{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T21:44:06Z","timestamp":1789767846794,"version":"4.0.1"},"reference-count":22,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T00:00:00Z","timestamp":1760054400000},"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:p>Antinuclear antibodies (ANAs) are central biomarkers in rheumatological conditions and can drive disease pathology. Much less is known about the role of ANAs in neurological symptoms, although a number of experimental studies have demonstrated direct effects on neuronal function, for example in neuropsychiatric lupus erythematosus. Moreover, it is unclear whether the ANAs detected in HEp-2 cell-based assays, the gold standard for ANA diagnostics, can also be recognized in modern screening assays for anti-neuronal autoimmunity, such as staining on rodent brain sections or neuronal cultures. In this study, we therefore conducted a comparative mapping of ANA-positive sera with well-characterized HEp-2 patterns to central nervous system (CNS) tissue, utilizing fixed and unfixed murine brain sections and primary murine neurons. We screened 74 ANA-positive sera classified into 14 individual patterns and combinations thereof. Majority of the samples reacted with fixed primary neurons (99%, 73\/74 sera), followed by fixed brain sections (93%, 69\/74), but much less to unfixed mouse brain (54%, 40\/74). While the PM\/SCL- and RPOI-positive sera showed no binding to unfixed brain sections, the U1RNP (U1 nuclear ribonucleoprotein particle) and FBLN (fibrillarin) ANAs reacted strongly across all assays, indicating differences in antigen accessibility. These findings suggest that the majority of ANAs can interact with neural components, which may obscure the detection of other anti-neuronal autoantibodies. The foundational mapping of ANA binding in CNS tissue provided here can also facilitate recognition of \u201cCNS-specific ANAs,\u201d which bind to neuronal autoantigens but not to HEp-2 cells. Future studies should explore the association with certain neurological manifestations and the role of ANAs in neuronal pathology.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1674907","type":"journal-article","created":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T05:28:47Z","timestamp":1760074127000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Binding of established antinuclear antibodies to neurons depends on tissue fixation and underlying autoantigens"],"prefix":"10.3389","volume":"16","author":[{"given":"Lucie Y.","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"H\u00f6ltje","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helle Foverskov","family":"Rasmussen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lennard","family":"Halle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Mayrhofer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Bl\u00fcthner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harald","family":"Pr\u00fcss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-024-01163-z","article-title":"Recent advances in the diagnosis and management of neuropsychiatric lupus","volume":"20","author":"Legge","year":"2024","journal-title":"Nat Rev Rheumatol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1101-1189","article-title":"A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus","volume":"7","author":"DeGiorgio","year":"2001","journal-title":"Nat Med"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1625","DOI":"10.3390\/jcm9061625","article-title":"Rheumatoid meningitis a rare extra-articular manifestation of rheumatoid arthritis: report of 6 cases and literature review","volume":"9","author":"Trabelsi","year":"2020","journal-title":"J Clin Med"},{"key":"B4","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/j.ncl.2009.09.004","article-title":"Neurologic manifestations of systemic lupus erythematosus in children and adults","volume":"28","author":"Muscal","year":"2010","journal-title":"Neurol Clin"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2018-214819","article-title":"2019 European League Against Rheumatism\/American College of Rheumatology classification criteria for systemic lupus erythematosus","volume":"78","author":"Aringer","year":"2019","journal-title":"Ann Rheum Dis"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.45.2.384","article-title":"Frequency of anti-nuclear antibodies in multiple sclerosis","volume":"45","author":"Barned","year":"1995","journal-title":"Neurology"},{"key":"B7","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1001\/archneurol.2007.17","article-title":"Neuromyelitis optica and non organ-specific autoimmunity","volume":"65","author":"Pittock","year":"2008","journal-title":"Arch Neurol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1002\/brb3.1865","article-title":"Serum antinuclear antibodies associate with worse prognosis in AQP4-positive neuromyelitis optica spectrum disorder","volume":"11","author":"Fan","year":"2021","journal-title":"Brain Behav"},{"key":"B9","doi-asserted-by":"publisher","first-page":"798","DOI":"10.1038\/s41577-021-00543-w","article-title":"Autoantibodies in neurological disease","volume":"21","author":"Pr\u00fcss","year":"2021","journal-title":"Nat Rev Immunol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"116619","DOI":"10.1016\/j.jns.2019.116619","article-title":"Central nervous system-specific antinuclear antibodies in patients with multiple sclerosis","volume":"409","author":"Fujii","year":"2020","journal-title":"J Neurol Sci"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2024.04.001","article-title":"Association of rheumatological markers with neuronal antibodies, cerebrospinal fluid, electroencephalography, and magnetic resonance imaging findings in 224 patients with psychotic syndromes","volume":"119","author":"Endres","year":"2024","journal-title":"Brain Behav Immun"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2004.07.011","article-title":"Cognition and immunity; 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