{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:16:44Z","timestamp":1787026604707,"version":"build-2736575974"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T00:00:00Z","timestamp":1750118400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>This study aimed to examine the clinical and muscle histological characteristics of anti-Ku-positive patients. A preliminary investigation into the involvement of autophagy was conducted as well.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Clinical characteristics, laboratory findings, and muscle histological features were collected from patients with isolated anti-Ku antibodies at the Department of Neurology, First Medical Center of the PLA General Hospital, between February 2011 to June 2024. Autophagy-related protein levels were semi-quantitatively assessed on muscle tissue samples using western blot (WB), with sporadic inclusion body myositis (sIBM) and immune-mediated necrotizing myopathy (IMNM) patients as comparison groups.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>A total of 6 patients were recruited in the study (50% female, mean age at onset 47.6 \u00b1 15.56 years, mean disease duration 7 \u00b1 5.58 months). Extramuscular involvement was observed in most cases, including subcutaneous edema (33.3%), skin rash (33.3%), hyperpigmentation (33.3%), hair loss (33.3%), arthralgia (50%), and interstitial lung disease (ILD) (33.3%), etc. Coexisting connective tissue diseases included systemic sclerosis (SSc) (83.3%), systemic lupus erythematosus (SLE) (16.7%), and arthritis (16.7%). The distribution of muscle weakness was generally symmetrical and proximal (83.3%). Distal (50%) and axial (50%) muscle weakness could also be found. 2 patients exhibited peripheral nerve damage and myogenic damage in EMG, while 4 showed myogenic damage. Creatine kinase (CK) was mildly or moderately elevated. Muscle biopsy demonstrated two patterns: a neurogenic atrophy pattern and a myositis pattern characterized by a varying degree of necrotizing fibers (100%) with rimmed vacuoles (50%) or non-rimmed vacuoles (50%). Immunohistochemical (IHC) analysis revealed sarcolemma deposition of major histocompatibility complex class I (MHC-I) (83.3%) and MHC-II (83.3%), as well as predominant CD68-positive inflammatory infiltrates (66.7%). IHC for p62 revealed a sarcoplasmic punctate pattern (50%), along with a focal coarse staining pattern (50%) and occasional fine granular staining (33.3%). Electron microscopy (EM) demonstrated filamentous and lipid accumulation within vacuoles. WB analysis showed that p62 levels significantly differed between the anti-Ku and IMNM groups. Additionally, Parkin levels were highest in sIBM, while lysosome-associated membrane protein 2 (LAMP2) and microtubule-associated protein 1A\/1B-light chain 3 (LC3) expression was highest in the anti-Ku-positive group in tendency.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The muscular features were heterogeneous in anti-Ku-positive patients. A predominant myositis pattern was characterized by necrotizing fibers and vacuolar changes in muscle histology, which differ from sIBM and IMNM. Autophagy appeared to be a key mechanism implicated in the pathogenesis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1608735","type":"journal-article","created":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T01:28:29Z","timestamp":1750123709000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["The clinical features, muscle pathology, and role of autophagy in anti-Ku-positive patients"],"prefix":"10.3389","volume":"16","author":[{"given":"Lingya","family":"Qiao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengyang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqi","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.mrrev.2014.06.002","article-title":"The Ku heterodimer: function in DNA repair and beyond","volume":"763","author":"Fell","year":"2015","journal-title":"Mutat Res Rev Mutat Res"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI110295","article-title":"Characterization of a high molecular weight acidic nuclear protein recognized by autoantibodies in sera from patients with polymyositis-scleroderma overlap","volume":"68","author":"Mimori","year":"1981","journal-title":"J Clin Invest"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2010.05.020","article-title":"Anti-Ku antibodies: Clinical, genetic and diagnostic insights","volume":"9","author":"Belizna","year":"2010","journal-title":"Autoimmun Rev"},{"key":"B4","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1007\/s13317-014-0060-4","article-title":"Myositis autoantibodies and clinical phenotypes","volume":"5","author":"Ghirardello","year":"2014","journal-title":"Auto Immun Highlights"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keab492","article-title":"Autoantibody profiles delineate distinct subsets of scleromyositis","volume":"61","author":"Leclair","year":"2022","journal-title":"Rheumatol (Oxford)"},{"key":"B6","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.cell.2007.12.018","article-title":"Autophagy in the pathogenesis of disease","volume":"132","author":"Levine","year":"2008","journal-title":"Cell"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathmechdis-012419-032618","article-title":"Autophagy defects in skeletal myopathies","volume":"15","author":"Margeta","year":"2020","journal-title":"Annu Rev Pathol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0111490","article-title":"Autophagy, inflammation and innate immunity in inflammatory myopathies","volume":"9","author":"Cappelletti","year":"2014","journal-title":"PloS