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,Clinical & Experimental Immunology

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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
Clinical & Experimental Immunology ( IF 3.4 ) Pub Date : 2020-12-22 , DOI: 10.1111/cei.13568
B Rösler ₁ , B Heinhuis ₁ , X Wang ₁ , R Silvestre _{2,

3} , L A B Joosten ₁ , M G Netea _{1,

4} , P Arts ₅ , T Mantere ₅ , D J Lefeber ₆ , A Hoischen _{1,

5} , F L van de Veerdonk ₁

Affiliation

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.

中文翻译：

模仿 Behçet 病：一个患有 Behçet 病样疾病的家庭的 GM-CSF 功能突变获得性，其特点是极度病态

白塞病 (BD) 是一种炎症性疾病，主要影响古代丝绸之路沿线的男性。在本研究中，我们描述了一个患有 BD 样疾病的荷兰家庭，具有极端的病理反应，但没有全身炎症。遗传评估揭示了人类白细胞抗原 (HLA)-B*51 风险等位基因与CSF2中罕见的杂合变异体的组合通过全外显子组测序发现编码粒细胞-巨噬细胞集落刺激因子 (GM-CSF) 的基因 (c.130A>C, p.N44H)。我们利用人类肝细胞系中的过表达载体系统来产生 GM-CSF 的异常变体。使用流式细胞术在野生型外周单核细胞 (PBMC) 中通过信号转导和转录激活因子 5 (STAT-5) 磷酸化（GM-CSF 受体的下游分子）测量蛋白质的生物活性。与野生型或重组蛋白相比，突变的 GM-CSF 导致 STAT-5 磷酸化增加。脑脊液2p.N44H 导致蛋白质的两个 N-糖基化位点之一被破坏。酶促去糖基化的野生型 GM-CSF 也增强了 STAT-5 磷酸化。患者对抗肿瘤坏死因子 (TNF)-α 治疗反应良好，这可能与 TNF-α 在佛波醇 12-肉豆蔻酸酯 13-乙酸 (PMA) 治疗的 PBMC 中诱导 GM-CSF 的能力有关，而 GM ‐CSF 本身仅诱导剂量依赖性白细胞介素 (IL)‐1Ra 的产生。确定的CSF2通路可以为 BD 样疾病的病理反应提供新的见解，并为个性化治疗提供新的机会。

更新日期：2021-01-29

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