Kovács András L, Gyömörei Csaba, Horváth Szabina, Németh Viktória, Dudley Réka, Nagy Zsuzsanna, Berki Tímea, Lengyel Zsuzsanna, Gyulai Rolland
Department of Dermatology, Venereology and Oncodermatology, Medical School, University of Pécs, 7622 Pécs, Hungary.
Department of Pathology, Medical School, University of Pécs, 7622 Pécs, Hungary.
Int J Mol Sci. 2025 Mar 19;26(6):2750. doi: 10.3390/ijms26062750.
Antiphospholipid antibody (aPL)-induced activation of the mTOR (mammalian target of rapamycin) signaling pathway in endothelial cells plays a role in the pathogenesis of vascular lesions in antiphospholipid syndrome (APS). However, there are no data on whether this mechanism also contributes to the development of skin ulcers commonly observed in APS. We investigated the activation of mTOR in skin specimens from aPL-positive and aPL-negative patients with leg ulcers. Patients with leg ulcers who had primary or secondary APS or no detectable aPLs were included in the study. Biopsies were taken from the ulcer edges and the adjacent non-ulcerated skin areas. Activation of mTORC1 (mTOR Complex1) and mTORC2 (mTOR Complex2) in endothelial cells was determined by immunohistochemical analysis of phosphorylated ribosomal S6 protein (pS6RP) and phosphorylated protein kinase B (pAKT), respectively. In all aPL-positive patients, regardless of whether they had primary or secondary APS, we found a positive immunohistochemical reaction to pS6RP (mTORC1 activation) in the endothelial cells of the ulcer samples. On the other hand, pS6RP could not be detected in samples from aPL-negative chronic venous ulcers. Furthermore, pS6RP was not present in samples taken from the unaffected skin adjacent to the ulcers in aPL-positive patients. The pAKT reaction (mTORC2) was negative in both aPL-positive and aPL-negative patients, both in the ulcers and in the periulcer skin. Activation of the mTOR pathway may contribute to ulcer development in APS. The mTORC1 may be a target for therapeutic modification in APS-associated skin ulcers.
抗磷脂抗体(aPL)诱导内皮细胞中mTOR(雷帕霉素哺乳动物靶点)信号通路的激活,在抗磷脂综合征(APS)血管病变的发病机制中起作用。然而,尚无数据表明该机制是否也促成了APS中常见的皮肤溃疡的发生。我们研究了aPL阳性和aPL阴性腿部溃疡患者皮肤标本中mTOR的激活情况。患有原发性或继发性APS或未检测到aPL的腿部溃疡患者被纳入研究。从溃疡边缘和相邻的未溃疡皮肤区域取活检组织。分别通过对磷酸化核糖体S6蛋白(pS6RP)和磷酸化蛋白激酶B(pAKT)进行免疫组织化学分析,来确定内皮细胞中mTORC1(mTOR复合物1)和mTORC2(mTOR复合物2)的激活情况。在所有aPL阳性患者中,无论他们患有原发性还是继发性APS,我们在溃疡样本的内皮细胞中均发现对pS6RP呈阳性免疫组织化学反应(mTORC1激活)。另一方面,在aPL阴性慢性静脉溃疡的样本中未检测到pS6RP。此外,在aPL阳性患者溃疡附近的未受影响皮肤样本中也不存在pS6RP。在aPL阳性和aPL阴性患者的溃疡及溃疡周围皮肤中,pAKT反应(mTORC2)均为阴性。mTOR信号通路的激活可能促成APS中溃疡的发生。mTORC1可能是APS相关皮肤溃疡治疗性干预的一个靶点。