One"},{"key":"B9","doi-asserted-by":"publisher","first-page":"103817","DOI":"10.1016\/j.autrev.2025.103817","article-title":"Autophagy in myositis, a dysregulated pathway, and a target for therapy","volume":"24","author":"Kamalanathan","year":"2025","journal-title":"Autoimmun Rev"},{"key":"B10","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1186\/2051-5960-1-29","article-title":"Comparative utility of LC3, p62 and TDP-43 immunohistochemistry in differentiation of inclusion body myositis from polymyositis and related inflammatory myopathies","volume":"1","author":"Hiniker","year":"2013","journal-title":"Acta Neuropathol Commun"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1111\/bpa.12772","article-title":"Sequestosome-1 (p62) expression reveals chaperone-assisted selective autophagy in immune-mediated necrotizing myopathies","volume":"30","author":"Fischer","year":"2020","journal-title":"Brain Pathol"},{"key":"B12","article-title":"Differential diagnosis of vacuolar muscle biopsies: use of p62, LC3 and LAMP2 immunohistochemistry","volume":"36","author":"Vittonatto","year":"2017","journal-title":"Acta Myol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1007\/BF01451281","article-title":"Scleromyositis: a scleroderma\/polymyositis overlap syndrome","volume":"17","author":"Jablonska","year":"1998","journal-title":"Clin Rheumatol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1422.029","article-title":"Systemic sclerosis-associated myopathy","volume":"1108","author":"Ranque","year":"2007","journal-title":"Ann N Y Acad Sci"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.101248","article-title":"Clinical and serological hallmarks of systemic sclerosis overlap syndromes","volume":"38","author":"Pakozdi","year":"2011","journal-title":"J Rheumatol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"103261","DOI":"10.1016\/j.autrev.2022.103261","article-title":"Systemic sclerosis associated myopathy","volume":"22","author":"Chaigne","year":"2023","journal-title":"Autoimmun Rev"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keac361","article-title":"Clinico-pathological phenotypes of systemic sclerosis-associated myopathy: analysis of a large multicentre cohort","volume":"62","author":"Matas-Garcia","year":"2023","journal-title":"Rheumatol (Oxford)"},{"key":"B18","doi-asserted-by":"publisher","first-page":"102851","DOI":"10.1016\/j.autrev.2021.102851","article-title":"Histopathological features of systemic sclerosis-associated myopathy: A scoping review","volume":"20","author":"Lefebvre","year":"2021","journal-title":"Autoimmun Rev"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.semarthrit.2021.04.012","article-title":"The phenotype of myositis patients with anti-Ku autoantibodies","volume":"51","author":"Casal-Dominguez","year":"2021","journal-title":"Semin Arthritis Rheum"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbspin.2018.03.013","article-title":"Camptocormia with trigeminal involvement revealing myositis with anti-Ku antibodies","volume":"86","author":"De Chaves Almeida","year":"2019","journal-title":"Joint Bone Spine"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.2169\/internalmedicine.9363-17","article-title":"Dropped head syndrome and the presence of rimmed vacuoles in a muscle biopsy in scleroderma-polymyositis overlap syndrome associated with anti-ku antibody","volume":"57","author":"Yoshida","year":"2018","journal-title":"Intern Med"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2020-217096","article-title":"Immune-mediated necrotizing myopathies and interstitial lung disease are predominant characteristics in anti-Ku positive patients with idiopathic inflammatory myopathies","volume":"81","author":"Yang","year":"2022","journal-title":"Ann Rheum Dis"},{"key":"B23","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1097\/MD.0b013e31824d9cec","article-title":"Inflammatory myopathies with anti-Ku antibodies: a prognosis dependent on associated lung disease","volume":"91","author":"Rigolet","year":"2012","journal-title":"Med (Baltimore)"},{"key":"B24","doi-asserted-by":"publisher","first-page":"e49","DOI":"10.1136\/annrheumdis-2020-217106","article-title":"Response to: \u2018Immune-mediated necrotizing myopathies and interstitial lung disease are predominant characteristics in anti-Ku positive patients with idiopathic inflammatory myopathies\u2019 by Yang et\u00a0al","volume":"81","author":"Spielmann","year":"2022","journal-title":"Ann Rheum Dis"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.2169\/internalmedicine.55.5816","article-title":"Sarcoid myositis with anti-ku antibody consistent with both sarcoidosis and polymyositis","volume":"55","author":"Awano","year":"2016","journal-title":"Intern Med"},{"key":"B26","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1007\/s00401-024-02765-3","article-title":"Anti-Ku + myositis: an acquired inflammatory protein-aggregate myopathy","volume":"148","author":"Holzer","year":"2024","journal-title":"Acta Neuropathol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000209268","article-title":"Pathologic features of anti-ku myositis","volume":"102","author":"Oyama","year":"2024","journal-title":"Neurology"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000000642","article-title":"Evaluation and construction of diagnostic criteria for inclusion body myositis","volume":"83","author":"Lloyd","year":"2014","journal-title":"Neurology"},{"key":"B29","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1016\/j.nmd.2017.09.016","article-title":"224th ENMC International Workshop:: Clinico-sero-pathological classification of immune-mediated necrotizing myopathies Zandvoort, The