{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:22:12Z","timestamp":1785424932275,"version":"3.56.0"},"posted":{"date-parts":[[2026,4,3]]},"group-title":"Immunology","reference-count":44,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T00:00:00Z","timestamp":1775174400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["R21NS126845"],"award-info":[{"award-number":["R21NS126845"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01NS121130"],"award-info":[{"award-number":["R01NS121130"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"publisher"}]},{"award":["T32NS115705"],"award-info":[{"award-number":["T32NS115705"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004856","name":"New York State Department of Health","doi-asserted-by":"crossref","award":["SCIRB C38332GG"],"award-info":[{"award-number":["SCIRB C38332GG"]}],"id":[{"id":"10.13039\/100004856","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","award":["HD103536"],"award-info":[{"award-number":["HD103536"]}]},{"name":"Harry T. Mangurian Jr. Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>SEZ6L2 autoantibodies have been identified in patients with subacute cerebellar ataxia, but the underlying immune mechanisms and pathogenic pathways remain poorly understood. We previously established a C57BL\/6 mouse model of SEZ6L2 autoimmunity that recapitulates key features of the disease. Here, we evaluated whether genetic background influences the magnitude and organization of SEZ6L2-directed immune responses. Pilot screening of autoimmune-prone strains identified SJL mice as exhibiting accelerated and enhanced antibody responses following SEZ6L2 immunization. In a large-cohort study, SEZ6L2-immunized SJL mice developed robust and sustained antibody responses, along with antigen-specific CD4\u207a and CD8\u207a T-cell activation. Expanded immune profiling revealed increased CNS infiltration of multiple lymphocyte populations, including CD4\u207a T cells, CD8\u207a T cells, B cells, and dendritic cells, as well as the presence of SEZ6L2-specific B cells within the brain. In addition, SJL mice exhibited strain-specific immunodominant T-cell epitopes distinct from those observed in C57BL\/6 mice. Functionally, SEZ6L2-immunized SJL mice developed motor deficits consistent with cerebellar dysfunction. Integration of behavioral outcomes demonstrated a consistent overall impairment, and multivariate analysis revealed that coordinated humoral and cellular immune responses were associated with behavioral deficits. Together, these findings demonstrate that SEZ6L2-directed immune responses produce coordinated adaptive immune activation linked to neurological dysfunction and establish the SJL strain as an enhanced model for studying SEZ6L2 autoimmunity. This model also provides a platform for investigating disease mechanisms and therapeutic strategies.<\/jats:p>","DOI":"10.64898\/2026.03.31.715689","type":"posted-content","created":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T20:05:20Z","timestamp":1775246720000},"source":"Crossref","is-referenced-by-count":0,"title":["Genetic background shapes SEZ6L2 autoimmunity and reveals coordinated immune responses linked to neurological dysfunction"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1580-3853","authenticated-orcid":false,"given":"Carlos J.","family":"Reyes-Sep\u00falveda","sequence":"first","affiliation":[{"name":"Immunology, Microbiology, and Virology Graduate Program, University of Rochester Medical Center, Rochester, NY, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Randolph","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Rochester Medical Center, Rochester, NY United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6596-4079","authenticated-orcid":false,"given":"Julia M.","family":"Granato","sequence":"additional","affiliation":[{"name":"Neuroscience Graduate Program, University of Rochester Medical Center, Rochester, NY United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison","family":"Hobbins","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Rochester Medical Center, Rochester, NY United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3949-1594","authenticated-orcid":false,"given":"Jennetta W.","family":"Hammond","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Rochester Medical Center, Rochester, NY United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026040702300710000_2026.03.31.715689v1.1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-024-12596-7"},{"key":"2026040702300710000_2026.03.31.715689v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-025-01136-0"},{"key":"2026040702300710000_2026.03.31.715689v1.3","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-013-7134-5"},{"key":"2026040702300710000_2026.03.31.715689v1.4","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-018-9115-1"},{"key":"2026040702300710000_2026.03.31.715689v1.5","doi-asserted-by":"publisher","DOI":"10.1212\/NXI.0000000000000916"},{"key":"2026040702300710000_2026.03.31.715689v1.6","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2022-330194"},{"key":"2026040702300710000_2026.03.31.715689v1.7","doi-asserted