Mimicking Behçet’s disease: GM‐CSF gain of function mutation in a family suffering from a Behçet’s disease‐like disorder marked by extreme pathergy

Summary Behçet’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...

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Bibliographic Details
Published in:Clinical and experimental immunology 2021-05, Vol.204 (2), p.189-198
Main Authors: Rösler, B., Heinhuis, B., Wang, X., Silvestre, R., Joosten, L. A. B., Netea, M. G., Arts, P., Mantere, T., Lefeber, D. J., Hoischen, A., Veerdonk, F. L.
Format: Article
Language:English
Subjects:
Acetic acid
Behcet Syndrome - genetics
Behcet's syndrome
Behçet
Biological activity
Cell Line
Cell Line, Tumor
cytokine
Editors' Choice
Exome - genetics
Female
Flow cytometry
Gain of Function Mutation - genetics
Glycosylation
Granulocyte-Macrophage Colony-Stimulating Factor - genetics
Hep G2 Cells
Histocompatibility antigen HLA
Humans
IL‐1Ra
Inflammatory diseases
Leukocytes (granulocytic)
Leukocytes (mononuclear)
Macrophages
Mimicry
Original
pathergy
Phosphorylation
Phosphorylation - genetics
Proteins
TNF
Transcription
Tumor necrosis factor
Tumor necrosis factor-TNF
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Summary:Summary Behçet’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)‐α treatment, which may be linked to the capacity of TNF‐α 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. Loss of N44 glycosylation in GM‐CSF leads to increased signaling activity resulting in a BD‐like phenotype marked by extreme pathergy. The GM‐CSF pathway may provide a novel target to reshape individual patient care in the pathogenesis of pathergy in BD.
ISSN:0009-9104
1365-2249
DOI:10.1111/cei.13568