{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T01:49:40Z","timestamp":1779932980483,"version":"3.53.1"},"reference-count":20,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,3,19]],"date-time":"2025-03-19T00:00:00Z","timestamp":1742342400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Culture and Innovation of Hungary from the National Research, Development and Innovation Fund","award":["TKP2021-EGA-10"],"award-info":[{"award-number":["TKP2021-EGA-10"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/ijms26062750","type":"journal-article","created":{"date-parts":[[2025,3,19]],"date-time":"2025-03-19T06:10:53Z","timestamp":1742364653000},"page":"2750","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Activation of the Mammalian Target of Rapamycin Pathway in Endothelial Cells in Antiphospholipid Antibody-Positive Patients with Leg Ulcers"],"prefix":"10.3390","volume":"26","author":[{"given":"Andr\u00e1s L.","family":"Kov\u00e1cs","sequence":"first","affiliation":[{"name":"Department of Dermatology, Venereology and Oncodermatology, Medical School, University of P\u00e9cs, 7622 P\u00e9cs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Csaba","family":"Gy\u00f6m\u00f6rei","sequence":"additional","affiliation":[{"name":"Department of Pathology, Medical School, University of P\u00e9cs, 7622 P\u00e9cs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5168-1622","authenticated-orcid":false,"given":"Szabina","family":"Horv\u00e1th","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology and Oncodermatology, Medical School, University of P\u00e9cs, 7622 P\u00e9cs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6452-9817","authenticated-orcid":false,"given":"Vikt\u00f3ria","family":"N\u00e9meth","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology and Oncodermatology, Medical School, University of P\u00e9cs, 7622 P\u00e9cs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8699-4648","authenticated-orcid":false,"given":"R\u00e9ka","family":"Dudley","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Veszpr\u00e9m County Csolnoky Ferenc Hospital, 8200 Veszpr\u00e9m, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zsuzsanna","family":"Nagy","sequence":"additional","affiliation":[{"name":"2nd Department of Internal Medicine and Nephrological Center, Medical School, University of P\u00e9cs, 7622 P\u00e9cs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T\u00edmea","family":"Berki","sequence":"additional","affiliation":[{"name":"Department of Immunology and Biotechnology, Medical School, University of P\u00e9cs, 7622 P\u00e9cs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zsuzsanna","family":"Lengyel","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology and Oncodermatology, Medical School, University of P\u00e9cs, 7622 P\u00e9cs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3286-8846","authenticated-orcid":false,"given":"Rolland","family":"Gyulai","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology and Oncodermatology, Medical School, University of P\u00e9cs, 7622 P\u00e9cs, Hungary"},{"name":"Department of Dermatology and Allergology, Albert-Szent Gy\u00f6rgyi Medical School, University of Szeged, 6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"101463","DOI":"10.1016\/j.berh.2019.101463","article-title":"Antiphospholipid Syndrome","volume":"34","author":"Sammaritano","year":"2020","journal-title":"Best Pract. Res. Clin. Rheumatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1111\/j.1538-7836.2006.01753.x","article-title":"International Consensus Statement on an Update of the Classification Criteria for Definite Antiphospholipid Syndrome (APS)","volume":"4","author":"Miyakis","year":"2006","journal-title":"J. Thromb. Haemost."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"S43","DOI":"10.1016\/S0049-3848(17)30066-X","article-title":"Antiphospholipid Syndrome","volume":"151","author":"Cervera","year":"2017","journal-title":"Thromb. Res."