-by":"publisher","DOI":"10.1186\/s42466-022-00218-4"},{"key":"2026040702300710000_2026.03.31.715689v1.8","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-023-12128-9"},{"key":"2026040702300710000_2026.03.31.715689v1.9","doi-asserted-by":"publisher","DOI":"10.5692\/clinicalneurol.cn-001869"},{"key":"2026040702300710000_2026.03.31.715689v1.10","doi-asserted-by":"publisher","DOI":"10.1212\/NXI.0000000000200145"},{"key":"2026040702300710000_2026.03.31.715689v1.11","doi-asserted-by":"publisher","DOI":"10.1212\/NXI.0000000000001131"},{"key":"2026040702300710000_2026.03.31.715689v1.12","doi-asserted-by":"publisher","DOI":"10.1007\/s10072-022-06244-z"},{"key":"2026040702300710000_2026.03.31.715689v1.13","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-023-11756-5"},{"key":"2026040702300710000_2026.03.31.715689v1.14","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-024-12756-9"},{"key":"2026040702300710000_2026.03.31.715689v1.15","doi-asserted-by":"publisher","DOI":"10.1007\/s12311-025-01824-z"},{"key":"2026040702300710000_2026.03.31.715689v1.16","doi-asserted-by":"publisher","DOI":"10.1007\/s10072-025-08047-4"},{"key":"2026040702300710000_2026.03.31.715689v1.17","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-025-03637-7"},{"key":"2026040702300710000_2026.03.31.715689v1.18","doi-asserted-by":"publisher","DOI":"10.1093\/cercor\/bhz230"},{"key":"2026040702300710000_2026.03.31.715689v1.19","doi-asserted-by":"publisher","DOI":"10.1152\/physiolgenomics.00120.2018"},{"key":"2026040702300710000_2026.03.31.715689v1.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2012.11.018"},{"key":"2026040702300710000_2026.03.31.715689v1.21","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/203435"},{"key":"2026040702300710000_2026.03.31.715689v1.22","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.1501678"},{"key":"2026040702300710000_2026.03.31.715689v1.23","doi-asserted-by":"publisher","DOI":"10.21203\/rs.3.rs-6264481\/v1"},{"key":"2026040702300710000_2026.03.31.715689v1.24","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-024-01385-6"},{"key":"2026040702300710000_2026.03.31.715689v1.25","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4598"},{"key":"2026040702300710000_2026.03.31.715689v1.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.02.039"},{"key":"2026040702300710000_2026.03.31.715689v1.27","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0017289"},{"key":"2026040702300710000_2026.03.31.715689v1.28","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-022-01148-2"},{"key":"2026040702300710000_2026.03.31.715689v1.29","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0004582"},{"key":"2026040702300710000_2026.03.31.715689v1.30","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa075974"},{"key":"2026040702300710000_2026.03.31.715689v1.31","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.179374"},{"key":"2026040702300710000_2026.03.31.715689v1.32","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2017.10.047"},{"key":"2026040702300710000_2026.03.31.715689v1.33","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-018-8785-z"},{"key":"2026040702300710000_2026.03.31.715689v1.34","doi-asserted-by":"publisher","DOI":"10.1101\/2020.09.11.292623"},{"key":"2026040702300710000_2026.03.31.715689v1.35","doi-asserted-by":"crossref","unstructured":"Qiu WQ , Luo S , Ma SA , Saminathan P , Li H , Gunnersen JM , Gelbard HA , Hammond JW . The Sez6 Family Inhibits Complement by Facilitating Factor I Cleavage of C3b and Accelerating the Decay of C3 Convertases. Frontiers in immunology. 2021;12(1171). doi: 10.3389\/fimmu.2021.607641.","DOI":"10.3389\/fimmu.2021.607641"},{"key":"2026040702300710000_2026.03.31.715689v1.36","doi-asserted-by":"publisher","DOI":"10.64898\/2025.12.31.697214"},{"key":"2026040702300710000_2026.03.31.715689v1.37","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2006.06.043"},{"key":"2026040702300710000_2026.03.31.715689v1.38","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2018.03.001"},{"key":"2026040702300710000_2026.03.31.715689v1.39","doi-asserted-by":"publisher","DOI":"10.1093\/ilar\/ily026"},{"key":"2026040702300710000_2026.03.31.715689v1.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2020.102647"},{"key":"2026040702300710000_2026.03.31.715689v1.41","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-025-01535-9"},{"key":"2026040702300710000_2026.03.31.715689v1.42","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2106478118"},{"key":"2026040702300710000_2026.03.31.715689v1.43","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1009234107"},{"key":"2026040702300710000_2026.03.31.715689v1.44","doi-asserted-by":"publisher","DOI":"10.1002\/mds.22129"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.03.31.715689","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T09:30:18Z","timestamp":1775554218000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.03.31.715689"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,3]]},"references-count":44,"URL":"https:\/\/doi.org\/10.64898\/2026.03.31.715689","relation":{},"subject":[],"published":{"date-parts":[[2026,4,3]]},"subtype":"preprint"}}