Yaglikara Ece, Boluk Oguz, Bayindir Yagmur, Bilginer Yelda, Tasar Medine Aysin, Ozen Seza, Sag Erdal
Department of Pediatrics, Ankara Training and Research Hospital, 06230 Ankara, Turkey.
Department of Pediatric Rheumatology, Hacettepe University, 06230 Ankara, Turkey.
Diagnostics (Basel). 2024 Sep 13;14(18):2031. doi: 10.3390/diagnostics14182031.
FMF is the most common autoinflammatory disease. The activation of the pyrin inflammasome is the mainstay of the pathogenesis, which might lead to a specific cell-death mechanism, pyroptosis. Pyroptosis is a programmed inflammatory cell death mediated by gasdermin proteins, featuring cell swelling, membrane rupture, and release of inflammatory contents Aim: In this study we aimed to analyze the cell-death mechanisms in the pathogenesis of FMF attacks.
Twenty-five FMF patients were included, and PFAPA patients ( = 10) and healthy controls (HC, = 10) served as controls. We collected plasma samples from FMF and PFAPA patients during the attack and the attack-free period. We measured the soluble plasma levels of sFas, sFasL, granzyme A, granzyme B, perforin, granulysin, IL-2, IL-4, IL-10, IL-6, IL-17A, TNF-α, and IFN-γ by commercial pre-defined cytometric bead array kits.
There was no significant difference between groups in terms of sex and age between FMF patients and HCs, but PFAPA patients were younger than other groups due to the nature of the disease. We then analyzed the components of apoptosis and pyroptosis. The levels of sFasL ( = 0.035) and granzyme A ( = 0.038) in FMF patients were significantly increased during the attack period and decreased to levels comparable to HCs during the attack-free period. This increase was not seen in the PFAPA patients, with comparable levels with the HC group both during attack period and attack-free period. During the attack period of FMF patients, granzyme B ( = 0.145) and perforin ( = 0.203) levels were also increased; however, the differences were not statistically significant. The levels of sFasL, granzyme A, granzyme B, and perforin were closely correlated with each other during the attack period of FMF patients.
Our study on death pathways during an FMF attack, suggests an upregulation in both pyroptosis through the granzyme-gasdermin pathway and apoptosis with the increased FasL and perforin levels, which was different from PFAPA patients. These findings might shed light on the reason for the nature of self-limited attacks, but further studies are needed to prove this hypothesis.
家族性地中海热（FMF）是最常见的自身炎症性疾病。吡啉炎性小体的激活是发病机制的主要环节，这可能导致一种特定的细胞死亡机制——焦亡。焦亡是一种由gasdermin蛋白介导的程序性炎症细胞死亡，其特征为细胞肿胀、细胞膜破裂以及炎性内容物释放。目的：在本研究中，我们旨在分析FMF发作期发病机制中的细胞死亡机制。
纳入25例FMF患者，以周期性发热伴口疮性口炎、咽炎和颈淋巴结炎综合征（PFAPA）患者（n = 10）和健康对照者（HC，n = 10）作为对照。我们在FMF和PFAPA患者的发作期和发作间期采集血浆样本。我们使用商用预定义细胞计数珠阵列试剂盒测量血浆中可溶性sFas、sFasL、颗粒酶A、颗粒酶B、穿孔素、颗粒溶素、白细胞介素-2（IL-2）、白细胞介素-4（IL-4）、白细胞介素-10（IL-10）、白细胞介素-6（IL-6）、白细胞介素-17A（IL-17A）、肿瘤坏死因子-α（TNF-α）和干扰素-γ（IFN-γ）的水平。
FMF患者与健康对照者在性别和年龄方面无显著差异，但由于疾病性质，PFAPA患者比其他组更年轻。然后我们分析了凋亡和焦亡的成分。FMF患者在发作期sFasL（P = 0.035）和颗粒酶A（P = 0.038）水平显著升高，在发作间期降至与健康对照者相当的水平。PFAPA患者未出现这种升高，在发作期和发作间期其水平与健康对照组相当。在FMF患者的发作期，颗粒酶B（P = 0.145）和穿孔素（P = 0.203）水平也升高；然而，差异无统计学意义。在FMF患者的发作期，sFasL、颗粒酶A、颗粒酶B和穿孔素水平彼此密切相关。
我们对FMF发作期死亡途径的研究表明，通过颗粒酶-gasdermin途径的焦亡和FasL及穿孔素水平升高导致的凋亡均上调，这与PFAPA患者不同。这些发现可能有助于揭示自限性发作本质的原因，但需要进一步研究来证实这一假设。
