine (CiiM), a joint venture between the Helmholtz-Centre for Infection Research (HZI) and Hannover Medical School (MHH), Hannover, Germany; TWINCORE, a joint venture between the Helmholtz-Centre for Infection Research (HZI) and Hannover Medical School (MHH), Hannover, Germany
Leo A.B. Joosten
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud university medical center, Nijmegen, the Netherlands; Department of Medical Genetics, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj- Napoca, Romania
Mihai G. Netea
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud university medical center, Nijmegen, the Netherlands; Department of Immunology and Metabolism, Life and Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany; Corresponding author
Summary: Familial Mediterranean fever (FMF) is a periodic fever syndrome caused by variation in MEFV. FMF is known for IL-1β dysregulation, but the innate immune landscape of this disease has not been comprehensively described. Therefore, we studied circulating inflammatory proteins, and the function of monocytes and (albeit less extensively) neutrophils in treated FMF patients in remission. We found that monocyte IL-1β and IL-6 production was enhanced upon stimulation, in concordance with alterations in the plasma inflammatory proteome. We did not observe changes in neutrophil functional assays. Subtle differences in chromatin accessibility and transcriptomics in our small patient cohort further argued for monocyte dysregulation. Together, these observations suggest that the MEFV-mutation-mediated primary immune dysregulation in monocytes leads to chronic inflammation that is subsequently associated with counterregulatory epigenetic/transcriptional changes reminiscent of tolerance. These data increase our understanding of the innate immune changes in FMF, aiding future management of chronic inflammation in these patients.