},{"key":"ref_4","first-page":"69717","article-title":"Antiphospholipid Syndrome: Advances in Diagnosis, Pathogenesis, and Management","volume":"380","author":"Knight","year":"2023","journal-title":"BMJ"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2010","DOI":"10.1056\/NEJMra1705454","article-title":"Diagnosis and Management of the Antiphospholipid Syndrome","volume":"378","author":"Garcia","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1177\/0961203310395052","article-title":"Task Force on Catastrophic Antiphospholipid Syndrome (APS) and Non-Criteria APS Manifestations (II): Thrombocytopenia and Skin Manifestations","volume":"20","author":"Cervera","year":"2011","journal-title":"Lupus"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Vel\u00e1squez, M., Rojas, M., Abrahams, V.M., Escudero, C., and Cadavid, \u00c1.P. (2018). Mechanisms of Endothelial Dysfunction in Antiphospholipid Syndrome: Association With Clinical Manifestations. Front. Physiol., 9.","DOI":"10.3389\/fphys.2018.01840"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1007\/s12016-008-8104-z","article-title":"Microthrombotic\/Microangiopathic Manifestations of the Antiphospholipid Syndrome","volume":"36","author":"Praprotnik","year":"2009","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1007\/s00281-022-00916-w","article-title":"Mechanisms of Immunothrombosis and Vasculopathy in Antiphospholipid Syndrome","volume":"44","author":"Knight","year":"2022","journal-title":"Semin. Immunopathol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1385\/CRIAI:25:1:61","article-title":"Unusual Manifestations of the Antiphospholipid Syndrome","volume":"25","author":"Asherson","year":"2003","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Kov\u00e1cs, A.L., K\u00e1rteszi, J., Proh\u00e1szka, Z., Kalm\u00e1r, T., K\u00e9sm\u00e1rky, G., Koltai, K., Nagy, Z., Seb\u0151k, J., Vas, T., and Moln\u00e1r, K. (2022). Hemizygous Nonsense Variant in the Moesin Gene (MSN) Leads to a New Autoimmune Phenotype of Immunodeficiency 50. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.919411"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1056\/NEJMoa1312890","article-title":"Inhibition of the MTORC Pathway in the Antiphospholipid Syndrome","volume":"371","author":"Canaud","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1056\/NEJMe1406870","article-title":"The MTORC Pathway in the Antiphospholipid Syndrome","volume":"371","author":"Eikelboom","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.3899\/jrheum.220049","article-title":"Mammalian Target of Rapamycin Pathway Assessment in Antiphospholipid Antibody-Positive Patients with Livedo","volume":"49","author":"Sevim","year":"2022","journal-title":"J. Rheumatol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1016\/j.cell.2017.02.004","article-title":"MTOR Signaling in Growth, Metabolism, and Disease","volume":"168","author":"Saxton","year":"2017","journal-title":"Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1042\/BJ20070540","article-title":"Identification of Protor as a Novel Rictor-Binding Component of MTOR Complex-2","volume":"405","author":"Pearce","year":"2007","journal-title":"Biochem. J."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"M\u00e1rk, \u00c1., Hajdu, M., V\u00e1radi, Z., Sticz, T.B., Nagy, N., Csomor, J., Berczi, L., Varga, V., Cs\u00f3ka, M., and Kopper, L. (2013). Characteristic MTOR Activity in Hodgkin-Lymphomas Offers a Potential Therapeutic Target in High Risk Disease\u2014A Combined Tissue Microarray, In Vitro and In Vivo Study. BMC Cancer, 13.","DOI":"10.1186\/1471-2407-13-250"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1038\/nrrheum.2015.172","article-title":"Activation of MTOR (Mechanistic Target of Rapamycin) in Rheumatic Diseases","volume":"12","author":"Perl","year":"2015","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1111\/bjd.13248","article-title":"Ribosomal Protein S6 Is Hyperactivated and Differentially Phosphorylated in Epidermal Lesions of Patients with Psoriasis and Atopic Dermatitis","volume":"171","author":"Ruf","year":"2014","journal-title":"Br. J. Dermatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1759720X20910855","DOI":"10.1177\/1759720X20910855","article-title":"An Update on the Management of Antiphospholipid Syndrome","volume":"12","author":"Rodziewicz","year":"2020","journal-title":"Ther. Adv. Musculoskelet. Dis."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/6\/2750\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:56:17Z","timestamp":1760028977000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/6\/2750"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,19]]},"references-count":20,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,3]]}},"alternative-id":["ijms26062750"],"URL":"https:\/\/doi.org\/10.3390\/ijms26062750","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,19]]}}}