PMID- 33349924 OWN - NLM STAT- MEDLINE DCOM- 20211203 LR - 20220503 IS - 1365-2249 (Electronic) IS - 0009-9104 (Print) IS - 0009-9104 (Linking) VI - 204 IP - 2 DP - 2021 May TI - Mimicking Behcet's disease: GM-CSF gain of function mutation in a family suffering from a Behcet's disease-like disorder marked by extreme pathergy. PG - 189-198 LID - 10.1111/cei.13568 [doi] AB - Behcet's disease (BD) is an inflammatory disease mainly affecting men along the ancient Silk Route. In the present study we describe a Dutch family suffering from BD-like disease with extreme pathergic responses, but without systemic inflammation. Genetic assessment revealed a combination of the human leukocyte antigen (HLA)-B*51 risk-allele together with a rare heterozygous variant in the CSF2 gene (c.130A>C, p.N44H) encoding for granulocyte-macrophage colony-stimulating factor (GM-CSF) found by whole exome sequencing. We utilized an over-expression vector system in a human hepatocyte cell line to produce the aberrant variant of GM-CSF. Biological activity of the protein was measured by signal transducer and activator of transcription 5 (STAT-5) phosphorylation, a downstream molecule of the GM-CSF receptor, in wild-type peripheral mononuclear cells (PBMCs) using flow cytometry. Increased STAT-5 phosphorylation was observed in response to mutated GM-CSF when compared to the wild-type or recombinant protein. CSF2 p.N44H results in disruption of one of the protein's two N-glycosylation sites. Enzymatically deglycosylated wild-type GM-CSF also enhanced STAT-5 phosphorylation. The patient responded well to anti-tumor necrosis factor (TNF)-alpha treatment, which may be linked to the capacity of TNF-alpha to induce GM-CSF in phorbol 12-myristate 13-acetate (PMA)-treated PBMCs, while GM-CSF itself only induced dose-dependent interleukin (IL)-1Ra production. The identified CSF2 pathway could provide novel insights into the pathergic response of BD-like disease and offer new opportunities for personalized treatment. CI - (c) 2021 British Society for Immunology. FAU - Rosler, B AU - Rosler B AUID- ORCID: 0000-0003-4810-2666 AD - Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands. FAU - Heinhuis, B AU - Heinhuis B AD - Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands. FAU - Wang, X AU - Wang X AD - Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands. FAU - Silvestre, R AU - Silvestre R AD - Microbiology and Infection Research Domain, Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal. AD - ICVS/3B's, PT Government Associate Laboratory, Guimaraes, Portugal. FAU - Joosten, L A B AU - Joosten LAB AD - Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands. FAU - Netea, M G AU - Netea MG AD - Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands. AD - Department for Genomics and Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany. FAU - Arts, P AU - Arts P AD - Department of Human Genetics and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands. FAU - Mantere, T AU - Mantere T AUID- ORCID: 0000-0003-3284-4403 AD - Department of Human Genetics and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands. FAU - Lefeber, D J AU - Lefeber DJ AD - Department of Neurology, Translational Metabolic Laboratory, Radboud University Medical Centre, Nijmegen, the Netherlands. FAU - Hoischen, A AU - Hoischen A AD - Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands. AD - Department of Human Genetics and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands. FAU - van de Veerdonk, F L AU - van de Veerdonk FL AUID- ORCID: 0000-0002-1121-4894 AD - Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands. LA - eng GR - 667837/European Union Horizon 2020 research and innovation program/ GR - IN-CONTROL/Heart Foundation Netherlands/ GR - Spinoza/Netherlands Organization for Scientific Research/ GR - ZonMW/NWO VIDI/ GR - 310372/ERC Consolidator Grant/ GR - EURO-CMC/the ERA-Net for Research Programmes on Rare Diseases/ PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210128 PL - England TA - Clin Exp Immunol JT - Clinical and experimental immunology JID - 0057202 RN - 83869-56-1 (Granulocyte-Macrophage Colony-Stimulating Factor) SB - IM MH - Behcet Syndrome/*genetics MH - Cell Line MH - Cell Line, Tumor MH - Exome/genetics MH - Female MH - Gain of Function Mutation/*genetics MH - Granulocyte-Macrophage Colony-Stimulating Factor/*genetics MH - Hep G2 Cells MH - Humans MH - Phosphorylation/genetics PMC - PMC8062987 OTO - NOTNLM OT - Behcet OT - IL-1Ra OT - TNF OT - cytokine OT - pathergy COIS- The authors declare no competing interests. EDAT- 2020/12/23 06:00 MHDA- 2021/12/15 06:00 PMCR- 2022/05/01 CRDT- 2020/12/22 05:47 PHST- 2020/11/10 00:00 [revised] PHST- 2019/09/01 00:00 [received] PHST- 2020/11/10 00:00 [accepted] PHST- 2020/12/23 06:00 [pubmed] PHST- 2021/12/15 06:00 [medline] PHST- 2020/12/22 05:47 [entrez] PHST- 2022/05/01 00:00 [pmc-release] AID - CEI13568 [pii] AID - 10.1111/cei.13568 [doi] PST - ppublish SO - Clin Exp Immunol. 2021 May;204(2):189-198. doi: 10.1111/cei.13568. Epub 2021 Jan 28.