Netherlands, 14\u201316 October 2016","volume":"28","author":"Allenbach","year":"2018","journal-title":"Neuromuscul Disord"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1177\/0961203308089442","article-title":"Prevalence and clinical associations of anti-Ku antibodies in systemic autoimmune diseases","volume":"17","author":"Cavazzana","year":"2008","journal-title":"Lupus"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2019-216375","article-title":"Overlap of systemic lupus erythematosus and myositis is rare in anti-Ku antibody-positive patients","volume":"80","author":"Ogawa-Momohara","year":"2021","journal-title":"Ann Rheum Dis"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.974078","article-title":"Scleromyositis: A distinct novel entity within the systemic sclerosis and autoimmune myositis spectrum. Implications for care and pathogenesis","volume":"13","author":"Giannini","year":"2022","journal-title":"Front Immunol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-011-6166-y","article-title":"Facial nerve palsy and anti-Ku autoantibodies","volume":"259","author":"Sutter","year":"2012","journal-title":"J Neurol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.20452\/pamw.616","article-title":"Anti-Ku autoantibodies: series of 5 cases","volume":"119","author":"Gryga","year":"2009","journal-title":"Pol Arch Med Wewn"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1136\/rmdopen-2020-001357","article-title":"Recognising the spectrum of scleromyositis: HEp-2 ANA patterns allow identification of a novel clinical subset with anti-SMN autoantibodies","volume":"6","author":"Landon-Cardinal","year":"2020","journal-title":"RMD Open"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-021-02305-3","article-title":"Systemic sclerosis-associated myositis features minimal inflammation and characteristic capillary pathology","volume":"141","author":"Siegert","year":"2021","journal-title":"Acta Neuropathol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-021-02335-x","article-title":"Capillary basement membrane reduplication in myositis patients with mild clinical features of systemic sclerosis supports the concept of \u2018scleromyositis\u2019","volume":"142","author":"Ellezam","year":"2021","journal-title":"Acta Neuropathol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2013-004552","article-title":"A retrospective cohort study identifying the principal pathological features useful in the diagnosis of inclusion body myositis","volume":"4","author":"Brady","year":"2014","journal-title":"BMJ Open"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-016-1683-5","article-title":"The hnRNP family: insights into their role in health and disease","volume":"135","author":"Geuens","year":"2016","journal-title":"Hum Genet"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1080\/09553000903009548","article-title":"Response of heterogeneous ribonuclear proteins (hnRNP) to ionising radiation and their involvement in DNA damage repair","volume":"85","author":"Haley","year":"2009","journal-title":"Int J Radiat Biol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb1214","article-title":"Distinct faces of the Ku heterodimer mediate DNA repair and telomeric functions","volume":"14","author":"Ribes-Zamora","year":"2007","journal-title":"Nat Struct Mol Biol"},{"key":"B42","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1016\/j.molcel.2017.06.020","article-title":"HEXIM1 and NEAT1 long non-coding RNA form a multi-subunit complex that regulates DNA-mediated innate immune response","volume":"67","author":"Morchikh","year":"2017","journal-title":"Mol Cell"},{"key":"B43","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/j.bbrc.2009.02.019","article-title":"hnRNP-U is a specific DNA-dependent protein kinase substrate phosphorylated in response to DNA double-strand breaks","volume":"381","author":"Berglund","year":"2009","journal-title":"Biochem Biophys Res Commun"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.159392","article-title":"TNF-alpha induces macroautophagy and regulates MHC class II expression in human skeletal muscle cells","volume":"286","author":"Keller","year":"2011","journal-title":"J Biol Chem"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0706700105","article-title":"Regulation of the proapoptotic factor Bax by Ku70-dependent deubiquitylation","volume":"105","author":"Amsel","year":"2008","journal-title":"Proc Natl Acad Sci U.S.A"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1038\/ncb950","article-title":"Ku70 suppresses the apoptotic translocation of Bax to mitochondria","volume":"5","author":"Sawada","year":"2003","journal-title":"Nat Cell Biol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-017-0017-z","article-title":"Autophagy induced during apoptosis degrades mitochondria and inhibits type I interferon secretion","volume":"25","author":"Lindqvist","year":"2018","journal-title":"Cell Death Differ"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1136\/ard-2024-225773","article-title":"Pathological autoantibody internalisation in myositis","volume":"83","author":"Pinal-Fernandez","year":"2024","journal-title":"Ann Rheum Dis"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1608735\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T01:28:30Z","timestamp":1750123710000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1608735\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,17]]},"references-count":48,"alternative-id":["10.3389\/fimmu.2025.1608735"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1608735","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,17]]},"article-number":"1608735"}}